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CONTENTS
Section 30. Clinical and Experimental Pharmacology
1.
2.
3.
4.
5.
GENERAL ASPECTS
LABORATORY METHODS AND TECHNIQUES
PHARMACOKINETICS
PHARMACODYNAMICS
EFFECTS ON ORGANS AND SYSTEMS
5.1. Central nervous system and sense organs
5.2. Autonomic and motor nervous system
5.3. Cardiovascular system
5.4. Hemopoietic and lymphoreticular systems
5.5. Respiratory system
5.6. Digestive system
5.7. Urinary system
5.8. Reproductive system
5.9. Endocrine system
6. PHARMACOLOGICAL AGENTS
6.1. Anesthetics
6.2. Opiates and other analgesics
6.3. Antiinflammatory agents
6.4. Antineoplastic agents
6.5. Antiinfective agents
6.6. Immunologic agents
6.7. Emetics and antiemetics
6.8. Autacoids and prostaglandins
6.9. Medicinal plants and herbal medicines
73
73
75
87
87
95
95
100
100
101
101
102
103
104
112
113
114
119
129
137
140
141
141
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RECORD FORMAT
Chapter heading
7. BACTERIOLOGY
Sub-chapter heading
Abstract number
7.2. Gram-negative rods and cocci
Title of article in English
3179. Two patients with fever, chills and pain in the
right upper abdominal quadrant accompanied by
hyperbilirubinaemia: Pylephlebitis (Dutc)
Code of article language
Non-English title
TWEE PATIËNTEN MET KOORTS, KOUDE
RILLINGEN EN PIJN RECHTS IN DE BOVENBUIK EN
HYPERBILIRUBINEMIE: PYLEFLEBITIS
Author name(s)
Van den Berg M.K., Aarts N.J.M. and Van ’t Wout J.W.
Corresponding author, plus
the correspondence address
[Dr. J.W. Van ’t Wout, Leids Universitair Medisch Centrum,
Afd. Infectieziekten, Leiden, Netherlands]
Country
Abbreviated journal title
NED. TIJDSCHR. GENEESKD. 2003 147/28 (1337-1340)
Code of summary languages
Summ in ENGL
Year of publication, volume
number and issue number
Page numbers of the article
in the original journal
Abstract in English
Two male patients aged 55 and 77 years, respectively, presented to the casualty department with fever, chills and right abdominal upper quadrant tenderness. They also had hyperbilirubinaemia. Based on CT scan findings and blood cultures
yielding Bacteroides fragilis, a diagnosis of pylephlebitis
(septicthrombophlebitis of the mesenteric veins and/or the
portal vein) was made. This is a condition with a mortality rate
of 10-70%. Primary sources such as diverticulitis are often
seen in patients with pylephlebitis, in which bacteria are
drained by the mesenteric veins and cause a thrombus in the
portal system. In the two patients no primary focus was detected. They were treated with intravenous antibiotic therapy
followed by oral antibiotics, and were discharged in good
health. Pylephlebitis can be complicated by liver abscesses.
Treatment consists of broad-spectrum antibiotics which are
adjusted based on the blood cultures results. The duration of
treatment is between two and six weeks, depending on the
presence of liver abscesses. In patients with abscesses that
cannot be drained, longer treatment may be indicated.
2. LABORATORY METHODS AND TECHNIQUES
376. Stability-indicating HPTLC determination of tizanidine
hydrochloride in bulk drug and pharmaceutical formulations
- Mahadik K.R., Paradkar A.R., Agrawal H. and Kaul N. [K.R.
Mahadik, Dept. of Qual. Assurance Techniques, Poona College
of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane,
Pune 411038, India] - J. PHARM. BIOMED. ANAL. 2003 33/4
(545-552) - summ in ENGL
A simple, selective, precise and stability-indicating high-performance thin-layer chromatographic method of analysis of tizanidine
hydrochloride both as a bulk drug and in formulations was developed and validated. The method employed TLC aluminium plates
precoated with silica gel 60F-254 as the stationary phase. The solvent system consisted of toluene-acetone-ammonia (5:5:0.1, v/v/v).
This system was found to give compact spots for tizanidine hydrochloride (Rf value of 0.320.01). Tizanidine hydrochloride was
subjected to acid and alkali hydrolysis, oxidation and photodegradation. Also, the degraded product was well separated from the
pure drug. Densitometric analysis of tizanidine hydrochloride was
carried out in the absorbance mode at 315 nm. The linear regression
analysis data for the calibration plots showed good linear relationship with r2 =0.9922 in the concentration range 300-1000 ng per
spot. The mean value of correlation coefficient, slope and intercept
were 0.99220.002, 0.0640.001 and 38.091.71, respectively.
The method was validated for precision, recovery and robustness.
The limits of detection and quantitation were 88 and 265 ng per
spot, respectively. The drug does not undergo degradation under
acidic and basic conditions. The samples degraded with hydrogen
peroxide showed additional peak at Rf value of 0.12. This indicates
that the drug is susceptible to oxidation. Statistical analysis proves
that the method is repeatable and selective for the estimation of said
drug. As the method could effectively separate the drug from its
degradation product, it can be employed as a stability-indicating
one. © 2003 Elsevier B.V. All rights reserved.
377. Flow-injection chemiluminescence detection for studying
protein binding of terbutaline sulfate with on-line microdialysis
sampling - Wang Z., Zhang Z., Fu Z. et al. [Z. Zhang, Department
of Chemistry, Institute of Analytical Science, Southwest China Normal University, Beibei, Chongqing, 400715, China] - J. PHARM.
BIOMED. ANAL. 2003 33/4 (765-773) - summ in ENGL
The binding of terbutaline sulfate to bovine serum albumin was
studied in vitro using the technique of microdialysis sampling combined with flow-injection chemiluminescence analysis (FIA-CL).
In the presence of formaldehyde, terbutaline sulfate can be oxidized
by KMnO4 to produce high chemiluminescence emission in sulfate
acid media. The concentration of terbutaline sulfate is proportional
with the CL intensity in the range of 110-7 -210-5 mol l-1 with
a detection limit of 310-8 mol l-1 . The drug and protein were
mixed in different molar ratios in 0.067 mol l-1 phosphate buffer,
pH 7.4, and incubated at 37°C in a water bath. The microdialysis
probe was utilized to sample the mixed solution at a perfusion rate
of 5 l min-1 and the dialytic efficiency of terbutaline sulfate under the experimental conditions was 26.3%. The data obtained by
proposed microdialysis flow-injection chemiluminescence method
was analyzed with Scrathard analysis and Klotz plot. The estimated
association constant (K) and the number of the binding site (n) on
one molecule of BSA by Scrathard analysis were 4.11104 l mol-1
and 1.06, respectively. The proposed system proved that FIA-CL
coupled with on-line microdialysis sampling is a simple and reliable
technique for the study of drug-protein interaction. © 2003 Elsevier
B.V. All rights reserved.
378. Hydroxamic acids: Proton donor and acceptor strength for
use in drug design - Vanjari H. and Pande R. [R. Pande, School of
Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur,
C.G. 492 010, India] - J. PHARM. BIOMED. ANAL. 2003 33/4
Hydroxamic acids, the naturally occurring and synthetic products,
generally have low toxicities and are of interest for many therapeutic
applications. The present investigation describes the measurement
of hydrogen bond donor (HBD) strength of ten hydroxamic acids
by measuring their logP(O/W) values. Hydroxamic acid functional
group contains two oxygen and one nitrogen atom as the acceptor
Section 30 vol 126.2
sites. Thus, HBA strength of these reagents is also computed. A
knowledge of these parameters is valuable in the field of toxicology,
pharmacology and environmental sciences. © 2003 Published by
Elsevier B.V.
379. Determination of imipramine in presence of iminodibenzyl
and in pharmaceutical dosage form - El Zeany B.A., Moustafa
A.A. and Farid N.F. [N.F. Farid, Department of Analytical Chemistry, Faculty of Pharmacy, Cairo University, 23 El-ahrar St., Cairo,
Egypt] - J. PHARM. BIOMED. ANAL. 2003 33/4 (775-782) - summ
in ENGL
Two spectrophotometric methods for the determination of imipramine in presence of iminodibenzyl as an impurity are described.
The first method is a ratio-spectra first derivative spectrophotometry,
the signals were measured at 240.2 nm for imipramine. Calibration
graph was found linear in the range 5-30 g ml-1 . The second
method is based on the reaction of imipramine base, being an electron donor, with p-chloranilic acid, being acceptor, to form a
purple colored charge transfer complex. The absorbance was measured at 520.5 nm without interference with iminodibenzyl. Both
methods are rapid, simple and do not require any preliminary separation or treatment of the samples. Furthermore, the two methods
were applied to pharmaceutical dosage form. © 2003 Elsevier B.V.
All rights reserved.
See also: 381, 389, 392, 395, 492, 540, 584, 592, 593, 612, 675,
679, 700, 707, 713, 732, 733.
3. PHARMACOKINETICS
380. A review of the effects of chronic exercise and physical
fitness level on resting pharmacokinetics - Persky A.M., Eddington N.D. and Derendorf H. [Dr. A.M. Persky, Div. of Drug
Delivery/Disposition, School of Pharmacy, Univ. of N. Carolina at
Chapel Hill, C.B. No. 7360 Beard Hall, Chapel Hill, NC 275997360, United States] - INT. J. CLIN. PHARMACOL. THER. 2003
41/11 (504-516) - summ in ENGL
Pharmacological intervention in cooperation with physical activity is currently being used in the prevention and treatment of
diseases like cardiovascular disease and obesity. Physical activity,
both acute and chronic, can cause changes in physiology that can
alter the observed pharmacokinetics of drugs. Objective: The purpose of this paper is to focus on how chronic exercise can change
pharmacokinetics. Results: Chronic exercise can affect drug absorption by the increase in collateral blood flow and absorption
may also be affected by changes in gastrointestinal transit times.
Chronic exercise may affect volume of distribution of drugs by the
increases in lean body mass, decreased fat mass, increased plasma
protein and increased plasma volume that occurs with physical conditioning. Changes in hepatic clearance of drugs may explain the
differences in systemic clearance seen when comparing physically
trained subjects to sedentary ones. Some studies have shown that
hepatic enzymes are increased with training but other studies have
found no change or lower activities. Finally, renal elimination of
drugs may be altered by changes in protein binding but there is
little evidence that renal elimination of drugs changes with longterm exercise. Conclusion: Therefore, changes in pharmacokinetics
associated with chronic exercise can differ from those during acute
exercise and in sedentary subjects. The differences between the
physically active and sedentary individuals may require individualization of dosing regimens. It should be noted that there are no
standardized protocols to evaluate the influence of exercise on drug
disposition.
381. Center specificity in the limited sampling model (LSM):
Can the LSM developed from healthy subjects be extended to
disease states? - Mahmood I. [Dr. I. Mahmood, Office of Therapeut. Research/Review, Div. of Clin. Trial Design/Analysis, Clin.
Pharmacology/Toxicology Branch, 1401 Rockville Pike, Rockville,
MD 20852, United States] - INT. J. CLIN. PHARMACOL. THER.
2003 41/11 (517-523) - summ in ENGL
Background and objectives: Area under the curve (AUC) can
be related to the therapeutic or toxic effect of a drug. In order
to accurately measure AUC, multiple blood samples are required,
73
but in a clinical setting, frequent blood sampling from the patients
is time-consuming and expensive. The limited sampling model
(LSM) is one of the approaches that is gaining popularity due to its
simplicity for the estimation of AUC using 1-3 samples. Despite
its simplicity, the LSM has some shortcomings. One of the major
drawbacks of the LSM is that the LSM developed under a given
condition may not be extended to other conditions. For example,
the LSM developed from healthy subjects may not be extended to
disease states such as renal or hepatic impairment or vice versa.
This characteristic of the LSM can be referred to as "center-specific". In this investigation, the LSM developed from the healthy
subjects was used to predict AUC in patients with renal or hepatic
impairment. Methods: Two sets of simulated plasma concentration
versus time data for 2 antihypertensive drugs and measured plasma
concentration versus time data for 2 representative drugs (A and
B) were used in the analysis. Results and conclusion: The results
of the study indicate that the LSM developed from healthy subjects is inadequate to predict AUC in patients with hepatic or renal
impairment, indicating center specificity of the LSM.
382. Increase in tacrolimus trough levels after steroid withdrawal - Van Duijnhoven E.M., Boots J.M.M., Christiaans M.H.L.
et al. [E.M. Van Duijnhoven, Department of Internal Medicine,
University Hospital of Maastricht, P.O. Box 5800, 6202 AZ Maastricht, Netherlands] - TRANSPLANT INT. 2003 16/10 (721-725) summ in ENGL
Although there are experimental reports of cytochrome P450 3A4
iso-enzyme (CYP3A4) induction by glucocorticoids, there are no
clinical reports about an interaction between tacrolimus and steroids.
Therefore, tacrolimus trough level and dose were compared after
dose-normalization before and after withdrawal of prednisolone.
After withdrawal of 5 mg prednisolone, the median tacrolimus
dose-normalized level increased by 14% in the retrospective (n
= 54), and by 11% in the prospective (n = 8) part of the study. After
withdrawal of 10 mg, this increase was 33% (n = 30) and 36% (n =
14), respectively. An additional pharmacokinetic part of the study
(n = 8) revealed an 18% increase in AUC (P = 0.05) after withdrawal of 5 mg prednisolone, which is compatible with a reduced
metabolism after steroid withdrawal. The significant increase in
tacrolimus exposure after steroid withdrawal may on the one hand
counteract the reduction in immunosuppression intended by steroid
withdrawal, and, on the other hand, may result in an increase of
serum creatinine which could be misinterpreted as rejection.
383. Considerations in Analyzing Single-Trough Concentrations
Using Mixed-Effects Modeling - Booth B.P. and Gobburu J.V.S.
[Dr. B.P. Booth, Ctr. for Drug Eval. and Research, Off. Clin.
Pharmacol./Biopharmaceut., Div. of Pharmaceutical Evaluation I,
5600 Fishers Lane, Rockville, MD 20857, United States] - J. CLIN.
PHARMACOL. 2003 43/12 (1307-1315) - summ in ENGL
The purpose of this study was to assess the effect of trial design
and data analysis choices on the bias and precision of pharmacokinetic (PK) parameter estimation. NONMEM was used to simulate
and analyze plasma concentrations collected according to a dense
(five samples) or sparse (single-trough samples) sampling scheme
for a one-compartment open model with intravenous administration. The results indicated that the bias on estimates of CL with
only single-trough data was 17% compared to less than 1% for
only dense data. The estimates of CL were improved by fixing
all other parameters and estimating only mean and variance of CL
(-11% to 1.4%, depending on the estimation method). Adding
dense data led to further improvements (-2.3% to 0.3%, depending
on further improvements). In these cases, first-order conditional
estimation (FOCE) methods resulted in better estimates of CL than
first-order (FO) methods. These steps also improved the Bayesian
estimates of CL. These studies support the following recommendations: (1) avoid collecting single-trough concentrations unless there
is reasonable knowledge about the PK of the drug; (2) if collecting
single-trough concentrations is inevitable, avoid estimating all parameters when modeling single-trough concentration data; (3) use
prior information by modeling the single-trough concentration data
along with dense data from other studies; and (4) use Bayes estimates if the PK model and its parameters are known with reasonable
certainty.
74
384. Improvement of physicochemical and biopharmaceutical
properties of theophylline by poly(ethylene glycol) conjugates
- Zacchigna M., Di Luca G., Cateni F. et al. [M. Zacchigna, Dipto.
di Scienze Farmaceutiche, piazzale Europa 1, 34127 Trieste, Italy]
- FARMACO 2003 58/12 (1307-1312) - summ in ENGL
In the present paper two theophylline esters with poly (ethylene
glycol) (PEG) and methoxy poly (ethylene glycol) (mPEG) were
prepared. Quantitative yields of the pure products were obtained.
Unlike the free drug, the drug-polymer conjugates are freely water-soluble at room temperature. In vitro release experiments in
aqueous buffer demonstrate that both conjugates are stable in buffer
of pH 7.4 and 1.2. In vivo release studies after oral administration of
theophylline conjugates demonstrate a good release of parent drug.
© 2002 Éditions scientifiques et médicales Elsevier SAS. All rights
reserved.
385. Determination of the Dermal Penetration of Esterom Components Using Microdialysis Sampling - McDonald S. and Lunte
C. [C. Lunte, Department of Chemistry, University of Kansas,
Lawrence, KS 66045, United States] - PHARM. RES. 2003 20/11
(1827-1834) - summ in ENGL
Purpose. Esterom® Solution, an investigational pharmaceutical
product, is derived from the esterification of benzoylmethylecgonine (cocaine) in 1,2 propanediol. The resulting solution contains
a mixture of components. Esterom Solution is intended to be a
topical analgesic to relieve pain and increase the range of motion in
patients suffering from acute inflammation of the shoulder or back.
Although the components of Esterom are known, the components
that are responsible for analgesia have only recently been identified.
The purpose of this research is to evaluate which components have
the ability to penetrate the skin, how much actually penetrates,
and if and/or how each component is metabolized and distributed
locally. Methods. Linear microdialysis probes were implanted
into rat dermis. The individual components present in the Esterom
Solution were applied separately to the dermis directly over a probe.
Dermal dialysis samples were collected to evaluate the dermal penetration of each compound following topical application. Results.
Following a 10 mg/50 L application, 1.8 0.6 mM benzoic acid
was detected at the plateau after approximately 220 min. Following hydroxypropyl benzoic acid application, complete hydrolysis to
benzoic acid was observed with a plateau concentration of 137 19 M (150 min plateau). When applied separately, hydroxypropyl
benzoylecgonine and ecgonine penetrate the skin with plateau concentrations of 32 9 M (15 h plateau) and 36 5 M (150 min
plateau) respectively. Benzoylecgonine, the hydrolytic product of
HP-BE, was also detected with a plateau concentration of 3.9 0.1
M (16 h plateau) Applied topically, ecgonidine, methylecgonidine,
benzoylecgonine, and hydroxypropyl ecgonidine were not detected.
Conclusions. Of the components with analgesic activity, the only
compound that penetrates the skin is hydroxypropyl benzoylecgonine. Dermal microdialysis was shown to be an effective technique
to monitor the skin penetration of topically applied compounds.
386. High Bioavailabilty of -Tocopherol Loaded into Poly
(DL-Lactic-co-Glycolic Acid) Microspheres in Apolipoprotein
B Knockout Mice - Yokogawa K., Shima Y., Hashimoto T. et
al. [K.-I. Miyamoto, Department of Hospital Pharmacy, School
of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa
920-8641, Japan] - PHARM. RES. 2003 20/11 (1846-1850) - summ
in ENGL
Purpose. To assess the potential clinical value of -tocopherolloaded poly (DL-lactic-co-glycolic acid) (PLGA) microspheres, we
examined the disposition kinetics of -tocopherol after administration of the microspheres to apolipoprotein B (apo B) knockout mice
as a model of abetalipoproteinemia. Methods. PLGA microspheres
containing -tocopherol were prepared by a solvent-evaporation
method. The concentration of -tocopherol was measured by gas
chromatography-mass spectrometry. Results. The mean value of
particle size of -tocopherol-loaded PLGA microspheres was 108
m. The loading and the trapping efficiency of -tocopherol in
PLGA microspheres were 20.8% and 86.6%, respectively. When
-tocopherol solution (25 mg/kg) was subcutaneously administered
to apob (+/-) and apob (+/-) mice, the plasma concentrations of tocopherol reached a peak at 6 h and decreased to the endogenous
level within 4 days in both types of mice. However, the area under the plasma concentration-time curve (AUC) of apob (+/-) mice
was significantly smaller than that in the case of apob (+/+) mice.
When -tocopherol-loaded PLGA microspheres (100 mg/kg) were
subcutaneously administered, the plasma concentrations of -tocopherol increased slowly and remained about 2-fold higher than
the endogenous level at 5 to 10 days after administration in both
types of mice, and there was no significant difference between the
AUC values. Conclusions. The PLGA microsphere preparation of
-tocopherol is expected to be a very useful drug delivery system
in vitamin E supplementation therapy for abetalipoproteinemia.
387. Solubilization of Cationic Drugs in Lung Surfactant - Liao
X. and Wiedmann T.S. [T.S. Wiedmann, University of Minnesota,
Department of Pharmaceutics, 308 Harvard St. SE, Minneapolis,
MN 55455, United States] - PHARM. RES. 2003 20/11 (18581863) - summ in ENGL
Purpose. The association of Hydrophobic, cationic drugs with
lung surfactant was determined to assess the pharmacokinetic implications on drug disposition and retention in the lung. Methods.
The distribution coefficients, K, were determined at 25 and 37° in
normal saline solution buffered at pH 7.4 for a series of structurally
related, cationic drugs. Drugs were dispersed into lung surfactant,
equilibrated, and then centrifuged to separate the aqueous phase
from the surfactant pellet. Drug concentrations in the supernatant
and pellet were determined following dilution using spectrophotometric assays. In addition, the apparent acid dissociation constant
of quinacrine in the presence and absence of surfactant was determined by measuring the pH-dependent absorption spectra. The
effect of stereochemistry on the distribution of drugs into surfactant
was examined with (R)- and (S)-propranolol. Results. The mole
fraction distribution coefficients for amitriptyline, promethazine,
promazine, ethopropazine, imipramine, R-propranolol, and S-propranolol at 25°C were 6,560 500, 28,400 1,500,12,100 840,
5,480 330, 4,490 250, 8,680 260,8,190 530, respectively.
At 37°C, the distribution coefficients were generally smaller indicating a significant exothermic heat of transfer for these solutes from
aqueous solution to the lung surfactant. The pKa of quinacrine
was 7.43 0.04 in aqueous solution and was shifted to 7.62 0.06 in the presence of lung surfactant. From this shift, the double
layer potential for quinacrine-lung surfactant was estimated to be
-0.012 V assuming a dielectric constant equivalent to that of water.
Conclusions. Cationic drugs have very favorable distributions from
an aqueous solution to the lipid phase of lung surfactant. The
transfer process generally has both a large entropic and enthalpic
contribution. The latter thermodynamic aspect may be related to
the charge interaction between the solute and the negatively charged
surfactant. Finally, no significant effect of stereochemistry was
evident with the distribution of (R)- and (S)-propranolol.
388. Biotransformation of tamoxifen in a human endometrial
explant culture model - Sharma M., Shubert D.E., Sharma M.
et al. [J.R. Olson, Dept. of Pharmacology and Toxicology, State
Univ. of New York at Buffalo, 102 Farber Hall, Buffalo, NY 14214,
United States] - CHEM.-BIOL. INTERACT. 2003 146/3 (237-249) summ in ENGL
Although long-term tamoxifen therapy is associated with increased risk of endometrial cancer, little is known about the
ability of endometrial tissue to biotransform tamoxifen to potentially reactive intermediates, capable of forming DNA adducts.
The present study examined whether explant cultures of human
endometrium provide a suitable in vitro model to investigate the
tissue-specific biotransformation of tamoxifen. Fresh human endometrial tissue, microscopically uninvolved in disease, was cut into
12-mm uniform explants and incubated with media containing
either 25 or 100 M tamoxifen in a 24-well plate. Metabolites
were analyzed by reversed-phase HPLC using postcolumn, online,
photochemical activation and fluorescence detection. Three metabolites, namely, -hydroxytamoxifen, 4-hydroxytamoxifen, and
N-desmethyltamoxifen were identified in culture medium and tissue lysates. N-desmethyltamoxifen was found to be the major
metabolite in both tissue and media extracts of tamoxifen-exposed
explants. Incubations of tamoxifen with recombinant human cytochrome P-450s (CYPs) found that CYP2C9 and CYP2D6 produced
all three of the above tamoxifen metabolites, while CYP1A1 and
CYP3A4 catalyzed the formation of -hydroxytamoxifen and Ndesmethyltamoxifen, and CYP1A2 and CYP1B1 only formed the
-hydroxy metabolite. CYP2D6 exhibited the greatest activity
for the formation of all three tamoxifen metabolites. Western immunoblots of microsomes from human endometrium detected the
presence of CYPs 2C9, 3A, 1A1 and 1B1 in fresh endometrium,
while CYPs 2D6 and 1A2 were not detected. Immunohistochemical (IHC) analysis also confirmed the presence of CYPs 2C9, 3A
and 1B1 in fresh human endometrium and in viable tissue cultured
for 24 h with or without tamoxifen. Together, the results support
the use of explant cultures of human endometrium as a suitable in
vitro model to investigate the biotransformation of tamoxifen in this
target tissue. In addition, the results support the role of CYPs 2C9,
3A, 1A1 and 1B1 in the biotransformation of tamoxifen, including
the formation of the DNA reactive -hydroxytamoxifen metabolite,
in human endometrium. © 2003 Elsevier Ireland Ltd. All rights
reserved.
See also:
425, 431,
514, 522,
575, 576,
663, 667,
727, 738.
393, 395,
451, 452,
523, 534,
583, 595,
672, 673,
399, 400, 406, 408, 409,
453, 459, 472, 473, 474,
538, 539, 545, 546, 552,
598, 600, 622, 624, 625,
674, 677, 678, 679, 680,
410,
475,
553,
642,
681,
411,
480,
554,
650,
692,
412,
485,
555,
651,
706,
418,
495,
558,
658,
724,
4. PHARMACODYNAMICS
389. Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects
after treatment with folic acid, vitamin B12 and vitamin B6 :
A randomised trial - Lewerin C., Nilsson-Ehle H., Matousek
M. et al. [H. Nilsson-Ehle, Dept. of Med. Haematol./Coagulation,
Göteborg University, Göteborg SE 413 45, Sweden] - EUR. J. CLIN.
NUTR. 2003 57/11 (1426-1436) - summ in ENGL
Objectives: To investigate, in an elderly population: (1) the effects of oral B-vitamin therapy on P-tHcys, S-MMA and Hb/MCV,
(2) the appropriate decision limit for ’high’ metabolite concentrations and (3) the estimated prevalence of vitamin B12 /folate
deficiency on the basis of different decision limits. Design: Double-blind placebo-controlled intervention study. Setting: Outpatient
clinic. Subjects: A total of 209 community-dwelling subjects, median age 76 y (range 70-93) y. Intervention: Four months of oral
daily supplementation with 0.5 mg cyanocobalamin, 0.8 mg folic
acid and 3 mg vitamin B6 . Results: High P- tHcys; was found in
64% of men and 45% of women, high S-MMA in 11% of both.
Vitamin B12 deficiency was observed in 7.2% and folate deficiency
in 11% of all subjects. Health-related upper reference limits for
the metabolites at the start were higher than the laboratory’s upper
reference limits. The latter were, however, similar to those of the
vitamin replete group. There was a significant decrease in P-tHcys
(P< 0.001) and S-MMA (P = 0.009) after 4 months of vitamin
treatment. In a multivariate analysis, the P-Hcys change correlated positively with baseline P-tHcys and inversely with baseline
P-folate and transferrin saturation (Fe/TIBC ratio). The S-MMA
change correlated with baseline S-MMA and inversely with baseline vitamin B12 and age. Conclusions: Suboptimal vitamin status
is an important cause of elevated P-tHcys and S-MMA in apparently
healthy elderly subjects. Oral B-vitamin therapy is an effective and
convenient way to normalise P-tHcys and S-MMA.
390. Lanopylins A1 , B1 , and B2 , novel lanosterol synthase inhibitors from Streptomyces sp. K99-5041 - Sakano Y., Shibuya
M., Matsumoto A. et al. [Y. Ebizuka, Grad. School of Pharmaceutical Sci., The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-0033, Japan] - J. ANTIBIOT. 2003 56/10 (817-826) - summ in
ENGL
From an actinomycete strain, Streptomyces sp. K99-5041, lanopylins A1 , B1 , A2 and B2 were isolated as new natural products
that inhibited the reaction of recombinant human lanosterol synthase. The crude extract from the whole broth of this strain
was fractionated by silica gel column chromatography to afford
an active fraction that showed a single spot on TLC. Detailed
analyses of this fraction with liquid chromatography-atmospheric
pressure chemical ionization mass spectrometry revealed that it
75
contained 20 homologous compounds with differing side chain
lengths. The fraction was separated by preparative HPLC to afford
four of these homologues, lanopylins A1 , B1 , A2 and B2 . Detailed spectroscopic analyses of these isolated compounds led to the
identification of their structures. Lanopylins A1 and B1 were (3E
-isohexadecylmethylidene-2-methyl-1-pyrroline and (3E -hexadecylmethylidene-2-methyl-1-pyrroline, respectively, and lanopylins
A2 and B2 were homologues with the insertion of one cis-ethylenylidene in the side chain of lanopylins A1 and B1 , respectively. These
compounds inhibited recombinant human lanosterol synthase with
IC50 values of 15, 18, 33, and 41 M, respectively.
391. SMTP-4D, -5D, -7D and -8D, a new series of the non-lysineanalog plasminogen modulators with a D-amino acid moiety Hu W., Kitano Y. and Hasumi K. [K. Hasumi, Dept. of Applied Biological Science, Tokyo Noko University, 3-5-8 Saiwaicho, Fuchu,
Tokyo 183-8509, Japan] - J. ANTIBIOT. 2003 56/10 (832-837) summ in ENGL
Staplabin and SMTPs, triprenyl phenol metabolites of the fungus
Stachybotrys microspora, are a family of non-lysine-analog plasminogen modulators that enhance both activation and fibrin binding
of plasminogen by modulating plasminogen conformation. These
compounds, including SMTP-4, -5, -6, -7 and -8, have an amino
acid or an amino alcohol moiety in their structure, and precursor
amine feeding greatly increases the biosynthesis of a metabolite of
interest. In the present study, we have isolated five novel SMTPs
(designated SMTP-4D, -5D, -6D, -7D and -8D) from precursor Damino acid-fed cultures. Physico-chemical properties as well as
chromatographic behavior were distinct from those of the corresponding L-amino acid analogs, which are selectively accumulated
in L-amino acid-fed cultures and share common properties with
corresponding natural products. The D-series SMTPs enhanced
urokinase-catalyzed plasminogen activation by 10-fold at 80-180
M.
392. Biological evaluation of recombinant human erythropoietin in pharmaceutical products - Ramos A.S., Schmidt C.A.,
Andrade S.S. et al. [S.L. Dalmora, Departamento de Farmacia
Industrial, Centro de Ciencias da Saúde, Universidade Federal de
Santa Maria, Prédio 26, 97105-900 Santa Maria, RS, Brazil] - BRAZ.
J. MED. BIOL. RES. 2003 36/11 (1561-1569) - summ in ENGL
The potencies of mammalian cell-derived recombinant human
erythropoietin pharmaceutical preparations, from a total of five
manufacturers, were assessed by in vivo bioassay using standardized protocols. Eight-week-old normocythemic mice received a
single subcutaneous injection followed by blood sampling 96 h
later or multiple daily injections with blood sampling 24 h after
the last injection. Reticulocyte counting by microscopic examination was employed as the endpoint using the brilliant cresyl
blue or selective hemolysis methods, together with automated flow
cytometry. Different injection schedules were investigated and
dose-response curves for the European Pharmacopoeia Biological
Reference Preparation of erythropoietin were compared. Manual
and automated methods of reticulocyte counting were correlated
with respect to assay validity and precision. Using 8 mice per treatment group, intra-assay precision determined for all of the assays
in the study showed coefficients of variation of 12.1-28.4% for the
brilliant cresyl blue method, 14.1-30.8% for the selective hemolysis
method and 8.5-19.7% for the flow cytometry method. Applying
the single injection protocol, a combination of at least two independent assays was required to achieve the precision potency and
confidence limits indicated by the manufacturers, while the multiple
daily injection protocol yielded the same acceptable results within
a single assay. Although the latter protocol using flow cytometry
for reticulocyte counting gave more precise and reproducible results
(intra-assay coefficients of variation: 5.9-14.2%), the well-characterized manual methods provide equally valid alternatives for the
quality control of recombinant human erythropoietin therapeutic
products.
393. Tipranavir: A novel non-peptidic protease inhibitor for the
treatment of HIV infection - Mehandru S. and Markowitz M. [M.
Markowitz, Aaron Diamond AIDS Research Centre, Rockefeller
University, 455 First Avenue, New York, NY 10016, United States]
76
- EXPERT OPIN. INVEST. DRUGS 2003 12/11 (1821-1828) - summ
in ENGL
Tipranavir (TPV) is a non-peptidic protease inhibitor belonging
to the class of 4-hydroxy-5,6-dihydro-2-pyrones, which exhibits potent and specific activity against HIV type I (HIV-1) and 2 (HIV-2).
Clinically effective plasma levels of TPV are achieved by concomitant administration of ritonavir (RTV). Therefore, TPV has been
coadministered with RTV in clinical trials. TPV has demonstrated
antiviral activity against HIV-1 isolates that are resistant to reversetranscriptase and selected peptidic protease inhibitors. Therefore,
TPV is emerging as one of the newer drugs in the armamentarium
against HIV-1 in patients demonstrating multi-drug resistance. TPV
administered orally to humans exhibits linear pharmacokinetics at
doses of 100 - 2000 mg. Steady-state plasma levels are attained
within 7 days of initiating multiple dosing. The half-life of the
drug is 6 h at steady-state. The plasma concentration is lower
with repeated dosing than predicted from single-dose studies due
to induction of the cytochrome P450 3A4 isoform of the liver microsomal enzyme system. Phase II clinical trials have shown that
the administration of TPV and RTV in combination is safe and
generally well-tolerated in HIV-1-infected adults. Phase III trials
are underway to compare the efficacy of this drug versus other antiretroviral regimens. Gastrointestinal toxicity has been described
with TPV, the most frequently reported side effects being diarrhoea,
nausea, vomiting and abdominal pain. There is no known evidence
of teratogenicity or effect on fertility. TPV dosed twice-daily, in
the range of 500 - 1250 mg and combined with 100 - 200 mg of
RTV has been shown to substantially and durably reduce viral load
in HIV-1-infected drug-naive and -experienced patients.
394. Molecular mechanisms underlying midbrain dopamine
neuron development and function - Smidt M.P., Smits S.M. and
Burbach J.P.H. [M.P. Smidt, Dept. of Pharmacology and Anatomy,
Rudolf Magnus Inst. of Neuroscience, University Medical Center
Utrecht, Universiteitsweg 100, 3584 CG Utrecht, Netherlands] EUR. J. PHARMACOL. 2003 480/1-3 (75-88) - summ in ENGL
The mesencephalic dopaminergic system is involved in the control of multiple brain functions including movement control and
emotion and is of clinical importance because it is implicated in
several psychiatric disorders, of which many are considered to
have a neurodevelopmental origin. Studies into the developmental pathways of these neurons have led to the identification of the
transcription factors En1, Pitx3, Nurr1 and Lmx1b, all shown to be
important for the development of the mesencephalic dopaminergic
system. In this paper, we discuss the consequences of genetic ablation of essential developmental genes. Furthermore, we discuss the
consequences of changes in dopamine homeostasis for the function
of the mesencephalic dopaminergic system. Finally, we analyse
the potential of the mesencephalic dopaminergic system to adapt to
gene dysfunction. © 2003 Elsevier B.V. All rights reserved.
395. HPLC-UV method development and validation for 16-dehydropregnenolone, a novel oral hypolipidaemic agent, in rat
biological matrices for application to pharmacokinetic studies Singh S.K., Mehrotra N., Sabarinath S. and Gupta R.C. [R.C. Gupta,
Pharmacokin. and Metabolism Division, Central Drug Research Institute, Chattar Manzil Palace, P.O. Box No. 173, Lucknow 226001,
India] - J. PHARM. BIOMED. ANAL. 2003 33/4 (755-764) - summ
in ENGL
An accurate and precise HPLC assay has been developed and
validated for determination of dehydropregnenolone (DHP) in rat
plasma, bile, urine and feces. Separation was achieved using a C-18
reversed phase column with a mobile phase comprising of acetonitrile and deionized water (55:45% v/v) using a UV detector, set at a
wavelength of 248 nm. The method, applicable to 200-l plasma,
bile and urine, involved double extraction of the samples with nhexane. The sample clean up for feces involved single extraction
of 50 mg of sample with 3 ml of acetonitrile. The method was
sensitive with a limit of quantitation of 20 ng/ml in all the matrices
and absolute recovery >92%. Precision and accuracy were within
the acceptable limits, as indicated by relative standard deviation
varying from 4.7 to 11.2% and bias values ranging from 1.8 to 8.8%.
Moreover, DHP was stable in plasma, bile and urine up to 90 days
of storage at -60°C and after being subjected to three freeze-thaw
cycles. The method was applied to generate the pharmacokinetics
of DHP in rats after oral and intravenous administration. © 2003
Elsevier B.V. All rights reserved.
396. Health benefits and potential risks related to consumption
of fish or fish oil - Sidhu K.S. [K.S. Sidhu, Inst. for Environmental
Toxicology, Michigan State University, C231 Holden Hall, East
Lansing, MI 48824, United States] - REGUL. TOXICOL. PHARMACOL. 2003 38/3 (336-344) - summ in ENGL
The nutritional benefits of fish consumption relate to the utilization of proteins of high biological value, as well as certain minerals
and vitamins that fish provide. Fish or fish oil contains omega3 polyunsaturated fatty acids (PUFAs) that appear to play several
useful roles for human health. Conversely, some carcinogenic contaminants are also stored in the adipose tissue of fish. The objective
of this paper is to evaluate the potential health benefits and risks
related to the consumption of fish or fish oil. Health benefits related
to the consumption of fish or omega-3 PUFAs were obtained by an
extensive literature search. Potential health risks related to carcinogenic contaminants (e.g., dioxin, PCB, etc.) in fish were estimated
using the U.S. EPA-approved cancer risk assessment guidelines.
Potential health risk estimates were evaluated by comparing them
with the acceptable excess risk level of 10-6 -10-4 . Scientific data
indicate that the consumption of fish or fish oil containing omega-3
PUFAs reduces the risk of coronary heart disease, decreases mild
hypertension, and prevents certain cardiac arrhythmias and sudden
death. Risk estimates in humans for carcinogenic environmental
contaminants in fish ranged from an excess risk level of 310
-6 -910-4 . These risk estimates appeared to meet the acceptable
excess risk level criteria. Therefore, consumption of fish in accordance with the State of Michigan Fish Advisory Guidelines is safe
and should be encouraged. The top 11 fish species [e.g., sardines,
mackerel, herring (Atlantic and Pacific), lake trout, salmon (Chinook, Atlantic, and Sockeye), anchovy (European), sablefish, and
bluefish] provide an adequate amount of omega-3 PUFAs (2.77.5g/meal) and appear to meet the nutritional recommendation of
the American Heart Association. © 2003 Elsevier Inc. All rights
reserved.
397. Diving emergencies - DeGorordo A., Vallejo-Manzur F.,
Chanin K. and Varon J. [J. Varon, Baylor College of Medicine, University of Texas, Health Science Center-Houston, 2219 Dorrington
St., Houston, TX 77030, United States] - RESUSCITATION 2003
59/2 (171-180) - summ in ENGL, PORT, SPAN
Self-Contained Underwater Breathing Apparatus (SCUBA) diving popularity is increasing tremendously, reaching a total of 9
million people in the US during 2001, and 50,000 in the UK in
1985. Over the past 10 years, new advances, equipment improvements, and improved diver education have made SCUBA diving
safer and more enjoyable. Most diving injuries are related to the
behaviour of the gases and pressure changes during descent and
ascent. The four main pathologies in diving medicine include:
barotrauma (sinus, otic, and pulmonary) ; decompression illness
(DCI); pulmonary edema and pharmacological; and toxic effects
of increased partial pressures of gases. The clinical manifestations
of a diving injury may be seen during a dive or up to 24 h after it.
Physicians living far away from diving places are not excluded from
the possibility of encountering diver-injured patients and therefore
need to be aware of these injuries. This article reviews some of the
principles of diving and pathophysiology of diving injuries as well
as the acute treatment, and further management of these patients. ©
2003 Elsevier Ireland Ltd. All rights reserved.
398. Membrane lipid microdomains differentially regulate intracellular signaling events in human neutrophils - Tuluc F.,
Meshki J. and Kunapuli S.P. [S.P. Kunapuli, Department of Physiology, Temple University Medical School, 3420 N. Broad Street,
Philadelphia, PA 19140, United States] - INT. IMMUNOPHARMACOL. 2003 3/13-14 (1775-1790) - summ in ENGL
The integrity of lipid microdomains is disrupted after cell
treatment with cholesterol-depleting reagents, such as methyl- -cyclodextrin (MCD). We investigated the roles of lipid microdomains
in the regulation of intracellular signaling events and functional
responses in isolated human neutrophils. Treatment of neutrophils with MCD caused inhibition of intracellular calcium increase
evoked by interleukin-8 (IL-8) or low concentrations of formyl-MetLeu-Phe (fMLP). No significant decrease of the initial peak of the
calcium response was measured when neutrophils were stimulated
with 100 nM or higher concentrations of fMLP. MCD inhibited
the phosphorylation of extracellular signal-regulated kinase (Erk)induced by IL-8 or lower concentrations of fMLP. However, Erk
phosphorylation evoked by higher concentrations of fMLP was
only slightly affected. MCD treatment increased phosphorylation of p38 MAP kinase and caused strong up-regulation of both
CD11b and CD66b in resting neutrophils. Cholesterol depletion
greatly inhibited IL-8-induced elastase release but had little effect of fMLP-induced degranulation. Our study brings evidence
suggesting that lipid microdomains are critically required for the
signaling events triggered by IL-8. Calcium mobilization and elastase release induced by WKYMVM, a selective agonist for formyl
peptide receptor-like 1 (FPRL1), were significantly inhibited by
MCD, suggesting that the resistance of fMLP-mediated responses
to MCD is not related to the partition of receptor subtypes to lipid
microdomains. It is more probable that cholesterol depletion interferes with the ability of different G proteins to couple to their
corresponding receptors and this might account for the differential
effects of MCD treatment on chemoattractant-induced effects in
human neutrophils. © 2003 Elsevier B.V. All rights reserved.
399. Drug affinity to immobilized target bio-polymers by
high-performance liquid chromatography and capillary electrophoresis - Bertucci C., Bartolini M., Gotti R. and Andrisano
V. [V. Andrisano, Dipto. di Scienze Farmaceutiche, Università di
Bologna, Via Belmeloro 6, 40126 Bologna, Italy] - J. CHROMATOGR. B ANAL. TECHNOL. BIOMED. LIFE SCI. 2003 797/1-2
This review addresses the use of high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) as affinity
separation methods to characterise drugs or potential drugs-biopolymer interactions. Targets for the development of new drugs
such as enzymes (IMERs), receptors, and membrane proteins were
immobilized on solid supports. After the insertion in the HPLC
system, these immobilized bio-polymers were used for the determination of binding constants of specific ligands, substrates and
inhibitors of pharmaceutical interest, by frontal analyses and zonal
elution methods. The most used bio-polymer immobilization techniques and methods for assessing the amount of active immobilized
protein are reported. Examples of increased stability of immobilized enzymes with reduced amount of used protein were shown
and the advantages in terms of recovery for reuse, reproducibility
and on-line high-throughput screening for potential ligands are evidenced. Dealing with the acquisition of relevant pharmacokinetic
data, examples concerning human serum albumin binding studies
are reviewed. In particular, papers are reported in which the serum
carrier has been studied to monitor the enantioselective binding of
chiral drugs and the mutual interaction between co-administered
drugs by CE and HPLC. Finally CE, as merging techniques with
very promising and interesting application of microscale analysis
of drugs’ binding parameters to immobilized bio-polymers is examined. © 2003 Elsevier B.V. All rights reserved.
400. Assaying protein unbound drugs using microdialysis techniques - Tsai T.-H. [T.-H. Tsai, Laboratory of Pharmacokinetics,
Natl. Res. Inst. of Chinese Medicine, Taipei 112, Taiwan] - J.
CHROMATOGR. B ANAL. TECHNOL. BIOMED. LIFE SCI. 2003
797/1-2 (161-173) - summ in ENGL
Compared with traditional sampling methods, microdialysis is a
technique for protein unbound drug sampling without withdrawal of
biological fluids and involving minimal disturbance of physiological
function. Conventional total drug sample consists of unbound drugs
and protein bound drugs, which are loosely bound to plasma proteins
such as albumin and alpha-1 acid glycoprotein, forming an equilibrium ratio between bound and unbound drugs. However, only the
unbound fraction of drug is available for absorption, distribution,
metabolism and elimination, and delivery to the target sites for
pharmacodynamic actions. Although several techniques have been
used to determine protein unbound drugs from biological fluids, including ultrafiltration, equilibrium dialysis and microdialysis, only
microdialysis allows simultaneous sampling of protein unbound
chemicals from plasma, tissues and body fluids such as the bile juice
77
and cerebral spinal fluid for pharmacokinetic and pharmacodynamic
studies. This review article describes the technique of microdialysis and its application in pharmacokinetic studies. Furthermore, the
advantages and limitations of microdialysis are discussed, including the detailed surgical techniques in animal experiments from rat
blood, brain, liver, bile duct and in vitro cell culture for unbound
drug analysis. © 2003 Elsevier B.V. All rights reserved.
GAGs (heparan sulfate, chondroitin sulfates B and C) completely
blocked transfection, except in the case of liposomes with DOPE.
Sulfated GAGs relaxed and released DNA from some complexes,
but these events were not prerequisites for the inhibition of transfection. Furthermore, preliminary results suggest that cell surface
GAGs, particularly heparan sulfate, inhibit gene transfer by cationic
lipids and polymers. © 2003 Elsevier B.V. All rights reserved.
401. Separation methods applicable to the evaluation of enzyme-inhibitor and enzyme-substrate interactions - Burns K.L.
and May S.W. [S.W. May, School of Chemistry and Biochemistry,
Georgia Institute of Technology, Atlanta, GA 30332, United States]
- J. CHROMATOGR. B ANAL. TECHNOL. BIOMED. LIFE SCI.
2003 797/1-2 (175-190) - summ in ENGL
Enzymes catalyze a rich variety of metabolic transformations, and
do so with very high catalytic rates under mild conditions, and with
high reaction regioselectivity and stereospecificity. These characteristics make biocatalysis highly attractive from the perspectives
of biotechnology, analytical chemistry, and organic synthesis. This
review, containing 128 references, focuses on the use of separation
techniques in the elucidation of enzyme-inhibitor and enzyme-substrate interactions. While coverage of the literature is selective,
a broad perspective is maintained. Topics considered include
chromatographic methods with soluble or immobilized enzymes,
capillary electrophoresis, biomolecular interaction analysis tandem
mass spectrometry (BIA-MS), phage and ribosomal display, and
immobilized enzyme reactors (IMERs). Examples were selected to
demonstrate the relevance and application of these methods for determining enzyme kinetic parameters, ranking of enzyme inhibitors,
and stereoselective synthesis and separation of chiral entities. ©
2003 Elsevier B.V. All rights reserved.
404. Serotonin receptors in platelets of bipolar and schizoaffective patients: Effect of lithium treatment - Pandey G.N., Pandey
S.C., Ren X. et al. [G.N. Pandey, Psychiatric Institute, Department
of Psychiatry, University of Illinois at Chicago, 1601 West Taylor
Street, Chicago, IL 60612, United States] - PSYCHOPHARMACOLOGY 2003 170/2 (115-123) - summ in ENGL
Rationale: Abnormalities of serotonin (5HT) function have been
implicated in mood disorders, and lithium treatment may produce
its beneficial effects by modifying serotonergic mechanisms. It
has also been observed that 5HT 2A receptors are upregulated both
in the postmortem brain and platelets of patients with depression
and suicidal behavior. However, the role of 5HT2A receptors in
bipolar disorders and in the mechanism of action of lithium is unclear. Objective: The major objective of this study was to examine
if abnormalities of 5HT2A receptors are associated with bipolar
or schizoaffective disorders and if treatment with lithium would
cause changes in the 5HT2A receptors. Methods: 5HT2A receptors
were studied in the platelets obtained from drug-free normal control
subjects and patients with bipolar (n=41) or schizoaffective (n=20)disorders during a drug-free washout period and after treatment
(4.00.44 weeks) with lithium (n=16). The Bmax and KD of 5HT2A
receptors were quantitated by binding techniques using [125 I] lysergic acid diethylamide (LSD) as a ligand. Results: We observed
that the 5HT2A receptor Bmax was increased in platelets obtained
from drug-free bipolar or schizoaffective patients as compared with
normal control subjects. The 5HT2A receptor density was even
more increased in bipolar or schizoaffective suicidal patients, and
the 5HT2A receptor Bmax in the non-suicidal bipolar or schizoaffective subgroup also was significantly higher than in normal control
subjects. Treatment with lithium caused a significant increase in
the Bmax of platelet 5HT2A receptors in bipolar or schizoaffective
patients. Conclusions: Our studies indicate that increased 5HT2A
receptors may be associated with the pathophysiology of bipolar
illness and that treatment with lithium further increases the density
of 5HT2A receptors. Whether this increase in 5HT2A receptors
caused by lithium is associated with its therapeutic mechanism of
action is unclear. It is also not clear whether the increase in 5HT2A
receptors in bipolar or schizoaffective patients, or in suicidal bipolar
or schizoaffective patients, is a trait or state marker.
402. Capillary electrophoresis-based immunoassay - Yeung
W.S.B., Luo G.A., Wang Q.G. and Ou J.P. [W.S.B. Yeung, Dept.
of Obstetrics and Gynaecology, University of Hong Kong, Queen
Mary Hospital, Pokfulam Road, Hong Kong, Hong Kong] - J.
CHROMATOGR. B ANAL. TECHNOL. BIOMED. LIFE SCI. 2003
797/1-2 (217-228) - summ in ENGL
Capillary electrophoresis-based immunoassay (CEIA) is a developing analytical technique with a number of advantages over
conventional immunoassay, such as reduced sample consumption,
simpler procedure, easy simultaneous determination of multiple analytes, and short analysis time. However, there are still a number
of technical issues that researchers on CEIA have to solve before
the assay can be more widely used. These issues include method
to improve the concentration sensitivity of the assay, requirement
for robust separation strategy for different analytes, and method to
increase the throughput of the assay. The approaches to solve these
issues are reviewed. Several studies have been devoted to develop
general separation strategies for CEIA, and to enhance the sensitivity of detection. The recent development of microchip-based CEIA
is encouraging and is likely to address more drawbacks of CEIA,
particularly on the throughput issue. © 2003 Elsevier B.V. All rights
reserved.
403. Extracellular and intracellular barriers in non-viral gene
delivery - Ruponen M., Honkakoski P., Rönkkö S. et al. [A. Urtti,
Department of Pharmaceutics, University of Kuopio, Harjulantie
1 A, 70211 Kuopio, Finland] - J. CONTROL. RELEASE 2003 93/2
Complexes of DNA with cationic lipids and cationic polymers
are frequently used for gene transfer. Extracellular interactions
of the complexes with anionic glycosaminoglycans (GAGs) may
interfere with gene transfer. Interactions of GAGs with carrier
DNA complexes have been studied using tests for DNA relaxation
(ethidium bromide intercalation), DNA release (electrophoresis),
and transfection (pCMVbGal transfer into RAA smooth muscle
cells). Several cationic lipid formulations (DOTAP, DOTAP/Chol,
DOTAP/DOPE, DOTMA/DOPE, DOGS) and cationic polymers
(fractured dendrimer, polyethylene imines 25 and 800 kDa, polylysines 20 and 200 kDa) were tested. Polycations condensed DNA
more effectively than monovalent lipids. Hyaluronic acid did not
release or relax DNA in any complex, but it inhibited transfection by
some polyvalent systems (PEI, dendrimers, DOGS). Gene transfer
by other carriers was not affected by hyaluronic acid. Sulfated
78
405. Relationship between levels of insulin or triglycerides and
serum concentrations of the atypical antipsychotics clozapine
and olanzapine in patients on treatment with therapeutic doses
- Melkersson K.I. and Dahl M.-L. [K.I. Melkersson, Department of
Molecular Medicine, Sollentuna Psychiatric Polyclinic, Karolinska
Institute, Stockholm, Sweden] - PSYCHOPHARMACOLOGY 2003
170/2 (157-166) - summ in ENGL
Rationale: Recent results suggest that treatment with the atypical antipsychotics clozapine and olanzapine is associated with
increased insulin and lipid levels. Objective: The aim of the
present study was to investigate potential relationships between
insulin or other hormones related to glucose-insulin homeostasis
or lipids and steady-state serum concentrations of clozapine or olanzapine in patients on therapeutic doses. Methods: Thirty-four
patients, diagnosed with schizophrenia or related psychoses according to the DSM-IV criteria and treated with clozapine (n=18) or
olanzapine (n=16), were studied. Median treatment time with the
antipsychotics was 5.3 years (range 0.5-16.3 years). Fasting blood
samples for insulin, C-peptide, insulin-like growth factor I, insulinlike growth factor binding protein-1, leptin, glucose and lipids were
analyzed and investigated in relation to the patients’ drug serum
concentrations. Results: Hyperinsulinemia was found in 30-60%
of the patients, hyperglycemia in 10-30%, hyperlipidemia in 4060% and hyperleptinemia in 10-20%. Moreover, levels of insulin,
C-peptide and triglycerides correlated positively to the clozapine
serum concentration and to the ratio of olanzapine to N-desmethylolanzapine concentrations. In contrast, levels of C-peptide, leptin
and blood glucose were inversely correlated to the serum concentration of the metabolite N-desmethylolanzapine. Conclusions:
Metabolic abnormalities (i.e. hyperinsulinemia, hyperlipidemia and
hyperleptinemia) and insulin resistance were associated with both
clozapine and olanzapine treatments. Levels of insulin and triglycerides increased by increasing clozapine serum concentration and
by increasing ratio of olanzapine to N-desmethylolanzapine; the
last due to the metabolite N-desmethylolanzapine probably having
an inverse effect to the main compound olanzapine. Thus, the
metabolic abnormalities induced by these two drugs are clozapineconcentration dependent in clozapine-treated patients, and ratio of
olanzapine to N-desmethylolanzapine- concentration dependent in
olanzapine-treated patients.
406. Importance of P-glycoprotein for drug disposition in
humans - Fromm M.F. [Dr. M.F. Fromm, Dr. Margarete FischerBosch-Inst. C., Auerbachstr. 112, 70376 Stuttgart, Germany] EUR. J. CLIN. INVEST. SUPPL. 2003 33/2 (6-9) - summ in ENGL
The ATP-binding cassette transporter P-glycoprotein is now recognized as an important determinant for disposition of multiple
drugs.The use of P-glycoprotein-expressing cell lines, the generation of P-glycoprotein knockout mice as well as studies in animals
and humans contributed to a better understanding on the role of
active transport processes for drug disposition. P-glycoprotein is
located in tissues with excretory function such as intestine, liver and
kidney. Moreover, due to its expression in important blood-tissue
barriers (blood-brain and blood-testis barriers), in lymphocytes and
in placenta it limits tissue penetration of its substrates. Induction
and inhibition of P-glycoprotein have now been identified as important underlying mechanisms of drug interactions in humans. Using
selected examples, this review summarizes currently available data
on the impact of P-glycoprotein for bioavailability of drugs, drug
interactions and drug effects.
407. Teriparatide (rhPTH 1-34) for the treatment of osteoporosis
- Ebeling P.R. and Russell R.G.G. [Dr. R.G.G. Russell, Nuffield
Dept. of Orthopaed. Surgery, Nuffield Orthopaedic Centre, Headington, Oxford OX3 7LD, United Kingdom] - INT. J. CLIN. PRACT.
2003 57/8 (710-718) - summ in ENGL
Osteoporosis is a skeletal disorder characterised by compromised
bone strength predisposing a person to an increased risk of fracture.
Osteoporosis develops through an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts resulting in
increased bone loss. Numerous agents used for the prevention and
treatment of osteoporosis slow bone loss by decreasing both bone
resorption and formation. These include bisphosphonates, hormone
replacement therapy, selective oestrogen receptor modulators and
calcitonins. All reduce vertebral fracture risk and some reduce nonvertebral fracture risk, but none routinely increases bone mass and
strength or restores lost bone architecture. In many respects, antiresorptive therapies halt the progression of osteoporosis. However,
for patients who have osteoporosis, particularly those who have
sustained their first fracture and are at high risk for subsequent fractures, there is a need to develop agents that stimulate bone formation
and, thus, reverse osteoporosis. Teriparatide is the recombinant human 1-34 amino acid sequence of parathyroid hormone recently
approved in the US for the treatment of men and postmenopausal
women at high risk for osteoporotic fracture and in Europe for
the treatment of postmenopausal women with osteoporosis. When
given by once-daily injection, teriparatide increases bone mass by
stimulating formation of new bone, resulting in the restoration of
bone architecture.
408. Polymorphisms and the Pocketbook: The Cost-Effectiveness of Cytochrome P450 2C19 Genotyping in the Eradication
of Helicobacter pylori Infection Associated with Duodenal Ulcer
- Lehmann D.F., Medicis J.J. and Franklin P.D. [Dr. D.F. Lehmann,
SUNY Upstate Medical University, 750 E. Adams Street, Syracuse,
NY 13210, United States] - J. CLIN. PHARMACOL. 2003 43/12
(1316-1323) - summ in ENGL
The clinical outcome of duodenal ulcer treated with proton pump
inhibitor (PPI)-based, anti-Helicobacter pylori (H.p.) regimens
varies according to cytochrome P450 2C19 (CYP2C19) genotype.
CYP2C19 genotypes differ markedly in peoples of Pacific Rim
descent compared with another ethnicity. The authors sought to
determine the specific impact that these factors have on the costeffectiveness of duodenal ulcer management. Their model consisted
of two patient cohorts with Helicobacter pylori and duodenal ulcer,
trichotomized into CYP2C19 homozygous extensive metabolizers
(ENs), heterozygous EMs, and poor metabolizers (PMs), altering
the anti-H.p. regimen in the genotyped cohort only. The authors
took the perspective of a third-party payer, and the denominator
was ulcer episode prevented. In the reference case, the use of
CYP2C19 genotyping prior to initiating anti-H.p. therapy was dominant (costs were saved with each ulcer episode prevented) in all
geographic regions of the United States. The subsequent breakeven analysis showed a range of $89.20 to $118.96-fTom Hawaii
to the Midwest, respectively-required to eliminate the cost-savings
from each genotype test performed. Using probabilities most unfavorable to genotyping, the variation of peoples with Pacific Rim
origins from 0% to 100% altered the cost-effectiveness from $495
to $2125 per ulcer event prevented, respectively. The results suggest that treatment decisions for H.p. infection that are based on
a patient’s CYP2C19 genotype decreases expenses for health plans
implementing testing. This analysis provides an economic basis to
support recent calls to expand this technology into routine clinical
care to prevent toxicity of narrow therapeutic index drugs.
409. Pharmacokinetics and Pharmacodynamics of Mesna-Mediated Plasma Cysteine Depletion - Smith P.F., Booker B.M.,
Creaven P. et al. [P.F. Smith, Roswell Park Cancer Institute, Elm
and Carlton Streets, Buffalo, NY 14263, United States] - J. CLIN.
Cellular glutathione (GSH) levels are related to the resistance of
tumor cells to platinum and alkylating agents, and depletion of GSH
may enhance the activity of these drugs. The pharmacodynamic effects of mesna on depleting plasma cysteine, a GSH precursor, were
evaluated in 22 patients as part of a Phase I study. Escalating doses
of ifosfamide and mesna were administered; carboplatin was administered to achieve an AUC of 4 mgmin/mL. Plasma samples were
collected and assayed by reverse-phase high-performance liquid
chromatography (HPLC) for total mesna and total cysteine concentrations at 0, 1, 3, 6, 24, 25, 28, and 48 hours. A one-compartment
pharmacokinetic model was fit to the mesna plasma concentrations,
using M.A.P Bayesian estimation (ADAPT II). Pharmacodynamics
were evaluated by fitting an inhibitory Emax model to the cysteine concentration data. Both the pharmacokinetic (median R2 =
0.95; range = 0.85-0.98) and pharmacodynamic (median R 2 =
0.96; range = 0.74-1.0) models fit the data well. Mean (coefficient
of variation [CV%]) mesna pharmacokinetic parameter estimates
were as follows: Vss of 15.3 (29) L/m2 , CL of 4.6 (29) L/h/m2 ,
and half-life of 2.2 (37) hours. Mean (CV%) pharmacodynamic
parameter estimates were as follows: Emax of 31.7 (19) g/mL and
EC50 of 10.3 (52) g/mL. Mesna produced a rapid, concentrationdependent reduction in plasma cysteine concentrations that could be
adequately characterized by an inhibitory Emax pharmacodynamic
model. The depletion of plasma cysteine was facilitated by ifosfamide, suggesting a pharmacodynamic interaction between these two
agents. Further increases in mesna doses beyond those administered
in this study would be unlikely to provide additional benefit.
410. Pharmacokinetics and Dosage Adaptation of Meropenem
during Continuous Venovenous Hemodiafiltration in Critically
Ill Patients - Robatel C., Decosterd L.A., Biollaz J. et al. [Dr. T.
Buclin, Div. of Clin. Pharmacol./Toxicol., Hopital Beaumont 6eme
Etage, 1011 Lausanne-CHUV, Switzerland] - J. CLIN. PHARMACOL. 2003 43/12 (1329-1340) - summ in ENGL
Meropenem, a carbapenem broad-spectrum antibiotic, is regularly used in patients undergoing continuous venovenous
hemodiafiltration (CVVHDF). Its disposition was studied over one
dosage interval in 15 patients under CVVHDF on a steady regimen
of 500 or 1000 mg every 8 to 12 hours. Meropenem levels were measured in plasma and filtrate-dialysate by high-performance liquid
chromatography (HPLC) with UV detection. The mean CVVHDF
flow rates were 7.1 0.9 L/h for blood (mean SD), 0.5 0.3 L/h
for predilution solution, 1.2 0.3 L/h for countercurrent dialysate,
and 1. 8 0.5 L/h for the total filtrate-dialysate. The pharmacokinetic analysis was based both on a noncompartmental approach and
on a four-compartment modeling. The mean (coefficient of variation [CV]) total body clearance, volume of distribution at steady
79
state, and mean residence time were, respectively, 5.0 L/h (46%),
14.3 L (29%), and 4.8 h (36%). The hemodiafiltration clearances
calculated from plasma data alone and plasma with filtrate-dialysate data were 1.2 L/h (26%) and 1.6 L/h (39%), respectively. The
compartmental model was used to optimize the therapeutic schedule
of meropenem, considering reference minimal inhibitory concentration (MIC) of sensitive strains (4 mm/L). The results indicate
that two different therapeutic schedules of meropenem are equally
applicable to patients receiving CVVHD: either 750 mg tid or 1500
bid.
411. Effect of Food on Pharmacokinetics of an Inhaled Drug:
A Case Study with a VLA-4 Antagonist, HMR1031 - Shah B.,
Jensen B.K., Zhang J. et al. [Dr. S. Rohatagi, Drug Metabolism and
Pharmacokinetics, Aventis Pharmaceuticals, Inc., Mail Stop 303B,
Route 202-206, Bridgewater, NJ 08807, United States] - J. CLIN.
HMR1031 is a potent and specific antagonist of the integrin VLA-4 (4 1 ) binding to vascular cell adhesion molecule-1
(VCAM-1) and fibronectin. HMR1031 is an inhaled drug being developed for the treatment of asthma using an Ultrahaler®
dry-powder inhalation device. A pharmacoscintigraphic study of
HMR1031 suggests a lung deposition of 25% and gastrointestinal
tract deposition of 75%. Since oral absorption may be contributing
to systemic plasma concentrations, the effect of food on HMR1031
was assessed. This was a single-dose (3 mg), open-label, randomized, two-way crossover (fasted vs. fed) study in 8 healthy
male subjects. Blood samples were collected at predose and up to
24 hours postdose. Plasma concentrations were determined by the
LC/MS/MS method. HMR1031 was rapidly absorbed, with median
tmax values of 1.0 and 0.75 hours under fasted and fed conditions,
respectively. Under fasted conditions, mean AUC ∞ and Cmax
values were 16.4 ngh/mL and 4.56 ng/mL, respectively. Under
fed conditions, mean AUC∞ and C max values decreased to 11.7
ngh/mL and 2.81 ng/mL, respectively. The mean terminal elimination half-life (t1/2 ) for both treatment groups was similar (2.7 h).
HMR1031 population estimates of the apparent clearance, apparent
volume of distribution, and absorption rate were 225 L/h (4.1% coefficient of variation [CV]), 44.5 L (26% CV), and 0.340 h -1 (7.0%
CV), respectively. Food is a significant covariate on clearance.
These data suggest that food unexpectedly decreases the systemic
exposure of inhaled HMR1031 by 30%, probably due to increased
liver blood flow and increased biliary excretion. This decrease in
systemic exposure is unlikely to affect the topical effect of the drug
but may result in increased variability in plasma pharmacokinetics.
The disposition and food effect of HMR1031 can be described using
mixed-effect modeling.
412. Interaction Study between Fluvoxamine and Quazepam Kanda H., Yasui-Furukori N., Fukasawa T. et al. [Dr. K. Otani, Department of Neuropsychiatry, Yamagata Univ. School of Medicine,
Yamagata 990-9585, Japan] - J. CLIN. PHARMACOL. 2003 43/12
(1392-1397) - summ in ENGL
It has been reported that fluvoxamine, an inhibitor of various
cytochrome P450 enzymes, markedly inhibits the metabolism of
several drugs. The purpose of the present study was to examine a
possible interaction between fluvoxamine and quazepam. Twelve
healthy male volunteers received fluvoxamine 50 mg/day or placebo
for 14 days in a double-blind randomized crossover manner, and
on the 4th day thev received a single oral 20-mg dose of quazepam. Blood samplings and evaluation of psychomotor function by
the Digit Symbol Substitution Test and Stanford Sleepiness Scale
were conducted up to 240 hours after quazepam dosing. Plasma
concentrations of quazepam and its active metabolites 2-oxoquazepam (OQ) and N-desalkyl-2-oxoquazepam (DOQ) were measured
by high-performance liquid chromatography (HPLC). Fluvoxamine
did not change plasma concentrations of quazepam but significantly
decreased those of OQ from 6 to 12 hours and those of DOQ from
3 to 48 hours. The AUC ratio of OQ to quazepam was significantly
lower in the fluvoxamine phase. Fluvoxamine did not affect psychomotor function at most of the time points. The present study
suggests that fluvoxamine slightly inhibits the metabolism of quazepam to OQ, but this interaction appears to have minimal clinical
significance.
80
413. Antiparasitic activity of highly conjugated pyrimidine-2,4dione derivatives - Azas N., Rathelot P., Djekou S. et al. [N.
Azas, Laboratoire de Parasitologie, EA 864, Faculté de Pharmacie,
27 Boulevard Jean Moulin, 13385 Marseille Cedex 5, France] FARMACO 2003 58/12 (1263-1270) - summ in ENGL
4- [2- (1,3- Dimethyl- 5- nitro- 2,6- dioxo- 1,2,3,6- tetrahydropyrimidin-4-yl) vinyl]benzaldehyde was synthesized in four steps
from 6-methyl-1H,3H-pyrimidine- 2,4-dione.
This aldehyde
was functionalized by various substituted anilines or substituted
benzylamines.
Antiparasitic activities of the corresponding
azomethines were assessed against Plasmodium falciparum,
Trichomonas vaginalis and Leishmania infantum compared to
their toxicity versus human cells. © 2003 Published by Éditions
scientifiques et médicales Elsevier SAS.
414. Synthesis of aniline-type analogues of farnesyl diphosphate
and their biological assays for prenyl protein transferase inhibitory activity - Minutolo F., Bertini S., Betti L. et al. [M.
Macchia, Dipto. di Scienze Farmaceutiche, Università di Pisa, Via
Bonanno 6, 56126 Pisa, Italy] - FARMACO 2003 58/12 (12771281) - summ in ENGL
Stable analogues of farnesyl diphosphate, possessing an
aniline-type portion in the prenyl-mimic moiety and phosphonoacetamido(oxy) groups in the place of the metabolically unstable
diphosphate unit, were synthesised and submitted to biological assays. The enzyme inhibition tests performed on FTase and GGTase I
show that the newly synthesised compounds based on a combination
of the aniline-containing portions with (phosphonoacetamido)oxy
groups do not afford potent inhibitors. © 2003 Éditions scientifiques
et médicales Elsevier SAS. All rights reserved.
415. Synthesis and hypolipidemic activity of N-substituted
phthalimides. Part V - Sena V.L.M., Srivastava R.M., Silva R.O.
and Lima V.L.M. [R.M. Srivastava, Depto. de Quı́mica Fundamental, Universidade Federal de Pernambuco, Cidade Universitária, Av.
Luis Freire, S/N, CEP 50.740-540 Recife, PE, Brazil] - FARMACO
2003 58/12 (1283-1288) - summ in ENGL
A series of N-aryl- or N-(1,2,4-triazol-yl)-phthalimides (4a-4i)have been synthesized starting from phthalic anhydride (1) and an
appropriate amine (2a-2i). All compounds presented hypolipidemic
activity, but compound 4d proved to be the most active and reduced
plasma cholesterol and triglyceride levels in Swiss white mice significantly. © 2003 Published by Éditions scientifiques et médicales
Elsevier SAS.
416. Salicylate regulates cyclooxygenase-2 expression through
ERK and subsequent NF-k B activation in osteoblasts - Chae
H.-J., Lee J.-K., Byun J.-O. et al. [H.-R. Kim, Department of
Dental Pharmacology, School of Dentistry, Wonkwang University,
Iksan, Jeonbuk 570-749, South Korea] - KOREAN J. PHYSIOL.
The expression of cyclooxygenase-2 (COX-2) is a characteristic response to inflammation and can be inhibited with sodium
salicylate. TNF- plus IFN- can induce extracellular signal-regulated kinase (ERK), IKK, IB degradation and NF-B
activation. The inhibition of the ERK pathway with selective inhibitor, PD098059, blocked cytokine-induced COX-2 expression
and PGE2 release. Salicylate treatment inhibited COX-2 expression
induced by TNF-/IFN- and regulated the activation of ERK,
IKK and IB degradation and subsequent NF-B activation in
MC3T3E1 osteoblasts. Furthermore, antioxidants such as catalase, N-acetyl-cysteine or reduced glutathione attenuated COX-2
expression in combined cytokines-treated cells, and also inhibited
the activation of ERK, IKK and NF-B in MC3T3E1 osteoblasts.
In addition, TNF-/IFN- stimulated ROS release in the osteoblasts. However, salicylate had no obvious effect on ROS release
in DCFDA assay. The results showed that salicylate inhibited the
activation of ERK and IKK, IB degradation and NF-B activation
independent of ROS release and suggested that salicylate exerts its
anti-inflammatory action in part through inhibition of ERK, IKK,
IB, NF-B and resultant COX-2 expression pathway.
417. Metabolites of orally administered Magnolia officinalis extract in rats and man and its antidepressant-like effects in mice
- Nakazawa T., Yasuda T. and Ohsawa K. [K. Ohsawa, Department
of Phytochemistry, Tohoku Pharmaceutical University, 4-1 Komatsushima 4-chome, Aoba-ku, Sendai, Miyagi 981-8558, Japan] - J.
PHARM. PHARMACOL. 2003 55/11 (1583-1591) - summ in ENGL
As a part of our search for the active metabolite from the bark
of Magnolia officinalis (Magnoliaceae), the aqueous extract was
orally administered to rats, and metabolites in the urine were
analysed by a high-performance liquid chromatograph equipped
with a photodiode array detector. When the extract was given
to rats, five metabolites (sinapic acid-4-O-sulfate (1), sinapic
acid-4-O- -glucuronide (2), sinapic acid (3), 3-[2 ,6-dihydroxy-5 (2-propenyl)[1,1 -biphenyl]-3-yl]-(E)-2-p ropenoic acid (4), and an
unchanged form, magnolol (5)) were detected in the urine. It was
revealed that metabolites 1-3 and 4 were respectively derived from
syringin and magnolol contained in the extract. In a human urine
sample, metabolites 3-5 and dihydroxydihydromagnolol (6) were
detected. These structures were identified by a combination of
spectral methods and/or by comparison with authentic compounds
obtained by synthesis. Among these free form metabolites (3-6), acute treatments with magnolol and dihydroxydihydromagnolol
(50-100 mg kg-1 , i.p.) attenuated the forced swim-induced experimental depression in mice. The results indicated that magnolol and
dihydroxydihydromagnolol were the antidepressant constituents of
Magnolia officinalis.
418. Injectable bisphosphonates in the treatment of postmenopausal osteoporosis - Sartori L., Adami S., Filipponi P. and
Crepaldi G. [Dr. L. Sartori, Clinica Medica I, Dept. of Medical/Surgical Sciences, University of Padova, Via Giustiniani 2, 35128
Padova, Italy] - AGING CLIN. EXP. RES. 2003 15/4 (271-283) summ in ENGL
Osteoporosis is a "silent" disease and the patient has usually no
clue of it until the occurrence of a fragility fracture. Prevention
requires a continuous daily treatment that could be uncomfortable
to the patient. Besides the recently introduced weekly oral schedules, injectable bisphosphonates have often been used as an off-label
option to ameliorate compliance. In general, although with different
efficiency, almost all injectable bisphosphonates can improve bone
mineral density and suppress bone resorption markers. The effect
of intravenous infusions of bisphosphonates are, to a large extent,
similar to equivalent intramuscular administrations, but doses and
dosing intervals represent the critical issues. Pain at the injection
site and acute phase reactions are relatively common to intramuscular clodronate and intravenous infusions of nitrogen-containing
bisphosphonates, respectively. Under certain circumstances, intermittent treatment with injectable bisphosphonates might represent
a feasible alternative when compliance is at risk. © 2003, Editrice
Kurtis.
419. Clerocidin alkylates DNA through its epoxide function:
Evidence for a fine tuned mechanism of action - Richter S.,
Gatto B., Fabris D. et al. [M. Palumbo, Dept. of Pharmaceutical
Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy]
- NUCLEIC ACIDS RES. 2003 31/17 (5149-5156) - summ in ENGL
Clerocidin (CL) is an effective topoisomerase II-poison, which
has been shown to produce DNA depurination and strand breaks
per se at the guanine (G) level. To elucidate the roles played
by the different functional groups of CL in the reactivity towards
nucleic acids, we investigated CL derivatives with key structural
modifications. The derivatives were reacted with plasmid, single/double-stranded DNA and isolated 2 -deoxy-guanosines (dG). We
show here that an intact oxirane ring is essential to achieve DNA
modification and depurination. Through HPLC/MS and MS/MS
techniques we were able to unambiguously characterize adducts
obtained by reacting isolated dG and single-/double-stranded DNA
with the drugs, indicating beyond reasonable doubt that the structure of a typical adduct is formed by epoxide alkylation at N7 of
G with subsequent loss of the pentose unit. Further, we showed
that reduction of vicinal carbonyl functions affect drug activity to
a large extent. Our findings demonstrate that the characteristic
DNA-alkylating properties of CL arise from mutual action of the
functional groups present in this molecule. Its oxidation state seems
crucial to modulate the rates of reactivity by finely tuning the strain
applied on the oxirane ring.
420. Unusual intercalation of acridin-9-ylthiourea into the 5 GA/TC DNA base step from the minor groove: Implications
for the covalent DNA adduct profile of a novel platinum-intercalator conjugate - Baruah H. and Bierbach U. [U. Bierbach,
Department of Chemistry, Wake Forest University, Winston-Salem,
NC 27109-7486, United States] - NUCLEIC ACIDS RES. 2003
31/14 (4138-4146) - summ in ENGL
The binding of the novel cytotoxic acridine derivative, 1-[2(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea (ACRAMTU) to
various self-complementary oligonucleotide duplexes has been
studied by combined high-resolution NMR spectroscopy/restrained
molecular dynamics and equilibrium binding assays to establish
the sequence and groove specificity of intercalation. The binding
mode in the sequences d(GGACGTCC)2 and d(GGAGCTCC)2 was deduced from chemical shift changes and intermolecular
NOEs between the ligand and the oligonucleotides. ACRAMTU
intercalated into the 5 -CG/CG and 5 -GA/TC base steps, and
penetration of the duplexes occurred from the minor groove. Intercalation of ACRAMTU in d(GGTACC)2 occurs at the central
TA/TA step, based on the absence of the internucleotide A4H8T3H1 and A4H8-T3H3 cross-peaks in the 1:1 complex of this
sequence. An energy-minimized AMBER model of the 1:2 complex, [d(GGAGCTCC)2(ACRAMTU)2], was generated, which was
based on restricted molecular dynamics/mechanics calculations using 108 NOE distance restraints (including 11 DNA-drug distances
per ligand). Equilibrium dialysis experiments were performed using octamers containing various base steps present in the ’NMR
sequences’. The highest affinity for ACRAMTU was observed
in d(TATAT-ATA)2, followed by d(CGCGCGCG)2 and d(GAGATCTC)2 . The binding levels for CG/CG and GA/TC were virtually
the same. The unusual tolerance of the GA/TC intercalation site
and the pronounced groove specificity of ACRAMTU play a significant role in the molecular recognition between the corresponding
platinum conjugate, Pt-ACRAMTU, and DNA.
421. Unique actinomycin D binding to self-complementary
d(CXYGGCCYX G) sequences: Duplex disruption and binding to a nominally base-paired hairpin - Chen F.-M., Sha F., Chin
K.-H. and Chou S.-H. [F.-M. Chen, Department of Chemistry, Tennessee State University, Nashville, TN 37209-1561, United States]
- NUCLEIC ACIDS RES. 2003 31/14 (4238-4246) - summ in ENGL
Actinomycin D (ACTD) has been shown to bind weakly to the
sequence -GGCC-, despite the presence of a GpC site. It was subsequently found, however, that d(CATGGCCATG) binds relatively
well to ACTD but exhibits unusually slow association kinetics, contrary to the strong-binding -XGCY-sites. In an effort to elucidate the
nature of such WnWng and to delineate the origin of its interesting
kinetic behavior, studies have now been extended to include oligomers with the general sequence motifs of d(CXYGGCCY’X’G)2.
It was found that analogous binding characteristics are observed for
these self-duplex decamers and comparative studies with progressively base-truncated oligomers from the 5 -end led to the finding
that d(GGCCY’X’G) oligomers bind ACTD considerably stronger
than their parent decamers and exhibit 1:1 drug/strand binding stoichiometry. Melting profiles monitored at the drug spectral region
indicated additional drug binding prior to the onset of eventual
complex disruptions with near identical melting temperatures for
all the oligomers studied. These results are consistent with the
notion that the related oligomers share a common strong binding
mode of a hairpin-type, with the 3 -terminus G folding back to
base-pair with the C base of GGC. A binding scheme is proposed in
which the oligomers d(CXYGGCCY’X’G) exist predominantly in
the duplex form and bind ACTD initially at the central GGCC weak
site but subsequently disrupt to accommodate the stronger hairpin
binding and thus the slow association kinetics. Such a mechanism
is supported by the observation of distinct biphasic fluorescence
kinetic traces in the binding of 7-amino-ACTD to these duplexes.
422. Therapeutic modulation of endogenous gene function by
agents with designated DNA-sequence specificities - Uil T.G.,
Haisma H.J. and Rots M.G. [M.G. Rots, Dept. of Therapeutic Gene
Modulation, University Center for Pharmacy, PO Box 196, 9700
AD Groningen, Netherlands] - NUCLEIC ACIDS RES. 2003 31/21
(6064-6078) - summ in ENGL
81
Designer molecules that can specifically target pre-determined
DNA sequences provide a means to modulate endogenous gene
function. Different classes of sequence-specific DNA-binding
agents have been developed, including triplex-forming molecules,
synthetic polyamides and designer zinc finger proteins. These different types of designer molecules with their different principles of
engineered sequence specificity are reviewed in this paper. Furthermore, we explore and discuss the potential of these molecules as
therapeutic modulators of endogenous gene function, focusing on
modulation by stable gene modification and by regulation of gene
transcription.
423. Energetics of echinomycin binding to DNA - Leng F.,
Chaires J.B. and Waring M.J. [M.J. Waring, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge
CB2 1PD, United Kingdom] - NUCLEIC ACIDS RES. 2003 31/21
(6191-6197) - summ in ENGL
Differential scanning calorimetry and UV thermal denaturation
have been used to determine a complete thermodynamic profile for
the bis-intercalative interaction of the peptide antibiotic echinomycin with DNA. The new calorimetric data are consistent with all
previously published binding data, and afford the most rigorous and
direct determination of the binding enthalpy possible. For the association of echinomycin with DNA, we found G° = -7.6 kcal mol-1 ,
H = +3.8 kcal mol-1 and S = +38.9 cal mol-1 K-1 at 200°C. The
binding reaction is clearly entropically driven, a hallmark of a process that is predominantly stabilized by hydrophobic interactions,
though a deeper analysis of the free energy contributions suggests
that direct molecular recognition between echinomycin and DNA,
mediated by hydrogen bonding and van der Waals contacts, also
plays an important role in stabilizing the complex.
424. Paroxetine-Induced Increase in Metabolic End Products of
Nitric Oxide - Lara N., Archer S.L., Baker G.B. and Le Mellédo
J.-M. [Dr. J.-M. Le Mellédo, 1E7.05 Mackenzie Centre, Edmonton,
Alta. T6G 2B7, Canada] - J. CLIN. PSYCHOPHARMACOL. 2003
23/6 (641-645) - summ in ENGL
Decreased production of endothelium-derived nitric oxide (NO)has been implicated in the pathogenesis of cardiovascular diseases.
Metabolic end products of nitric oxide (NOx ) are often used as
markers for endothelial NO production in humans. Decreased endothelium-derived NO has been suggested to mediate some of the
deleterious effects of conventional cardiovascular risk factors such
as hypercholesterolemia, smoking, and physical inactivity because
they induce a decrease in plasma NOx . A substantial number of
patients with cardiovascular diseases suffer from comorbid major
depressive disorder, which is a predictor of a poorer cardiovascular
outcome. Paroxetine is a first-line antidepressant and has been
reported to decrease plasma NOx , theoretically suggesting a potential deleterious effect on the cardiovascular system. We assessed
the hypothesis that paroxetine would induce a decrease in plasma
NOx in healthy volunteers. Plasma NOx levels were measured by
chemiluminescence at baseline, after 8 weeks of paroxetine administration, and at postdiscontinuation. Contrary to our hypothesis, we
found that paroxetine administration induced a significant increase
in plasma NOx that normalized after paroxetine discontinuation. It
remains to be demonstrated that the paroxetine-induced increase in
plasma NOx is associated with a modification of the cardiovascular
risk in patients with major depressive disorder.
425. Uptake of Chitosan and Associated Insulin in Caco-2 Cell
Monolayers: A Comparison between Chitosan Molecules and
Chitosan Nanoparticles - Ma Z. and Lim L.-Y. [L.-Y. Lim, Department of Pharmacy, National University of Singapore, 18 Science
Drive 4, Singapore 117543, Singapore] - PHARM. RES. 2003 20/11
(1812-1819) - summ in ENGL
Purpose. To evaluate the uptake of chitosan molecules (fCS) and
nanoparticles (fNP), and their ability to mediate insulin transport in
Caco-2 cell monolayers. Methods. Cell-associated fCS and fNP
were evaluated by fluorometry, trypan blue quenching, and confocal microscopy using FITC-labeled chitosan. Chitosan-mediated
transport of FITC-labeled insulin was studied in Caco-2 cell monolayers cultured on permeable inserts. Results. Caco-2 cells showed
twofold higher association with fNP than fCS after 2-h incubation
with 1 mg/ml samples. fNP uptake was a saturable (Km 1.04 mg/ml;
82
V max 74.15 g/mg/h), concentration- and temperature-dependent
process that was inhibited by coadministered chlorpromazine. fCS
uptake was temperature dependent, but was less sensitive to concentration and was inhibited by filipin. Postuptake quenching with 100
g/ml of trypan blue suggests a significant amount of intracellular
fNP, although the bulk of fCS was extracellular. Internalized fNP
were located by confocal microscopy at 15 m from the apical
membrane, but there was no apparent breaching of the basal membrane. This might explain the failure of the nanoparticles to mediate
significant insulin transport across the Caco-2 cell monolayer. Conclusions. Formulation of chitosan into nanoparticles transforms its
extracellular interactions with the Caco-2 cells to one of cellular
internalization via clathrin-mediated endocytosis.
426. Unexpected Clobetasol Propionate Profile in Human Stratum Corneum after Topical Application in Vitro - Mueller B.,
Anissimov Y.G. and Roberts M.S. [M.S. Roberts, Princess Alexandra Hospital, TAFE 3 Building, Wooloongabba, QLD 4102,
Australia] - PHARM. RES. 2003 20/11 (1835-1837) - summ in
ENGL
Purpose. The validity of using drug amount-depth profiles in
stratum corneum to predict uptake of clobetasol propionate into
stratum corneum and its transport into deeper skin layers was investigated. Methods. In vitro diffusion experiments through human
epidermis were carried out using Franz-type glass diffusion cells. A
saturated solution of clobetasol propionate in 20% (V/V) aqueous
propylene glycol was topically applied for 48 h. Steady state flux
was calculated from the cumulative amount of drug permeated vs.
time profile. Epidermal partitioning was conducted by applying a
saturated drug solution to both sides of the epidermis and allowing
time to equilibrate. The tape stripping technique was used to define
drug concentration-depth profiles in stratum corneum for both the
diffusion and equilibrium experiments. Results. The concentration-depth profile of clobetasol propionate in stratum corneum for
the diffusion experiment is biphasic. A logarithmic decline of the
drug concentration over the first four to five tape strips flattens to
a relatively constant low concentration level in deeper layers. The
drug concentration-depth profile for the equilibrium studies displays
a similar shape. Conclusions. The shape of the concentration-depth
profile of clobetasol propionate is mainly because of the variable
partitioning coefficient in different stratum corneum layers.
427. Poly-L-Arginine Enhances Paracellular Permeability via
Serine/Threonine Phosphorylation of ZO-1 and Tyrosine Dephosphorylation of Occludin in Rabbit Nasal Epithelium Ohtake K., Maeno T., Ueda H. et al. [H. Natsume, Faculty of
Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado,
Saitama 350-0295, Japan] - PHARM. RES. 2003 20/11 (1838-1845)- summ in ENGL
Purpose. The purpose of the present study is to explore whether a
poly-L-arginine (poly-L-Arg)-induced increase in tight junctions
(TJ) permeability of fluorescein isothiocyanate-labeled dextran
(MW 4.4 kDa, FD-4) is associated with the Ca2+ -dependent signaling and occurs following the phosphorylation/dephosphorylation of
TJ proteins. Methods. Excised rabbit nasal epithelium was mounted
in an Ussing-type chamber for measurement of FD-4 transport and
membrane conductance (Gt) in the presence of various inhibitors
that are involved in the Ca2+ -dependent pathway and the phosphorylation/ dephosphorylation of TJ proteins. The resultant distribution
of TJ proteins was observed using confocal laser scanning microscopy (CLSM) in an immunostaining. Results. The increase
in TJ permeability of FD-4 induced by 0.2 mg/ml poly-L-Arg was
not altered by treatment with inhibitors of possible Ca2+ mobilization pathways followed by exposure of poly-L-Arg, suggesting that
the promoting effect of poly-L-Arg is independent of Ca 2+ -related
signaling. On the other hand, the protein kinase C (PKC) and tyrosine phosphatase inhibitors suppress the increase in TJ permeability
by poly-L-Arg, indicating that serine/threonine phosphorylation by
way of Ca 2+ -independent PKC and tyrosine dephosphorylation of
junction proteins may have occurred. Furthermore, immunofluorescent monitoring of ZO-1, a TJ associated protein, and occludin,
an integral membrane protein localizing at TJ, after preincubation
with PKC and tyrosine phosphatase inhibitors followed by polyL-Arg treatment has shown that the internalization of ZO-1 and
occludin occurred by way of serine/threonine phosphorylation by
PKC activation and by way of tyrosine dephosphorylation, respectively, providing TJ disassembly. Conclusions. We conclude that
poly-L-Arg enhances the paracellular permeability of FD-4 (i.e.,
macromolecules), at least, by way of both serine/threonine phosphorylation of ZO-1 and tyrosine dephosphorylation of occludin in
rabbit nasal epithelium.
428. 3D-QSAR studies of indole derivatives as phosphodiesterase IV inhibitors - Chakraborti A.K., Gopalakrishnan B., Sobhia
M.E. and Malde A. [A.K. Chakraborti, Department of Medicinal
Chemistry, Natl. Inst. Pharmaceutical Educ. R., Sector-67, S.A.S.
Nagar 160 062, Punjab, India] - EUR. J. MED. CHEM. 2003 38/1112 (975-982) - summ in ENGL
The 3D-QSAR studies of some indole derivatives as phosphodiesterase (PDE) type IV inhibitors was performed by Comparative
Molecular Field Analysis (CoMFA) and Comparative Molecular
Similarity Indices Analysis (CoMSIA) methods to determine the
factors required for the activity of these compounds. The global
minimum energy conformer of the template molecule, 3 the most
active molecule of the series, was obtained by simulated annealing
method and used to build the structures of the molecules in the
dataset. The CoMFA model produced statistically significant results with cross-validated and conventional correlation coefficients
of 0.494 and 0.986 respectively. The combination of steric, electrostatic and hydrophobic fields in CoMSIA gave the best results
with cross-validated and conventional correlation coefficients of
0.541 and 0.967 respectively. The predictive ability of CoMFA
and CoMSIA were determined using a test set of seven indole
derivatives giving predictive correlation coefficients of 0.56 and
0.59 respectively indicating good predictive power. Further, the
robustness of the models was verified by bootstrapping analysis.
Based upon the information derived from CoMFA and CoMSIA,
we have identified some key features that may be used to design
new indole derivatives and predict their PDE IV affinities prior to
synthesis. © 2003 Éditions scientifiques et médicales Elsevier SAS.
429. N6 -Cycloalkyl-2-phenyl-3-deaza-8-azaadenines: A new
class of A1 adenosine receptor ligands. A comparison with the
corresponding adenines and 8-azaadenines - Biagi G., Giorgi
I., Livi O. et al. [I. Giorgi, Dipto. di Scienze Farmaceutiche,
Università di Pisa, via Bonanno, 6-56126 Pisa, Italy] - EUR. J.
MED. CHEM. 2003 38/11-12 (983-990) - summ in ENGL
Several 9-benzyl-N6 -cycloalkyl-2-phenyladenines, 9-benzyl-N
6 -cycloalkyl-2-phenyl-8-azaadenines and 4-cycloalkylamino-1benzyl-6- phenyl-1H-1,2,3-triazolo[4,5-c]pyridines were prepared
and assayed as A 1 adenosine receptor ligands.
The
1H-1,2,3-triazolo[4,5-c]pyridines were obtained starting from N,Ndiethyl-1-benzyl-4-carboxyamido-5-methyl-1H-1,2, 3-triazole by
lithiation in anhydrous tetrahydrofurane in the presence of
benzonitrile. The usual work up afforded the isolation of 1-benzyl6-phenyl-1H- 1,2,3-triazolo[4,5-c]pyridin-4-one which was treated
with phosphorous oxychloride and cycloalkylamines. Some compounds showed high affinity and selectivity and the trend of Ki
values corresponds to the series of 9-benzyl-N6 -cycloalkyl-2-phenyladenines and 9-benzyl-N 6 -cycloalkyl-2-phenyl-8-azaadenines,
therefore they can be considered bioisosteres. The affinity data
permitted us to ascertain the role and the importance of the N(3) in
the adenine or 8-azaadenine moiety in the receptor binding and to
study the dimension of the receptor lipophilic pocket which is filled
by the N6 substituent of adenosine derivatives. © 2003 Éditions
scientifiques et médicales Elsevier SAS. All rights reserved.
430. Hydrogen bond interactions of a series of N-substituted
TXA2 receptor antagonists - Taylor D.M., Halushka P.V. and
Meier G.P. [G.P. Meier, Department of Chemistry, 402 Fulmer
Hall, Washington State University, PO Box 643140, Pullman, WA
99164-4630, United States] - EUR. J. MED. CHEM. 2003 38/11-12
(1015-1024) - summ in ENGL
A series of N-substituted sulphonamide based thromboxane A2
(TXA2 ) receptor antagonists were synthesised with the objective to
explore the role of hydrogen bond donation properties in the binding
of these ligands to the TXA2 receptor. Pharmacological evaluation
of these compounds revealed that the binding affinity decreased
significantly with the removal of the hydrogen bond donor. This
indicates that a hydrogen bond donor is important for the binding of these antagonists to the TXA2 receptor. © 2003 Éditions
431. Fullerene derivatives: An attractive tool for biological applications - Bosi S., Da Ros T., Spalluto G. and Prato M. [T. Da
Ros, Dipto. di Scienze Farmaceutiche, Univ. degli Studi di Trieste,
Piazzale Europa 1, 34127 Trieste, Italy] - EUR. J. MED. CHEM.
2003 38/11-12 (913-923) - summ in ENGL
The fullerene family, and especially C60 , has very appealing
photo-, electro-chemical and physical properties, which can be exploited in many and different biological fields. Fullerene is able to
fit inside the hydrophobic cavity of HIV proteases, inhibiting the
access of substrates to the catalytic site of the enzyme. It can be
used as radical scavenger; in fact some water-soluble derivatives are
able to reduce ROS concentrations. At the same time, if exposed to
light, fullerene can produce singlet oxygen in high quantum yields.
This action, together with the direct electron transfer from excited
state of fullerene and DNA bases, can be used to cleave DNA. In
this review we report the most recent aspects of fullerene biological
applications. © 2003 Éditions scientifiques et médicales Elsevier
SAS. All rights reserved.
432. Topical administration of the nitric oxide donor glyceryl
trinitrate modifies the structural and biomechanical properties
of ovine articular cartilage - Cake M.A., Appleyard R.C., Read
R.A. et al. [Dr. P. Ghosh, Institute of Bone and Joint Research,
Royal North Shore Hospital, St. Leonards, NSW 2065, Australia] OSTEOARTHRITIS CARTILAGE 2003 11/12 (872-878) - summ in
ENGL
Objective: To examine the effect of topical administration of
glyceryl trinitrate (GTN), an exogenous nitric oxide (NO) donor, on
the structural and biomechanical properties of uncalcified articular
cartilage (UCC) in aged ewes. Design: Twelve ewes were used for
this study. Six of these were treated with 2% GTN ointment (0.7
mg/kg) twice per week (GTN), and the remaining six were used
as normal controls (NOC). After sacrifice at 26 weeks, dynamic
biomechanical indentation testing and thickness determination (by
needle penetration) were performed on tibial plateau articular cartilage at 18 locations. Using histological sections prepared from
the lateral and medial femoral condyles (LFC, MFC) and tibial
plateau (LTP, MTP), the thickness of UCC, cartilage proteoglycan content (intensity of toluidine blue staining; LFC, MFC only),
and collagen birefringence (LTP, MTP, LFC only) were quantified
by computer-assisted image analysis. Results: Phase lag of tibial plateau cartilage was reduced in GTN sheep relative to NOC
(mean of all testing locations 11.01.9° vs 12.12.3°; P=0.0001).
GTN treatment also globally reduced UCC thickness across the
joint (ANOVA for all measured zones, P<0.0001). UCC thinning
was most pronounced in the MFC (P=0.025) and LTP (P=0.0002).
Proteoglycan content was reduced in the MFC (P=0.019), while
collagen birefringence, was increased in superficial cartilage zones
of the LTP. Conclusions: NO donation via topical administration
of GTN to normal ewes reduced the thickness and phase lag of
femoro-tibial articular cartilage, suggesting a disturbance in chondrocyte metabolism. Regional alterations of collagen organisation
and proteoglycan content were consistent with this interpretation.
© 2003 OsteoArthritis Research Society International. Published
by Elsevier Ltd. All rights reserved.
433. Transient induction of cytochromes P450 1A1 and 1B1 in
MCF-7 human breast cancer cells by indirubin - Spink B.C.,
Hussain M.M., Katz B.H. et al. [D.C. Spink, New York State Department of Health, Wadsworth Center, Albany, NY 12201-0509,
United States] - BIOCHEM. PHARMACOL. 2003 66/12 (23132321) - summ in ENGL
The aryl hydrocarbon receptor (AhR), when activated by exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD),
regulates expression of several phase I and phase II enzymes and is
also involved in the regulation of cell proliferation. Several studies
suggest that endogenous AhR ligand(s) may exist. One putative
endogenous ligand is indirubin, which was recently identified in
83
human urine and bovine serum. We determined the effect of indirubin in MCF-7 breast cancer cells on induction of the activities of
cytochromes P450 (CYP) 1A1 and 1B1, as measured by estradiol
and ethoxyresorufin metabolism, and on induction of the CYP1A1
and CYP1B1 mRNAs. With 4-hr exposure, the effects of indirubin and TCDD at 10nM on CYP activity were comparable, but
the effects of indirubin, unlike those of TCDD, were transitory.
Indirubin-induced ethoxyresorufin-O-deethylase activity was maximal by 6-9hr post-exposure and had disappeared by 24hr, whereas
TCDD-induced activities remained elevated for at least 72hr. The
effects of indirubin on CYP mRNA induction were maximal at
3hr. Indirubin was metabolized by microsomes containing cDNAexpressed human CYP1A1 or CYP1B1. The potency of indirubin
was comparable to that of TCDD in a CYP1B1-promoter-driven
luciferase assay, when MCF-7 cells were co-exposed to the AhR
ligands together with the CYP inhibitor, ellipticine. Thus, if indirubin is an endogenous AhR ligand, then AhR-mediated signaling
by indirubin is likely to be transient and tightly controlled by the
ability of indirubin to induce CYP1A1 and CYP1B1, and hence its
own metabolism. © 2003 Elsevier Inc. All rights reserved.
434. Inhibition of arterial contraction by dinitrosyl-iron complexes: Critical role of the thiol ligand in determining rate of
nitric oxide (NO) release and formation of releasable NO stores
by S-nitrosation - Alencar J.L., Chalupsky K., Sarr M. et al. [B.
Muller, Fac. Pharm., Pharmacologie Phys.-C., Université Louis
Pasteur, 67401 Illkirch, France] - BIOCHEM. PHARMACOL. 2003
66/12 (2365-2374) - summ in ENGL
The inhibition of arterial tone produced by two nitric oxide (NO)derivatives of biological relevance, dinitrosyl-iron complexes with
cysteine (DNIC-CYS) or with glutathione (DNIC-GSH), was compared. Both compounds induced vasorelaxation within the same
concentration range (3-300nM) in endothelium-denuded rat aortic
rings. Consistent with a faster rate of NO release from DNICCYS than from DNIC-GSH, the relaxant effect of DNIC-CYS was
rapid in onset and tended to recover with time, whereas the one
of DNIC-GSH developed slowly and was sustained. In addition,
DNIC-GSH (0.3 and 1M) but not DNIC-CYS (1M) induced,
even after washout of the drug, a persistent hyporesponsiveness
to vasoconstrictors and a relaxant effect of low molecular weight
thiols like N-acetylcysteine (NAC, which can displace NO from
preformed NO stores). Both effects of DNIC-GSH were associated
with elevation of cyclic GMP content and were attenuated by NO
scavengers or a cyclic GMP-dependent protein kinases inhibitor.
In rings previously exposed to DNIC-GSH, addition of mercuric
chloride (which can cleave the cysteine-NO bond of S-nitrosothiols) elicited relaxation, completely blunted the one of NAC and also
abolished the persistent elevation of NO content. In conclusion, this
study shows that whereas both DNIC-CYS and DNIC-GSH elicited
a NO release-associated relaxant effect in isolated arteries, only
DNIC-GSH induced an inhibition of contraction which persisted
after drug removal. The persistent effect of DNIC-GSH was attributed to the formation of releasable NO stores in arterial tissue,
most probably as S-nitrosothiols. Thus, the nature of the thiol ligand
plays a critical role in determining the mechanisms and duration of
the effect of LMW-DNIC in arteries. © 2003 Elsevier Inc. All
rights reserved.
435. Glycyrrhetinic acid-induced permeability transition in rat
liver mitochondria - Salvi M., Fiore C., Armanini D. and Toninello
A. [A. Toninello, Dipartimento di Chimica Biologica, Universita’
di Padova, Unita’ Stud. delle Biomembrane, Via G. Colombo
3, 35121 Padua, Italy] - BIOCHEM. PHARMACOL. 2003 66/12
(2375-2379) - summ in ENGL
Glycyrrhetinic acid, a hydrolysis product of one of the main constituents of licorice, the triterpene glycoside of glycyrrhizic acid,
when added to rat liver mitochondria at micromolar concentrations
induces swelling, loss of membrane potential, pyridine nucleotide
oxidation, and release of cytochrome c and apoptosis inducing
factor. These changes are Ca2+ dependent and are prevented by
cyclosporin A, bongkrekic acid, and N-ethylmaleimide. All these
observations indicate that glycyrrhetinic acid is a potent inducer
of mitochondrial permeability transition and can trigger the proapoptotic pathway. © 2003 Elsevier Inc. All rights reserved.
84
436. Naturally occurring 2 -hydroxyl-substituted flavonoids as
high-affinity benzodiazepine site ligands - Huen M.S.Y., Hui
K.-M., Leung J.W.C. et al. [H. Xue, Department of Biochemistry,
Hong Kong Univ. of Sci./Technology, Clear Water Bay, Kowloon,
Hong Kong] - BIOCHEM. PHARMACOL. 2003 66/12 (2397-2407)- summ in ENGL
Screening of traditional medicines has proven invaluable to drug
development and discovery. Utilizing activity-guided purification,
we previously reported the isolation of a list of flavonoids from
the medicinal herb Scutellaria baicalensis Georgi, one of which
manifested an affinity for the benzodiazepine receptor (BDZR) comparable to that of the synthetic anxiolytic diazepam (Ki =6.4nM).
In the present study, this high-affinity, naturally occurring flavonoid derivative, 5,7,2 - trihydroxy-6,8-dimethoxyflavone (K36),
was chosen for further functional and behavioral characterization.
K36 inhibited [3 H]flunitrazepam binding to native BDZR with a
Ki value of 6.05nM. In electrophysiological experiments K36 potentiated currents mediated by rat recombinant 1 2 2 GABAA
receptors expressed in Xenopus oocytes. This potentiation was
characterized by a threshold (1nM) and half-maximal stimulation
(24nM) similar to diazepam. This enhancement was demonstrated
to act via the BDZR, since co-application of 1M of the BDZR
antagonist Ro15-1788 reversed the potentiation. Oral administration of K36 produced significant BDZR-mediated anxiolysis in
the mice elevated plus-maze, which was abolished upon co-administration of Ro15-1788. Sedation, myorelaxation and motor
incoordination were not observed in the chosen dosage regimen.
Structure-activity relationships utilizing synthetic flavonoids with
different 2 substituents on the flavone backbone supported that 2 hydroxyl-substitution is a critical moiety on flavonoids with regard
to BDZR affinities. These results further underlined the potential
of flavonoids as therapeutics for the treatment of BDZR-associated
syndromes. © 2003 Elsevier Inc. All rights reserved.
437. Inhibition of plasmalemmal Na+ /Ca2+ exchange by
mitochondrial Na+ /Ca2+ exchange inhibitor 7-chloro-5(2- chlorophenyl)- 1,5- dihydro- 4,1- benzothiazepin- 2(3H)- one
(CGP-37157) in cerebellar granule cells - Czyz A. and
Kiedrowski L. [L. Kiedrowski, Department of Psychiatry,
Psychiatric Institute, University of Illinois at Chicago, 1601 W.
Taylor St., Chicago, IL 60612, United States] - BIOCHEM.
In the heart, 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin- 2(3H)-one (CGP-37157) inhibits mitochondrial but
not sarcolemmal Na + /Ca2+ exchange. Therefore, CGP-37157
is often used as an experimental tool to study the role of mitochondrial Na+ /Ca 2+ exchange in Ca2+ homeostasis in various
cells, including neurons. However, neurons express several K+ dependent (NCKX) and/or K+ -independent (NCX) isoforms of
plasmalemmal Na + /Ca2+ exchange not expressed in the sarcolemma. Because it has never been determined whether CGP-37157
inhibits plasmalemmal NCKX and/ or NCX isoforms in neurons,
we tested this possibility. As an index of NCKX and/or NCX
activity, we studied Na-dependent and gramicidin-induced 45 Ca2+
accumulation in the presence and absence of K + , respectively.
In primary cultures of cerebellar granule cells, CGP-37157 with
IC50 of 13M inhibited over 70% of plasmalemmal NCX activity
(P<0.01) but not NCKX activity. Our data suggest that the effects
of CGP-37157 on neuronal Ca2+ homeostasis include inhibition of
certain plasmalemmal NCX isoform(s). Because cerebellar granule
cells robustly express NCX3 transcripts, which are not expressed in
the heart, it appears that this isoform may be CGP-37157 sensitive.
© 2003 Elsevier Inc. All rights reserved.
438. Selective agonist binding of (S)-2-amino-3-(3-hydroxy5-methyl-4- isoxazolyl)propionic acid (AMPA) and 2S(2,3 ,4 )-2-carboxy-4- (1-methylethenyl)-3-pyrrolidineacetic acid (kainate) receptors: A molecular modeling study Pentikäinen O.T., Settimo L., Keinänen K. and Johnson M.S. [M.S.
Johnson, Dept. of Biochemistry and Pharmacy, Åbo Akademi University, Tykistökatu 6A, FIN-20520 Turku, Finland] - BIOCHEM.
Molecular models were constructed, using the published X-ray
structure of rat glutamate receptor 2 (GluR2), for the ligand-binding
domains of the human (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA)- and kainate-selective ionotropic
glutamate receptors (iGluRs): GluR1-7 and KA1-2. Based on
the analysis of the known X-ray structures of GluR2 in complex
with glutamate, kainate, and AMPA, we have constructed binding
motifs (relative positioning of a ligand in the binding site and the
physico-chemical interactions that take place) for selected agonist
ligands and found explanations for ligand-binding selectivity to
homomeric receptors among the different iGluRs. Even a single
sequence difference can explain significant differences in ligandbinding affinities between two receptors. In total, there are seven
residues surrounding the binding cavity that affect agonist selectivity: in GluR2, these residues are Pro478, Thr480, Leu650, Ser654,
Thr686, Tyr702, and Met708. Each of these seven positions has
been shown, or is predicted, to influence the presence of one or
more water molecules that, when present, may form bridging hydrogen bonds between particular ligands and receptors. By using
this knowledge it should be possible to design new selective agonist
ligands with high affinity for any AMPA/kainate receptor. © 2003
Elsevier Inc. All rights reserved.
439. Agonist-induced desensitization and endocytosis of heterodimeric GABA B receptors in CHO-K1 cells - González-Maeso
J., Wise A., Green A. and Koenig J.A. [J. González-Maeso, Department of Neurology, Box 1137, Mount Sinai School of Medicine,
One Gustave L Levy Pl, New York, NY 10029, United States] EUR. J. PHARMACOL. 2003 481/1 (15-23) - summ in ENGL
-Aminobutyric acid B (GABAB) receptor is the first discovered
G protein-coupled receptor that requires two subunits, GB1 and
GB2, to form a functional receptor. Whereas the molecular and
functional characteristics of GABAB receptors have been recently
extensively studied, the mechanisms underlying receptor desensitization and endocytosis are still poorly understood. We have
investigated the effect of continuous agonist exposure on the human GABAB receptor functional response and redistribution when
expressed in Chinese hamster ovary (CHO-K1) cells. The wild-type
GABAB receptor-mediated inhibition of the adenylate cyclase activity appeared desensitized after 2 h in the presence of GABA (100
M). Fusion proteins were generated by attachment of cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) to GB1 and
GB2, respectively, and confocal microscopy experiments in intact
living cells semi-stably expressing the constructs were performed.
Incubation of co-expressing CFP-GB1 and YFP-GB2 cells in the
presence of GABA (100 M) for 2 h induced a profound receptor
internalization, and CFP-GB1 and YFP-GB2 appeared co-localized
in the endosome (labelled with Cy3-transferrin). The internalization was blocked by a selective GABAB receptor antagonist. These
results represent the first clear visualization of agonist-induced internalization of the unique heterodimeric GABAB receptor. © 2003
440. Effects of calycosin on the impairment of barrier function
induced by hypoxia in human umbilical vein endothelial cells Fan Y., Wu D.-Z., Gong Y.-Q. et al. [D.-Z. Wu, Institute of Chinese
Materia Medica, WHO Collaborating Ctr. T., Shanghai Univ. Traditional C., 530 LingLing Road, Shanghai 200032, China] - EUR.
J. PHARMACOL. 2003 481/1 (33-40) - summ in ENGL
The purpose of the present study was to examine the effects of
calycosin, an isoflavonoid isolated from Astragali Radix, on the impairment of barrier function induced by hypoxia in cultured human
umbilical vein endothelial cells. Hypoxia induced an increase in
endothelial cell monolayer permeability, indicating endothelial cell
barrier impairment. Endothelial barrier dysfunction induced by hypoxia was accompanied by decreases in cytosolic ATP concentration
and cAMP level, the development of actin stress fibers and intercellular gap formation, suggesting that the decreases in cytosolic
ATP and cAMP levels and rearrangements of F-actin could be associated with an increase in permeability of endothelial monolayers.
Application of calycosin inhibited the hypoxia-induced increase in
endothelial permeability in a dose-dependent fashion, which is compatible with inhibition of lactate dehydrogenase release, decrease
of the fall in ATP and cAMP contents, and improvement of F-actin
rearrangements. These findings indicate that calycosin protected
endothelial cells from hypoxia-induced barrier impairment by increasing intracellular energetic sources and promoting regeneration
of the cAMP level, as well as improving cytoskeleton remodeling.
© 2003 Elsevier B.V. All rights reserved.
441. Antimigraine dotarizine blocks P/Q Ca2+ channels and
exocytosis in a voltage-dependent manner in chromaffin cells
- Ruiz-Nuño A., Mayorgas I., Hernández-Guijo J.M. et al. [L.
Gandı́a, Depto. de Farmacol. y Terap., Facultad de Medicina,
Univ. Autónoma de Madrid, c/ Arzobispo Morcillo, 4, 28029 Madrid, Spain] - EUR. J. PHARMACOL. 2003 481/1 (41-50) - summ in
ENGL
The mechanism of blockade of P/Q Ca2+ channels by antimigraine, dotarizine, was studied in voltage-clamped bovine adrenal
chromaffin cells. Inward currents through P/Q channels were pharmacologically isolated by superfusing the cells with ! -conotoxin
GVIA (1 M) plus nifedipine (3 M). Dotarizine (10-30 M)blocked the P/Q fraction of IBa and promoted current inactivation.
Thus, dotarizine caused a greater blockade of the late IBa , compared with blockade of the early peak I Ba . This effect was more
prominent, the longer was the duration of the depolarising pulse.
The blockade of IBa was also greater at more depolarising holding
potentials (i.e. -60 mV), than was the blockade produced at more
hyperpolarising holding potentials (i.e. -80 or -110 mV). Catecholamine secretory responses to brief pulses (2 s) of a Krebs-HEPES
solution containing 100 mM K+ and 2 mM Ca2+ was blocked by
3 M dotarizine. Blockade was faster and greater when dotarizine
was applied on cells that were previously depolarised with KrebsHEPES deprived of Ca2+ and containing increasing concentrations
of K+ . This voltage-dependent blockade of P/Q channels and exocytosis might be the underlying mechanism explaining the dotarizine
prophylaxis of migraine attacks. © 2003 Elsevier B.V. All rights
reserved.
442. Ovariectomy aggravates nifedipine-induced flushing of tail
skin in mice - Kai M., Tominaga K., Okimoto K. et al. [Y. Kataoka,
Dept. Pharmaceutical Care Hlth. Sci., Faculty of Pharmaceutical
Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan, Fukuoka
814-0180, Japan] - EUR. J. PHARMACOL. 2003 481/1 (79-82) summ in ENGL
Flushing is one of the most common vasodilation-related adverse
effects associated with Ca2+ channel antagonist treatment. This
symptom is known to occur more frequently in women than men.
The present study aimed at investigating the effect of ovariectomy
on nifedipine-induced flushing in mice. Ovariectomy markedly
increased the tail skin temperature, a parameter of skin flushing,
induced by nifedipine at a dose showing no influence on blood pressure. This event was blocked by estradiol replacement. Estrogen
withdrawal is, therefore, included in the risk factors for nifedipineinduced flushing and this risk is lessened by estrogen replacement.
443. Effects of a melanogenic bicyclic monoterpene diol on cell
cycle, p53, TNF-, and PGE2 are distinct from those of UVB Kraus E., Galvin J.W., Boumakis S. et al. [D.A. Brown, AGI Dermatics, 205 Buffalo Avenue, Freeport, NY 11520, United States]
- PHOTODERMATOL. PHOTOIMMUNOL. PHOTOMED. 2003
19/6 (295-302) - summ in ENGL
Purpose: Bicyclic monoterpene (BMT) diols are small-molecule
compounds that mimic ultraviolet radiation (UVR) by inducing
melanogenesis. The objective of this study was to compare the
effects of 2,2-dimethyl-3-propanyldiol-norbornane (AGI-1140), a
novel BMT diol, and ultraviolet B (UVB) on additional cellular
responses. Methods: S91 mouse melanoma cells were treated with
a range of concentrations of AGI-1140, and examined for induction
of melanogenesis and nitric oxide (NO). The effect of AGI-1140
on dendrite outgrowth from human melanocytes was examined by
quantitative microscopy. The effect of AGI-1140 and UVB on
phosphorylation of p53 serine 15 in human keratinocytes was examined by Western blotting, while the release of tumor necrosis
factor- (TNF-) and prostaglandin E2 (PGE2 ) was determined
by enzyme-linked immunosorbent assay. The effects of AGI-1140
and UVB on cell cycle arrest of human melanocytes, keratinocytes,
fibroblasts, and endothelial cells were compared using fluorescenceactivated cell sorting. Results: Similar to UVB, AGI-1140 induced
both melanogenesis and NO in melanoma cells. AGI-1140 also
85
induced dendrite outgrowth from melanocytes, indicative of differentiation. However, whereas UVB induced G2 cell cycle arrest
with phosphorylation of p53 at serine 15, AGI-1140 induced G1
cell cycle arrest without this phosphorylation. Additionally, unlike
UVB, AGI-1140 did not increase the secretion of TNF- or PGE2 ,
mediators of UVB-induced immunosuppressive and inflammatory
responses in the skin that may contribute to carcinogenesis. Conclusion: This study shows that melanogenesis can be induced by
AGI-1140 without many of the deleterious effects associated with
UVB.
444. Enhancement of photodynamic effect in normal rat keratinocytes by treatment with 1,25 dihydroxy vitamin D3 Matsuyama A., Nakano H., Harada K. et al. [Dr. K. Hanada,
Department of Dermatology, Hirosaki Univ. School of Medicine,
Hirosaki 036-8562, Japan] - PHOTODERMATOL. PHOTOIMMUNOL. PHOTOMED. 2003 19/6 (303-308) - summ in ENGL
Background: To better understand the pathogenesis of photodynamic therapy (PDT)-induced apoptosis cytosolic calcium [Ca2+ ]i
was measured using cultured fetal rat keratinocytes (FRSKs).
Moreover, the influence of 1,25 dihydroxy vitamin D3 (1,25(OH)2+
2 D3 ) with the action of increasing [Ca ]i on the PDT effect was
studied. Methods: FRSKs were treated with a medium containing
the photosensitizer, aluminum phthalocyanine tetrasulfonate (AlPcTs), and were then exposed to selective visible light derived from
a halogen lamp. Electrophoresis of DNA extracted from the PDTtreated cells revealed DNA fragmentation, a sign of apoptosis in
cultured FRSKs under the condition with or without 1,25(OH)2D3 .
Results: PDT-treated FRSKs exhibited increased levels of [Ca2+ ]i ;
these levels were significantly elevated further by the treatment of
cells with 1,25(OH 2 D3 . However, cells treated with ethylene glycol bis (b-aminoethyl ether)-N,N,N ,N -tetraacetic acid (EGTA), a
chelator of extracellular calcium, prior to PDT did not show any
DNA fragmentation either in the presence or absence of 1,25(OH
2 D3 . Conclusion: PDT-induced apoptosis in FRSKs may be caused
by the influx of extracellular calcium. Addition of 1,25(OH 2 D3
clearly enhanced the DNA fragmentation in the cultured FRSKs,
indicating the effect of increased [Ca2+ ]i . The combination therapy of AlPcTs-PDT with the administration of 1,25(OH)2 D3 may
contribute to the enhancement of the AlPcTs-PTD effect.
445. Thiamine protects against paraquat-induced damage:
Scavenging activity of reactive oxygen species - Jung I.L. and
Kim I.G. [I.G. Kim, Department of Radiation Biology, Environment
Radiation Research Group, Korea Atom. Ener. Research Institute,
P.O. Box 105, Yusong, Taejon 305-600, South Korea] - ENVIRON.
TOXICOL. PHARMACOL. 2003 15/1 (19-26) - summ in ENGL
To demonstrate the superoxide anion (. O2 - ) scavenging activity
of thiamine, we comparatively investigated the inhibition of cell
growth reduction and repression of the oxidative stress-inducible
gene expression (soxS, sodA, zwf and soi-19::lacZ) triggered by
paraquat, intracellular . O-2 generator, using an Escherichia coli
system. When thiamine (>1 M) was added to the culture, a
decrease of growth rate caused by paraquat was significantly recovered. Paraquat treatment (1 M) to aerobically grown E. coli
highly increased the expression of soxS and its regulons sodA and
zwf, genes for manganese-containing superoxide dismutase (MnSOD) and glucose-6-phosphate dehydrogenase (G6PDH) to cope
with the oxidative stress. However, the induction of Mn-SOD and
G6PDH was suppressed by the thiamine supplement. The induction of the soi-19::lacZ gene, whose expression was dependent on
paraquat, was also repressed by more than 10 M of the thiamine
addition to the culture. To characterize the role of thiamine, which
challenges the paraquat toxicity, an in vitro experiment of nitroblue
tetrazolium (NBT) reduction was performed. The NBT reduction by
. O- generated in the xanthine/hypoxanthine system was inhibited
2
by the thiamine supplement in a dose-dependent manner. Moreover,
it competed with the 2-deoxy-D-ribose in absorbing the hydroxyl
radical (. OH) generated by -irradiation (800 Gy) and thus inhibited the formation of malondialdehyde in vitro. In conclusion, this
evidence suggests that thiamine may partly act as an antioxidant
to scavenge . O2 - (or . OH) directly and thus affect the cellular
response to oxidative stress induced by reactive oxygen species. ©
86
446. Increase in number of annexin V-positive living cells of
rat thymocytes by intracellular Pb2+ - Nishizaki Y., Nakao H.,
Umebayashi C. et al. [Y. Oyama, Department of Life Sciences,
Fac. of Integrated Arts and Sciences, University of Tokushima,
Minami-Jyosanjima 1-1, Tokushima 770-8502, Japan] - ENVIRON.
TOXICOL. PHARMACOL. 2003 15/1 (45-51) - summ in ENGL
Lead is ubiquitous in our environment and lead poisoning is a
major public health problem worldwide. In this study, to see if
intracellular Pb 2+ induces the exposure of phosphatidylserine in
rat thymocyte membranes, we have examined the effect of PbCl2
on rat thymocytes treated with A23187 using a flow cytometer
with appropriate fluorescent indicators under nominally-Ca2+ -free
condition. PbCl2 at 1-30 M dose-dependently induced the exposure of phosphatidylserine on outer membranes, associated with
increasing the concentration of intracellular Pb 2+ . The potency
of intracellular Pb2+ to induce the apoptotic change in thymocyte
membranes seems to be greater than those of intracellular Ca2+ and
Cd2+ . Results suggest that intracellular Pb2+ triggers apoptosis of
rat thymocytes. This action of Pb2+ may be one of mechanisms for
the lead-induced changes in immunity. © 2003 Elsevier B.V. All
rights reserved.
447. Captopril enhanced insulin-stimulated glycogen synthesis in skeletal muscle but not fatty acid synthesis in adipose
tissue of hereditary hypertriglyceridemic rats - Cahová M.,
Vavrinková H., Tutterova M. et al. [M. Cahová, Center of
Experimental Medicine, Inst.
for Clin./Experimental Med.,
Vı́deňská 1958/9, Prague 140 21, Czech Republic] - METAB. CLIN.
EXP. 2003 52/11 (1406-1412) - summ in ENGL
In addition to their hypotensive action, angiotensin-converting
enzyme (ACE) inhibitors exert a beneficial effect on glucoregulation. In the present study, the effect of ACE inhibition by captopril
on glucose utilization in peripheral tissues was investigated in nonobese rats with hereditary hypertriglyceridemia (HHTg) associated
with hyperinsulinemia and insulin resistance. Normotriglyceridemic Wistar rats served as controls (C). Rats of both groups received
a high-sucrose diet, and a half of each group also captopril in drinking water (10 mg/kg body weight [bw]) for 2 weeks. Captopril
administration reduced fasting glycemia and postprandial triglyceridemia in HHTg rats, while the fasting levels of nonesterified fatty
acids (NEFA), glycerol, and lactate were decreased in both groups.
The sensitivity of skeletal muscle to insulin action evaluated as
in vitro 14 C-glucose incorporation into glycogen was significantly
increased by captopril treatment both in HHTg (3.51 0.48 v2.0
0.12 mol glucose/g wet weight [ww]) and C (3.32 0.21 v
2.48 0.09 mol glucose/g ww). In isolated adipose tissue, the
insulin-stimulated 14 C-glucose incorporation into neutral lipids was
increased, after captopril administration, by 137% in C and by 35%
only in HHTg. After captopril treatment, insulin-stimulated de
novo fatty acid synthesis rose significantly in C while remaining
low in HHTg. The increase in esterification was comparable in both
groups. Separate experiments were designed to assess the possible
involvement of bradykinin in mediating captopril action. Both C
and HHTg rats fed a high-sucrose diet for 2 weeks were treated with
captopril (50 mg/kg orally) for 1 hour; half of each group received
the specific inhibitor of bradykinin receptor HOE-140 (100 g/kg
intraperitoneally [IP]) 1 hour before captopril administration. In
C, captopril administration enhanced the insulin-stimulated in vitro
glucose incorporation into lipids in adipose tissue by 255%, and into
glycogen in the musculus soleus by 45%; this effect was eliminated
by HOE-140. In HHTg, neither a single dose of captopril nor
HOE-140 had any effect. We conclude that long-term captopril
administration increased the insulin sensitivity of peripheral tissue
in both C and HHTg rats, but with different efficacy. While the
insulin-sensitizing action of captopril on skeletal muscle was comparable in HHTg and C rats, there were differences in the effect
of captopril on adipose tissue. The difference became particularly
manifest in de novo fatty acid synthesis. © 2003 Elsevier Inc. All
rights reserved.
See also:
462, 463,
477, 478,
490, 491,
503, 504,
451,
464,
479,
492,
505,
452, 453, 454, 455, 456, 457, 458,
465, 466, 467, 468, 469, 470, 471,
480, 481, 482, 483, 484, 485, 486,
493, 494, 495, 496, 497, 498, 499,
506, 507, 508, 509, 510, 511, 512,
459,
473,
487,
500,
513,
460,
474,
488,
501,
514,
461,
476,
489,
502,
515,
517, 518, 520, 521, 522, 523, 524, 525, 526, 528, 529, 530, 531,
532, 533, 534, 535, 536, 537, 541, 543, 549, 550, 556, 562, 565,
567, 569, 571, 572, 574, 575, 576, 577, 579, 580, 581, 582, 583,
584, 585, 586, 587, 588, 589, 590, 592, 593, 594, 595, 596, 597,
599, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 612, 614,
615, 616, 617, 618, 619, 620, 623, 626, 627, 628, 629, 630, 631,
632, 633, 634, 635, 636, 637, 639, 640, 641, 642, 643, 644, 645,
646, 647, 648, 649, 650, 651, 652, 654, 656, 658, 659, 660, 661,
662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674,
677, 678, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690,
691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703,
704, 705, 707, 708, 710, 711, 712, 713, 714, 715, 716, 717, 718,
719, 720, 721, 722, 723, 725, 726, 728, 729, 730, 731, 735, 736,
737, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750.
5. EFFECTS ON ORGANS AND SYSTEMS
448. Effect of Pamidronate on Excretion of Pyridinium Crosslinks of Collagen after Total Hip Arthroplasty - Wilkinson J.M.,
Jackson B. and Eastell R. [J.M. Wilkinson, Div. of Clinical Sciences
(North), University of Sheffield, Northern General Hospital, Herries
Road, Sheffield, S5 7AU, United Kingdom] - CALCIF. TISSUE INT.
2003 73/4 (326-331) - summ in ENGL
Periprosthetic bone loss is an important factor that limits implant survival after total hip arthroplasty (THA). In a randomized
trial we previously reported that pamidronate therapy prevented
periprosthetic bone loss and decreased urinary excretion of N-telopeptide collagen cross-links over the first 6 months after THA, but
had no apparent effect on free deoxypyridinoline excretion (J Bone
Miner Res 2001; 16:556-564). In this study we investigated this
discrepant observation that pamidronate reduced conjugated crosslink excretion but had no effect on free cross-links. Free and total
deoxypyridinoline (DPD) were assayed by reverse-phase high-performance liquid chromatography (HPLC) and by immunosorbent
assay (ELISA) at preoperative baseline and at week 6 after surgery
in 46 subjects who had taken part in the trial. Randomly selected,
22 subjects received a single 90 mg intravenous infusion of pamidronate and 24 received placebo. Acute rises in free and total DPD
occurred in both study groups at week 6 (P < 0.05). Total DPD
excretion was lower in the pamidronate group than in the placebo
group when measured by both HPLC and ELISA (P < 0.05). No
difference in free DPD was found between groups. A rise in the
ratio of free to total DPD occurred in the pamidronate group at week
6 (P = 0.03), but not in the placebo group. Pamidronate treatment
suppresses excretion of total DPD. This is consistent with the effect
of pamidronate on other turnover markers and periprosthetic bone
loss after THA. Urinary-free DPD is a poor marker of response
to treatment as the ratio of free-to-total cross-links is affected by
amino-bisphosphonate therapy.
449. Carbamazepine Does Not Alter Biochemical Parameters of
Bone Turnover in Healthy Male Adults - Brämswig S., Zittermann A. and Berthold H.K. [H.K. Berthold, Department of Clinical
Pharmacology, University of Bonn, 53105 Bonn, Germany] - CALCIF. TISSUE INT. 2003 73/4 (356-360) - summ in ENGL
It is still not completely clear whether or not carbamazepine
(CBZ) causes alterations in vitamin D status and in bone metabolism. The objective of this study was therefore to investigate
prospectively in healthy adults the effects of CBZ on serum levels
of 25-hydroxyvitamin D (25OHD) and on biomarkers of bone formation and resorption. Twenty-one free-living male adults were
taking 800 mg/day CBZ for 10 weeks. The study was performed
from December 1997 until September 1998 at a geographic latitude
of 51°N. Blood samples were collected before treatment (t1 ), 33
days (SE 2.5) after starting treatment (t2 ), and 70 days (SE 3.6)after starting treatment (t 3 ). In 13 out of the 21 subjects blood
samples were also drawn 64 days (SE 9.0) after treatment had been
terminated (t4 ). Serum 25OHD levels remained constant during
study periods t1 -t3 . 25OHD levels were, however, significantly
higher at t4 compared to t1 -t3 . Serum concentrations of intact
osteocalcin, a bone formation marker, and C-telopeptide, a bone
resorption marker, were similar during all examinations. Moreover,
serum levels of parathyroid hormone, calcium, and inorganic phosphate did not change. Data indicate that CBZ per se does not alter
bone metabolism and does not lead to decreased circulating 25OHD
levels in young males without epilepsy. Variations in 25OHD levels
are in line with the seasonal fluctuations in vitamin D status.
450. Effects of Fondaparinux Compared with Dalteparin, Enoxaparin and Unfractionated Heparin on Human Osteoblasts
- Matziolis G., Perka C., Disch A. and Zippel H. [G. Matziolis,
Department of Orthopaedics, Charité University Hospital, Schumannstr. 20-21, 10117 Berlin, Germany] - CALCIF. TISSUE INT.
2003 73/4 (370-379) - summ in ENGL
The objective of the this study was to examine the effects of
fondaparinux, a synthetic anticoagulant substance similar to heparin, on osteoblasts compared with previously used heparins. Its
effects have been shown in clinical trials to be highly effective
in thromboembolism prophylaxis. Unfractionated heparin (UFH),
dalteparin, enoxaparin and fondaparinux were added to osteoblast
cultures in the therapeutic range and two decimal powers above and
below it in each case. The results showed that the mitochondrial activity and protein synthesis of osteoblasts treated with fondaparinux
were significantly higher than in the other groups. Similar effects
could be demonstrated for the matrix collagen type II content and
calcification. In contrast enoxaparin, dalteparin and UFH lead to
a significant decrease of matrix collagen type II content and calcification in concentrations equal or higher than the therapeutic one.
No inhibitory in-vitro effects of fondaparinux on human osteoblasts
could be demonstrated within the concentration range investigated
(0.01 - 100 g/ml). We conclude that fondaparinux can be used to
avoid the heparin-related negative influence on osteoblast-dependent fracture healing and endoprosthetic implant integration.
See also: 548, 552, 565, 626, 738.
5.1. Central nervous system and sense organs
451. Verteporfin: A Review of its Use in the Management of
Subfoveal Choroidal Neovascularisation - Keam S.J., Scott L.J.
and Curran M.P. [S.J. Keam, Adis International Limited, 41 Centorian Drive, Mairangi Bay, Auckland 1311, New Zealand] - DRUGS
2003 63/22 (2521-2554) - summ in ENGL
Verteporfin (Visudyne®) therapy (photodynamic therapy with
intravenous liposomal verteporfin) is the first treatment to effectively prevent the loss of visual acuity in patients with subfoveal
choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD), pathological myopia or presumed ocular
histoplasmosis syndrome (POHS). In adult patients with classic
subfoveal CNV or occult with no classic subfoveal CNV secondary
to AMD, or subfoveal CNV secondary to pathological myopia or
POHS, verteporfin therapy slows or prevents loss of visual acuity.
In well designed clinical trials, verteporfin therapy was superior to
placebo in patients with subfoveal classic-containing CNV and occult with no classic CNV secondary to AMD at 12 and/or 24 months
(Treatment of Age-related macular degeneration with Photodynamic therapy [TAP] Investigation and Verteporfin In Photodynamic
therapy [VIP-AMD] trial) and in patients with pathological myopia
at 12 months (Verteporfin In Photodynamic therapy [VIP-PM] trial).
Limited data suggest that verteporfin therapy also prevents loss of
visual acuity in patients with subfoveal CNV secondary to POHS.
Verteporfin therapy was generally well tolerated in clinical trials;
most adverse events were mild to moderate in intensity and transient.
The most frequently reported verteporfin therapy-related adverse
events (incidence >2%) were visual disturbance, injection-site reactions, photosensitivity reactions and infusion-related back pain.
Approximately 5% of patients with occult with no classic subfoveal
CNV secondary to AMD reported severe vision decrease within 7
days of treatment in clinical trials; 3 months later, several patients
had recovered some of this loss. Conclusion: Photodynamic therapy
with verteporfin, the first photosensitiser approved for the treatment
of subfoveal CNV, is a well tolerated treatment that stabilises or
slows visual acuity loss in adult patients with predominantly classic
or occult with no classic subfoveal CNV secondary to AMD, and
subfoveal CNV secondary to pathological myopia or POHS. Thus,
verteporfin therapy provides a valuable option for the management
of these patients for whom treatment options are few, and should
87
be considered as a first-line therapy in these difficult-to-manage
conditions.
452. Carbonic anhydrase inhibitors: Topically acting antiglaucoma sulfonamides incorporating esters and amides of 3- and
4-carboxybenzolamide - Casini A., Scozzafava A., Mincione F.
et al. [C.T. Supuran, Università degli Studi, Lab. di Chim. Inorg.
e Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino,
Florence, Italy] - BIOORG. MED. CHEM. LETT. 2003 13/17 (28672873) - summ in ENGL
Reaction of 3- and 4-carboxybenzenesulfonyl chloride
with 5-amino-1,3,4-thiadiazole-2-sulfonamide/5-imino-4-methyl-
2 -1,3,4-thiadiazoline-2-sulfonamide afforded two series of benzolamide analogues to which the carboxyl moiety has been derivatized
as esters or amides, in order to reduce their very polar character. The
new derivatives showed low nanomolar affinity for three carbonic
anhydrase (CA) isozymes, CA I, II and IV, and were effective as
topical antiglaucoma agents in normotensive rabbits. Efficacy of
several of the new sulfonamides reported was better than that of the
standard drugs dorzolamide and brinzolamide, whereas their duration of action was prolonged as compared to that of the clinically
used drugs. © 2003 Elsevier Ltd. All rights reserved.
453. Dopamine agonists in Parkinson’s disease - Tintner R. and
Jankovic J. [R. Tintner, Parkinson’s Disease Center, Department
of Neurology, Baylor College of Medicine, 6550 Fannin, Houston,
TX 77030, United States] - EXPERT OPIN. INVEST. DRUGS 2003
12/11 (1803-1820) - summ in ENGL
Levodopa (LD), the immediate precursor of dopamine, is the
most effective agent in the treatment of Parkinson’s disease (PD).
While quite successful in treating the primary motor deficits of
PD, most patients eventually develop LD-related motor fluctuation,
dyskinesias and other adverse effects associated with chronic LD
therapy. There is also concern that LD is neurotoxic, although
this has not been demonstrated in any in vivo studies. Dopamine
agonists (DAs) have been shown to be about as effective as LD in
symptomatic treatment of mild-to-moderate PD. In addition, there
is a lower tendency to develop motor fluctuations and dyskinesias
with DA treatment than after initiation of therapy with LD. Furthermore, there is preclinical and clinical data to suggest a slowing
of neurodegeneration with DAs. The adverse effects of DAs are
similar to those experienced with LD, except that the ergot agents
are associated with a small risk of tissue fibrosis not noted with the
non-ergot DAs.
454. Dopamine Receptor Ligands. Part VII [1]: Novel 3-Substituted 5-Phenyl-1,2,3,4,5,6-hexahydro-azepino-[4,5-b]indoles as
Ligands for the Dopamine Receptors - Decker M. and Lehmann J. [J. Lehmann, Inst. Pharm., Pharmazeut./Med. Chem.,
Friedrich-Schiller-Universitat Jena, Philosophenweg 14, D-07743
Jena, Germany] - ARCH. PHARM. 2003 336/10 (466-476) - summ
in ENGL
A number of 5-phenyl-1,2,3,4,5,6-hexahydro-azepino-[4,5-b]indoles 3 were synthesized with different substituents at the azepine-N
position (methyl-, allyl-, 2-phenyl-ethyl-, cyclopropylmethyl- and
unsubstituted). Furthermore, the indole-N-methylated compound
was generated and by using norephedrines and norpseudoephedrines
as a chiral pool, 4-methyl-5-phenyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indoles were prepared which contained racemisation at the
reacting C-atom. These compounds, as well as the ring-open aminoalcohols, were screened for their affinity to the hD 1 -, hD5 -, hD2L -,
and hD4 -receptors (ş please check sentence). They had micromolar
affinities for the receptors and showed the highest affinity to the
D1 -subtype family. The cyclic compounds possessed the highest
affinity, with the cyclo-propylmethyl-(3 c) and methyl-substituents
(3 e) being the most active of the tested compounds. Based on
an intracellular cAMP-assay, the unsubstituted compound (at the
azepine-N position) turned out to be an agonist for the D 1 - and
D5 -subtype family, whereas the substituted compounds showed
(partial) agonistic, or even inverse agonistic activity.
455. Anatomical and functional brain variables associated with
clozapine response in treatment-resistant schizophrenia - Molina V., Reig S., Sarramea F. et al. [V. Molina, Department
of Psychiatry, Hospital Doce de Octubre, Edificio de Medicina
88
Comunitaria, Avda de Córdoba, km 5.4, 28041, Madrid, Spain]
- PSYCHIATRY RES. NEUROIMAGING 2003 124/3 (153-161) summ in ENGL
Clozapine alleviates the symptoms of a significant proportion of
treatment-resistant schizophrenic patients. Previous studies suggest
that the response to clozapine may be associated with prefrontal
and temporal anatomy as well as with prefrontal, basal ganglia
and thalamic metabolism. A sample of 25 treatment-resistant
(TR) schizophrenic patients underwent magnetic resonance imaging (MRI) and 18 F-deoxyglucose positron emission tomography
(PET) before and after treatment with clozapine. We investigated
the association between changes in positive, disorganized, and
negative schizophrenic syndromes with clozapine treatment and
a set of cerebral variables that included total intracranial volume
(ICV); hippocampal, dorsolateral prefrontal (DLPF) and temporal
gray-matter volume and metabolism; and metabolic activity of the
thalamus, pallidum/putamen, and caudate head. Improvement in
positive symptoms with clozapine was directly related to temporal gray-matter volume, whereas improvement of disorganization
symptoms was inversely related to ICV and hippocampal volume.
Patients with high baseline DLPF cortical volume and metabolic activity were more likely to experience improvement in their negative
symptoms. We conclude that clinical improvement with clozapine
may be related with the anatomy and metabolic activity of specific
brain areas, with the structural integrity of the DLPF and temporal
regions showing the maximum predictive capacity. © 2003 Elsevier
Science Ireland Ltd. All rights reserved.
456. Hypothalamic melanocortin neurons integrate signals of
energy state - Cowley M.A. [M.A. Cowley, Division of Neuroscience, OR National Primate Research Center, OR Heath and Science
University, 505 NW 185th Avenue, Beaverton, OR 97006, United
States] - EUR. J. PHARMACOL. 2003 480/1-3 (3-11) - summ in
ENGL
Neurons of the arcuate nucleus of the hypothalamus appear to
be sites of convergence of central and peripheral signals of energy stores, and profoundly modulate activity of the melanocortin
circuits, providing strong rationale for pursuing these circuits as
therapeutic targets for disorders of energy homeostasis. Recent
studies in our lab and those of our collaborators have shown that
leptin modulates different populations of hypothalamic cells in different ways. In this report, we outline an integrated model of leptin’s
action in the arcuate nucleus, derived from our electrophysiological
studies of brain slice preparations taken from transgenic mice bred
to express a variety of fluorescent proteins in specific cell types.
We also discuss the recently withdrawn obesity drug fenfluramine,
which appears to act on proopiomelanocortin neurons via serotonin
2C receptors. Finally, we review current inquiries into the ability of
the hormone ghrelin to stimulate appetite by its activation of neuropeptide Y neurons and inhibition of proopiomelanocortin neurons.
457. Anorexia nervosa: Towards a neurobiologically based therapy - Södersten P., Bergh C. and Ammar A. [P. Södersten, Sect. of
Applied Neuroendocrinology, Center for Eating Disorders, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden] - EUR. J.
PHARMACOL. 2003 480/1-3 (67-74) - summ in ENGL
Eating disorders, i.e. anorexia and bulimia nervosa, are disorders
of eating behavior and body weight regulation. Most likely because there are few, if any, effective treatments, eating disorders are
considered to be chronic disorders interrupted only by intermittent
periods of short-lived remission. The neurobiology of eating, most
of which explores hypothalamic mechanisms, has had no influence
on the treatment of eating disorders, with the exception of psychopharmacology. However, while most patients are treated with
psychoactive drugs, there is no evidence that these are effective.
This may be because pharmacological attempts so far have targeted
the wrong symptoms. We review the symptomatology of anorexia
and bulimia and the outcome of presently used interventions. Everybody agrees that outcome must improve and to attack this clinical
problem, we suggest a neurobiologically plausible framework for
how the disorders develop and how they are maintained and outline
a method of treatment and its results. © 2003 Elsevier B.V. All
rights reserved.
458. Brain-derived neurotrophic factor controls dopamine D3
receptor expression: Therapeutic implications in Parkinson’s
disease - Guillin O., Griffon N., Bezard E. et al. [O. Guillin,
U. Neurobiologie/Pharmacologie M., INSERM U 573, Centre Paul
Broca, 2 ter rue d’Alésia, 75014 Paris, France] - EUR. J. PHARMACOL. 2003 480/1-3 (89-95) - summ in ENGL
Brain-derived neurotrophic factor (BDNF) belongs to a family of
proteins related to nerve growth factor, which are responsible for
neuron proliferation, survival and differentiation. A more diverse
role for BDNF as a neuronal extracellular transmitter has, nevertheless, been proposed. Here we show that BDNF synthesized by
dopamine neurons is responsible for the appearance of the dopamine
D3 receptor during development and maintains its expression in
adults. Moreover, BDNF triggers behavioral sensitization to levodopa in hemiparkinsonian rats. In monkeys rendered parkinsonian
with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which develop
levodopa-induced dyskinesia, we show an overexpression of this
receptor. Administration of a dopamine D3 receptor-selective partial agonist strongly attenuated levodopa-induced dyskinesia, while
leaving unaffected the therapeutic effect of levodopa. These results suggest that the dopamine D3 receptor participates in both
dyskinesia and the therapeutic action of levodopa and that partial
agonists may normalize dopamine D3 receptor function and correct
side-effects of levodopa therapy in PD patients. © 2003 Elsevier
459. Serotonin and drug reward: Focus on 5-HT2C receptors
- Higgins G.A. and Fletcher P.J. [G.A. Higgins, Schering-Plough
Research Institute, K15-2-2600, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States] - EUR. J. PHARMACOL. 2003
480/1-3 (151-162) - summ in ENGL
Pharmacological manipulation of the 5-hydroxytryptamine (5HT; serotonin) system has long been associated with a regulation of
feeding behaviour, however, the initial part of this article reviews evidence that central 5-HT systems similarly modulate reward-related
behaviours, particularly drug reward. The second part of this article
considers what we believe to be strong emerging pharmacological
and genetic evidence that many of these effects are mediated through
5-HT2C receptor signalling mechanisms. Finally, we consider the
potential for selective 5-HT2C agonists as therapies for substance
abuse disorders and the medical implications for different 5-HT 2C
receptor isoforms generated by RNA editing. © 2003 Elsevier B.V.
460. Characterization of a novel effect of serotonin 5-HT1A and
5-HT2A receptors: Increasing cGMP levels in rat frontal cortex
- Regina M.J., Winter J.C. and Rabin R.A. [R.A. Rabin, SUNYBuffalo, Dept. of Pharmacology and Toxicology, 102 Farber Hall,
Buffalo, NY 14214-3000, United States] - NEUROPHARMACOLOGY 2003 45/8 (1041-1049) - summ in ENGL
Elucidating the mechanisms of action of hallucinogens has become an increasingly important area of research as their abuse has
grown in recent years. Although serotonin receptors appear to
play a role in the behavioral effects of the phenethylamine and indoleamine hallucinogens, the signaling pathways activated by these
agents are unclear. Here it is shown that administration of serotonin
(5-hydroxytryptamine, 5-HT) increased cyclic guanosine monophosphate (cGMP) production in frontal cortical slices of rat brain.
The effect of 5-HT was greater than that of N-methyl-D-aspartate
(NMDA), a stimulant of cGMP formation in the central nervous
system. The 5-HT 2A/2C receptor phenethylamine agonist, 2,5-dimethoxy-4- methylamphetamine (DOM), increased cGMP content
in the slices. Additionally 8-hydroxy-2-(di-n-propylamino)tetralin
(DPAT), a 5-HT1A/7 receptor agonist also increased cGMP production. Stimulation of cGMP formation by DOM was prevented
by a 5-HT2A/2C receptor antagonist, pirenperone, as well as by
a 5-HT2A receptor selective antagonist, MDL100907. A 5-HT2C
receptor antagonist, SB242084, did not block the effect of DOM.
Stimulation of cGMP production by DPAT was blocked by the 5-HT
1A receptor antagonist, WAY100635. Stimulation of cGMP formation by serotonin could be prevented by pirenperone orWAY100635.
In summary, activation of serotonin 5-HT1A and 5-HT2A receptors
increase brain cGMP levels. © 2003 Elsevier Ltd. All rights
reserved.
461. Regulation by 5-HT1A receptors of the in vivo release of 5HT and DA in mouse frontal cortex - Ago Y., Koyama Y., Baba
A. and Matsuda T. [T. Matsuda, Laboratory of Medicinal Pharmacology, Grad. Sch. of Pharmaceutical Sci., Osaka University, 1-6
Yamada-oka, Suita, Osaka 565-0871, Japan] - NEUROPHARMACOLOGY 2003 45/8 (1050-1056) - summ in ENGL
This study examines the effects of serotonin (5-HT)1A receptor
ligands on the in vivo release of 5-HT and dopamine (DA) in the
prefrontal cortex of mice. Oral MKC-242 and 8-OH-DPAT, selective 5-HT1A receptor agonists, decreased cortical 5-HT release
at low and high doses, while the receptor agonists increased cortical DA release only at a high dose. Local application of the
selective 5-HT1A receptor antagonist, WAY100635, via a dialysis
probe, antagonized oral MKC-242-induced increase in cortical DA
release, but did not affect the decrease in cortical 5-HT release.
Local application of 8-OH-DPAT at 100 and 300 nM via a dialysis
probe increased cortical DA release, but did not affect cortical 5-HT
release. The effects of oral MKC-242 and 8-OH-DPAT on 5-HT
release were blocked by low and high doses of WAY100635, while
blocking the agonist-induced increase in DA release required a high
dose of WAY100635. These results suggest that 5-HT release and
DA release in the frontal cortex of mice are regulated by pre- and
postsynaptic 5-H1A receptors, respectively, and that the presynaptic
5-HT 1A receptor-mediated response is more sensitive to inhibition
by WAY100635 than the postsynaptic 5-HT1A receptor-mediated
response in mice. © 2003 Elsevier Ltd. All rights reserved.
462. Contribution of the serotonin 5-HT1A receptor agonism of
8-OH-DPAT and EMD 128130 to the regulation of haloperidolinduced muscle rigidity in rats - Lorenc-Koci E., Wardas J.,
Bartoszyk G.D. and Wolfarth S. [E. Lorenc-Koci, Dept. of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy
of Sciences, 12, Smȩtna St., PL 31-343, Cracow, Poland] - NEUROPHARMACOLOGY 2003 45/8 (1057-1069) - summ in ENGL
The aim of the present study was to find out whether ()-8hydroxy- 2(di-n-propylamino)tetralin (8-OH-DPAT), a prototypical
5-HT1A agonist, and (R)-(-)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane HCl (EMD 128130), a compound with
serotonin 5-HT1A -agonist and dopamine D2 -like antagonist properties, are able to attenuate the haloperidol-induced (1 mg/kg) muscle
rigidity in rats. Muscle tone was examined using a combined mechano- and electromyographic (EMG) method that simultaneously
measured the mechanical muscle resistance (MMG) of the rat’s
hind foot to passive movements in the ankle joint, and the EMG
activity of two antagonist muscles. Both 8-OH-DPAT (0.125-0.5
mg/kg i.p.) and EMD 128130 (1-10 mg/kg i.p.) dose-dependently
decreased the haloperidol-enhanced MMG to passive movements,
as well as the tonic and the long-latency reflex EMG activities.
Provided these results can be extrapolated to humans, the efficacy
of EMD 128130 in relieving the haloperidol-induced muscle rigidity
supports the concept that novel antipsychotics with 5-HT1A agonist
and dopamine D2 antagonist activities should have a favourable
extrapyramidal side-effect profile. © 2003 Elsevier Ltd. All rights
reserved.
463. Noradrenaline increases the firing rate of a subpopulation of rat subthalamic neurones through the activation of
1 -adrenoceptors - Arcos D., Sierra A., Nuñez A. et al. [J.A. Arias-Montaño, Depto. Fisiol., Biofis. N., Ctro. Invest. y de
Estud. Avanzados, Mexico, DF, Mexico] - NEUROPHARMACOLOGY 2003 45/8 (1070-1079) - summ in ENGL
In the rat subthalamic nucleus, which plays a critical role in the
control of motor behaviour, specific binding of [3 H]-prazosin was
detected by radioligand binding to homogenates and by autoradiography in slices. [ 3 H]-Prazosin binding to homogenates (Bmax
715 fmol/mg protein; Kd 0.270.05 nM) was competed for by
1 -antagonists. In subthalamic nucleus slices and in the presence
of 10 mM LiCl, noradrenaline (100 M) produced a modest,
but consistent, stimulation of [3 H]-inositol phosphate accumulation (1466% of basal), reversed by the 1 -antagonist prazosin (1
M). Extracellular single-unit recordings in slices showed that in a
subpopulation (61 out of 94 cells) of rat subthalamic neurones with
regular, single-spike firing pattern, noradrenaline induced a concentration-dependent increase in the firing rate (EC50 2.50.2 M,
maximum effect 27233% of basal). The action of noradrenaline
89
was mimicked by the selective 1 -agonist phenylephrine but not by
selective 2 - or -agonists, and was blocked by the 1 -antagonist
prazosin but not by 2 - or -antagonists. The excitatory effect of
noradrenaline was not prevented by perfusion with low Ca2+ /high
Mg2+ solution. In four out of 11 neurones perfusion with 3 M noradrenaline resulted in a shift from bursting to regular firing. Taken
together, our results indicate that rat subthalamic neurones express
1 -adrenoceptors responsible for noradrenaline-induced stimulation of the firing rate of a subpopulation of neurones. By modulating
the spontaneous activity of STN neurones, noradrenergic pathways
might have a significant role in regulating basal ganglia function
and thus motor activity. © 2003 Elsevier Ltd. All rights reserved.
464. MK-801 and 7-Ni attenuate the activation of brain NF-B
induced by LPS - Glezer I., Munhoz C.D., Kawamoto E.M. et al.
[C. Scavone, Department of Pharmacology, Inst. of Biomedical Science-ICB-1, University of São Paulo, Ave. Professor Lineu Prestes,
1524, Sao Paulo 05508-900, Brazil] - NEUROPHARMACOLOGY
2003 45/8 (1120-1129) - summ in ENGL
The activation of nuclear factor-B (NF-B) leads to an increase
in the expression of genes involved in important events in the central nervous system (CNS), such as development, plasticity and
inflammation. It has been shown that inflammatory stimulus in the
brain increases excitatory glutamatergic transmission, especially at
N-methyl-D-aspartate (NMDA) receptor. These receptors have an
important role in glutamate neurotoxicity and are in general coupled
with the generation of nitric oxide (NO) through the activation of
neuronal nitric oxide synthase (NOS). We have investigated the
involvement of NMDA-NO pathway in LPS induction of NF-B in
CNS. Our results demonstrate that systemic LPS activates NF-B
in several regions of the CNS, which was partially reduced by the
NMDA receptor antagonist dizolcipine (MK-801) and by the selective brain NOS inhibitor 7-Nitroindazol (7-Ni). 7-Ni effects were
not synergic to MK-801 effects, suggesting that these compounds
act through the same pathway. Dexamethasone caused a stronger
reduction in LPS induction of NF-B in CNS, demonstrating that
MK-801 and 7-Ni act on a pathway that is responsible only by a
fraction of the overall NF-B activation. These results suggest
that a considerable part of NF-B activation by LPS is linked to
the NMDA/NO pathway in CNS. © 2003 Elsevier Ltd. All rights
reserved.
465. Inhibition of rat sympathetic neuron apoptosis by ceramide. Role of p75NTR in ceramide generation - Song M.-S. and
Posse De Chaves E.I. [E.I. Posse De Chaves, Department of Pharmacology, Faculty of Medicine, University of Alberta, Edmonton,
Alta. T6G 2S2, Canada] - NEUROPHARMACOLOGY 2003 45/8
(1130-1150) - summ in ENGL
C6 -ceramide protects sympathetic neurons from apoptosis caused
by nerve growth factor (NGF) deprivation. Here, we report for the
first time that ceramide generated "de novo" is also anti-apoptotic.
Moreover, C6 -ceramide is converted to long-chain ceramides in a
process inhibited by fumonisin B1. The anti-apoptotic effect of
C6 -ceramide is due to the short analogue as to the long-chain ceramides. C 6 -ceramide shares mechanisms of action with NGF. C
6 -ceramide induces TrkA phosphorylation and selective activation
of the phosphatidyl inositol 3-kinase (PI3-kinase)/Akt pathway but
not the MAPK/ ERK pathway. Importantly, the PI3-kinase inhibitor LY294002 abolishes the pro-survival effect of C6 -ceramide.
We identified a novel way to activate retrograde-mediated neuronal
survival in the absence of NGF. Using compartmented cultures we
show that addition of C6 -ceramide exclusively to distal axons is
sufficient to abort nuclear apoptosis. Our system offers a very
unique alternative to understand the molecular bases of retrograde
signaling in the absence of retrograde transport of neurotrophins.
In search for a natural ligand that leads to ceramide generation we
examined the activation of the sphingomyelin (SM) cycle downstream the p75 neurotrophin receptor (p75NTR ). We found that
in sympathetic neurons, selective activation of p75NTR by brainderived neurotrophin factor or NGF plus K252a induces elevation
of ceramide that correlates with SM hydrolysis. However, p75NTR
activation does not generate sufficient ceramide to block apoptosis
probably due to the rapid decrease in p75NTR expression that occurs
upon NGF withdrawal. © 2003 Elsevier Ltd. All rights reserved.
90
466. Modulation of cellular activity and synaptic transmission in
the ventral tegmental area - Mathon D.S., Kamal A., Smidt M.P.
and Ramakers G.M.J. [G.M.J. Ramakers, Dept. of Pharmacology
and Anatomy, Rudolf Magnus Inst. of Neuroscience, University
Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht,
Netherlands] - EUR. J. PHARMACOL. 2003 480/1-3 (97-115) summ in ENGL
The mesolimbic dopamine system, of which the cell bodies are
located in the ventral tegmental area, has been implicated in the
physiology of reward and the related pathophysiology of drug abuse.
This area has been a site of significant interest to study the effects
of drugs of abuse and neurotransmitter systems implicated in the
rewarding effects of these compounds. One important aspect of synaptic transmission is the ability of synapses to strengthen or weaken
their connection as a consequence of synaptic activity. Recently,
it has become apparent that this phenomenon is also present in the
ventral tegmental area and that this may bear important functional
consequences for the ways in which drugs of abuse assert their
effect. Here, we will review the effects of neurotransmitter systems
and drugs of abuse on cellular activity and synaptic transmission in
the ventral tegmental area. © 2003 Elsevier B.V. All rights reserved.
467. Augmented responses to morphine and cocaine in mice
with a 12-lipoxygenase gene disruption - Walters C.L., Wang
B.-C., Godfrey M. et al. [J.A. Blendy, Department of Pharmacology, 125 John Morgan Building, Univ. of PA School of Medicine,
3620 Hamilton Walk, Philadelphia, PA 19104-6084, United States]
- PSYCHOPHARMACOLOGY 2003 170/2 (124-131) - summ in
ENGL
Rationale: Recent studies have shown that pharmacological inhibition of the 12-lipoxygenase pathway selectively blocks opioid
inhibition of GABAergic synaptic currents. A similar mechanism
has been shown for the regulation of glutamate release in the ventral tegmental area (VTA) during acute withdrawal from morphine,
although the functional significance of these effects in vivo are
not known. Objectives: We have utilized mice with a disruption
of the "leukocyte-type" 12-lipoxygenase gene (12-LO-/- mice) to
examine a variety of general behavioral responses as well as several
specific responses to morphine and cocaine. Methods: Behavioral
responses to morphine include sensitivity to thermal stimuli and
withdrawal from chronic morphine treatment. Responses to cocaine were measured through locomotor activity. Results: General
behavioral responses in 12-LO-/- mice are not different from their
wild-type controls. However, these mutant mice showed enhanced
morphine-induced analgesia. However, this effect is eliminated
following chronic morphine treatment. In addition, 12-LO-/- mice
demonstrated enhanced somatic signs of opiate withdrawal relative to littermate controls. Lastly, cocaine-mediated increases in
locomotor activity was augmented acutely but not chronically in
12-LO-/- mice. Conclusions: Together, these results suggest a role
for metabolites of arachidonic acid metabolism in morphine- and
cocaine-induced behavioral responses and may reflect a utilization
of this pathway following acute but not chronic drug administration.
468. Effects of olanzapine infusions to the ventral tegmental area
on lordosis and midbrain 3,5-THP concentrations in rats
- Frye C. and Seliga A. [C. Frye, Department of Psychology, University at Albany-SUNY, 1400 Washington Avenue, Albany, NY
12222, United States] - PSYCHOPHARMACOLOGY 2003 170/2
Rationale: The progesterone metabolite and neurosteroid 5pregnane-3-ol-20-one (3,5-THP) facilitates sexual behavior of
estradiol-primed rodents through its actions in the ventral tegmental area (VTA). Olanzapine, an atypical antipsychotic, may exert
some of its actions by increasing 3,5-THP levels. Objective: If
olanzapine has effects by increasing 3,5-THP levels, then olanzapine administration to the VTA should facilitate feminine sexual
behavior of estradiol-primed rodents concomitant with increasing
midbrain levels of 3,5-THP. Methods: In experiment 1, ovariectomized rats with bilateral cannulae to the VTA were primed with
estradiol at 0 h, infused with olanzapine (10 or 20 g) or vehicle
at 47 h, and tested for sexual behavior at 47.5 h. In experiment 2,
estradiol-primed ovariectomized rats were infused with olanzapine
(10 g) or vehicle, tested for sexual behavior, then tissues were
collected for measurement of midbrain progesterone and 3,5THP, and plasma corticosterone, progesterone, and 3,5-THP. In
experiment 3, estradiol-primed, ovariectomized rats were administered progesterone (500 g, SC), tested for sexual behavior, then
tissues were collected for midbrain and plasma progesterone and
3,5-THP levels. Results: Infusions of 10 or 20 g olanzapine to
the VTA significantly increased the incidence and intensity of lordosis, and the occurrence of proceptive and aggressive behaviors.
Rats infused with olanzapine to the VTA had significantly greater
levels of midbrain 3,5-THP than did vehicle-administered rats.
Olanzapine did not increase progesterone or corticosterone levels.
Conclusions: Olanzapine increases lordosis and midbrain 3,5THP when infused to the VTA which suggest that olanzapine’s
behavioral effects may result, in part, through actions of 3,5THP, independent of progesterone or corticosterone.
469. Motor effects of GABAA antagonism in globus pallidus:
Studies of locomotion and tremulous jaw movements in rats
- Wisniecki A., Correa M., Arizzi M.N. et al. [J.D. Salamone,
Department of Psychology, University of Connecticut, Storrs, CT
06269-1020, United States] - PSYCHOPHARMACOLOGY 2003
170/2 (140-149) - summ in ENGL
Rationale: Although most rodent studies related to parkinsonian
symptoms have focused on locomotion, tremulous jaw movements
also have been used as a rodent model of tremor for investigating
the circuitry of the basal ganglia. Objective: There are multiple
pathways involved in the generation of parkinsonian symptoms.
The globus pallidus is a basal ganglia relay nucleus, and the present
study was conducted to investigate the effect of pallidal GABA
antagonism on locomotion and tremulous jaw movements. Methods: Suppression of locomotion and induction of tremulous jaw
movements were produced by repeated (i.e., 14 day) systemic administration of the dopamine D2 antagonist haloperidol, and by
acute systemic injection of the muscarinic agonist pilocarpine.
The GABAA antagonist bicuculline was injected into the globus
pallidus, and its effects on locomotion in haloperidol- and pilocarpine-treated rats were assessed in the first group of experiments.
In the second group of experiments, the effects of intrapallidal
infusions of bicuculline on haloperidol- and pilocarpine-induced
jaw movements were observed. Results: Pallidal GABA antagonism stimulated locomotion when no other treatment was present,
and also when animals were coadministered haloperidol or pilocarpine. Bicuculline suppressed haloperidol-induced jaw movements
in a dose-related manner, and had no effect on pilocarpine-induced
jaw movements. Conclusions: These results support the notion
that there are distinct pathways conveying basal ganglia outflow
and demonstrate that the striatopallidal pathway is involved in the
generation of the haloperidol-induced tremulous jaw movements.
These findings are consistent with some features of current models
of basal ganglia function and may lead to an understanding of the
specific mechanisms that generate parkinsonian symptoms.
470. Role of corticotropin releasing factor (CRF) receptors 1
and 2 in CRF-potentiated acoustic startle in mice - Risbrough
V.B., Hauger R.L., Pelleymounter M.A. and Geyer M.A. [M.A.
Geyer, Department of Neurosciences, University of California San
Diego, Mail Code 0804, 9500 Gilman Drive, San Diego, CA 920930804, United States] - PSYCHOPHARMACOLOGY 2003 170/2
Rationale: Hypersecretion of corticotropin releasing factor
(CRF) has been implicated in both severe anxiety disorders and
major depression. Although the role of the CRF1 receptor in the
anxiogenic effects of CRF is well supported, the role of CRF2
receptors in anxiety-like behaviors is less clear. In rats, CRF increases the acoustic startle reflex (ASR) via its action in the extended
amygdala, providing a putative measure of CRF-mediated anxiogenic activity. Objective: To characterize the effect of CRF on
ASR in mice and determine the respective roles of CRF1 and CRF2
receptors in CRF-potentiated ASR. Methods: The present study
examined: (1) the time course and dose response functions for the
effects of human/rat (h/r)-CRF (0.02-0.6 nmol, ICV (intracerebroventricular)) on ASR in two inbred strains of mice; (2) the effects
of the CRF1 receptor antagonist NBI-30775 (20 mg/kg, intraperitoneal) and the CRF2 receptor antagonist Antisauvagine-30 (1-10
nmol, ICV) on CRF-potentiated ASR and (3) the effects of the
CRF2 receptor agonist urocortin 2 (0.2-6 nmol, ICV) on ASR in
mice. Results: h/r-CRF significantly increased ASR in mice in a
time-dependent manner with maximal efficacy at the 0.2 and 0.6
nmol doses. 12986/SvEvTac mice exhibited a slightly increased
duration of action and lower minimal effective dose threshold for
CRF effects on ASR compared to C57BL/6J mice. Both selective
CRF1 and CRF2 antagonists attenuated h/r-CRF-potentiated ASR
without affecting acoustic startle when given alone. The selective
CRF 2 receptor agonist urocortin 2 increased ASR (1 and 2 nmol),
albeit with less efficacy than the non-selective CRF receptor agonist
h/r-CRF. Conclusions: Both CRF1 and CRF2 receptors appear to
contribute to the h/r-CRF-induced increases in ASR in mice. These
data support the hypothesis that both receptors contribute to the
anxiogenic effects of CRF.
471. Evaluation of the phencyclidine-like discriminative stimulus effects of novel NMDA channel blockers in rats - Nicholson
K.L. and Balster R.L. [K.L. Nicholson, Dept. of Pharmacology and
Toxicology, Medical College of Virginia, Virginia Commonwealth
University, Richmond, VA 23298-0613, United States] - PSYCHOPHARMACOLOGY 2003 170/2 (215-224) - summ in ENGL
Rationale: Because of their potential therapeutic effects,
N-methyl-D-aspartate (NMDA) receptor antagonists have been investigated for clinical use. Unfortunately, many channel-blocking
antagonists have been associated with the production of side effects, including motor impairment and phencyclidine (PCP)-like
subjective effects. Objective: This study investigated the relationship between NMDA receptor channel blockade and production of
PCP-like side effects by evaluating a variety of NMDA channel
blockers with different binding characteristics for the production of PCP-like discriminative stimulus effects. Methods: The
NMDA channel blockers were tested in rats trained to discriminate 2 mg/ kg PCP, i.p., from saline using a standard two-lever
drug discrimination procedure with responding under a fixed ratio
(FR) 32 schedule of food reinforcement. Results: The high-affinity channel blockers PD 138289, PD 137889 and FR 115427,
produced full, dose-dependent substitution for PCP. Of the moderate-affinity channel blockers, MRZ 2/579 fully substituted for
PCP while 1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, 8(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline and alaproclate
produced partial substitution. Drugs with the lowest affinity
for the channel site and/ or higher affinity for non-NMDA CNS
sites, antazoline, idazoxan, 1-phenyl-1,2,3,4-tetrahydroisoquinoline, -benzyl-N-methyl-phenethylamine and orphenadrine, failed
to substitute for PCP. Conclusions: The results demonstrate that
the cellular actions of the individual channel-blocking NMDA antagonists, in particular affinity for the channel site and NMDA
receptor specificity, are important determinants of their discriminative stimulus effects. While higher affinity channel blockers show
a correlation between affinity and PCP-like discriminative stimulus
effects, behavioral disruption through action at non-NMDA receptors probably prevents achieving sufficient concentrations of the
lower affinity compounds at NMDA receptors to produce PCP-like
discriminative stimulus effects.
472. Acetyl-L-carnitine permeability across the blood-brain
barrier and involvement of carnitine transporter OCTN2 Inano A., Sai Y., Nikaido H. et al. [I. Tamai, Dept. of Molecular Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo
University of Science, 12 Ichigaya-Funagawara-machi, Shinjukuku, Tokyo 162-0826, Japan] - BIOPHARM. DRUG DISPOS. 2003
24/8 (357-365) - summ in ENGL
OCTN2 (SLC22A5), an organic cation /carnitine transporter, is
widely distributed throughout the body, including the brain. In
the present study, the involvement of OCTN2 in acetyl-L-carnitine
(ALCAR) permeation across the blood-brain barrier (BBB) was
examined using a microdialysis method in mouse. OCTN2 function was examined by comparison of wild-type mice with jvs mice,
which express defective OCTN2 and are considered a model for primary systemic carnitine deficiency. Zero-net-flux method analysis
indicated higher in vivo recovery of ALCAR and lower physiological ALCAR concentration in thalamus extracellular fluid (ECF) in
jvs mice compared with wild-type mice. Externally added ALCAR
showed significantly slower initial uptake across the BBB in jvs
mouse. These results indicated that OCTN2 is functionally involved
91
in ALCAR transfer across the BBB. Total radioactivity in ECF after
i.v. administration of radiolabelled ALCAR remained constant for
the rest of the experimental period. Accordingly, our results indicate
that ALCAR is transported from blood to brain ECF by OCTN2 at
least in part, and its concentration in brain ECF is regulated by other
events such as protein binding and anabolic reactions in the brain,
as well as by transport across the BBB. Copyright © 2003 John
Wiley & Sons, Ltd.
473. Antioxidant activity, lipid peroxidation and skin diseases.
What’s new - Briganti S. and Picardo M. [S. Briganti, Cutaneous
Physiopathology Laboratory, San Gallicano Dermatological Inst.,
25/A Via S. Gallicano, 00153-Rome, Italy] - J. EUR. ACAD. DERMATOL. VENEREOL. 2003 17/6 (663-669) - summ in ENGL
Due to its interface function between the body and the environment, the skin is chronically exposed to both endogenous and
environmental pro-oxidant agents, leading to the harmful generation
of reactive oxygen species (ROS). There is compelling evidence that
oxidative stress is involved in the damage of cellular constituents,
such as DNA, cell membrane lipids or proteins. To protect the
skin against the over-load of oxidant species, it contains a well-organised system of both chemical and enzymatic antioxidant which
are able to work in a synergistic manner. Skin antioxidant network
protects cells against oxidative injury and prevent the production
of oxidation products, such as 4-hydroxy-2-nonenal or malonaldehyde, which are able to induce protein damage, apoptosis or
release of pro-inflammatory mediators, such as cytokines. When
oxidative stress overwhelms the skin antioxidant capacity the subsequent modification of cellular redox apparatus leads to an alteration
of cell homeostasis and a generation of degenerative processes.
Topical application or oral administration of antioxidants has been
recently suggested as preventive therapy for skin photoaging and
UV-induced cancer. The recognition that ROS can act as second
messengers in the induction of several biological responses, such as
the activation of NF-kB or AP-1, the generation of cytokines, the
modulation of signalling pathways, etc., has led many researchers
to focus on the possible effects of antioxidants in many pathological
processes. The recent demonstration that the peroxisome proliferators-activated receptors, whose natural ligands are polyunsaturated
fatty acids and theirs oxidation products, have a central role in the
induction of some skin diseases, such as psoriasis or acne, has indicated new links between free radicals and skin inflammation. Based
on these findings, the review summarises the possible correlations
between antioxidant imbalance, lipid oxidative breakage and skin
diseases, from both a pathological and therapeutic points of view.
474. Pharmacokinetic and Pharmacodynamic Profiles of BIA 3202, a Novel Catechol-O-Methyltransferase (COMT) Inhibitor,
during Multiple-Dose Administration to Healthy Subjects - Almeida L. and Soares-Da-Silva P. [Dr. P. Soares-Da-Silva, Dept. of
Research and Development, BIAL, A Av. do Siderurgia Nacional,
4745-457 S. Mamede do Coronado, Portugal] - J. CLIN. PHARMACOL. 2003 43/12 (1350-1360) - summ in ENGL
The tolerability, pharmacodynamics, and pharmacokinetics of
BIA 3-202 (50 mg, 100 mg, and 200 mg twice daily and 200
mg thrice daily), a novel catechol-O-methyltransferase (COMT)inhibitor, were investigated in healthy volunteers. BIA 3-202 was
administered to four sequential groups of 8 healthy male subjects under a double-blind, randomized, placebo-controlled design. Within
each group, 2 subjects were randomized to treatment with placebo.
Treatment duration was 9 days: single dose on the first and last days
and twice or thrice daily on days 3 to 8. BIA 3-202 was well tolerated at all dose regimens tested. Median maximum plasma BIA
3-202 concentrations were attained at 0.5 to 2.5 hours postdose.
Thereafter, concentrations declined with a t 1/2 , of approximately
2 to 4 hours. The increase in the extent of systemic exposure, as
measured by AUC0-v , was approximately proportional to the administered dose. Steady state of plasma BIA 3-202 concentrations
occurred by day 4 in all dose groups. Less than 1% of the total
dose administered was excreted in urine up to 48 hours postdose.
BIA 3-202 markedly reduced soluble COMT (S-COMT) activity
in erythrocytes, with maximum inhibition occurring at 1 to 2 hours
postdose; enzyme activity returned to baseline levels by approximately 8 hours. Inhibition of S-COMT activity appeared to increase
with increasing doses of BIA 3-202 on both day 1 and day 9. In
92
conclusion, BIA 3-202 was well tolerated in all the oral multipledose regimens tested. BIA 3-202 was shown to inhibit S-COMT
activity in erythrocytes, and its pharmacokinetics appeared to be
linear (i.e., dose independent and time invariant).
475. Levetiracetam: Relative Bioavailability and Bioequivalence of a 10% Oral Solution (750 mg) and 750-mg Tablets
- Coupez R., Straetemans R., Sehgal G. et al. [Dr. Z. Lu, UCB
Pharma, Inc., 1950 Lake Park Drive, Smyrna, GA 30080, United
States] - J. CLIN. PHARMACOL. 2003 43/12 (1370-1376) - summ
in ENGL
Levetiracetam, an antiepileptic drug, is used worldwide as an
adjunctive treatment for partial-onset seizures. The availability of a
new oral solution formulation would provide an additional treatment
option for patients who have difficulty swallowing tablets. A phase
I single-center, randomized, open-label, two-way crossover, single-dose study was conducted to confirm that a 10% oral solution
of levetiracetam was bioequivalent to the 750-mg oral tablet and
to characterize its pharmacokinetics. Each of 24 healthy subjects
received a single oral 750-mg dose of the randomized levetiracetam formulation (7.5 mL of 10% solution or 750-mg tablet) on
day 1 and a single oral dose of the alternate formulation on day
8, Serial blood samples were collected from 0 to 36 hours after
each dose administration for determination of plasma levetiracetam
concentrations. Pharmacokinetic parameters were calculated, and
bioequivalence of the two formulations was evaluated. The mean
levetiracetam plasma concentration-time curves and pharmacokinetic parameters essentially were identical for the oral 10% solution
and tablet and consistent with previously reported levetiracetam
pharmacokinetics. The 90% confidence limits of the geometric
mean ratio of the two formulations for area under the plasma concentration-time curve from time 0 to infinity, area under the plasma
concentration-time curve from time 0 to last measurable time point,
and maximum plasma concentration were within the 80% to 125%
range, demonstrating bioequivalence of the two formulations. Both
levetiracetam formulations were well tolerated. The levetiracetam
10% oral solution is a bioequivalent, well-tolerated alternative to
the tablet formulation in patients who have difficulty swallowing.
476. Synthesis and anticonvulsant properties of new
N-[(4-arylpiperazin-1-yl)- methyl] derivatives of 3-aryl pyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane- 1,3-dione Obniska J. and Zagorska A. [J. Obniska, Department of Medicinal Chemistry, Jagiellonian Univ. Medical College, Medyczna 9,
Pl 30-688 Cracow, Poland] - FARMACO 2003 58/12 (1227-1234) summ in ENGL
A series of N-[(4-arylpiperazin-1-yl)-methyl] derivatives of
3-arylpyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione were synthesized and tested for anticonvulsant activity
in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc.MET) tests.
The most potent
in the series were N-[f4-(3-chlorophenyl)-piperazin-1-ylgmethyl]-3-(2- chlorophenyl)-pyrrolidine-2,5-dione (ED50 =14.18
mg/kg) and N-[f4-(2-methoxyphenyl)-piperazin-1-ylg-methyl]-3(3-bromophenyl)-pyrrolidine-2, 5-dione (ED50 =33.64 mg/kg).
Structures of the novel compounds were confirmed by elemental
and spectral analyses. © 2003 Éditions scientifiques et médicales
Elsevier SAS. All rights reserved.
477. Molecular mechanisms of tolerance to and withdrawal of
GABAA receptor modulators - Biggio G., Dazzi L., Biggio F. et
al. [G. Biggio, Dept. of Exp. Biology Bernardo Loddo, University of Cagliari, Via Palabanda 12, Cagliari 09123, Italy] - EUR.
NEUROPSYCHOPHARMACOL. 2003 13/6 (411-423) - summ in
ENGL
Here, we summarize recent data pertaining to the effects of GABA
A receptor modulators on the receptor gene expression in order
to elucidate the molecular mechanisms behind tolerance and dependence induced by these drugs. Drug selectivity and intrinsic
activity seems to be important to evidence at the molecular level the
GABAA receptor tolerance. On the contrary, we suggested that all
drug tested are equally potentially prone to induce dependence. Our
results demonstrate that long-lasting exposure of GABAA receptors
to endogenous steroids, benzodiazepines and ethanol, as well as
their withdrawal, induce marked effects on receptor structure and
function. These results suggest the possible synergic action between
endogenous steroids and these drugs in modulating the functional
activity of specific neuronal populations. We report here that endogenous steroids may play a crucial role in the action of ethanol
on dopaminergic neurons. © 2003 Elsevier B.V./ECNP. All rights
reserved.
478. Neuroadaptive mechanisms of addiction: Studies on the
extended amygdala - Koob G.F. [G.F. Koob, Division of Psychopharmacology, Department of Neuropharmacology, Scripps
Research Institute, 10550 North Torrey Pines Road, San Diego,
CA 92037, United States] - EUR. NEUROPSYCHOPHARMACOL.
2003 13/6 (442-452) - summ in ENGL
A conceptual structure for drug addiction focused on allostatic
changes in reward function that lead to excessive drug intake provides a heuristic framework with which to identify the neurobiologic
neuroadaptive mechanisms involved in the development of drug
addiction. The brain reward system implicated in the development of addiction is comprised of key elements of a basal forebrain
macrostructure termed the extended amygdala and its connections.
Neuropharmacologic studies in animal models of addiction have
provided evidence for the dysregulation of specific neurochemical mechanisms not only in specific brain reward circuits (opioid
peptides, -aminobutyric acid, glutamate and dopamine) but also
recruitment of brain stress systems (corticotropin-releasing factor)that provide the negative motivational state that drives addiction,
and also are localized in the extended amygdala. The changes in
the reward and stress systems are hypothesized to maintain hedonic
stability in an allostatic state, as opposed to a homeostatic state, and
as such convey the vulnerability for development of dependence
and relapse in addiction. © 2003 Elsevier B.V./ECNP. All rights
reserved.
479. Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naı̈ve healthy volunteers: Results from
a large cohort - Abi-Dargham A., Kegeles L.S., Martinez D. et
al. [M. Laruelle, Division of Functional Brain Mapping, Columbia
Univ. Coll. of Phys./Surgs., New York State Psychiatric Institute,
1051 Riverside Drive, New York, NY 10032, United States] - EUR.
NEUROPSYCHOPHARMACOL. 2003 13/6 (459-468) - summ in
ENGL
A positive experience during a first encounter with a drug of abuse
is predictive of subsequent use and might represent a vulnerability
factor to develop addiction. This paper presents a meta-analysis of
data acquired in 60 healthy volunteers who underwent a low-dose
amphetamine challenge (0.3 mg/kg, i.v.) during imaging of dopamine D2 receptor availability with SPECT and the D2 /D3 radiotracer
[123 I]IBZM. Amphetamine-stimulated DA release induced a small,
significant and highly variable decrease in striatal D2 receptor availability (-8.36.7%). The magnitude of the decrease in D2 receptor
availability was significantly associated with the positive reinforcing effects of the drug reported by the subject (r2 =0.14, p=0.003).
Age was associated with decreased potency of dopamine to elicit
positive reinforcing effects. This study indicates that both a large
dopaminergic response and young age during a first encounter with
a drug of abuse potential contribute to higher positive reinforcing
effects. © 2003 Elsevier B.V./ECNP. All rights reserved.
480. Acamprosate and naltrexone treatment for alcohol dependence: An evidence-based risk-benefits assessment - Mason B.J.
[B.J. Mason, Department of Neuropharmacology, Scripps Research
Institute, San Diego, CA, United States] - EUR. NEUROPSYCHOPHARMACOL. 2003 13/6 (469-475) - summ in ENGL
This paper provides an evidence-based risk-benefit assessment of
acamprosate and naltrexone in the treatment of alcohol dependence.
A risk-benefit assessment is based on the premise that the choice
of treatment depends on a number of factors, notably the adverse
event profile and efficacy. An evidence-based approach attempts to
operationalize how such risk-benefit assessments are made to inform
physician choices. This approach involves a systematic assessment
of all published double-blind, placebo-controlled trials. Based on
this review, we conclude acamprosate and naltrexone are both useful
in the treatment of alcohol dependence. However, the two drugs act
in different ways in the brain, and their clinical profiles are different.
Treatment effects seem to be more reliable for acamprosate, and this
drug is better tolerated. The safety of the two drugs in combination
has been supported by two independent double-blind studies, and
combination treatment may offer an advantage for some patients.
© 2003 Elsevier B.V./ECNP. All rights reserved.
481. Effects of Sertraline on Sleep Architecture in Patients with
Depression - Jindal R.D., Friedman E.S., Berman S.R. et al. [Dr.
R.D. Jindal, W. Psychiatric Institute and Clinic, 3811 O’Hara Street,
Pittsburgh, PA 15213, United States] - J. CLIN. PSYCHOPHARMACOL. 2003 23/6 (540-548) - summ in ENGL
Previous studies indicate that selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, fluvoxamine, citalopram and
paroxetine, suppress rapid eye movement sleep, and increase nocturnal arousals. There has been no published report of the impact of
sertraline on the sleep of depressed patients. This study examines
such effects. Forty-seven patients with major depressive disorder,
randomized to double-blind treatment with sertraline or placebo,
completed sleep studies before and after 12 weeks of pharmacotherapy. Groups were compared using multivariate analyses of
covariance and/or analyses of covariance to examine 4 empirically
defined sets of sleep measures. Compared to the placebo-treated
group, patients who received sertraline experienced an increase in
delta wave sleep in the first sleep cycle and prolonged rapid eye
movement (REM) sleep latency. Although, sertraline therapy decreased the average number of REM periods (from 3.86 to 2.40),
the activity of both REM period 1 and REM period 2 was significantly increased. Aside from an increase in sleep latency, sertraline
therapy was not associated with a worsening of measures of sleep
continuity. There was also no significant difference between the
groups on a measure of subjective sleepiness. These findings are
both similar and different from those observed in previous studies
of other SSRIs. The increase in delta sleep ratio and consolidation
of REM sleep may have some other clinical implications. However,
the generalizability of these findings is limited because of a number
of reasons. Further studies are needed to examine the effects of
SSRIs in acute treatment of depressed patients with severe insomnia, and the relationship of acute changes and relapse prevention of
recurrent depression.
482. African Women with Depression: The Effect of Imipramine and Fluoxetine on Body Mass Index and Leptin Secretion
- Moosa M.Y.H., Panz V.R., Jeenah F.Y. and Joffe B.I. [M.Y.H.
Moosa, P.O. Box 4581, Johannesburg 2000, South Africa] - J. CLIN.
PSYCHOPHARMACOL. 2003 23/6 (549-552) - summ in ENGL
Treatment of depression is often accompanied by weight changes.
Previous studies indicate that leptin plays no role in this change despite showing a strong correlation with body mass index (BMI) in
healthy people. The aim of this study was to evaluate the effect of
imipramine and fluoxetine on BMI and its correlation with leptin.
Eighteen depressed female patients randomly received either drug
for 3 months. BMI was calculated and fasting blood samples were
assayed for glucose, leptin, insulin, free fatty acids (FFA), and
lipids. The difference between the changes in BMI (imipramine
+1.0 kg/m2 , fluoxetine -0.5 kg/m2 ) was statistically significant (P
< 0.05, t = 2.106). There was a significant positive correlation
between overall BMI and leptin (r = 0.784, P < 0.001) but not
between BMI and insulin or FFA. However, fasting insulin levels
and calculated insulin resistance levels dropped substantially in the
imipramine group. We conclude that the use of tricyclic antidepressants (TCAs) in depressed patients at risk for developing type
2 diabetes remains unresolved at this stage.
483. Sertraline and Cognitive Behavioral Therapy for Depressed Alcoholics: Results of a Placebo-Controlled Trial Moak D.H., Anton R.F., Latham P.K. et al. [Dr. D.H. Moak,
Department of Psychiatry, Medical University of South Carolina,
67 President Street, Charleston, SC 29425, United States] - J. CLIN.
PSYCHOPHARMACOL. 2003 23/6 (553-562) - summ in ENGL
Alcoholism and depression are common disorders that frequently
cooccur in the same individual. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of depression and
also had decreased drinking in some studies of heavy drinkers and
alcoholics. The reported effect of serotonergic medications on alcohol intake in depressed alcoholics has not been consistent. Most
previous studies have not investigated the use of an SSRI in the
93
context of cognitive behavioral therapy (CBT), a known efficacious
treatment of both alcoholism and depression. The study presented
here was a randomized placebo-controlled 12-week trial of sertraline combined with individual CBT focused on both alcoholism
relapse prevention and depressive symptoms. Subjects were 82
currently depressed, actively drinking alcohol-dependent individuals. Subjects had either primary (independent) major depression (70
subjects) or substance-induced mood disorder and at least 1 firstdegree relative (parent, sibling, or child) with an affective disorder
(12 subjects). Depression and alcohol consumption outcomes were
measured weekly over 12 weeks. Sertraline was well tolerated and
all subjects had decreases in both depression and alcohol use during
the study compared with baseline. Subjects who received sertraline had fewer drinks per drinking day than subjects who received
placebo, but other drinking outcomes were not different between the
2 treatment groups. Treatment with sertraline was associated with
less depression at the end of treatment in female subjects compared
with female subjects who received placebo. Less drinking during
the study was associated with improved depression outcome. The
findings in this study suggest that sertraline, compared with placebo,
may provide some modest benefit in terms of drinking outcome and
also may lead to improved depression in female alcohol-dependent
subjects. Additionally, alcohol relapse prevention CBT, delivered
according to manual guidelines with modifications that provide specific attention to depression, appeared to be of benefit to subjects,
although this interpretation is limited by the design of the study.
484. Sertraline in Panic Disorder: Initial Treatment Versus
Switch Strategy - Mavissakalian M.R. [Dr. M.R. Mavissakalian,
Anxiety Disorders Program, University Hospitals of Cleveland,
11100 Euclid Avenue, Cleveland, OH 44106, United States] - J.
CLIN. PSYCHOPHARMACOL. 2003 23/6 (646-651) - summ in
ENGL
The study explored whether there is differential efficacy for patients with panic disorder treated with sertraline initially (primary
group) versus those switched (transfer group) after intolerance or
nonresponse to imipramine in the context of the open 24-week
treatment phase of a long-term maintenance/discontinuation study.
Similar assessment and treatment procedures were used in the 2
groups and there were no concurrent cognitive behavioral interventions. A consistent pattern suggesting decreased efficacy for the
transfer treatment group (n = 11, 68 25 mg/d) compared with the
primary treatment group (n = 11, 70 25 mg/d) was found on response rates, univariate repeated measures analysis of variance and
within group effect sizes in intent to treat, and completer samples.
These preliminary findings concord well with clinical intuition but
are contrary to findings in the treatment of depression. Replication
studies seem warranted.
485. Chlorpromazine Equivalents Versus Defined Daily Doses:
How to Compare Antipsychotic Drug Doses? - Rijcken C.A.W.,
Monster T.B.M., Brouwers J.R.B.J. and De Jong-Van Den Berg
L.T.W. [Dr. L.T.W. De Jong-Van Den Berg, Dept. Social Pharm.
Pharmacoepidem., Groningen Univ. Inst. Drug Explor., Antonius
Deusinglaan 1, 9713 AV Groningen, Netherlands] - J. CLIN. PSYCHOPHARMACOL. 2003 23/6 (657-659) - summ in ENGL
Classic chlorpromazine (CPZ) equivalents can be used to chart
relative antipsychotic potencies of antipsychotic drugs. Values of
CPZ equivalents per drug are ambiguous in literature. In drug use
evaluation studies, antipsychotic doses are frequently compared by
use of the defined daily dose (DDD). The DDD is the assumed
average maintenance dose per day for a drug if used for its main
indication in adults. The DDD is based on review of the available
older and recent literature. In this report, we evaluated discrepancy
between CPZ-equivalent values and DDD-equivalent values. We
plotted CPZ-equivalent values against DDD-equivalent values and
performed linear regression to determine the mean relationship between the 2 methods. About 67% of the DDD-equivalent values
demonstrated lower potencies for antipsychotic drug compared with
CPZ-equivalent values. The slope of the regression line was 0.68
(r2 = 0.81). Because we found a great discrepancy between these
2 methods of comparing antipsychotic drug doses, we think further
research is necessary to develop a standardized way of antipsychotic
drug comparison.
94
486. Predictors of Clinical Outcome in Schizophrenic Patients
Responding to Clozapine - Mauri M.C., Volonteri L.S., Dell’Osso
B. et al. [Dr. M.C. Mauri, Clinical Psychiatry, IRCCS Ospedale
Maggiore, Via F. Sforza 35, 20122 Milano, Italy] - J. CLIN. PSYCHOPHARMACOL. 2003 23/6 (660-664) - summ in ENGL
Many of the patients who respond better to clozapine (CLZ) than
to typical antipsychotics still have residual psychopathology, but
CLZ drug resistance data are lacking. The aim of this study was
to evaluate the possible predictive factors of a clinical response to
CLZ in a group of 20 schizophrenic patients (DSM-IV: 13 males
and 7 females with a mean age of 35.5 years 7.1 SD) resistant to
typical antipsychotics but CLZ responders as assessed by the Brief
Psychiatric Rating Scale (BPRS) (>20% improvement). After a 1week washout period, CLZ was started at a dose of 25 mg/d, which
was increased by the third week up to a maximum of 600 mg/d (mean
365.00 129.88 mg/d SD) and remained unchanged until the end of
the study (week 8). The patients showed a significant improvement
in the mean scores of the rating scales for positive (SAPS) and
negative symptoms of schizophrenia (Scale for the Assessment of
Negative Symptoms, SANS) (P < 0.003, P < 0.02). All of the
patients included in the study were BPRS responders; 65% were
also SAPS and 75% SANS responders (>20% improvement). The
improvement in the SANS score was significantly greater among the
female patients (P < 0.05). The SAPS and SANS responders had a
significantly higher mean metabolic ratio [MR = (NCLZ/CLZ)] than
the nonresponders (P < 0.01), and the percentage of improvement
significantly correlated with the increase in MR. This finding suggests that the individual pharmacogenetics indicated by metabolic
capacity may be related to clinical response. All of the patients
showed a reduction in white blood cell counts, but this was significantly less in the SANS responders than the SANS nonresponders
(P = 0.047). The SAPS responders had significantly lower neutrophil counts than the nonresponders (P = 0.03). Our results seem
to suggest the importance of pharmacodynamic, constitutional, and
genetic data over strict pharmacokinetics in determining the clinical
response to CLZ.
487. Anxiolytic effects of the novel anti-epileptic drug levetiracetam in the elevated plus-maze test in the rat - Gower A.J.,
Falter U. and Lamberty Y. [Y. Lamberty, UCB S.A., Pharma Sector,
Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium] - EUR. J.
There is clinical evidence of anxiolytic action of several anti-epileptic drugs. We evaluated the effects of levetiracetam (Keppra™),
a new generation anti-epileptic drug, in the plus-maze animal test
for anxiolytic activity. Levetiracetam at 17 and 54 mg/kg intraperitoneally (i.p.) was without effect when tested in naive rats.
A modified version of the test was subsequently used in which
open-arm exploration was decreased by exposure of the rats to a
four-open-arm maze 24 h prior to drug treatment and testing. Under these conditions of enhanced anxiety, levetiracetam, 5.4 to 54
mg/kg, dose-dependently increased open-arm exploration. Chlordiazepoxide 5 mg/kg had similar effects although buspirone 0.1 to
1.0 mg/kg was inactive. The results with levetiracetam substantiate
similar findings of its anxiolytic actions against chlordiazepoxide
withdrawal-induced anxiety in mice and in a modified Vogel test in
rats and support a potential clinical use of this drug in anxiety states.
488. 5-HT1A receptor full agonist, 8-OH-DPAT, exerts antidepressant-like effects in the forced swim test in ACTH-treated
rats - Kitamura Y., Araki H., Shibata K. et al. [Y. Kitamura,
Division of Pharmacy, Misasa Medical Center, Okayama University Medical School, 827 Yamada Misasa-cho, Tohaku-Gun, Tottori
682-0192, Japan] - EUR. J. PHARMACOL. 2003 481/1 (75-77) summ in ENGL
We examined the effect of adrenocorticotropic hormone (ACTH)on the immobilization of rats in the forced swim test after
administration of the 5-HT1A receptor agonist, 8-hydroxy-2-din-propylamino tetralin (8-OH-DPAT). Imipramine (3-30 mg/kg,
i.p.) or 8-OH-DPAT (0.1-1 mg/kg, s.c.) significantly decreased the
duration of immobility in normal rats. The immobility-decreasing
effect of imipramine was blocked when ACTH was administered
for 14 days. On the other hand, the immobility-decreasing effect
induced by 8-OH-DPAT was not blocked by chronic administration
of ACTH for 14 days. These findings indicate that 8-OH-DPAT can
be useful in an animal model of depressive conditions resistant to
antidepressant treatment. © 2003 Elsevier B.V. All rights reserved.
489. Methylenedioxymethamphetamine (MDMA, ’ecstasy’)serves as a robust positive reinforcer in a rat runway procedure
- Wakonigg G., Sturm K., Saria A. and Zernig G. [Dr. G. Zernig, Division of Neurochemistry, Department of Psychiatry, Anichstrasse
35, AT-6020 Innsbruck, Austria] - PHARMACOLOGY 2003 69/4
Although ’ecstasy’ (3,4-methylenedioxymethamphetamine,
MDMA) is, after marijuana, the second most prevalent illegal drug
of abuse in European adolescents, animal experimental evidence
of MDMA’s reinforcing effect has remained scarce, particularly
in the rodent model, raising questions about the robustness of
MDMA’s reinforcing effect under controlled laboratory conditions.
In the present rat runway study, Sprague-Dawley and Long-Evans
rats were given the opportunity to run for intravenous injections
of saline or MDMA (1 mg/kg). MDMA significantly decreased
runtimes in both rat strains. Thus, MDMA’s positive reinforcing
effect can be demonstrated not only across rat strains but also
across operant conditioning paradigms. These findings should
reassure the drug abuse research community that the investigation
of MDMA’s reinforcing effect in the inexpensive and widely used
rodent model is indeed feasible. Copyright © 2003 S. Karger AG,
Basel.
490. Modulatory effect of cyclooxygenase inhibitors on sildenafil-induced antinociception - Patil C.S., Jain N.K., Singh A. and
Kulkarni S.K. [Prof. S.K. Kulkarni, Univ. Inst. of Pharmaceutical
Sci., Panjab University, Chandigarh 160014, India] - PHARMACOLOGY 2003 69/4 (183-189) - summ in ENGL
Peripheral activation of the NO-cGMP pathway has been implicated in various nociceptive conditions. The antinociceptive
effect of the PDE-5 inhibitor, sildenafil, alone or in combination
with cyclooxygenase inhibitor diclofenac and nimesulide, was assessed in the different animal models of peripheral nociception. In
the present study we investigated the possible interaction between
cyclooxygenase and NO-cGMP pathway in writhing assay and
carrageenan-induced hyperalgesia in mice and rats, respectively.
Sildenafil [1-2 mg/kg, i.p. or 50-100 g/paw, intraplantar (i.pl.)],
nimesulide (1-2 mg/kg, i.p. or 25-50 g/paw, i.pl.) and diclofenac
(1-2 mg/kg, i.p. or 25-50 g/paw, i.pl.) exhibited an antinociceptive effect in both the models. When ineffective doses of sildenafil
(0.5 mg/kg, i.p and 25 g/paw, i.pl.) were co-administered with
ineffective doses of nimesulide (0.5 mg/kg, i.p. and 10 g/paw,
i.pl.) and diclofenac (0.5 mg/kg, i.p. and 10 g/paw, i.pl.), there
was a significant increase in the antinociceptive effect in both the
models of peripheral nociception. Further, the potentiation of the
effect was blocked by L-NAME (20 mg/kg, i.p., 100 g/paw, i.pl.),
a non-selective NOS inhibitor and methylene blue (1 mg/kg, i.p.),
a guanylate cyclase inhibitor. L-NAME or methylene blue itself
had little or no effect on both the models of hyperalgesia. These
results suggest that cyclooxygenase, NO and cGMP are relevant in
the combination-induced antinociception. In conclusion, sildenafil
induced antinociception, and its potentiation of the effect of the
cyclooxygenase inhibitors nimesulide and diclofenac was probably
mediated through the activation of the NO-cGMP pathway and
inhibition of cyclic GMP degradation. Copyright © 2003 S. Karger
AG, Basel.
See also: 529, 530, 533, 551, 567, 579, 580, 594, 610, 624, 625,
693, 694, 695, 722, 723.
5.2. Autonomic and motor nervous system
491. Role for standards in assays of botulinum toxins: International collaborative study of three preparations of botulinum
type A toxin - Sesardic D., Leung T. and Das R.G. [D. Sesardic, Division of Bacteriology, Natl. Inst. for Biol. Std./Control, Blanche
Lane, Potters Bar, Hertfordshire EN6 3QG, United Kingdom] BIOLOGICALS 2003 31/4 (265-276) - summ in ENGL
The biological activity of therapeutic preparations of botulinum
type A toxin is currently expressed in units defined on the basis of
the median lethal intraperitoneal dose of that preparation in mice
at 72 h, the LD50 dose. In this study we describe the comparison,
by ten laboratories in five countries, of three different formulations
of botulinum type A toxin using the mouse lethality test, and also
using the relative activities of the preparations. The results of this
study show that use of a standard preparation and expression of relative potency gives substantially greater consistency between and
within laboratories than when mouse LD50 unit is used to define
activity of botulinum toxin. © 2003 The International Association
for Biologicals. Published by Elsevier Ltd. All rights reserved.
See also: 572.
5.3. Cardiovascular system
492. Folic acid supplement decreases the homocysteine increasing effect of filtered coffee. A randomised placebo-controlled
study - Strandhagen E., Landaas S. and Thelle D.S. [E. Strandhagen, Department of Medicine, Cardiovascular Institute, Sahlgrenska
Univ. Hospital/Ostra, SE-416 85 Göteborg, Sweden] - EUR. J.
CLIN. NUTR. 2003 57/11 (1411-1417) - summ in ENGL
Objective: Elevated levels of plasma total homocysteine (tHcy)are identified as independent risk factors for coronary heart disease
and for fetal neural tube defects. tHcy levels are negatively associated with folic acid, pyridoxine and cobalamine, and positively
associated with coffee consumption and smoking. A total of 600 ml
of filtered coffee results in a tHcy increase that 200 g of folic acid
or 40 mg of pyridoxine supplementation might eliminate. Design:
Randomised, blinded study with two consecutive trial periods. Setting: Free living population. Volunteers. Subjects: A total of 121
healthy, nonsmoking men and women (78%) aged 29-65y. Interventions: (1) A coffee-free period of 3 weeks, (2) 600 ml coffee/day
and a supplement of 200 g folic acid/day or placebo for 4 weeks,
(3) 3-week coffee-free period, (4) 600 ml coffee/day and 40 mg
pyridoxine/day or placebo for 4 weeks. Main outcome measures:
The difference between the change in tHcy in the supplement group
and the change in tHcy in the placebo group during the 4-week trial
period. Results: Coffee abstention resulted in a tHcy decrease of
1.04 mol/l for the whole group. In the subsequent coffee period, a
further decrease of 0.17 mol/l was observed in the folic acid group
whereas an increase of 1.26 mol/l was observed in the placebo
group, the difference was 1.43 mol/l (95% Cl: 0.80, 2.07). Pyridoxine supplement had no impact on tHcy levels. Conclusions:
Supplementation of 200 g folic acid/day eliminates the tHcy increasing effect of 600 ml filtered coffee in subjects not already on
folic acid supplements. A supplement of 40 mg pyridoxine/day
does not have the same efffect.
493. Long-term administration of pravastatin reduces serum
lipoprotein(a) levels - Horimoto M., Hasegawa A., Takenaka T. et
al. [Dr. M. Horimoto, Division of Cardiovascular Disease, Chitose
City Hospital, Hokkou 2-Choume 1-1, Chitose City, Hokkaido 0668550, Japan] - INT. J. CLIN. PHARMACOL. THER. 2003 41/11
Background: The long-term effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum lipoprotein(a) (Lp(a)) levels has been poorly investigated. Objective: This study sought
to examine the effect of 24 months’ administration of pravastatin
on serum Lp(a) levels. Subjects: 23 patients with coronary artery
disease and serum low-density lipoprotein (LDL) cholesterol levels
of 120 mg/dl or above were included. Method: Serum levels of
lipids and Lp(a) were serially determined after the administration
of pravastatin for 24 months. Results: Serum LDL-cholesterol
(LDL-C) levels significantly decreased from 1 month after the drug
administration and the reduction persisted for 24 months, whereas
Lp(a) levels did not decrease at 3 months after the administration but
significantly decreased at 12 months or more. The reduction in the
Lp(a) levels was not related to the dose of pravastatin. Conclusions:
The results indicated that long-term administration of pravastatin
for 12 months or more significantly reduced serum Lp(a) levels
and the reduction of Lp(a) levels occurred much later than that of
LDL-C levels. The delayed reduction in serum Lp(a) levels after
the administration of pravastatin may be associated with a retarded
inhibition of Lp(a) synthesis by the drug.
95
494. Effects of losartan combined with exercise training in
spontaneously hypertensive rats - Azevedo L.F., Brum P.C.,
Mattos K.C. et al. [C.E. Negrão, Instituo de Coração, Unidad
de Reabilitação, Cardiovasc. e Fisiol. do Exercicio, Av. Dr. Enéas
C. Aguiar 44, 05403-000 São Paulo, SP, Brazil] - BRAZ. J. MED.
BIOL. RES. 2003 36/11 (1595-1603) - summ in ENGL
We investigate whether combined treatment with losartan, an
angiotensin II receptor blocker, and exercise training (ET) in spontaneously hypertensive rats (SHR) would have an additive effect in
reducing hypertension and improving baroreflex sensitivity when
compared with losartan alone. Male SHR (8 weeks old) were assigned to 3 groups: sedentary placebo (SP, N = 16), sedentary under
losartan treatment (SL, N = 11; 10 mg kg-1 day-1 , by gavage), and
ET under losartan treatment (TL, N = 10). ET was performed on
a treadmill 5 days/week for 60 min at 50% of peak VO2 , for 18
weeks. Blood pressure (BP) was measured with a catheter inserted
into the carotid artery, and cardiac output with a microprobe placed
around the ascending aorta. The baroreflex control of heart rate
was assessed by administering increasing doses of phenylephrine
and sodium nitroprusside (iv). Losartan significantly reduced mean
BP (178 16 vs 132 12 mmHg) and left ventricular hypertrophy
(2.9 0.4 vs 2.5 0.2 mg/g), and significantly increased baroreflex
bradycardia and tachycardia sensitivity (1.0 0.3 vs 1.7 0.5 and
2.0 0.7 vs 3.2 1.7 bpm/ mmHg, respectively) in SL compared
with SP. However, losartan combined with ET had no additional
effect on BP, baroreflex sensitivity or left ventricular hypertrophy
when compared with losartan alone. In conclusion, losartan attenuates hypertension and improves baroreflex sensitivity in SHR.
However, ET has no synergistic effect on BP in established hypertension when combined with losartan, at least at the dosage used in
this investigation.
495. New drugs for the treatment of hypercholesterolaemia Iglesias P. and Dı́ez J.J. [P. Iglesias, Department of Endocrinology,
Hospital General, Ctra. de Avila s/n, 40002 Segovia, Spain] EXPERT OPIN. INVEST. DRUGS 2003 12/11 (1777-1789) - summ
in ENGL
Endogenous and exogenous pathways determine plasma levels
of cholesterol and lipoproteins. Plasma cholesterol levels and
coronary heart disease risk can be reduced pharmacologically by
decreasing cholesterol synthesis, increasing its elimination and/or
reducing its absorption from the intestine. The more profound
knowledge about cholesterol homeostasis has allowed the development of several lipid-lowering drugs with different mechanisms
of action, with the purpose of reducing both morbidity and mortality associated with coronary heart disease. Two new and more
potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), also called superstatins (rosuvastatin
and pitavastatin), are being studied for their ability to improve lipid
profiles. Rosuvastatin is a potent, hepato-selective and relatively
hydrophilic statin with a low propensity for muscle toxicity and
drug interactions. Pitavastatin is another statin with a high oral bioavailability and minimal propensity for cytochrome P450-mediated
drug interactions. Rosuvastatin seems to be more potent than other
available statins while pitavastatin presents with a similar potency to
that of atorvastatin. Another promising approach for lowering total
and low-density lipoprotein cholesterol levels is inhibition of cholesterol absorption. A wide variety of new agents with the capacity
for inhibiting the intestinal cholesterol absorption is currently being
investigated. Ezetimibe is a selective cholesterol absorption inhibitor whose clinical efficacy has been recently demonstrated both
in monotherapy and in combination with other lipid-lowering drugs.
Colesevelam, a new bile acid sequestrant, has shown a clinical efficacy similar to that of other resins, with minimal gastrointestinal
side effects, improving tolerability and patient compliance. Other
lipid-lowering drugs with the ability to act at the enterocyte level,
such as avasimibe and implitapide, are currently being investigated
in humans.
496. Novel pharmacological treatments for heart failure - Tang
W.H.W. and Francis G.S. [Dr. W.H.W. Tang, Kaufman Centre for
Heart Failure, Dept. of Cardiovascular Medicine, Cleveland Clinic
Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, United
States] - EXPERT OPIN. INVEST. DRUGS 2003 12/11 (17911801) - summ in ENGL
96
Pharmacological therapies remain the primary strategy for treating patients with acute and chronic heart failure. Several novel
neurohormonal antagonists, inotropic agents, immune modulators,
and metabolic and replacement therapies are currently in development to meet the demands of an increasing number of patients with
heart failure. The success in drug development in this field will
require a better understanding of the effects of heart failure on drug
dosing, better integration of novel and existing drug therapies, the
development of more reliable surrogate markers to effectively tailor
medical therapy to individual needs and the ability to detect and
treat patients at risk before the onset of heart failure.
497. Experimental and clinical studies show that the probucol
derivative AGI-1067 prevents vascular growth - Doggrell S.A.
[S.A. Doggrell, Doggrell Biomedical Communications, 47 Caronia
Crescent, Lynfield, Auckland, New Zealand] - EXPERT OPIN. INVEST. DRUGS 2003 12/11 (1855-1859) - summ in ENGL
AGI-1067 is a derivative of probucol that is a promising new
development for the treatment of restenosis and possibly atherosclerosis. In monkeys fed a high-fat diet for 1 year, AGI-1067 prevented
the development of atherosclerosis. In these monkeys, AGI-1067
lowered plasma levels of low-density lipoprotein (LDL)-cholesterol
and, in contrast to probucol, was capable of increasing high-density lipoprotein (HDL)-cholesterol levels. Although AGI-1067 did
not have marked lipid-lowering effects in two transgenic mouse
models (the LDL-receptor-deficient and apolipoprotein-E-deficient
models) fed a high-fat chow, it decreased the atherosclerotic lesion
area in the aorta. In a mouse model of acute inflammation, the
mRNA for the pro-inflammatory vascular cell adhesion molecule1 and monocyte chemoattractant protein-1 was upregulated and
this was inhibited by AGI-1067. AGI-1067 inhibited the TNF-
induction of redox-sensitive inflammatory proteins, vascular cell
adhesion molecule-1, monocyte chemoattractant protein-1 and Eselectin, in cell culture. In addition, AGI-1067 is an antioxidant. In
the Canadian Antioxidant Restenosis Trial (CART-1) of AGI-1067
in percutaneous coronary interventions, AGI-1067 had no effect
on LDL-cholesterol but lowered HDL-cholesterol. At 6 months
follow up, the lumen area of the percutaneous coronary interventions segments was greater in patients treated with AGI-1067 than
in untreated patients. Restenosis rates were 37.5% in the placebo
group and 26% in the AGI-1067 group. The lumen area of reference
segments was reduced in the placebo group but increased with the
higher doses of AGI-1067. Unlike probucol, AGI-1067 did not alter
QTc interval.
498. Diazepam and melatonin effects upon circadian variation
of cultured murine myocardiocytes - Zhou B., Wang Z., Wan C. et
al. [Z. Wang, School of Basic Medical Sciences, Second University
Hospital, Sichuan University, Chengdu, Sichuan 610041, China]
- NEUROENDOCRINOL. LETT. 2003 24/SUPPL. 1 (216-222) summ in ENGL
We determined that melatonin and diazepam affected the persisting rhythm in contraction rates in cultured murine myocardiocytes.
The effect of different concentrations of melatonin (10-4 M, 10-6 M
and 10-8 M) and diazepam (10-4 M, 10-6 M and 10-8 M) was tested
at six different times of day 4h apart in continuous light allowing
a condition free-running from the alternation of light and darkness.
Circadian variations with graded concentrations of melatonin or
diazepam were observed by the cosinor fit of a 24h cosine function
and the rejection of the zero-amplitude (no-rhythm) assumption.
Melatonin and diazepam induced decreases in time structure or
chronome-adjusted averages (MESORs) and amplitudes (measures
of extent of predictable change), and generally delayed acrophases
(peak time) by several hours. At the highest melatonin concentration (10-4 M), the circadian rhythm could not be detected. In
combination, melatonin and diazepam also reduced the MESOR,
with phase delays similar to treatment with diazepam alone. The
free-running circadian rhythm in peripheral tissue, in the beating of
murine myocardiocytes in vitro, is under endogenous coordination,
affected by melatonin and diazepam. In doses that are physiological,
in the sense that effects occur within the usual range of variability,
melatonin and diazepam can affect characteristics of a persisting
circadian rhythm, with altered MESOR, amplitude and/or phase.
499. Individualized time series-based assessment of melatonin
effects on blood pressure: Model for pediatricians - Zaslavskaya
R.M., Makarova L.A., Shakarova A.N. et al. [R.M. Zaslavskaya,
Hospital No. 60, Moscow, Russian Federation] - NEUROENDOCRINOL. LETT. 2003 24/SUPPL. 1 (238-246) - summ in ENGL
A patient treated for essential hypertension monitored her blood
pressure and heart rate during an 11-day span. During the first
5 days of monitoring, one 24-hour span was perfectly acceptable;
the others showed circadian hyper-amplitude-tension, CHAT, either
systolic or diastolic or both. The case demonstrates, in the context of
assessing the blood pressure lowering effects of melatonin and losartan potassium, the indispensability of dealing with blood pressure
on an individualized time series basis at any age. We here quantify
and reinterpret melatonin effects on the chronome (time structure)of blood pressure. Whenever possible, in practice, effects upon a
variable’s chronome must be interpreted first on an individualized
basis before summarizing the results for the population.
500. In Vivo Cardioprotection by N-Acetylcysteine and Isosorbide 5-Mononitrate in a Rat Model of Ischemia-Reperfusion Calvillo L., Masson S., Salio M. et al. [Dr. R. Latini, Dept. of
Cardiovascular Research, Ist. Ric. Farmacologiche Mario Negri,
20157 Milano, Italy] - CARDIOVASC. DRUGS THER. 2003 17/3
Aims: We evaluated the effect of N-acetylcysteine (NAC, infused i.v.), isosorbide 5-mononitrate (IS5MN, by gavage), or their
combination on cardiac injury in an in vivo rat model of 30-min
ischemia followed by 24 hours or 7 days of reperfusion. Results:
When administered immediately prior to reperfusion with continuous infusion for 24 h, the combination of NAC +IS5MN reduced
infarct size (29 6 vs. 59 4% area-at-risk, p < 0.01) and the
infiltration of polymorphonuclear leukocytes (226 15 vs. 315
18 cells mm-2 of area-at-risk, p = 0.002) and monocytes/macrophages (118 8 vs. 194 22 cells mm -2 , p = 0.012), compared
to vehicle. NAC or IS5MN alone did not reduce infarct size at 24
hours of reperfusion. The same dose regimen of NAC and IS5MN
did not reduce infarct size with permanent ischemia for 24 hours
not followed by reperfusion. After 7 days of reperfusion (3 days of
treatment with NAC +IS5MN or vehicle and 4 days of wash-out),
infarct size was similar in the vehicle and NAC +IS5MN groups,
but LV end-diastolic pressure and diastolic LV chamber wall stress
were significantly lower in the animals treated with NAC +IS5MN
(5 1 mmHg and 62 7 dyne mm-2 , respectively) compared
to vehicle (9 1 mmHg and 123 18 dyne mm -2 , p < 0.05).
Conclusion: We demonstrate in a rat model of cardiac ischemiareperfusion treated with NAC and IS5MN, according to a regimen
that mimicked a clinical situation (drugs started at time of reperfusion), that the short-term benefit seen after 24 h of reperfusion (51%
reduction of infarct size) is maintained after one week, possibly
through modulation of the inflammatory response to cardiac injury.
501. Post-Ischemic Treatment with Dipyruvyl-Acetyl-Glycerol
Decreases Myocardial Infarct Size in the Pig - Stanley W.C.,
Kivilo K.M., Panchal A.R. et al. [H. Brunengraber, Department of
Nutrition, Case Western Reserve University, 11000 Cedar Rd, Cleveland, OH 44106-7139, United States] - CARDIOVASC. DRUGS
THER. 2003 17/3 (209-216) - summ in ENGL
The beneficial effects of pyruvate in organ reperfusion injury have
been documented, however the therapeutic use of pyruvate has been
hindered by the lack of an appropriate delivery method. Pyruvic
acid is unstable and high rates of sodium pyruvate infusion are toxic.
Dipyruvyl-acetyl-glycerol (DPAG) ester was developed as a novel
method for intravenous pyruvate delivery at a high rate without
sodium overload. We tested the ability of DPAG to reduce myocardial infarct size when administered after severe myocardial ischemia
in an anesthetized open-chest pig model of ischemia-reperfusion injury. Ischemia was induced by total occlusion of the distal 2/3 of
the left anterior descending coronary artery for one hour, followed
by two hours of reperfusion. Animals were either untreated (n = 7),
or treated with intravenous DPAG (8.0 mg/kg-1 min-1 , n = 8) during
the two hours of reperfusion. Infarct size was measured on blinded
samples using tetrazolium staining. The DPAG treated group had
elevated pyruvate levels (0.82 0.07 mM) and reduced infarct size
(20.1 4.2% of the volume at risk, compared to 30.8 4.6%
in the untreated animals (p < 0.05)), with no difference in blood
pressure or heart rate between groups. In conclusion, an intravenous
infusion of DPAG safely increases arterial pyruvate concentration
and reduces myocardial infarct size following myocardial ischemia.
502. Comparison between Ischaemic and Anisomycin-Induced
Preconditioning: Role of p38 MAPK - Lochner A., Genade S.,
Hattingh S. et al. [Dr. A. Lochner, Dept. of Med. Physiol. and
Biochem., Faculty of Health Science, P.O. Box 19063, Tygerberg
7505, South Africa] - CARDIOVASC. DRUGS THER. 2003 17/3
To further evaluate the significance of p38 MAPK as trigger or
mediator in ischaemic preconditioning, anisomycin and SB 203580
were used to manipulate its activation status. Special attention was
given to the concentration of the drugs and protocols used. The isolated perfused rat heart, subjected to either 25 min global ischaemia
or 35 min regional ischaemia, was used as experimental model. This
was preceded by anisomycin (2 or 5 M: 3 x 5 min; 5 M: 5 min
or 10 min; 5 M: 10 min + 10 min washout or 20 M: 20 min) or
SB 203580 (2 M: 3 x 5 min; before and during 3 x 5 min or 1 x
5 min ischaemic preconditioning; 10 min). Endpoints were functional recovery during reperfusion and infarct size. Anisomycin,
regardless of the protocol, reduced infarct size, but did not improve
functional recovery. In a number of experiments activation of JNK
by anisomycin was blocked by SP 600125 (10 M). SP 600125 had
no effect on the anisomycin-induced reduction in infarct size. SB
203580 when administered for 10 min before sustained ischaemia,
improved functional recovery and reduced infarct size. SB 203580
could not abolish the beneficial effects of a multicycle preconditioning protocol, but it significantly reduced the outcome of 1 x 5
min preconditioning. In all hearts improved functional recovery
and reduction in infarct size were associated with attenuation of
p38 MAPK activation during sustained ischaemia-reperfusion. The
results indicate that activation of p38 MAPK acts as a trigger of
preconditioning, while attenuation of its activation is a prerequisite
for improved recovery and a reduction in infarct size.
503. Effects of Olmesartan, an Angiotensin II Receptor Blocker,
on Mechanically-Modulated Genes in Cardiac Myocytes - Ohki
R., Yamamoto K., Ueno S. et al. [Dr. K. Yamamoto, Division of
Cardiovascular Medicine, Jichi Medical School, MinamikawachiMachi, Tochigi 329-0498, Japan] - CARDIOVASC. DRUGS THER.
2003 17/3 (231-236) - summ in ENGL
Background: Angiotensin II plays an important role in cardiac hypertrophy or remodeling. Angiotensin II receptor blockers
(ARB) are clinically useful for the treatment of hypertension and
heart failure. However, the molecular effects of ARB in the mechanically-stressed myocardium have not been completely defined.
We investigated the effects of ARB on mechanically-modulated
genes in cardiac myocytes. Methods: We used powerful DNA
microarray technology to study the effects of the ARB, CS-886
(olmesartan), on genes modulated in neonatal rat cardiac myocytes
using mechanical stimuli. Mechanical deformation was applied
to a thin and transparent membrane on which neonatal rat cardiac
myocytes were cultured in the presence or absence of RNH-6270,
an active metabolite of CS-886. Expression profiles of 8000 rat
genes using the Affymetrix GeneChip (Rat Genome U34A) were
investigated with mRNA obtained from the samples above. Results:
Nine genes induced under 4% mechanical strain were significantly
suppressed by RNH-6270 in rat cardiac myocytes: monoamine oxidase B, neuromedine B receptor, olfactory receptor, synaptotagmin
XI, retinol-binding protein, and 4 expressed sequence tags (ESTs). In contrast, 21 genes suppressed under mechanical strain were
significantly restored by RNH-6270: major acute phase alpha 1protein, Sp-1, Bcl-Xalpha, JAK2, 2 genes encoding detoxification,
few genes for receptor, structure, metabolism or ion channel, and
10 ESTs. Conclusions: As some of these genes may be involved
in promoting or modulating cardiac remodeling, these findings suggest that ARB may affect cardiovascular morbidity and mortality
partially via these molecular alterations.
504. Refractoriness and Conduction Interaction during Modulation of Non-Ischemic Ventricular Fibrillation by Flecainide Amitzur G., Shenkar N., Mueller M. et al. [Dr. G. Amitzur, Neufeld
Cardiac Research Institute, Sheba Medical Center, Tel Hashomer,
97
52621, Israel] - CARDIOVASC. DRUGS THER. 2003 17/3 (237247) - summ in ENGL
Purpose: To study refractoriness and conduction interaction during modulation of non-ischemic ventricular fibrillation (VF) by
flecainide. Methods: Isolated feline and rabbit hearts were used.
(a) In the feline hearts (n = 8), electrophysiological parameters were
measured before and after flecainide administration (0.6, 1.2 10-6
M). During pacing the parameters were: epicardial conduction time,
refractoriness and 1:1 pacing/response capture. During 8 min of
electrically-induced tachyarrhythmias they included heart rate and
normalized entropy reflecting the degree of organization. (b) In rabbit hearts (n = 4), three-dimensional mapping was performed before
and after flecainide administration (2 10-6 M). To follow changes
in organization, local RR-intervals and differences in activation time
between adjacent epicardial electrodes were measured immediately
and 80 sec after VF induction. Results: In feline hearts with flecainide, fibrillation was more difficult to induce, more frequently
terminated spontaneously and was slower and more organized; conduction time was markedly lengthened, and refractoriness less than
1:1 capture, was moderately prolonged. An inverse correlation was
observed between arrhythmia properties, rate and organization, and
changes in refractoriness and conduction time. In rabbit, the number
of wave fronts was reduced, RR-intervals were prolonged but at the
same time activation time differences between adjacent electrodes
were smaller following flecainide administration. Conclusions: It is
suggested that flecainide modulation of VF properties is associated
with conduction suppression and refractoriness prolongation, which
act in a synergistic, additive way.
505. Serum MCP-1 and VEGF Levels are not Affected by Inhibition of the Renin-Angiotensin System in Patients with Acute
Myocardial Infarction - Murakami Y., Kurosaki K., Matsui K.
et al. [Dr. U. Ikeda, Department of Organ Regeneration, Shinshu
Univ. Grad. Sch. of Medicine, 3-1-1 Asahi, Matsumoto 390-8621,
Japan] - CARDIOVASC. DRUGS THER. 2003 17/3 (249-255) summ in ENGL
Monocyte chemoattractant protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) stimulate angiogenesis in ischemic
tissues, and both of their expression are stimulated by angiotensin
II. We measured the serum concentrations of MCP-1 and VEGF in
patients with acute myocardial infarction (AMI) and investigated
the effects of an early administration of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 receptor blocker
(ARB) on their levels. Thirty-six patients with AMI were divided
randomly into 3 therapeutic groups; the ACEI perindopril, the ARB
candesartan and control (without perindopril and candesartan), and
the drugs were administered within 36 hours after the onset of
AMI. Peripheral blood mononuclear cells (PBMC) obtained from
the patients were incubated for 24 hours. The levels of MCP-1 and
VEGF in the serum and the supernatant of PBMC were measured
by ELISA. The serum MCP-1 and VEGF levels in AMI patients
at the time of admission were not significantly different from those
in healthy control subjects, but both MCP-1 and VEGF levels in
the patients were increased significantly after 7 days. There was no
significant difference in the serum MCP-1 and VEGF levels among
the 3 therapeutic groups. The production of MCP-1 and VEGF by
PBMC was also increased in AMI patients compared with healthy
control subjects, and there was also no difference in their production
among the 3 therapeutic groups. In conclusion, circulating MCP-1
and VEGF levels and their production by PBMC are elevated during
the course of AMI, and early administration of ACEI and ARB does
not affect their levels.
506. Calphostin C as a rapid and strong inducer of apoptosis
in human coronary artery smooth muscle cells - Krueger K.D.,
Hunter III W.J., DelCore M.G. and Agrawal D.K. [D.K. Agrawal,
Creighton Univ. School of Medicine, CRISS I, 2500 California
Plaza, Omaha, NE 68178, United States] - INT. IMMUNOPHARMACOL. 2003 3/13-14 (1751-1759) - summ in ENGL
Vascular smooth muscle cells (VSMCs) play a major role in the
development of atherosclerotic and restenotic lesions. The apoptotic
process has been implicated in the development of this pathology. In
this study, we characterized the induction of apoptosis by calphostin C (CC), a protein kinase C (PKC) inhibitor, in primary human
coronary artery smooth muscle cells in the presence and absence of
98
insulin-like growth factor-I (IGF-I). Additionally, we investigated
the signal transduction pathways important for IGF-I mediated protection. Calphostin C induced apoptosis, as measured by terminal
deoxy-UTP nick-end labeling (TUNEL), in a time- and dose-dependent manner, approaching 20% within 6 h of 50 nM calphostin
C treatment. The amount of apoptosis increased to 44.588.08%,
47.541.66% and 78.111.9% after 8, 10 and 12 h of treatment,
respectively (p<0.01 vs. control). IGF-I offered significant protection (p<0.05) at 8 and 10 h of treatment (60.6% and 52.5%
protection, respectively). DNA ELISA confirmed the apoptotic
effect of calphostin C and the protective effect of IGF-I. After 6
h of calphostin C treatment, DNA ELISA revealed 11.201.53
fold greater apoptosis as compared to baseline values. IGF-I treatment offered a level of protection of 46.6% as measured by DNA
ELISA (p=0.06). Apoptosis was further qualitatively confirmed
by time-lapse video microscopy and scanning electron microscopy.
Interestingly, inhibitors of phosphatidylinositol-3-kinase (PI-3-K),
p38 and extracellular regulated kinase (ERK) activation significantly (p<0.05 vs. calphostin C only treatment) increased apoptosis
when used in conjunction with calphostin C. Inhibitors of phospatidylinositol-3-kinase and ERK activation reversed IGF-I protection.
However, the p38 inhibitor SB203580 failed to reverse IGF-I protection. This study characterized an apoptotic system for human
coronary artery smooth muscle cells offering a rapid and strong
induction of programmed cell death (PCD) that remains responsive
to the survival effects of IGF-I. Studies utilizing this system may
prove useful in understanding the apoptotic response of VSMCs in
the arterial wall. © 2003 Elsevier B.V. All rights reserved.
507. Homocysteine and Essential Hypertension - Rodrigo R.,
Passalacqua W., Araya J. et al. [Dr. R. Rodrigo, Laboratorio de
Fisiopatologia Renal, Facultad de Medicina, Universidad de Chile,
Casilla 70058, Santiago 7, Chile] - J. CLIN. PHARMACOL. 2003
43/12 (1299-1306) - summ in ENGL
The authors examine the available clinical and experimental data
supporting the view that homocysteine, an alternative risk factor
of cardiovascular disease, may play a role in the pathogenesis of
essential hypertension. The mechanism of this disease has not
been elucidated, but it may be related to impairment of vascular
endothelial and smooth muscle cell function. Therefore, the occurrence of endothelial dysfunction could contribute to alterations of
the endothelium-dependent vasomotor regulation. Elevated homocysteinemia diminishes the vasodilation by nitric oxide, increases
oxidative stress, stimulates the proliferation of vascular smooth
muscle cells, and alters the elastic properties of the vascular wall.
Thus, homocysteine contributes to elevate the blood pressure. Also
it is known that elevated plasma levels of homocysteine could lead
to oxidant injury to the endothelium. The correction of elevated homocysteinemia by administration of vitamins B12 and B6 plus folic
acid, could be a useful adjuvant therapy of hypertension. However,
further controlled randomized trials are necessary to establish the
efficacy and tolerability of these potentially therapeutic agents.
508. Differential vasoconstrictions induced by angiotensin II:
Role of AT1 and AT2 receptors in isolated C57BL/6J mouse
blood vessels - Zhou Y., Dirksen W.P., Babu G.J. and Periasamy
M. [M. Periasamy, Dept. of Physiology and Cell Biology, Ohio State
Univ. Coll. of Med., 304 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, United States] - AM. J. PHYSIOL. HEART CIRC.
PHYSIOL. 2003 285/6 54-6 (H2797-H2803) - summ in ENGL
Genetically altered mice are increasingly used as experimental
models. However, ANG II responses in mouse blood vessels have
not been well defined. Therefore, the aim of this study was to
determine the role of ANG II in regulating major blood vessels in
C57/BL6J mice with isometric force measurements. Our results
showed that in mouse abdominal aorta ANG II induced a concentration-dependent contraction (EC50 4.6 nM) with a maximum
contraction of 75.1 4.9% at 100 nM compared with that of 60
mM K + . Similarly, femoral artery also exhibited a contractile
response of 76.0 3.4% to the maximum concentration of ANG
II (100 nM). In contrast, ANG II (100 nM)-induced contraction
was significantly less in carotid artery (24.5 6.6%) and only
minimal (3.5 0.31%) in thoracic aorta. The nitric oxide synthase
inhibitor Nω -nitro-L-arginine methyl ester and the AT2 antagonist
PD-123319 failed to enhance ANG II-induced contractions. However, an AT1 antagonist, losartan (10 M), completely inhibited
ANG II (100 nM) response in abdominal aorta and carotid artery.
An AT1 agonist, [Sar1 ]-ANG II (100 nM), behaved similarly to
ANG II (100 nM) in abdominal aorta and carotid artery. RT-PCR
analyses showed that mouse thoracic aorta has a significantly lower
AT1 mRNA level than abdominal aorta. These results demonstrate
that major mouse vessels exhibit differential contractions to ANG
II, possibly because of varied AT1 receptor levels.
509. Negative functional effects of cyclic GMP are altered by
cyclic AMP phosphodiesterases in rabbit cardiac myocytes Weiss H.R., Lazar M.J., Punjabi K. et al. [H.R. Weiss, Dept. of
Physiology and Biophysics, Univ. of Med. and Dent. of NJ, Robert
Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ
08854-5635, United States] - EUR. J. PHARMACOL. 2003 481/1
In this study, we tested the hypothesis that the negative functional effects of cyclic GMP on cardiac myocytes would be affected
by the actions of cyclic GMP on cyclic AMP phosphodiesterases.
Ventricular myocytes from eight rabbits were used to determine
the functional and cyclic AMP changes caused by 10-7 , 10-6 ,
10-5 M 8-Bromo-cGMP alone and after the administration of 10-6
M milrinone (cyclic GMP-inhibited cyclic AMP phosphodiesterase inhibitor) or 10-6 M erythro-9-(2-Hydroxy-3-3-nonyl)adenine
(EHNA, cyclic GMP-stimulated cyclic AMP phosphodiesterase inhibitor). 8-Br-cGMP dose-dependently reduced %shortening by
354% of baseline at 10-5 M. This effect was significantly blunted
by EHNA at all doses. The maximum rate of shortening was reduced
by 313% by 10-5 M 8-Br-cGMP. This effect of 8-Br-cGMP was
significantly enhanced (424%) in the milrinone group. A similar pattern was observed in the maximum rate of relaxation data.
Cyclic AMP levels were significantly increased from a baseline
level of 4.00.8 pmol/10 5 myocytes by milrinone (+60%), EHNA
(+61%) and 8-Br-cGMP (+47%). The combination of EHNA plus
8-Br-cGMP increased cyclic AMP levels significantly more that
the combination of milrinone plus 8-Br-cGMP. Exogenous cyclic
GMP reduces myocyte function, while raising cyclic AMP possibly through cyclic GMP-inhibited cyclic AMP phosphodiesterase
effects. Blocking cyclic GMP-inhibited cyclic AMP phosphodiesterase enhances the functional effects cyclic GMP, while blocking
cyclic GMP-stimulated cyclic AMP phosphodiesterase reduced
these effects. The study demonstrated a functional interaction
between cyclic GMP and cyclic AMP related to the cyclic GMP
affected cyclic AMP phosphodiesterases. © 2003 Elsevier B.V. All
rights reserved.
510. Carvedilol blockade of rat myocardial 1 -adrenoceptors
- Qvigstad E., Osnes J.-B., Sandnes D. et al. [E. Qvigstad, Department of Pharmacology, University of Oslo, P.O. Box 1057 Blindern,
N-0316 Oslo, Norway] - EUR. J. PHARMACOL. 2003 481/1 (8389) - summ in ENGL
Carvedilol is a combined 1 - and -adrenoceptor antagonist.
The ability of carvedilol to antagonize functional effects mediated
through myocardial 1 -adrenoceptors has never been investigated.
We tested the ability of carvedilol to antagonize the inotropic effect
mediated by myocardial 1 -adrenoceptors compared to the antagonism of -adrenoceptors. Papillary muscles from rat heart left
ventricle were mounted in an organ bath and concentration-response
experiments for the inotropic effects of separate 1 - and -adrenoceptor stimulation were performed in the absence and presence of
carvedilol. Carvedilol antagonized myocardial 1 -adrenoceptors
with an inhibition constant (Ki ) of 11.03.0 nmol/l and the functional experiments were supported by radioligand-binding studies.
Corresponding functional studies on the response to -adrenoceptor stimulation revealed a Ki of 1.20.35 nmol/l. Thus, carvedilol
antagonizes the myocardial 1 -adrenoceptors with a 9-fold lower
potency than the -adrenoceptors. Antagonism of myocardial 1 adrenoceptor evoked effects may contribute to clinical effects of
carvedilol. © 2003 Elsevier B.V. All rights reserved.
511. Tempol, an antioxidant, restores endothelium-derived
hyperpolarizing factor-mediated vasodilation during hypertension - Adeagbo A.S.O., Joshua I.G., Falkner C. and Matheson
P.J. [A.S.O. Adeagbo, Dept. of Physiology and Biophysics, Health
Sciences Center, University of Louisville, Louisville, KY 40292,
United States] - EUR. J. PHARMACOL. 2003 481/1 (91-100) summ in ENGL
Acetylcholine releases a non-prostanoid endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide from physiological
salt solution perfused rat mesenteric arteries. This study reports an
impairment in EDHF-mediated vasodilation in deoxycorticosterone
acetate (DOCA)-salt hypertensive versus control normotensive rats.
Nitric oxide-mediated vasodilation to acetylcholine was not altered
in the animals. We hypothesize that free radical species generated
as by-products of arachidonic acid metabolism contribute to impaired EDHF-mediated dilation in DOCA-salt hypertension. With
or without reduced nicotinamide adenine dinucleotide phosphate
(NADPH) as co-factor, arterial microsomes generate free radical
species upon incubation with arachidonic acid. The production of
free radicals was significantly higher in DOCA-salt versus control
rat microsomes, and was totally eliminated by addition of cyclooxygenase-2 inhibitors NS-398 or celecoxib at 30 M. Treatment
of DOCA-salt rats with tempol (an antioxidant; 15 mg/kg, i.p.,
21 days) alleviates hypertension; improves acetylcholine- induced
EDHF-mediated vasodilation in DOCA-salt rats, and decreases
arachidonic acid-driven microsomal free radical production. Serum
level of 8-isoprostanes is elevated in DOCA-salt hypertension versus control or sham-salt rats, and the increase was reversed by
tempol treatment. These results show that EDHF-mediated dilation
of rat mesenteric arteries is impaired in DOCA-salt induced hypertension. Our data also suggest that cyclooxygenase-2 mediates
free radical production, and that free radicals modulate the EDHFmediated vascular response in DOCA-salt induced hypertension. ©
512. Effect of antiproliferative agents on vascular function in
normal and in vitro balloon-injured porcine coronary arteries
- Kennedy S., Wadsworth R.M. and Wainwright C.L. [S. Kennedy,
Dept. of Physiology and Pharmacology, Strathclyde Inst. of Biol.
Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4
0NR, United Kingdom] - EUR. J. PHARMACOL. 2003 481/1 (101107) - summ in ENGL
Local infusion of antiproliferative agents following coronary
balloon angioplasty is used in vivo.
This study examined the effects of the antiproliferative agents paclitaxel (5- ,
20-Epoxy-1,2-,4,7- , 10- ,13--Hexahydroxy-Tax-11-en-9-one
4,10-Diacetate 2 Benzoate 13-Ester with (2R,3S)-N-Benzoyl-3Phenylisoserine; 10 and 50 M), farnesyl protein transferase
inhibitor III (FPT III, (E,E)-2-[2-Oxo-2-[(3,7,11-trimethyl2,6,10-dodecatrienyl) oxy] amino] ethyl] phosphonic acid,
(2,2-dimethyl-1- oxopropoxy) methyl ester, sodium); 10 and 25
M), perillyl alcohol (4-isopropenyl-cyclohexenecarbinol; 1 and
2 mM) and Van 10/4 (Decahydro-1,1,4,7-tetramethyl-1H-cycloprop[e]azulen-4-o-[2-(3-methylpent-2- enoyl)-fucopyranoside]; 10
and 25 M) on normal and in vitro balloon-injured porcine coronary
arteries. Short-term (30 min) incubation had no effect on contraction
or relaxation. Overnight incubation with 25 M Van 10/4-attenuated contraction while perillyl alcohol abolished contractility
completely. Endothelium-dependent relaxation was significantly
attenuated by the higher concentration of paclitaxel, FPT III and
Van 10/4. Stretch injury significantly enhanced sensitivity to 3morpholinosydnonimine (SIN-1) while attenuating relaxation to
calcimycin. Drug incubation (15 min) had no effect on these responses. In conclusion, paclitaxel, FPT III and Van 10/4 have no
detrimental effects on vascular function after short-term administration to normal or stretch-injured arteries. © 2003 Elsevier B.V.
513. Vascular protective effects of dihydropyridine calcium antagonists. Involvement of endothelial nitric oxide - Berkels R.,
Taubert D., Rosenkranz A. and Rösen R. [Dr. R. Berkels, Institut für
Pharmakologie, Klin. der Univ. zu Köln, Gleueler Strasse 24, DE50931 Köln, Germany] - PHARMACOLOGY 2003 69/4 (171-176) summ in ENGL
Dihydropyridine calcium antagonists play an important role in
the treatment of hypertension and angina pectoris. They lower
blood pressure by a well-characterized mechanism of blocking
L-type calcium channels in smooth muscle cells. Additionally,
there is growing evidence that dihydropyridines also modulate
99
endothelial functions by other mechanisms, since macrovascular
endothelial cells do not express L-type calcium channels. A number
of studies have demonstrated that dihydropyridine calcium antagonists enhance bioavailability of endothelial nitric oxide (NO).
Endothelium-derived NO plays a pivotal role in the regulation of
vasorelaxation, leukocyte adhesion and platelet aggregation and an
impaired NO release is associated with the genesis and progression of atherosclerotic diseases. This review summarizes results
from experimental findings that dihydropyridine calcium antagonists increase endothelial NO formation as well as studies which
demonstrate these effects in vivo both in animals and humans.
Moreover, the influence of dihydropyridine calcium antagonists
on the progression of atherosclerosis is discussed. These pleiotropic effects of dihydropyridine calcium antagonists may underlie
or contribute to antiatherosclerotic effects of this substance class.
Copyright © 2003 S. Karger AG, Basel.
See also: 540, 560, 561, 573, 705, 710, 730.
5.4. Hemopoietic and lymphoreticular systems
514. Platelets, atherosclerosis and the endothelium: New therapeutic targets?
- Tan K.T. and Lip G.Y.H. [G.Y.H. Lip,
Haemostasis Thrombosis/Vasc. Biol. U, University Department
of Medicine, City Hospital, Birmingham B18 7QH, United Kingdom] - EXPERT OPIN. INVEST. DRUGS 2003 12/11 (1765-1776) summ in ENGL
One of the major causes of morbidity and mortality in the developed world is atherosclerosis. Recent research has suggested that
the interaction of platelets with the endothelium is important in both
the progression of atherosclerosis and the development of the acute
complications of the disease. Both of these cells secrete various
signalling molecules and express adhesion molecules, which can
influence the development of pathological states. Certainly, there
may be a vicious cycle in which platelet activation promotes atherosclerosis; a process involving inflammation and the activation of
many other cell types (for example, leukocytes and smooth muscle
cells), which causes further platelet activation. Therefore, intense
effort has been made to develop therapeutic agents that can modulate
the function of these cells, with the ultimate aim to retard (or even
reverse) the progression of atheroma growth.
515. Thrombopoietin stimulates ex vivo expansion of mature
neutrophils in the early stages of differentiation - Terada Y.,
Hato F., Sakamoto C. et al. [M. Hino, Clin. Hematol./Clinical
Diagnostics, Graduate School of Medicine, Osaka City University,
1-4-3 Asahi-machi, Abeno-ku, 545-8585 Osaka, Japan] - ANN.
HEMATOL. 2003 82/11 (671-676) - summ in ENGL
We examined the effects of thrombopoietin (TPO) in combination
with stem cell factor (SCF), interleukin-3 (IL-3), and granulocyte
colony-stimulating factor (G-CSF) on the proliferation and differentiation of human neutrophils. Purified CD34+ hematopoietic
progenitor cells were cultivated with SCF, IL-3, and G-CSF for
7 days (early phase), and thereafter nonadherent cells were further
cultivated for 9 days with G-CSF alone (late phase). A large number
of highly selected neutrophils (>95%) was obtained on day 16. We
compared the expansion capacity in the presence or absence of TPO
in each culture phase. The significantly larger number of neutrophils
was obtained in the presence of TPO in the early culture phase. The
number of expanded cells plateaued at day 16. Ultimately, a 550fold increase in the number of neutrophils was achieved. These
neutrophils gained the ability to respond effectively with chemotaxis and superoxide release, and were appropriately primed by
G-CSF, granulocyte-macrophage colony-stimulating factor, tumor
necrosis factor-, and IL-1 for enhanced release Of O-2 . The
responsiveness of these cells was identical to that of peripheral
blood neutrophils. However, TPO did not accelerate the maturation
of neutrophils supported by G-CSF in the late phase of culture.
Furthermore, priming effects and triggering effects of TPO on the
production of superoxide metabolites from peripheral blood neutrophils were not observed. These results suggest that TPO regulates
the proliferation and differentiation of neutrophils in the early stages,
but not the late stages, of differentiation.
100
See also: 545, 546, 547, 556, 618, 619, 623, 631, 635, 643, 644,
727.
5.5. Respiratory system
516. The Bronchodilatory Effects of Loratadine, Terbutaline,
and Both Together Versus Placebo in Childhood Asthma - Orhan
F. and Baki A. [Dr. F. Orhan, K.T.U. tip Fakultesi, Cocuk Allerji
BD, TR-61080 Trabzon, Turkey] - J. INVEST. ALLERGOL. CLIN.
IMMUNOL. 2003 13/3 (189-192) - summ in ENGL
Aim: To assess the bronchodilatory effect of loratadine in children
with mild-to-moderate asthma and to determine whether loratadine
interacts with terbutaline. Methods: The effect on pulmonary functions of a 10 mg oral dose of loratadine, with and without inhaled
terbutaline powder (0.5 mg), was determined in 13 patients with
a mean (SE) age of 10.63 (0.77) years (range from eight to 17
years) at 11 time points during 8 h in a randomized, double-blind,
placebo controlled, crossover study. Forced expiratory volume in
1 s (FEV1 ) was the primary measure of efficacy. Results: Although
loratadine alone produced an increase in FEV1 relative to baseline, this was not statistically significant (p > 0.05). Terbutaline
with, and without loratadine, significantly increased FEV1 from 1
to 5 h according to baseline (p < 0.004). When compared with
the placebo, loratadine significantly increased FEV1 from 150 min
to 8 h (p < 0.05). Also, terbutaline alone, or in combination with
loratadine, significantly increased FEV1 from 30 min to 7h (p <
0.004, from 30 min to 5 h; p < 0.05, between 6-7 h). Although
the mean increase in FEV1 , with terbutaline + loratadine in combination, was greater than with terbutaline alone, the difference was
not significant (p > 0.05). Conclusion: Loratadine has a mild
bronchodilatory effect in the study period and does not interfere
with the bronchodilatory effect of terbutaline in childhood asthma.
517. State of the art in 2-agonist therapy: A safety review
of long-acting agents - Rabe K.F. [Prof. K.F. Rabe, University
Medical Centre Leiden, Department of Pulmonology, Albinusdreef
2, 2333 ZA Leiden, Netherlands] - INT. J. CLIN. PRACT. 2003 57/8
Despite concerns in the 1970s and 1980s about the safety of shortacting 2 -agonists, it is now generally accepted that these agents,
used at appropriate doses, provide safe and effective treatment for
asthma symptoms. After their introduction, 2 -agonists with a long
duration of action - formoterol and salmeterol - became widely used
as maintenance therapy with inhaled corticosteroids (ICS). Both 2 agonists are well tolerated in long-term studies, with no reduction
in lung function observed over time, indicating a lack of clinically relevant tolerance development in patients with asthma and
COPD. High-dose studies have indicated that formoterol produces
systemic effects of similar duration to, but less pronounced than,
salbutamol and terbutaline. Formoterol produces long-lasting bronchoprotection against exercise-induced bronchoconstriction, even
in patients receiving regular maintenance therapy; its fast onset of
effect (similar to salbutamol) allows formoterol to be used as a
reliever. Clinically the safety of formoterol and salmeterol has been
demonstrated in several studies, both with ICS and alone.
518. Insulin induces a hypercontractile airway smooth muscle
phenotype - Gosens R., Nelemans S.A., Hiemstra M. et al. [R.
Gosens, Department of Molecular Pharmacology, University Centre
for Pharmacy, A. Deusinglaan 1, 9713 AV Groningen, Netherlands]
- EUR. J. PHARMACOL. 2003 481/1 (125-131) - summ in ENGL
This study aims to investigate the effects of insulin on bovine
tracheal smooth muscle phenotype in vitro. Contractility of muscle
strips and DNA-synthesis ([3 H]thymidine incorporation) of isolated
cells were used as parameters for smooth muscle phenotyping. Insulin (1 M) was mitogenic for bovine tracheal smooth muscle and
potentiated DNA-synthesis induced by other growth factors. In
contrast, after pretreatment of unpassaged bovine tracheal smooth
muscle cells in culture, the mitogenic response induced by growth
factors was strongly diminished, with no difference in the basal incorporation. Pretreatment of bovine tracheal smooth muscle strips
in organ culture with insulin increased maximal contraction to methacholine and KCl. These results show that insulin acutely augments
DNA-synthesis in the presence of other growth factors. In contrast,
insulin pretreatment induces a hypercontractile phenotype with a
decreased mitogenic capacity. This mechanism may be involved
in the putative negative association between asthma and type I diabetes. In addition, these findings may have implications for the use
of aerosolized insulin in diabetes mellitus. © 2003 Elsevier B.V.
Salvia miltiorrhiza administration led to a dose-dependent increase
in hepatic glutathione levels and a decrease in peroxidation products. Additionally, it reduced the mRNA expression of markers
for hepatic fibrogenesis. In conclusion, long-term administration
of Salvia miltiorrhiza in rats ameliorated the CCl4 -induced hepatic
injury that probably related to a reduced oxidant stress and degree
of hepatic fibrosis.
See also: 559, 669.
5.6. Digestive system
519. Contribution of capsaicin-sensitive afferent nerves to rapid
recovery from ethanol-induced gastric epithelial damage in rats
- Sobue M., Joh T., Oshima T. et al. [Dr. T. Joh, First Dept.
of Internal Medicine, Nagoya City Univ. Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan] - J.
GASTROENTEROL. HEPATOL. 2003 18/10 (1188-1195) - summ
in ENGL
Background and Aim: It is well known that capsaicin-sensitive
nerve signaling acts as a protective factor against various ulcerogens. However, the contribution of topical capsaicin-sensitive
nerves within the stomach to rapid restitution has not been fully investigated. The present study was therefore conducted focusing on
recovery from gastric mucosal damage induced by ethanol in vivo.
Methods: Male Sprague-Dawley rats were fasted and anesthetized.
51 Cr-EDTA was administered intravenously and gastric mucosal
integrity was continuously monitored by measuring the blood to
lumen 51 Cr-EDTA clearance. Capsaicin or vehicle was irrigated
before, together with or after the perfusion of 20% ethanol, followed by perfusion with saline. In another experiment, ruthenium
red, a capsaicin-sensitive cation antagonist, was given before the
ethanol-capsaicin perfusion. Furthermore, this study was verified
using lafutidine, a histamine H2 -receptor antagonist, which has a
gastric mucosal protective action through the capsaicin-sensitive
afferent nerves. Results: When capsaicin was administered before
ethanol treatment, mucosal damage was significantly reduced and
recovery was significantly rapid compared to the control. When
capsaicin (160 M) and ethanol were administered simultaneously,
the mucosal damage was exacerbated but recovery was nevertheless
more rapid than the control group. With a lower dose of capsaicin
(80 M), mucosal damage was not exacerbated and recovery was
enhanced. When capsaicin or lafutidine was administered after the
induction of ethanol injury no change was detected regarding the
damage. However, recovery was significantly accelerated. Ruthenium red reversed the action of post-treatment with capsaicin on
restitution. Conclusions: These results indicate that luminal administration of capsaicin exerts protection against and accelerates
restitution from gastric damage in the very early phase after ethanol
injury. This action is probably due to activation of topical capsaicinsensitive afferent nerves in the rat. © 2003 Blackwell Publishing
Asia Pty Ltd.
520. Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in rats - Lee
T.-Y., Wang G.-J., Chiu J.-H. and Lin H.-C. [H.-C. Lin, Division of
Gastroenterology, Department of Medicine, Taipei Veterans General
Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan]
- J. PHARM. PHARMACOL. 2003 55/11 (1561-1568) - summ in
ENGL
Carbon tetrachloride (CCl4 ) is metabolized by cytochrome P450
to form a reactive trichloromethyl radical that triggers a chain of
lipid peroxidation. These changes lead to cell injury, and chronic
liver injury leads to excessive deposition of collagen in liver, resulting in liver fibrosis. The aim of this study was to evaluate
the effects of long-term Salvia miltiorrhiza administration in CCl4 induced hepatic injury in rats. Salvia miltiorrhiza (10, 25 or 50 mg
kg-1 twice a day) was given for 9 weeks, beginning at the same
time as the injections of CCl4 . Rats receiving CCl4 alone showed
a decreased hepatic glutathione level and an increased glutathioneS-transferase content. The hepatic thiobarbituratic acid-reactive
substance levels were increased. CCl4 also caused a prominent
collagen deposition in liver histology that was further supported
by the increased hepatic mRNA expression of transforming growth
factor- 1, tissue inhibitor of metallproteinase-1 and procollagen I.
521. Casein Enhances Stability of Peptides in Intestinal Lumen:
Role of Digested Products of Casein - Ohtani S., Ogawara K.-I.,
Higaki K. and Kimura T. [T. Kimura, Department of Pharmaceutics,
Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1
Tsushima-naka, Okayama 700-8530, Japan] - PHARM. RES. 2003
20/11 (1746-1751) - summ in ENGL
Purpose. To investigate the inhibitory activity of casein on proteases in detail, the effect of digested products of casein itself
on trypsin and chymotrypsin in rat small intestine was examined.
Methods. Male Sprague-Dawley rats weighing 200-300 g were
used as the animal model. The luminal content of the jejunum was
prepared, and the enzymatic activities of trypsin and chymotrypsin
were determined using a specific substrate for each protease. Then,
the effect of enzymatic digested products of casein on them was
examined. Results. The inhibitory activity of trypsin-digested
casein against trypsin decreased as its digestion proceeded, but its
inhibitory activity against chymotrypsin came to be more effective.
On the other hand, the inhibitory activity of chymotrypsin-digested
casein against chymotrypsin decreased with the degree of digestion, but no change in the inhibitory activity against trypsin was
observed. Even the completely digested products of casein with
trypsin or chymotrypsin showed inhibitory activities against the two
proteases. Conclusions. It was suggested that not only the intact
casein but also the products digested with trypsin or chymotrypsin
contribute to the inhibitory effect of casein on the proteases in the
intestinal lumen.
See also: 549, 550, 555, 558, 570, 571, 578, 591, 597, 600, 603,
616, 648, 653, 709, 734, 739, 746.
5.7. Urinary system
522. Determination of the pharmacokinetics of cerivastatin
when administered in combination with sirolimus and cyclosporin A in patients with kidney transplant, and review of
the relevant literature - Renders L., Czock D., Schöcklmann
H. and Kunzendorf U. [Dr. L. Renders, Klinik für Nephrologie,
Universitätsklinikum Kiel, Schittenhelmstraße 12, D-24105 Kiel,
Germany] - INT. J. CLIN. PHARMACOL. THER. 2003 41/11 (499503) - summ in ENGL
Objective: Therapy of elevated cholesterol serum concentrations
is often necessary in patients with kidney transplants. However, the
pharmacokinetics of HMG-CoA reductase inhibitors when administered in combination with sirolimus and cyclosporin A (CsA) have
not been determined. The aim of this study was to investigate the
pharmacokinetics of cerivastatin when administered in combination
with sirolimus in patients with kidney transplants, and to review the
literature with regard to the differences in pharmacological behavior between sirolimus, CsA and tacrolimus. Methods: Patients (n =
7) with a stable and functioning kidney transplant and elevated LDL
cholesterol serum concentrations were included in the study. After
an observation period of 3 months, and whilst receiving sirolimus
and CsA, cerivastatin (0.2 mg daily) was administered for a period
of 3 months. Pharmacokinetic parameters were calculated on Day
1 and 3 months after initiation of cerivastatin therapy. Routine
laboratory parameters and clinical adverse events were monitored
throughout the study period. Results: Single-dose cerivastatin AUC
was 2 to 3-fold higher in comparison to published values obtained
in healthy subjects. The accumulation ratio of cerivastatin (after 3
months/Day 1) was 1.6. Sirolimus and CsA trough levels, and the
sirolimus AUC did not differ after single dose and multiple doses of
cerivastatin. Conclusions: The combination therapy of cerivastatin
with sirolimus and CsA leads to a significant increase in cerivastatin
exposure. Additional drug monitoring of sirolimus and CsA is not
necessary.
101
523. Dutasteride: A new 5-alpha reductase inhibitor for men
with lower urinary tract symptoms secondary to benign prostatic hyperplasia - Brown C.T. and Nuttall M.C. [C.T. Brown,
Clinical Effectiveness Unit, Royal College of Surgeons of England,
35/43 Lincolns Inn Fields, London WC2A 3PE, United Kingdom]
- INT. J. CLIN. PRACT. 2003 57/8 (705-709) - summ in ENGL
Dutasteride is a new 5-alpha reductase inhibitor for the treatment
of men with moderate to severe lower urinary tract symptoms secondary to benign prostatic hyperplasia. It has been available in
the UK since March 2003. It is a competitive inhibitor of both
type I and type II isoforms of the 5-alpha reductase enzyme that
converts testosterone to the more potent androgen, dihydrotestosterone. Randomised controlled studies have shown dutasteride to
be statistically more effective than placebo in reducing lower urinary tract symptoms and increasing maximum urinary flow rates.
This is a consequence of a reduction in serum dihydrotestosterone
and hormone dependent prostate volume. Dutasteride has also been
shown to decrease the absolute risk of urinary retention and the need
for prostate-related surgery when compared to placebo taken over
a 24-month period. In this review article we discuss the pharmacology and clinical effects of dutasteride, a new dual-acting 5-alpha
reductase inhibitor.
524. Renal epithelial gene expression profile and bismuth-induced resistance against cisplatin nephrotoxicity - Leussink
B.T., Baelde H.J., Broekhuizen-van den Berg T.M. et al. [G.B.
van der Voet, Toxicology Laboratory, Leiden University Medical
Center, PO Box 9600, 2300 RC Leiden, Netherlands] - HUM. EXP.
TOXICOL. 2003 22/10 (535-540) - summ in ENGL
Nephrotoxicity is the most important dose-limiting factor in cisplatin based anti-neoplastic treatment. Pretreatment with bismuth
salts, used as pharmaceuticals to treat gastric disorders, has been
demonstrated to reduce cisplatin-induced renal cell death in clinical
settings and during in vivo and in vitro animal experiments. To
investigate the genomic basis of this renoprotective effect, we exposed NRK-52E cells, a cell line of rat proximal tubular epithelial
origin, to 33 M Bi3+ for 12 hours, which made them resistant
to cisplatin-induced apoptosis. Differentially expressed genes in
treated and untreated NRK-52E cells were detected by subtraction
PCR and microarray techniques. Genes found to be down regulated
(0.17-0.31-times) were cytochrome c oxidase subunit I, BAR (an
apoptosis regulator), heat-shock protein 70-like protein, and three
proteins belonging to the translation machinery (ribosomal proteins
S7 and L17, and S1, a member of the elongation factor 1-alpha
family). The only up-regulated gene was glutathione S-transferase
subunit 3A (1.89-times). Guided by the expression levels of these
genes, it may be possible to improve renoprotective treatments during anti-neoplastic therapies.
525. Pharmacological effects of darifenacin on human isolated
urinary bladder - Miyamae K., Yoshida M., Murakami S. et
al. [M. Yoshida, Department of Urology, Kumamoto University,
School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan] PHARMACOLOGY 2003 69/4 (205-211) - summ in ENGL
Darifenacin [(S)-2-f1-[2-(2,3-dihydrobenzfuran-5-yl)ethyl]-3pyrrolodinylg- 2,2-diphenylacetamide] is a novel antimuscarinic
drug currently undergoing phase III trials for the treatment of overactive bladder. We investigated the functional antagonist potency of
darifenacin, and the antimuscarinic drugs propiverine, oxybutynin
and atropine, on human detrusor smooth muscle. Urinary bladder
specimens were obtained from 20 patients who underwent total
cystectomy for malignant bladder tumor. Using an organ-bath technique, the effects of the compounds on carbachol-, KCl-, CaCl2 - or
electrical field stimulation (EFS)-induced contractions of the tissues
were evaluated. The order of antagonist potency (pA2 values) at
the muscarinic M3 receptors was: darifenacin (9.34)> atropine
(9.26)> oxybutynin (7.74)> propiverine (7.68). Darifenacin and
atropine, at concentrations up to 10 -6 mol/l, did not inhibit the KCland CaCl2 -induced contractions (concentrations 80 and 5 mmol/l,
respectively), while propiverine and oxybutynin (10-5 mol/l) significantly inhibited these contractions. Pretreatment with darifenacin
(10-9 -10-6 mol/l), propiverine (10-8 -10-5 mol/l), oxybutynin (10
-8 -10-5 mol/l) and atropine (10-9 -10 -6 mol/l) significantly inhibited maximum EFS-induced contractions. Darifenacin inhibited
contractions of human detrusor smooth muscle only through its
102
anti-muscarinic action, while propiverine and oxybutynin had both
antimuscarinic and Ca2+ channel antagonist actions. These findings
indicate that darifenacin is a potent (antagonist at the M3 receptor
and support its use as a treatment for overactive bladder. Copyright
© 2003 S. Karger AG, Basel.
See also: 724.
5.8. Reproductive system
526. Effect of cyproterone acetate on alpha1-adrenoceptor subtypes in rat vas deferens - Campos M., Morais P.L. and Pupo A.S.
[A.S. Pupo, Departamento de Farmacologia, Instituto de Biociências, UNESP, 18618-000 Botucatu, SP, Brazil] - BRAZ. J. MED.
BIOL. RES. 2003 36/11 (1571-1581) - summ in ENGL
Gonadal hormones regulate the expression of 1 -adrenoceptor
subtypes in several tissues. The present study was carried out to
determine whether or not cyproterone acetate, an anti-androgenic
agent, regulates the 1 -adrenoceptor subtypes that mediate contractions of the rat vas deferens in response to noradrenaline. The
actions of subtype selective 1 -antagonists were investigated in
vas deferens from control and cyproterone acetate-treated rats (10
mg/day, sc, for 7 days). Prazosin (pA2 9.5), phentolamine (pA2
8.3) and yohimbine (pA2 6.7) presented competitive antagonism
consistent with activation of 1 -adrenoceptors in vas deferens from
both control and treated rats. The pA2 values estimated for WB
4101 (9.5), benoxathian (9.7), 5-methylurapidil (8.5), indoramin (8.7) and BMY 7378 (6.8) indicate that 1A -adrenoceptors
are involved in the contractions of the vas deferens from control
and cyproterone acetate-treated rats. Treatment of the vas deferens
from control rats with the 1B /1D -adrenoceptor alkylating agent
chloroethylclonidine had no effect on noradrenaline contractions,
supporting the involvement of the 1A -subtype. However, this
agent partially inhibited the contractions of vas deferens from cyproterone acetate-treated rats, suggesting involvement of multiple
receptor subtypes. To further investigate this, the actions of WB
4101 and chloroethylclonidine were reevaluated in the vas deferens
from rats treated with cyproterone acetate for 14 days. In these
organs WB 4101 presented complex antagonism characterized by
a Schild plot with a slope different from unity (0.65 0.05). After treatment with chloroethylclonidine, the complex antagonism
presented by WB 4101 was converted into classical competitive
antagonism, consistent with participation of 1A -adrenoceptors as
well as 1B -adrenoceptors. These results suggest that cyproterone
acetate induces plasticity in the 1 -adrenoceptor subtypes involved
in the contractions of the vas deferens.
527. Hyperhomocysteinemia may be a resistance factor in tocolytic treatment with mimetics - Celik H., Ayar A. and Tug
N. [Dr. H. Celik, Dept. of Obstetrics and Gynecology, School
of Medicine, Frat University, Elazig TR 23119, Turkey] - MED.
HYPOTHESES 2003 61/5-6 (580-582) - summ in ENGL
Homocysteine is an intermediate amino acid in the methionine
metabolism which does not take place in the structure of proteins.
Plasma homocysteine levels can be elevated by a variety of genetic
and nutritional factors. Hyperhomocysteinemia is an independent
risk factor for cardiovascular diseases and common obstetric problems. Mildly elevated levels of homocysteine have been implicated
in a number of disease processes such as atherosclerotic vascular
disease and adverse obstetrical outcome. It was shown that the
presence of high homocysteine concentrations in the in vitro system
had an activating role in myometrial contractions. It is hypothesized
that hyperhomocysteinemia in pregnancy is associated with preterm
labor in consequence of myometrial contractions. Hyperhomocysteinemia, therefore, could be a treatable cause of this important
public health and obstetric concern. © 2003 Elsevier Ltd. All
rights reserved.
528. Detection of raised FSH levels among older women using
depomedroxyprogesterone acetate and norethisterone enanthate - Beksinska M.E., Smit J.A., Kleinschmidt I. et al. [M.E.
Beksinska, Reproductive Health Research Unit, Dept. of Obstetrics
and Gynaecology, University of the Witwatersrand, 143 Salmon
Grove, Durban, South Africa] - CONTRACEPTION 2003 68/5
The objective of this study was to investigate whether folliclestimulating hormone (FSH) levels can be used reliably to indicate
approaching menopause in older (aged 40-49), long-term users
of depomedroxyprogesterone acetate (DMPA) and norethisterone
enanthate (NET-EN). One-hundred and seventeen women using
DMPA, 60 NET-EN users and 161 nonusers of contraception were
recruited. At recruitment, serum FSH levels were measured and
questions were asked regarding menopausal symptoms, menstrual
cycle and date of last injection. Results of the recruitment blood test
showed that 32% of the nonusers had FSH levels in the menopausal
range >25.8 mIU/mL compared to 28% of the DMPA users and
9% of the NET-EN group. After adjusting for age, there was no
significant difference between the 3 groups (p = 0.13). An increase
of 1 year in age increased the FSH level by 3 mIU/mL (p < 0.001).
All the hormonal contraceptive users were between 1 day and 12
weeks of their injection interval. Many had been using the injectable
contraceptive method for over 10 years and almost all were amenorrheic at the time of recruitment. The data show that a raised FSH
level can be detected during use of DMPA and NET-EN and could
be used as a menopausal indicator without interrupting method use
in this group of contraceptive users. © 2003 Elsevier Inc. All rights
reserved.
See also: 541, 542, 543, 544, 564, 613.
5.9. Endocrine system
529. Neuropeptide Y and energy homeostasis: Insights from Y
receptor knockout models - Herzog H. [H. Herzog, Neurobiology
Program, Garvan Institute of Medical Research, 384 Victoria Street,
Darlinghurst, NSW 2010, Australia] - EUR. J. PHARMACOL. 2003
480/1-3 (21-29) - summ in ENGL
A complex system has evolved to regulate food intake and to
maintain energy homeostasis. A series of short-term hormonal
and neural signals that derive from the gastrointestinal tract, such
as cholecystokinin (CCK), pancreatic polypeptide (PP) and peptide YY-(3-36), recently discovered to regulate meal size. Others
such as ghrelin initiate meals, and insulin and leptin, together with
circulating nutrients, indicate long-term energy stores. All these
signals act on central nervous system sites which converge on the
hypothalamus, an area that contains a large number of peptide and
other neurotransmitters that influence food intake with neuropeptide
Y (NPY) being one of the most prominent ones. Five Y receptors
are known which mediate the action of neuropeptide Y and its two
other family members, peptide YY and pancreatic polypeptide. Elevated neuropeptide Y expression in the hypothalamus leads to the
development of obesity and its related phenotypes, Type II diabetes
and cardiovascular disease. The limited availability of specific
pharmacological tools and the considerable number of Y receptors
have made it difficult to delineate their individual contributions
to the regulation of energy homeostasis. However, recent studies
analysing transgenic and knockout neuropeptide Y and Y receptor mouse models have started to unravel some of the individual
functions of these Y receptors potentially also helping to develop
novel therapeutics for a variety of physiological disorders including
obesity. © 2003 Elsevier B.V. All rights reserved.
530. Neuropeptides and anticipatory changes in behaviour and
physiology: Seasonal body weight regulation in the Siberian
hamster - Mercer J.G. and Tups A. [J.G. Mercer, Div. of Energy
Balance and Obesity, Rowett Research Institute, Aberdeen Ctr. for
Ener. Reg./Obesity, Aberdeen, AB21 9SB, United Kingdom] EUR. J. PHARMACOL. 2003 480/1-3 (43-50) - summ in ENGL
The Siberian hamster, Phodopus sungorus, is a powerful model of
physiological body weight regulation. This seasonal model offers
the potential to distinguish between the compensatory neuroendocrine systems that defend body weight against imposed negative
energy balance, and those that are involved in the programming
of the level of body weight that will be defended - a seasonally
appropriate body weight. Of the known, studied, components of
the hypothalamic energy balance system, the anorexogenic peptide, cocaine- and amphetamine-regulated transcript (CART), is the
only candidate where gene expression changes in a manner consistent with a role in initiating or sustaining photoperiod-induced
differences in body weight trajectory. Siberian hamsters effect a
reversible biannual switch in leptin sensitivity in which only short
day (SD)-acclimated hamsters that have undergone a reduction in
body weight, adiposity and plasma leptin are sensitive to peripheral
exogenous leptin. The suppressor of cytokine signalling protein,
SOCS3, appears to be the molecular correlate of this seasonal sensitivity. © 2003 Elsevier B.V. All rights reserved.
531. Reduced dopaminergic tone in hypothalamic neural circuits: Expression of a "thrifty" genotype underlying the
metabolic syndrome? - Pijl H. [H. Pijl, Department of Internal Medicine, Leiden University Medical Center, C1-R39, PO Box
9600, 2300 RC Leiden, Netherlands] - EUR. J. PHARMACOL. 2003
480/1-3 (125-131) - summ in ENGL
The thrifty genotype hypothesis postulates that the genetically
determined ability to grow obese and insulin resistant in times of
food abundance confers a survival advantage in times of famine.
Obviously, this ability poses a major health threat in modern times,
where food is always available in large quantities. In the last 1015 years, many genes encoding pathways that orchestrate energy
balance and fuel flux have been discovered. This paper summarizes
the evidence that diminished dopaminergic tone in hypothalamic
nuclei contributes to the "thrifty" genotype/phenotype. Reduced
dopaminergic neurotransmission in the suprachiasmatic nucleus of
seasonally obese animals appears to drive noradrenalin and NPY
mediated transmissions in other nuclei to induce the obesity syndrome at the appropriate time of year. Treatment with dopamine
D2 receptor agonists can fully reverse the metabolic syndrome in
these animals. Similar mechanisms are operative in non-seasonal
obese animal models. In man, treatment with dopamine D2 receptor
antagonists induces obesity and type 2 diabetes mellitus, whereas
dopamine D2 receptor activation ameliorates the metabolic profile
in obese nondiabetic and diabetic humans. Various loss of function
mutations of the dopamine D2 receptor gene are associated with
overweight in humans. In concert, the data support the notion that
diminution of dopaminergic (dopamine D2 receptor mediated) transmission in relevant hypothalamic nuclei sets the stage for efficient
partitioning of ingested nutrients to contribute to a phenotype that
is not so thrifty anymore. © 2003 Elsevier B.V. All rights reserved.
532. Invesgations on the Influence of Halide Substituents on the
Estrogen Receptor Interaction of 2,4,5-Tris(4-hydroxyphenyl)imidazoles - Gust R., Busch S., Keilitz R. et al. [R. Gust, Institut fur
Pharmazie der FU Berlin, Königin Luise Str. 2 4, D-14195 Berlin,
Germany] - ARCH. PHARM. 2003 336/10 (456-465) - summ in
ENGL
Previously, we reported on the synthesis and estrogen receptor
(ER) interaction of imidazoles, which had to be 1-alkyl-4,5bis(2-halo-4-hydroxyphenyl) substituted for a high relative binding
affinity (RBA > 1 %). This led to the assumption that a shielding
of the polar heterocyclic system is a prerequisite for ER binding.
In continuation of this study we synthesized 2,4,5-tris(4-hydroxyphenyl)imidazoles with Cl- or F-atoms in the ortho-positions
of the aromatic rings and evaluated whether they mediate
sufficient hydrophobicity for ER interaction. 2-(2,6-Dichloro-3/4hydroxyphenyl)-4,5-bis(2-halo-4-hydroxyphenyl)imidazoles were
synthesized by reaction of the respective methoxy-substituted benzil
with either the 2,6-dichloro-4-methoxy- or the 2,6-dichloro-3-methoxybenzaldehyde in ammonium acetate solution. The required
ether cleavage was performed subsequently with BBr3 . In the
competition experiment with [ 3 H]estradiol the imidazoles with
the a C2-standing (2,6-dichloro-4-hydroxyphenyl) ring showed an
RBA > 0.02 %, but did not activate the luciferase gene in estrogen
receptor positive MCF-7-2a breast cancer cells stably transfected
with the plasmid EREwtc luc. In the test for antagonistic potency
only the 2-(2,6-dichloro-4-hydroxyphenyl)-4,5-bis(4-hydroxyphenyl)imidazole 3 antagonized the effects of 1 nM estradiol slightly.
From these data, it can be concluded that a C2-standing 2,6-dichloro-4-hydroxyphenyl ring is not appropriate to optimize the ER
interaction of 4,5-(4-hydroxyphenyl)imidazoles.
533. Neuroendocrinology of insulin resistance: Metabolic and
endocrine aspects of adiposity - Van Dijk G., De Vries K., Ben103
them L. et al. [G. Van Dijk, Department of Neuroendocrinology,
University of Groningen, P.O. Box 14, 9750 AA Haren, Netherlands] - EUR. J. PHARMACOL. 2003 480/1-3 (31-42) - summ in
ENGL
Abdominal obesity is a major risk factor to attract the insulin
resistance syndrome. It is proposed that abdominal obesity exposes
the liver to elevated levels of free fatty acids, which activate a
neuroendocrine reflex, leading to increased circulating levels of
glucocorticoids. Besides directly attenuating peripheral insulin
signaling, glucocorticoids oppose the activity of central nervous
regulatory systems that stimulate insulin action. Among the factors
that promote insulin action is leptin. Leptin regulates peripheral
fuel partitioning and insulin action mainly through hypothalamic
neuronal networks, which in turn, regulate endocrine activity of
adipose tissue in a way comparable to thiazolidinediones. These are
a class of insulin-sensitizing drugs, which exert their antidiabetic
effects through the gamma isoform of peroxisome proliferator-activated receptor (PPAR- ). Since glucocorticoids oppose leptin
action at several levels of control (including the central nervous
system, CNS), it is argued that subjects easily develop obesity and
associated metabolic disorders. © 2003 Elsevier B.V. All rights
reserved.
534. Nefazodone Inhibits Methylprednisolone Disposition and
Enhances its Adrenal-Suppressant Effect - Kotlyar M., Brewer
E.R., Golding M. and Carson S.W. [Dr. M. Kotlyar, University
of Minnesota, Dept. of Exp. and Clin. Pharmacology, College
of Pharmacy, 308 Harvard St SE, Minneapolis, MN 55455, United
States] - J. CLIN. PSYCHOPHARMACOL. 2003 23/6 (652-656) summ in ENGL
Nefazodone is a potent and selective inhibitor of cytochrome P450
3A4 (CYP3A4), an enzyme pathway responsible for the biotransformation of a number of steroid compounds. The potential therefore
exists that nefazodone inhibits the disposition of methylprednisolone. In this open label, repeated measures study, the effect of 9 days
of nefazodone administration on the pharmacokinetic disposition of
a single 0.6 mg/kg intravenous dose of methylprednisolone was
assessed. Additionally the effect of concomitant nefazodone use on
duration of cortisol suppression after methylprednisolone administration was assessed. Eight healthy volunteers completed the study.
Following nefazodone administration, the mean (SD) area under
the methylprednisolone concentration-time curve was significantly
higher (1393 343 vs. 2966 928 ugh/L; P < 0.005), apparent
clearance was lower (28.7 7.2 vs. 14.6 7.8 L/h; P < 0.02) and
the terminal elimination half-life was longer (2.28 0.49 vs. 3.32
0.95 hours; P < 0.02). The duration of cortisol suppression after
methylprednisolone administration was longer (32 vs. 23.3 3.43 hours) during nefazodone administration.
535. Aminoguanidine downregulates expression of cytokineinduced Fas and inducible nitric oxide synthase but not
cytokine-enhanced surface antigens of rat islet cells - Kuttler B.,
Steveling A., Klöting N. et al. [B. Kuttler, Institute of Pathophysiology, Ernst-Moritz-Arndt-Univ., Greifswald, Greifswalder Str. 11c,
D-17495 Karlsburg, Germany] - BIOCHEM. PHARMACOL. 2003
66/12 (2437-2448) - summ in ENGL
Autoimmune -cell destruction occurs directly by cell-mediated
cytotoxicity or indirectly by cytokines released from infiltrating
lymphocytes. Cytokines (IL-1 /IFN- ) modify or induce expression of MHC antigens and ICAM-1 on -cells which can lead
to an improved binding of T-lymphocytes to -cells and finally
to an enhanced cell-mediated cytotoxicity. Cytokines also induce
Fas-expression and inducible nitric oxide synthase (iNOS) causing
generation of nitric oxide (NO) which is toxic for -cells. The
iNOS inhibitor aminoguanidine (AG) delays diabetes onset, but
does not reduce diabetes incidence. We wanted to know whether
AG inhibits cytokine-induced expression of Fas, MHC antigens and
ICAM-1 on -cells of LEW.1W and BB/OK rat islets after culture
with IL-1 /IFN- . NO was completely inhibited by 5.0mmol/L AG
while 0.5mmol/L had no inhibitory effect. AG downregulated Fasexpression on the surface of -cells. Cytokine-induced/enhanced
expression of MHC class-II and ICAM-1 was not affected by any
AG concentration. AG syngergistically increased cytokine-induced
enhancement of MHC class-I antigen density. AG possibly blocks
the indirect pathway of -cell damage in vivo due to inhibition of
104
Fas and iNOS and improves direct cell-mediated cytotoxicity due
to drastic increased MHC class-I expression. Inhibition of only one
pathway of -cell destruction is not sufficient to prevent diabetes.
536. Neuroendocrinology of the pancreas; role of brain-gut axis
in pancreatic secretion - Konturek S.J., Zabielski R., Konturek
J.W. and Czarnecki J. [S.J. Konturek, Department of Clinical Physiology, Jagiellonian Univ. Sch. of Medicine, 16 Grzegorzecka
Street, Cracow 31-531, Poland] - EUR. J. PHARMACOL. 2003
481/1 (1-14) - summ in ENGL
Exocrine pancreatic secretion, attributed initially to neural reflexes (nervism), was then found to depend also on enterohormones,
especially secretin and cholecystokinin (CCK), released by the
intestinal mucosa and believed to act via an endocrine pathway.
Recently, CCK and other enterohormones were found to stimulate the pancreas by excitation of sensory nerves and by trigger
of long vagovagal or ("brain-gut axis") enteropancreatic reflexes.
Numerous neurotransmitters, such as acetylcholine, and certain
neuropeptides, such as gastrin-releasing peptide (GRP), generated
by neurons of the enteric nervous system (ENS) of the gut, have
been implicated in the regulation of exocrine pancreas. Recently,
peptides affecting appetite behavior and originating from the gut,
such as leptin and ghrelin, or from the pancreas, such as pancreatic
polypeptide and neuropeptide Y, appear to modulate the exocrine
pancreas via hypothalamic centers. The aim of this review is to
highlight the interaction of nerves and enterohormones in the regulation of exocrine pancreatic secretion. © 2003 Elsevier B.V. All
rights reserved.
537. Thyroid over-expression of type 1 and type 2 deiodinase
may account for the syndrome of low thyroxine and increasing
triiodothyronine during propylthiouracil treatment - Weetman
A.P., Shepherdley C.A., Mansell P. et al. [A.P. Weetman, The
University of Sheffield, Division of Clinical Sciences, Northern
General Hospital, Sheffield S5 7AU, United Kingdom] - EUR. J.
ENDOCRINOL. 2003 149/5 (443-447) - summ in ENGL
Although propylthiouracil inhibits type 1 deiodinase, leading to
a more rapid fall in triiodothyronine (T3 ) than thyroxine (T4 )levels in patients treated for hyperthyroidism, we report a patient
with Graves’ disease whose free T3 paradoxically rose during such
treatment, despite low free T4 levels and increasing doses of propylthiouracil. A similar response has previously been associated with
high levels of thyroid stimulating antibodies, but it has been unclear why there should be a dichotomy in the circulating thyroid
hormone profile. Thyroid tissue from our patient contained very
high levels of type 1 and, especially, type 2 deiodinase, in contrast
to other patients treated with Graves’ disease, which were most
likely secondary to high levels of thyroid stimulating antibodies.
This unusual response to propylthiouracil is important to recognise
therapeutically, and represents a further situation in which abnormal
expression of deiodinase enzymes has clinical significance.
See also: 554, 560, 566, 568, 569, 740.
6. PHARMACOLOGICAL AGENTS
538. Usefulness of microspheres composed of gelatin with various cross-linking density - Iwanaga K., Yabuta T., Kakemi M.
et al. [K. Iwanaga, Department of Pharmaceutics, Osaka Univ. of
Pharmaceutical Sci., 4-20-1 Nasahara, Takatsuki-city, Osaka 5691094, Japan] - J. MICROENCAPSULATION 2003 20/6 (767-776) summ in ENGL
The release rate of insulin, as a model peptide, from gelatin microspheres (GM) prepared with gelatin having various cross-linking
densities in vitro was examined. The release of insulin from GM
showed the burst effect, followed by a slow release phase regardless
of the cross-linking density of gelatin. The total amount of insulin
released in 2 weeks decreased with increasing cross-linking density
of gelatin. The release rate of insulin within 6 h was well correlated
with the cross-linking density of gelatin. The remaining amounts
of both insulin and GM after injection of insulin incorporated in
GM to mice femoral muscle tissue were also examined in vivo.
Both insulin and GM rapidly disappeared from the injection site
within 1 day, and thereafter slowly disappeared over 14 days. The
time courses of the remaining amounts were fairly similar to each
other. Furthermore, the remaining amount of insulin 1 day after
administration was well correlated with the cross-linking density
of gelatin. These data suggest that insulin was released from GM
with the degradation of GM in mice muscular tissue and that the
release rate of insulin can be controlled by modifying the crosslinking density of gelatin. In conclusion, the control of the release
rate of insulin from GM can be achieved under both in vitro and
in vivo conditions by gelatin through the alteration of cross-linking
conditions.
539. Oxprenolol-loaded bioadhesive microspheres: Preparation
and in vitro/in vivo characterization - Preda M. and Leucuta S.E.
[S.E. Leucuta] - J. MICROENCAPSULATION 2003 20/6 (777-789)- summ in ENGL
Biologically adhesive delivery systems offer important advantages over conventional drug-delivery systems. In this paper,
microspheres intended as a sustained release carrier for oral or
nasal administration have been prepared by associating a known
bioadhesive polymer, poly(acrylic acid), in gelatin microspheres.
A model drug oxprenolol hydrochloride was chosen. It was found
that some of the formulation variables can influence the characteristics of the beads in a controlled manner. The internal structure
of the microspheres studied by X-ray diffraction, thermal analysis
and optical microscopy showed the absence of drug crystals in
microspheres and a lowering in the glass transition temperature.
The dynamic swelling of the beads obeyed the square root of time
and a shift from the diffusional to the relaxational process dependent on the content of poly(acrylic acid) in gelatin microspheres
was observed. As expected, drug release from gelatin/poly(acrylic
acid) microspheres was influenced by the poly(acrylic acid) content in beads, by the particle size of microspheres and by the pH
of the medium. The mechanism of release was analysed by applying the empirical exponential equation and by calculation of
the approximate contribution of the diffusional and relaxational
mechanisms to the anomalous release process by fitting the data
to the coupled Fickian/Case II equation. In vitro and in vivo
experiments in rats showed good adhesive characteristics of the
gelatin/poly(acrylic acid) microspheres, which were greater if the
poly(acrylic acid) content was greater. A significant retardation in
gastric and intestinal emptying time of the beads was observed. This
was also suggested by the bioavailability of the model drug after
intragastric and intranasal administration of the microspheres. The
pharmacokinetic parameters after microsphere administration were
more appropriate to a slow release drug-delivery system. The work
suggests the potential of this pharmaceutical delivery system as an
alternative controlled-release dosage form, either for oral or nasal
administration.
540. Use of bisoprolol in heart failure. The BISOCOR observational study (Span) - EMPLEO DE BISOPROLOL EN LA INSUFICIENCIA
CARDÍACA. RESULTADOS DEL ESTUDIO BISOCOR - González-Juanatey
J.R., Alegrı́a Ezquerra E., Garcı́a Saavedra V. et al. [Prof. J.R.
González-Juanatey, Servicio de Cardiologı́a, Hospital Clinico Universitario, Avda. Choupana s/n, 15706 Vidan S. Compostela A
Coruna, Spain] - REV. ESP. CARDIOL. 2003 56/9 (873-879) - summ
in SPAN, ENGL
Introduction and objectives. The benefits of beta blockers in
heart failure are highly dependent on dosage. This study aimed to
analyze the degree of concordance between targeted (CIBIS II) and
achieved doses of bisoprolol in a group of patients with stable heart
failure on conventional treatment. We also evaluated functional
parameters, adverse effects and the reasons for withdrawal or dropout. Patients and method. The study group consisted of 334 patients
with stable systolic heart failure who were receiving conventional
treatment. Treatment with bisoprolol was initiated according to current guidelines (starting dose 1.25 mg/day, with weekly increments
to 5 mg/day, and then increments every four weeks to a targeted
dosis of 10 mg/day). The main endpoint was the comparison between targeted dose and dose reached at each follow-up. Secondary
endpoints were quality of life assessment (Minnesota Living with
Heart Failure Questionnaire), functional status (New York Heart
Association), ejection fraction change, and side effects during the
9-month follow-up period. Results. Thirty-four (10%) patients
did not finish the study: 1 because of sudden death, 2 because of
surgery, and 31 because of side effects. 63% of the patients attained
the maximum targeted dose; the mean dose at the end of follow-up
was 8.5 mg. Functional status, quality of life and ejection fraction
improved significantly between the beginning and the end of the
study. Only 4 patients had severe adverse effects. Conclusions.
This is the first study in Spain to show that bisoprolol can be used
effectively at the maximum recommended doses, for the outpatient
treatment of heart failure.
541. A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors
versus a ’standard’ dose of 150 IU/day in ’standard’ patients undergoing IVF/ICSI treatment - Popovic-Todorovic B., Loft A.,
Ejdrup Bredkjæer H. et al. [B. Popovic-Todorovic, Fertility Clinic
4071, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark] - HUM. REPROD. 2003 18/11
(2275-2282) - summ in ENGL
Background: The study aim was to compare the use of individual rFSH doses between 100 and 250 IU/day (calculated using the
rFSH dose normogram) with a standard dose of rFSH of 150 IU/day.
Methods: This prospective randomized dual-centre clinical trial included 267 first IVF/ICSI cycles using the long agonist protocol in
’standard’ patients. Following down-regulation, 262 patients were
randomized using computer-generated lists using ’clusters of 10’
into the individual dose (study) group (n = 131) or the standard dose
(control) group (n = 131). Results: In the study group, 101 patients
(77.1%) had an appropriate response (defined as 5-14 oocytes),
compared with 86 (65.6%) in the control group (P < 0.05). Fewer
than five oocytes were retrieved in two patients (1.5%) in the study
group, compared with 14 patients (10.7%) in the control group (P <
0.05). By comparison, >14 oocytes were retrieved from 27 patients
(20.6%) in the study group and from 26 (19.8%) control patients (P
= NS). Eighty-six per cent of the individual dose patients did not
require any dose adjustment on day 8, compared with 45% of the
standard dose patients (P < 0.01). The ongoing pregnancy rate per
initiated cycle was 36.6% in the study group and 24.4% in the control
group (P < 0.01). One patient (0.8%) in the study group, and four
patients (3.1%) in the control group, were hospitalized due to ovarian hyperstimulation syndrome. Conclusions: An individual dose
regimen in a well-defined ’standard’ patient population increased
the proportion of appropriate ovarian responses and decreased the
need for dose adjustments during controlled ovarian stimulation. A
higher ongoing pregnancy rate was observed in the individual dose
group.
542. A prospective, randomized, placebo-controlled trial on the
use of mifepristone with sublingual or vaginal misoprostol for
medical abortions of less than 9 weeks gestation - Tang O.S.,
Chan C.C.W., Ng E.H.Y. et al. [O.S. Tang, Dept. of Obstetrics and
Gynaecology, University of Hong Kong, Queen Mary Hospital, 102
Pokfulam Road, Hong Kong SAR, Hong Kong] - HUM. REPROD.
2003 18/11 (2315-2318) - summ in ENGL
Background: A combination of mifepristone and misoprostol
provides an effective method of medical abortion for early pregnancy. This is the first randomized trial comparing the use of
sublingual misoprostol with vaginal misoprostol in combination
with mifepristone for termination of early pregnancies up to 63 days.
Methods: A total of 224 women who requested legal termination of
pregnancy up to 63 days were randomized by computer-generated
list into two groups and given 200 mg of oral mifepristone followed
48 h later by either 800 g of sublingual (n = 112) or vaginal (n =
112) misoprostol. Results: Complete abortion occurred in 98.2%
(95% CI: 93-99) of women in the sublingual group and 93.8%
(95% CI: 88-97) in the vaginal group. There were three ongoing
pregnancies in the vaginal group but none in the sublingual group.
The median duration of vaginal bleeding was 17 days. There was
no serious complication. Fever, chills and gastrointestinal sideeffects (nausea, vomiting and diarrhoea) were significantly more
common in the sublingual group. Conclusions: The combination
of mifepristone and misoprostol is effective for medical abortion up
to 63 days. Both the sublingual and vaginal are effective routes of
administration. Further randomized trials are required to find out
the optimal dose of sublingual misoprostol that can give the highest
complete abortion rate and lowest incidence of side-effects.
105
543. Effectiveness and mechanism of action of desmopressin in
the treatment of copper intrauterine device-related menorrhagia: A pilot study - Mercorio F., De Simone R., Di Carlo C. et
al. [F. Mercorio, Dept. of Obstetrics and Gynaecology, University
Federico II, Naples, Italy] - HUM. REPROD. 2003 18/11 (23192322) - summ in ENGL
Background: Desmopressin, a synthetic analogue of the natural hormone vasopressin, stimulates endogenous haemostasis and
exerts a powerful myometrial and vasoconstrictor action in a variety of pharmacological preparations. Both mechanisms of action
may have therapeutic value for the treatment of intrauterine device (IUD)-related menorrhagia, which is believed to be caused
not only by altered local haemostasis but also-according to a new
hypothesis-by decreased vascular uterine resistance. The aim of
this prospective study was to evaluate the effect of vasopressin
drug on menstrual blood loss and on changes, if any, in uterine flow
impedance. Mefenamic acid, which is commonly used to treat IUDrelated menorrhagia, was administered as a comparison. Methods:
Twenty-four women with IUD-induced menorrhagia were recruited
and randomly allocated to treatment with either desmopressin or
mefenamic acid. Menstrual blood loss (measured by pictorial blood
loss assessment chart) and uterine artery resistance (measured with
transvaginal colour Doppler) performed in two pretreatment periods were compared with 3-month treatment periods. Results:
Menstrual blood loss was significantly reduced in both treatment
groups. In the desmopressin group, the effect was clinically useful
in all subjects, but in the mefenamic group menstrual blood loss
was consistently menorrhagic in two patients. No significant differences were observed in the uterine artery pulsatility index before
and during treatment. Conclusions: Desmopressin may be a useful
therapeutic tool for many women with IUD-related menorrhagia. Its
mechanism of action lies in an ability to enhance local haemostasis,
without affecting uterine blood flow.
544. High singleton live birth rate following classical ovulation induction in normogonadotrophic anovulatory infertility
(WHO 2) - Eijkemans M.J.C., Imani B., Mulders A.G.M.G.J. et
al. [B.C.J.M. Fauser, Division of Reproductive Medicine, Dept. of
Obstetrics and Gynaecology, Erasmus MC-Univ. Med. Ctr. Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, Netherlands]
- HUM. REPROD. 2003 18/11 (2357-2362) - summ in ENGL
Background: Medical induction of ovulation using clomiphene
citrate (CC) as first line and exogenous gonadotrophins as second
line forms the classical treatment algorithm in normogonadotrophic
anovulatory infertility. Because the chances of success following
classical ovulation induction are not well established, a shift in firstline therapy can be observed towards alternative treatment. The
study aim was to: (i) reliably assess the probability of singleton live
birth following classical induction of ovulation; and (ii) construct
a prediction model, based on individual patient characteristics assessed upon standardized initial screening, to help identify patients
with poor chances of success. Methods: A total of 240 consecutive
women visiting a specialist academic fertility unit with a history of
infertility, oligomenorrhoea or amenorrhoea, and normal FSH and
estradiol serum concentrations (WHO group 2) was prospectively
followed. The women had not been previously treated with ovulation-inducing agents. All patients commenced with CC. Patients
who did not ovulate within three treatment cycles of incremental
daily doses up to 150 mg for 5 consecutive days or ovulatory CC
patients who did not conceive within six cycles, subsequently underwent gonadotrophin induction of ovulation applying a step-down
dose regimen. The main outcome measure was pregnancy resulting
in singleton live birth. Cox regression was used to construct a
multivariable prediction model. Results: Overall, there were 134
pregnancies ending in a singleton live birth (56% of women). The
cumulative pregnancy rate after 12 and 24 months of follow-up was
50% and 71% respectively. Polycystic ovary syndrome (PCOS) patients (49%), clearly non-PCOS patients (13%) and the in-between
group did not differ in prognosis (P = 0.9). The multivariable Cox
regression model contained the woman’s age, the insulin:glucose
ratio and duration of infertility. With a cut-off value of 30% for
low chance, the model predicted probabilities at 12 months lower
than this cut-off for 25 out of 240 patients (10.4%). Conclusions:
Classical ovulation induction produces very good results in normogonadotrophic anovulatory infertility. Alternative treatment options
106
may not be indicated as first-line therapy in these patients, except for
subgroups with poor prognosis. These women can be identified by
older age, longer duration of infertility and higher insulin: glucose
ratio.
545. Pharmacokinetics and anticoagulant properties of the
factor VIIa-tissue factor inhibitor recombinant Nematode Anticoagulant Protein c2 following subcutaneous administration in
man: Dependence on the stoichiometric binding to circulating
factor X - Vlasuk G.P., Bradbury A., Lopez-Kinninger L. et al. [Dr.
G.P. Vlasuk, Corvas International, Inc., 3030 Science Park Road,
San Diego, CA 92121, United States] - THROMB. HAEMOST. 2003
90/5 (803-812) - summ in ENGL
Recombinant Nematode Anticoagulant Protein c2 (rNAPc2) is a
potent (Ki =10 pM), inhibitor of the factor Vila/tissue factor (fVIIa/TF) complex that requires the prerequisite binding to zymogen
or activated factor X (fX). In two double blind, placebo-controlled,
sequential dose-escalation phase I studies, rNAPc2 was found to be
safe and well tolerated following single and repeat subcutaneous
administrations in healthy human male volunteers at doses ranging from 0.3 to 5 g/kg. There was a dose-dependent elevation
of the prothrombin time reaching almost 4-fold above the baseline
value in the highest dose group that directly correlated with rNAPc2
plasma concentration. In contrast, there was little or no effect on
the activated partial thromboplastin time, thrombin time or template
bleeding time. The pharmacokinetic behavior of rNAPc2 revealed a
dose-independent and prolonged elimination half-life (t1/2 ) with
a mean of >50 hours. A high affinity interaction between rNAPc2
and plasma fX was shown to be essential for the prolonged t1/2 in man using crossed immunoelectrophoresis and was confirmed
by exploiting the considerably weaker interaction between rNAPc2
and bovine fX which resulted in an attenuated t1/2 of 1.5 hours
in calves. The accumulated data suggests that rNAPc2 is safe
and well tolerated following repeat subcutaneous administrations
at doses up to 5 g/kg in healthy volunteers. In addition, the in
vivo fate of rNAPc2 in man appears to be governed by its high
.affinity interaction with circulating fX. This data supports the continued development of this novel anticoagulant for the prevention
and treatment of acute thrombotic disorders.
546. The antiaggregating activity of clopidogrel is not affected
by N-acetyl L-cysteine - Lalé A., Herbert J.-M. and Savi P.
[J.-M. Herbert, Cardiovascular-Thrombosis Res. Dept., SanofiSynthélabo Research, 195 Route d’Espagne, 31036 Toulouse,
France] - THROMB. HAEMOST. 2003 90/5 (839-843) - summ in
ENGL
N-acetyl L-cysteine (NAC) is widely used to treat obstructive bronchopulmonary diseases. It has thiol reactive properties,
accounting for its mucolytic activity. Clopidogrel is a potent antithrombotic compound, metabolised by the liver which generates
an active metabolite containing a thiol reactive group, responsible
for an irreversible interaction with the platelet P2Y12 ADP receptor.
The aim of this study was to determine if NAC interferes with
the antiaggregating activity of clopidogrel. For this purpose, NAC
(100 M) was incubated with platelets from rats treated or not with
clopidogrel (5 mg/kg, PO, -2 h). Clopidogrel treatment strongly
inhibited aggregation but this effect was not modified by NAC. In
another experiment, a low concentration of the active metabolite of
clopidogrel (0.3 g/ml) was incubated with platelets from men or
rats, in the absence or presence of NAC (100 M). When stimulated by ADP (2.5 M), platelet aggregation was inhibited by the
active metabolite when incubated alone. In the presence of NAC,
the inhibition by the active metabolite was not modified, therefore
clearly indicating that NAC cannot reduce the thiol reactive part
of the active metabolite of clopidogrel and does not interfere with
its antiaggregating activity. Moreover, in rats treated for 5 days
with NAC (150 mg/kg), the activity of clopidogrel (5 or 10 mg/kg)against ADP-induced platelet aggregation was neither inhibited nor
increased. This demonstrates that the generation of the active metabolite of clopidogrel is not affected by NAC. In conclusion, we
have found that NAC does not restore the "normal" properties of
P2Y12 on platelets from clopidogrel-treated animals, it does not
interfere with the antiaggregating activity of the active metabolite
of clopidogrel, and does not interfere with the generation of the
active metabolite.
547. Mechanisms of the priming effect of low doses of lipopolysaccharides on leukocyte-dependent platelet aggregation in
whole blood - Montrucchio G., Bosco O., Del Sorbo L. et al. [Prof.
Dr. G. Camussi, Dipartimento di Medicina Interna, Universita degli
Studi di Torino, C.so Dogliotti 14, 10126 Turin, Italy] - THROMB.
HAEMOST. 2003 90/5 (872-881) - summ in ENGL
Several studies focused on the ability of bacterial lipopolysaccharides (LPS) in triggering platelet and/or leukocyte activation.
The aim of this study was to investigate the molecular mechanisms
involved in the aggregation of platelets and in their interaction
with leukocytes in whole blood after stimulation with low doses
of LPS. LPS did not directly induce platelet aggregation in whole
blood, but they primed the aggregation of platelets induced by epinephrine, adenosine diphosphate and arachidonic acid. As shown
by cytofluorimetry, platelets neither bind FITC-LPS, nor express
the LPS-receptors CD14 and toll-like receptor 4 (TLR4). On the
contrary, LPS primed monocytes and to a lesser extent polymorphonuclear neutrophils to adhere to platelets. Both platelet-leukocyte
interaction and platelet aggregation in whole blood were inhibited
by blockade of CD14 and TLR4. Moreover, the interaction between platelets and leukocytes was inhibited by P-selectin, and by
blockade of PAF and reactive oxygen species, suggesting a role of
P-selectin and of leukocyte-derived mediators. In conclusion, these
results elucidate the mechanisms leading to platelet activation and
interaction with leukocytes triggered by LPS. They suggest that the
activation of platelets by LPS is mainly dependent on leukocytes and
especially monocytes as a result of CD14 and TLR4 engagement.
Moreover, we found that leukocyte-platelet interaction was triggered by the synthesis of PAF and the generation of oxygen radicals
that induced upregulation of surface expression of P-selectin.
548. Antiinflammatory activity of astragaloside IV is mediated
by inhibition of NF-B activation and adhesion molecule expression - Zhang W.-J., Hufnagl P., Binder B.R. and Wojta J. [J.
Wojta, Department of Internal Medicine II, Waehringer Guertel 1820, A-1090 Vienna, Austria] - THROMB. HAEMOST. 2003 90/5
The regulated expression of adhesion molecules on the
surface of endothelial cells is a key process in the pathogenesis of inflammation.The saponin astragaloside IV (AS-IV), a
3-O- -D- xylopyranosyl-6-O- -D-glucopyranosylcycloastragenol
purified from the Chinese medical herb Astragalus membranaceus
(Fisch) Bge. has been shown to have anti-inflammatory effects
in vivo. In this study we have investigated the effect of AS-IV
on cytokine-and LPS-stimulated expression of adhesion molecules
in and leukocyte adhesion to endothelial cells. We have demonstrated that AS-IV significantly reduced the adhesion promoting
activity of LPS-stimulated HUVECs for polymorph-nuclear leukocytes (PMNs) and the monocytic cell line THP-I. Furthermore, by
using specific cell ELISAs we could show that AS-IV decreased
the LPS-induced expression of E-selectin and VCAM-1 on the surface of HUVECs in a dose and time dependent manner, whereas
the expression of ICAM-1 was not affected by AS-IV. AS-IV also
inhibits TNF-induced VCAM-1 expression.The saponin octyl-Dglucopyranoside had no effect on the LPS-induced expression of
E-selectin and VCAM-1 excluding an unspecific detergent-like effect of AS-IV. Moreover, AS-IV significantly inhibited LPS- and
TNF-induced specific mRNA levels for E-selectin and VCAM-1.
Finally, we could show that AS-IV completely abolished LPS- and
TNF-induced nuclear translocation of NF-B and NF-B DNA
binding activity in endothelial cells.We conclude that the ability
of AS-IV to inhibit the NF-B pathway might be one underlying
mechanism contributing to its anti-inflammatory potential in vivo.
549. Efficacy of esomeprazole in controlling reflux symptoms,
intraesophageal, and intragastric pH in patients with Barrett’s
esophagus - Yeh R.W., Gerson L.B. and Triadafilopoulos G. [Dr.
G. Triadafilopoulos, Gastroenterology Section (111-GI), VA Palo
Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA
94304, United States] - DIS. ESOPHAGUS 2003 16/3 (193-198) summ in ENGL
Barrett’s esophagus is a metaplastic condition associated with
gastroesophageal reflux disease and an increased risk for adenocarcinoma. Acid plays a significant role in the development and
progression of Barrett’s esophagus and high dose proton pump inhibitor (PPI) therapy is often needed. The aim of this study is to
assess the efficacy of esomeprazole, a new potent PPI, on symptom relief and intraesophageal and intra-gastric acid suppression in
patients with Barrett’s esophagus (BE). Patients were evaluated by
standardized questionnaires and dual sensor 24-h pH monitoring
while receiving esomeprazole at a dose (40-80 mg/day) needed for
control of symptoms. Analyses of intraesophageal and intragastric pH profiles were then made. Thirteen patients, mostly men,
were studied. All tolerated esomeprazole (40-80 mg/day) with
good symptom control. Sixty-two percent of patients with BE
had abnormal intraesophageal pH profiles despite adequate symptom control on esomeprazole which was associated with significant
breakthrough of intraesophageal acid control, particularly at night.
Low nocturnal intragastric pH correlated highly with nocturnal intraesophageal acid reflux (P = 0.004) and there was a relative failure
of nocturnal intragastric acid control with esomeprazole. A high percentage of patients with BE continue to exhibit pathologic GERD
and low intragastric pH despite esomeprazole for reflux symptom
control. For an antisecretory treatment aimed at chemoprevention
of esophageal adenocarcinoma to be effective, higher PPI dosing
confirmed by pH monitoring may be necessary.
550. Treatment of patients with achalasia with botulinum toxin:
A multicenter prospective cohort study - Martı́nek J., Široký M.,
Plottová Z. et al. [Dr. J. Martı́nek, Department of Hepatogastroenterology, IKEM, Vı̀denská 1958/9, 140 21 Praha 4, Czech Republic]
- DIS. ESOPHAGUS 2003 16/3 (204-209) - summ in ENGL
Botulinum toxin (BT) injection is an alternative treatment of
achalasia. The aim of the study was to examine outcomes of patients
treated with BT in the Czech Republic. Since 1997, 49 patients with
achalasia have been treated with BT. We prospectively evaluated the
effect of BT injection on 41 patients during a median follow-up of
24 months (range 9-62). Esophageal manometry was performed
before and at 3-5 months after the injection. In 16 patients, BT
was injected from the antegrade angle only (subgroup A), in 15
patients, BT was injected from both retrograde and antegrade angles (subgroup B) and, in 10 patients, BT injection was combined
with subsequent balloon dilatation (subgroup C). Immediate clinical response was achieved in 93% of patients. Clinical remission
was sustained beyond 3 months in 83% of patients (responders). Fourteen responders (41%) did not experience a relapse during
the median of 22 months. Twenty responders (59%) experienced
symptomatic relapse approximately 8 months after the injection.
Ten relapsers underwent BT reinjection, five (50%) of them were
asymptomatic for another 14 months. The remaining five (50%)patients reported a second relapse approximately 6 months after the
reinjection. Median duration of the symptom-free period was 11.5
months after the first BT injection, and 10.5 months after the second
(P = 0.21). We did not find any significant predictor of a favorable
outcome; responders tended to be older and to have a lower basal
lower-esophageal-sphincter pressure. Patients in subgroup C were
more likely to be in remission at 1 and 2 years as compared with
patients in subgroup A. BT injection is an effective treatment of
achalasra in the short term. However, almost 70% of patients experience a relapse within 2 years. BT injection should therefore
be reserved for patients at risk for more invasive procedures or for
patients who prefer this treatment.
551. Progress report of a Phase I study of the intracerebral
microinfusion of a recombinant chimeric protein composed of
transforming growth factor (TGF)- and a mutated form of the
Pseudomonas exotoxin termed PE-38 (TP-38) for the treatment
of malignant brain tumors - Sampson J.H., Akabani G., Archer
G.E. et al. [J.H. Sampson, Division of Neurosurgery, Duke University Medical Center, 4th Floor, Blue Zone, Busse Bldg., Durham,
NC 27710, United States] - J. NEURO-ONCOL. 2003 65/1 (27-35) summ in ENGL
TP-38 is a recombinant chimeric targeted toxin composed of the
EGFR binding ligand TGF- and a genetically engineered form of
the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum
tolerated dose (MTD), we investigated this agent in a Phase I trial.
The primary objective of this study was to define the MTD and
dose limiting toxicity of TP-38 delivered by convection-enhanced
107
delivery in patients with recurrent malignant brain tumors. Twenty
patients were enrolled in the study and doses were escalated from
25 ng/mL to 100 with a 40 mL infusion volume delivered by two
catheters. One patient developed Grade IV fatigue at the 100 ng/mL
dose, but the MTD has not been established. The overall median
survival after TP-38 for all patients was 23 weeks whereas for those
without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients,
with residual disease at the time of therapy, have demonstrated
radiographic responses and one patient with a complete response
and has survived greater than 83 weeks.
552. The potential of chitosam in ocular drug delivery - Alonso
M.J. and Sánchez A. [M.J. Alonso, Dept. of Pharm./Pharmaceut.
Technol., Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain] - J. PHARM.
This paper presents an overview of the potential of chitosan-based
systems for improving the retention and biodistribution of drugs
applied topically onto the eye. Besides its low toxicity and good
ocular tolerance, chitosan exhibits favourable biological behaviour,
such as bioadhesion- and permeability-enhancing properties, and
also interesting physico-chemical characteristics, which make it a
unique material for the design of ocular drug delivery vehicles. The
review summarizes the techniques for the production of chitosan
gels, chitosan-coated colloidal systems and chitosan nanoparticles,
and describes their mechanism of action upon contact with the ocular mucosa. The results reported until now have provided evidence
of the potential of chitosan gels for enhancing and prolonging the
retention of drugs on the eye surface. On the other hand, chitosanbased colloidal systems were found to work as transmucosal drug
carriers, either facilitating the transport of drugs to the inner eye
(chitosan-coated colloidal systems containing indometacin) or their
accumulation into the corneal/conjunctival epithelia (chitosan nanoparticles containing ciclosporin). Finally, the tolerance, toxicity and
biodegradation of the carriers under evaluation were reviewed.
553. Kinetic studies of the degradation of an aminopenicillin antibiotic (amoxicillin trihydrate) in aqueous solution using heat
conduction microcalorimetry - Chadha R., Kashid N. and Jain
D.V.S. [R. Chadha, Pharmaceutical Chemistry Division, Univ. Inst.
of Pharmaceut. Sciences, Panjab University, Chandigarh 160014,
India] - J. PHARM. PHARMACOL. 2003 55/11 (1495-1503) - summ
in ENGL
Recent developments in isothermal microcalorimetry allow the
direct determination of kinetic and thermodynamic parameters for
slow reactions from studies conducted at appropriate temperatures
and under designated environmental control. The degradation kinetics of amoxicillin trihydrate has been investigated as a function
of pH (1-10) and temperature (303.15-318.15 K) at 0.5 M ionic
strength using heat conduction microcalorimetry. Equations were
developed incorporating calorimetric accessible data, rate constants
and change in enthalpy, which showed that the degradation of amoxicillin trihydrate in aqueous solution followed pseudo-first-order
kinetics under our experimental conditions. The enthalpy of degradation reaction was found to be exothermic in nature. The values
of the rate constant k for individual steps were determined from
the values of the overall rate constants at different pH. Energy of
activation of overall reaction as a function of pH and for individual
rate constants was determined. The log k-pH profiles indicated specific-acid and specific-base catalysis and there were inflection points
near pH 3 and pH 7 corresponding to the pKa1 and pKa2 values.
Quantitatively, there was good correlation between calorimetric determined half-Kfe (t1/2) and the literature value in the acidic region
determined by other methods at 310.15 K. The presence of a lactam ring and of an -amino group in the C-6 side chain played
a critical role in the degradation of amoxicillin trihydrate and the
zwitterionic form of the drug was found to be more stable.
554. Transdermal iotophoresis of insulin. Part 1: A study on the
issues associated with the use of platinum electrodes on rat skin
- Pillai O., Kumar N., Dey C.S. et al. [R. Panchagnula, Department
of Pharmaceutics, Natl. Inst. Pharmaceut. Educ./Res., Sector 67,
SAS Nagar, Punjab 160062, India] - J. PHARM. PHARMACOL.
2003 55/11 (1505-1513) - summ in ENGL
108
We have studied the issues associated with the use of platinum
electrodes for transdermal iontophoretic delivery of peptides, using
insulin as a model peptide. Insulin permeation was studied using
full-thickness rat skin by varying the donor solution pH as a function
of electrode polarity. The stability of insulin under the iontophoretic conditions was studied using TLC, SDS-polyacrylamide gel
electrophoresis and HPLC. Large pH shifts were observed during
anodal iontophoresis (AI), when the donor solution pH was above
the isoelectric point of insulin and in cathodal iontophoresis (CI),
when the donor solution pH was below the isoelectric point of
insulin. The direction and magnitude of electroosmotic flow was
influenced by pH of the donor solution and the electrode polarity.
On the other hand, the buffer used to maintain the pH governed the
contribution of electrorepulsion to the overall transport of insulin.
Electrochemical degradation of insulin was significant during AI at
pH 7.4. Among the pH investigated, AI of insulin at pH 3.6 and CI
at pH 8.35 were better, as the pH shift was relatively less and electrochemically more stable during iontophoresis as compared with
other pH. In summary, the pH shift caused by platinum electrodes
had a significant influence on the permeation and stability of insulin.
555. Potential utility of various protease inhibitors for improving the intestinal absorption of insulin in rats - Liu H., Tang
R., Pan W.-S. et al. [H. Liu, Department of Pharmacy, Wuhan
General Hospital, 627 Wu-luo Road, Wuhan, China] - J. PHARM.
The aim of the investigation was to study the effects of protease
inhibitors on the absorption of insulin in-situ from closed small and
large intestinal loops in rats and to investigate the mechanism of various protease inhibitors in different intestinal loops. The intestinal
absorption of insulin was evaluated by its hypoglycaemic effect and
serum insulin level in the presence or absence of luminal contents.
No marked hypoglycaemic effect was observed after administration
of insulin alone in either region in the presence or absence of luminal contents. A significant hypoglycaemic effect of insulin was
obtained in the large intestinal loop in the presence or absence of
luminal contents when insulin was co-administered with bacitracin
(20, 30 mM), sodium glycocholate (20, 40 mM), bestatin (29 mM),
leupeptin (21 mM) and cystatin (0.8 mM). In contrast, there was
no hypoglycaemic effect in the small intestinal loop in the presence
of luminal contents following small intestinal co-administration of
insulin with these protease inhibitors. The effectiveness of protease
inhibitors was susceptible to their categories, concentrations and
activity of proteolytic enzymes in different regions. The degree of
improving insulin absorption in intestine was in the order of leupeptin > sodium glycocholate > bacitracin > bestatin > cystatin.
At the same time, the percutaneous enhancement effect was observed in the presence of either sodium glycocholate or bacitracin.
These results suggest that protease inhibitors could increase the
insulin efficacy more effectively in the large intestine than in the
small intestine.
556. Persistent reversal of P-glycoprotein-mediated daunorubicin resistance by tetrandrine in multidrug-resistant human
T lymphoblastoid leukemia MOLT-4 cells - Liu Z.-L., Hirano
T., Tanaka S. et al. [T. Hirano, Department of Clinical Pharmacology, School of Pharmacy, Tokyo Univ. of Pharm. and Life Sci,
1432-1 Horinouchi, Hachloji, Tokyo 192-0392, Japan] - J. PHARM.
Multidrug resistance (MDR) represents a major problem in cancer chemotherapy. P-glycoprotein (P-gp), the drug efflux pump
that mediates this resistance, can be inhibited by compounds with
a variety of pharmacological functions, thus circumventing the
MDR phenotype. The present study was performed to evaluate
a unique MDR-reversal feature of a bisbenzylisoquinoline alkaloid
tetrandrine (TET) in a P-gp expressing MOLT-4 MDR line (MOLT4/DNR) established in our laboratory. Cell viability was determined
by an MTT assay. P-gp function was characterized by determining the Rh123 accumulation/efflux capacity. P-gp overexpression
in resistant MOLT-4/DNR cells was confirmed by flow cytometry analysis after staining with phycoerythrin-conjugated anti-P-gp
monoclonal antibody 17F9. Compared to ciclosporin A (CsA),
TET exhibited stronger activity to reverse drug resistance to daunorubicin (DNR), vinblastine (VLB) and doxorubicin (DOX) in
MOLT-4/DNR cells. TET showed no cytotoxic effects on parental
MOLT-4 cells lacking P-gp expression or on the resistant MOLT4/DNR cells. TET modulated DNR cytotoxicity even after it was
washed with the medium for 24 h, while CsA almost completely lost
its reversal capability 24h after washing. TET and CsA similarly
increased the accumulation of Rh123 in resistant MOLT-4/DNR
cells. However, TET inhibited Rh123 efflux from resistant cells
even after washing with the medium, while CsA rapidly lost its
ability to inhibit Rh123 efflux after washing. The current study
suggests that TET enhances the cytotoxicity of anticancer drugs in
the P-gp expressing MDR cell line by modulating P-gp in a different
manner to the well-known P-gp inhibitor CsA.
557. Non-genomic effects of tamoxifen on the activation of membrane-bound guanylate cyclase GC-A - Chen Z.-J., Vetter M.,
Chang G.-D. et al. [C.-H. Chang, Department of Medicine, Division of Hypertension, Case Western Reserve Univ. Sch. Med.,
Cleveland, OH 44106, United States] - J. PHARM. PHARMACOL.
2003 55/11 (1539-1545) - summ in ENGL
Oestrogen is known to exert both genomic and non-genomic effects on target tissues. Unlike the genomic effects, the identity of
receptors mediating the non-genomic effects of oestrogen remains
controversial. 17 -Estradiol has been shown to activate membranebound guanylate cyclase GC-A in PC12cells in a non-genomic
manner. To examine whether 17 -estradiol exerts a similar effect
in other cell types, we measured the effect of 17 -estradiol and tamoxifen, an anti-oestrogen, on guanylate cyclase activity in porcine
kidney proximal tubular LLC-PK1 cells. 17 -Estradiol increased
cGMP levels in LLC-PK1 cells. Interestingly, addition of tamoxifen
also increased cGMP levels in a concentration-dependent manner in
LLC-PK1 cells. The effects of both 17 -estradiol and tamoxifen on
guanylate cyclase activity were not additive, suggesting that oestrogen and tamoxifen activate the same enzyme. Similar phenomena
were also observed in LLC-PK1 cell membrane preparation. LLCPK1 cells do not express membrane-bound guanylate cyclase GC-B
and express low levels of membrane-bound guanylate cyclase GCC. Tamoxifen inhibited the activation of GC-A by atrial natriuretic
factor (ANF). However, it did not affect membrane-bound guanylate
cyclase GC-C stimulated by guanylin or Escherichia coli heat-stable
toxin STa. These results indicate that 17 -estradiol and tamoxifen
activate GC-A in LLC-PK1 cells. Thus, tamoxifen functions as
an agonist rather than an antagonist for the membrane oestrogen
receptor coupled to the activation of GC-A.
558. Repetitive administration of Shaoyao-Gancao-tang to rats
restores the bioavailability of glycyrrhizin reduced by antibiotic treatment - He J.-X., Akao T. and Tani T. [T. Tani,
Division of Pharmacognosy, Institute of Natural Medicine, Toyama
Med./Pharmaceut. University, 2630 Sugitani, Toyama 930-0194,
Japan] - J. PHARM. PHARMACOL. 2003 55/11 (1569-1575) summ in ENGL
Shaoyao-Gancao-tang (SGT), a traditional Chinese formulation,
is often used together with antibiotics such as amoxicillin and metronidazole (AMPC-MET) for the treatment of peptic ulcers in Japan.
However, the bioavailability of glycyrrhizin (GL) in SGT is severely
reduced by a single administration of AMPC-MET, and the reducing
effect continues for 12 days. GL is one of the major pharmacologically important glycosides in SGT and is transformed into the active
metabolite 18 -glycyrrhetic acid (GA) by intestinal bacteria in the
gut, followed by absorption of the latter into the blood. In order
to reduce the negative effect of AMPC-MET on the bioavailability
of GL, the optimum scheduling of the medications was examined.
We found that the reduction in the plasma GA concentration and
the GL-metabolizing activity in faeces caused by a single dose
of AMPC-MET could be sharply attenuated by the repetitive administration of SGT for 4 days. The GA concentration and the
GL-metabolizing activity were strongly enhanced by further continuous administration of SGT. These findings suggest that repetitive
administration of SGT starting 1 or 2 days after the administration
of AMPC-MET speeds the recovery of the bioavailability of GL in
SGT. Similar strategies for administering medications may also be
useful for combination therapy of antibiotics with other traditional
Chinese formulations containing bioactive glycosides.
559. The effect of Montelukast on bronchial provocation tests
and exhaled nitrix oxide levels in asthmatic patients - BerkSection 30 vol 126.2
man N., Avital A., Bardach E. et al. [Dr. N. Berkman, Institute
of Pulmonology, Hadassah University Hospital, P.O. Box 12000,
Jerusalem 91120, Israel] - ISR. MED. ASSOC. J. 2003 5/11 (778781) - summ in ENGL
Background: Leukotriene antagonist therapy in asthmatic
patients alleviates symptoms and improves exercise tolerance, however the effect of these drugs on bronchial firovocation tests and
exhaled nitric oxide levels are less clearly established. Objective: To determine the effect, of montelukast treatment on airway
hyperresponsiveness to exercise, methacholine and adenosine-5 monophosphate and on exhaled nitric oxide levels in steroid-naive
asthmatics. Methods: Following a 2 week run-in period, 20 mild
to moderate asthmatics were enrolled in an open label 6 week
trial of oral montelukast-sodium therapy. Bronchial hyperreactivity (exercise, methacholine and adenosine-5 -monophospnate
challenges) and exhaled nitric oxide levels were measured before
and after the 6 week period. Results: Montelukast treatment resulted in a significant improvement in exercise tolerance: median
FEV1 20.0% (range 0-50) prior to treatment vs. 15.0% (range
0-50) post-treatment (P = 0.029). A significant difference was also
observed for exhaled NO following therapy: median NO 16.0 ppb
(range 7-41) vs. 13.0 (range 4.8-26) (P = 0.016). No change
was seen in baseline lung function tests (FEV1 MEF50 ) or in the
bronchial responsiveness (PC20 ) for methacholine and adenosine5 -monophosphate. Conclusions: This study demonstrates that
the leukotriene antagonist montelukast-sodium reduces bronchial
hyperreactivity in response to exercise and reduces exhaled nitric
oxide levels but has little effect on bronchial responsiveness to
methacholine and adenosine challenges.
560. Cardiovascular disease in type 2 diabetics: Epidemiology,
risk factors and therapeutic modalities - Khamaisi M., Wexler
I.D., Skrha J. et al. [Dr. M. Khamaisi, Diabetes Center, Department of Internal Medicine, Hadassah University Hospital, P.O. Box
12000, Jerusalem 91120, Israel] - ISR. MED. ASSOC. J. 2003 5/11
Macrovascular complications associated with chronic hyperglycemia in type 2 diabetes mellitus is a major global health problem
that is currently on the rise. Accelerated cardiovascular and cerebrovascular atherosclerosis is the major cause of mortality in patients
with type 2 diabetes. Many of the risk factors for cardiovascular disease are operative or even exacerbated in diabetic patients, including
hypercholesterolemia, hypertriglyceridemia, hypertension, central
obesity, and smoking. Other diabetes-specific factors, such as increased levels of plasminogen activator 1 and fibrinogen, chronic
inflammation, genetic susceptibility, and accelerated glycosylation
end-products-mediated vascular damage, are thought to play a role
in the development of CVD among patients with type 2 diabetes.
Further studies will hopefully elucidate the clinical relevance of
such factors. In addition, recent studies indicate that hyperglycemia
is an important and independent risk factor for CVD. Increased risk
of CVD is directly related to elevated 1 and 2 hour post-prandial
blood glucose averages, as well as to fasting hyperglycemia. Thus,
specific treatment regimens designed to reduce the development
rate of cardiovascular complications in patients with type 2 diabetes
must consider the impact of risk factors and their control, as well as
the need for optimal metabolic and glycemic control.
561. Lercanidipine vs lacidipine in isolated systolic hypertension
- Millar-Carig M., Shaffu B., Greenough A. et al. [Dr. C. McDonald, Napp Pharmaceuticals Limited, Cambridge Science Park,
Milton Road, Cambridge CB4 0GW, United Kingdom] - J. HUM.
HYPERTENS. 2003 17/11 (799-806) - summ in ENGL
This randomised, double-blind, double-dummy, parallel group,
multicentre study compared the efficacy and tolerability of lercanidipine with lacidipine. Elderly patients with isolated systolic
hypertension (supine blood pressure 160/95 mmHg) were enrolled and underwent a placebo run-in period of 14-27 days before
random allocation to lercanidipine tablets 10 mg once daily (n=111)or lacidipine tablets 2 mg once daily (n = 111) for the assessment
period (112-160 days). Titration to lercanidipine 20 mg once daily
(two 10 mg tablets) or lacidipine 4 mg once daily (two 2 mg tablets)was allowed after 8 weeks, if required. Both treatments decreased
supine and standing systolic and diastolic blood pressure between
the end of the run-in period and the end of the assessment period
109
(P<0.0001). At the end of the assessment period, the estimated
mean treatment difference (95% confidence intervals) in supine
systolic blood pressure was -0.81 (-4.45, 2.84) mmHg. These confidence intervals were within the limits specified for equivalence, that
is, (-5, 5) mmHg. Ambulatory blood pressure monitoring showed
that the antihypertensive effects of both drugs lasted for the full 24h dosing period and followed a circadian pattern. Both treatments
were well tolerated with a low incidence of adverse drug reactions
and a low withdrawal rate. Significantly fewer patients withdrew
from treatment with lercanidipine (P=0.015). Neither treatment had
any clinically significant effect on pulse rate or cardiac conduction.
In conclusion, both treatments were equally effective in controlling
supine systolic blood pressure in patients with isolated systolic hypertension.
562. Antifungal activity of fluconazole in combination with lovastatin and their effects on gene expression in the ergosterol and
prenylation pathways in Candida albicans - Song J.L., Lyons
C.N., Holleman S. et al. [T.C. White, Seattle Biomed. Research
Institute, Suite 200, 4 Nickerson Street, Seattle, WA 98109-1651,
United States] - MED. MYCOL. 2003 41/5 (417-425) - summ in
ENGL
The sterol pathway in Candida albicans is the target for several
classes of antifungal drugs. Intermediates in the sterol pathway are
involved in ergosterol synthesis, prenylation and dolichol synthesis. This study examines gene expression of the sterol pathway
in response to lovastatin, an inhibitor of HMG-CoA reductase (Hmglp), and fluconazole, an inhibitor of 14 -lanosterol demethylase
(Erg11p). Minimum inhibitory concentration (MIC) studies indicated that lovastatin acts synergistically with fluconazole in vitro.
Semi-quantitative reverse transcriptase-polymerase chain reaction
(RT-PCR) results indicated that genes in the early part of the sterol
pathway, such as HMG1 and ERG20, did not alter expression in
the presence of both lovastatin and fluconazole, whereas genes in
the later part of the sterol pathway, such as ERG9 and ERG11, had
increased expression in response to these drugs in mid-logarithmic
growth. Genes involved in prenylation, such as RAM1 and RAM2,
also respond to these drugs in mid-logarithmic growth, although
another prenylation gene, CDC43, was not affected. After 24 h of
growth, the relative expression of ERG20, ERG9, and ERG11 remained unchanged or increased in the presence of both drugs, while
all other genes decreased in expression under all drug treatments.
563. Critical review of the manner in which the efficacy of therapies for rosacea are evaluated - Gupta A.K. and Chaudhry M.M.
[Dr. A.K. Gupta, Suite 6, 490 Wonderland Road South, London,
Ont., Canada] - INT. J. DERMATOL. 2003 42/11 (909-916) - summ
in ENGL
Background: Rosacea is a relatively common disorder that may
affect individuals of all races, particularly those of northern European decent. Its onset generally occurs in individuals between
the ages of 20 and 50 years. Rosacea may be classified into four
subtypes and one variant. Although individuals with rosacea may
not pass through all of the stages, the primary features of the disorder
include frequent flushing and blushing, nontransient erythema, the
presence of papules and pustules, and telangiectasia. Many agents
have been used to treat rosacea stigmata, especially because none of
these is uniformly effective. Aim: To identify the parameters that
are used to evaluate the response to therapy when different agents are
used to treat rosacea. For a given parameter, to determine whether
the different trials are consistent in the manner in which this variable
is measured. Methods: The reports on the efficacy and safety of the
different drug therapies used to treat rosacea were identified. We
searched MEDLINE (1966 to June 2002) for studies where rosacea
was treated. The parameters used to evaluate the efficacy of therapy
were determined. For each parameter, the ways in which it has been
measured were identified. Results: Efficacy of treatment is generally judged by evaluating the effect of the intervention on papules
and pustules, erythema, and telangiectasia. Manual lesional counts
of papules and pustules are usually performed. There is, however,
substantial variation in the methodology chosen for comparison of
erythema and telangiectasias. Color scales are popular for erythema
and telangiectasia, while grading scales are most commonly used
for physician and patient evaluations. Conclusions: For each of
the parameters that are commonly used to measure the efficacy of
110
treatments for rosacea, the different approaches by which it has
been measured in the various trials have been highlighted; these
dissimilarities can make it problematic to compare between clinical
trials. A greater degree of uniformity in the manner in which the
various parameters are evaluated would enable a more objective
comparison between the studies.
564. Prolactin effect on pre-pubertal Sertoli cell proliferation
and metabolism - Scarabelli L., Caviglia D., Bottazzi C. and
Palmero S. [Dr. L. Scarabelli, Dipto. Biol. Sperim. Amb./Appl.,
Sez. di Fisiol. Gen. e Comparata, Universita degli Studi di Genova, Corso Europa 26, 16132 Genova, Italy] - J. ENDOCRINOL.
INVEST. 2003 26/8 (718-722) - summ in ENGL
Direct effects of PRL on Sertoli cell proliferation were investigated by using Sertoli cell primary cultures isolated from both
prepubertal rat and porcine testes. PRL metabolic effects were
analyzed in rat Sertoli cell primary cultures. Exposure to physiological doses of PRL resulted in a significant increase (+50-60%) of
basal DNA synthesis, as reflected by the pattern of [3 H] thymidine incorporation during culture; significant increases in lactate
secretion (about 50%), androgen binding protein (ABP) production
(about 30%) and basal protein synthesis (25-30%), as reflected in
the augmented [14 C] valine incorporation, were also evident. Taken
together, our present findings, indicating significant effects of PRL
on Sertoli cell proliferation and metabolism, demonstrate that Sertoli
cells are a potential target for PRL action at testicular level during
pre-pubertal development. ©2003, Editrice Kurtis.
565. Intravenous ibandronate in men with osteoporosis: An
open pilot study over 2 years - Lamy O., Sandini L., Pache I. et al.
[Dr. O. Lamy, Department of Internal Medicine, CHUV, BH10 CH1011 Lausanne, Switzerland] - J. ENDOCRINOL. INVEST. 2003
26/8 (728-732) - summ in ENGL
In the treatment of osteoporosis, the tolerance of oral bisphosphonates is often low. The high potency of ibandronate allows iv bolus
injections that can be repeated every 2 to 3 months. However, the
best dose and time interval of the treatment with iv ibandronate is
still debated. Efficacy of 2-mg ibandronate injected every 3 months
was tested in men with osteoporosis over 2 yr, in a prospective,
open study. Fourteen men with primary osteoporosis, mean age
5712 yr (range: 40-73), received 2-mg ibandronate iv every 3
months over 2 yr. All got 1 g/day calcium and 880 UI/day vitamin D for 2 yr. Bone mineral density (BMD) increased after 2 yr
by 6.71.5% (mean changeSEM) at lumbar spine (p<0.001), by
3.208% at trochanter (p<0.001) and by 1.41.1% at femoral neck
(ns). Serum -crosslaps and osteocalcin decreased significantly by
30-45 and 30%, respectively, during the 2 yr of treatment. Serum
calcium increased from the lower to the middle fertile of the normal
range during the 2 yr of the study. The observed decrease of bone
remodelling and the increase of BMD are of the same magnitude as
those described with oral bisphosphonates. The increase of plasma
calcium confirms the positive effect of the supplementation with
calcium and vitamin D. These results suggest that 3 months are a
good interval between two doses of iv ibandronate, when 2 mg are
given. ©2003, Editrice Kurtis.
566. Rapid desensitisation of the GH secretagogue (ghrelin) receptor to hexarelin in vitro - Orkin R.D., New D.I., Norman D.
et al. [Dr. M. Korbonits, Department of Endocrinology, St. Bartholomew’s Hospital, Dominion House, Unit 1.1, 59 Bartholomew
Close, London EC1A 7BE, United Kingdom] - J. ENDOCRINOL.
INVEST. 2003 26/8 (743-747) - summ in ENGL
Ghrelin, the recently identified hormone with GH-secreting and
appetite-inducing effects, acts on the GH secretagogue receptor
(GHS-R). GHS-R belongs to the G protein-coupled 7 transmembrane domain receptors and activates the phospholipase C pathway;
it then leads to the release of GH from somatotroph cells via an
elevation of intracellular calcium concentration. Both in vivo and
in vitro studies demonstrated that the effect of GH secretagogues
(GHS) could be desensitised similar to most receptor stimulation
systems. We have studied whether acute desensitisation of the
GHS-R occurs in response to the GHS hexarelin in vitro in terms
of intracellular calcium concentration. Chinese hamster ovary cells
were transiently transfected with cDNA encoding the human type
1a GHS-R. The presence of messenger RNA was confirmed with
RT-PCR, while no GHS-R was observed in mock-transfected cells.
Calcium responses to the peptide GHS analogue hexarelin were
measured using the fluorescent indicator fura-2. Cells were stimulated with the peptide GHS, hexarelin, at concentrations between
10-10 and 10-7 M. Cells transfected with the GHS-R cDNA demonstrated a significant an specific calcium response to hexarelin that
was not observed in mock-transfected cells. Marked desensitisation of the calcium response to hexarelin was observed 2-5 min
after the first dose of hexarelin (10-7 M) was administered. These
data show directly for the first time the desensitisation of the GHS
receptor signal at the second messenger level. The desensitisation
of the receptor may play a major role in the regulation of effect of
circulating or locally produced ghrelin both in the GH and in the
appetite-regulating system or in other systems where ghrelin has
been shown to be active, such as the cardiovascular system or cell
proliferation. ©2003, Editrice Kurtis.
567. All-trans retinoic acid- and N-(4-hydroxyphenil)-retinamide-induced growth arrest and apoptosis in orbital
fibroblasts in Graves’ disease - Pasquali D., Bellastella A., Colantuoni V. et al. [Dr. D. Pasquali, Istituto di Endocrinologia, Seconda
Università di Napoli, Building 16, Via Pansini 5, 80131 Napoli,
Italy] - METAB. CLIN. EXP. 2003 52/11 (1387-1392) - summ in
ENGL
In this study, we evaluated by reverse transcription-polymerase
chain reaction (RT-PCR) the expression pattern of retinoic acid
receptors (RAR) , , and and cellular retinoic acid binding protein-I (CRBP-I) genes in 12 primary cultures of fibroblasts (F) from
orbital tissue of Graves’ ophthalmopathy (GO) patients. We also
studied the in vitro effects of all-trans retinoic acid (RA) and N-(4hydroxyphenil)-retinamide (4HPR), a less toxic and better tolerated
synthetic derivative of RA, on cell morphology, growth, apoptosis,
and cyclic adenosine monophosphate (cAMP) accumulation. All
primary cultures expressed RAR , , , and CRBP-I. FGO treated
with RA and 4HPR (10-7 mol/L) presented morphologic changes
and significantly inhibited cell growth after 72 hours. At 96 hours of
drug exposure, apoptosis was detected in 15% and 50% of RA- and
4HPR (10-7 mol/L)-treated cells, and p53 protein increased in cell
lysates. 4HPR induced a 70% decrease of Bcl-2 protein. After 30
minutes of RA and 4HPR (10-7 mol/L) exposure, a 20% decrease of
basal cAMP accumulation was seen, and forskolin cAMP-induced
increase was abolished. The expression of RAR , , , and
CRBP-I in primary cultures of FGO indicates that they are targets
for retinoids. Moreover, we show that RA and 4HPR are able to induce morphologic changes, inhibition of cell growth, and apoptosis
in FGO exerting their effects through RAR-modulated pathways.
The rapid inhibition of cAMP accumulation indicates that a novel
nonclassic retinoid pathway may also be involved. Finally, the
potent in vitro effects of 4HPR, a retinoid derivative with fewer
adverse reactions in vivo, could justify further investigations on a
clinical application of retinoids in GO. © 2003 Elsevier Inc. All
rights reserved.
568. Contrasting effects of nateglinide and rosiglitazone on insulin secretion and phospholipase C activation - Zawalich W.S.,
Tesz G. and Zawalich K.C. [Dr. W.S. Zawalich, Yale University, School of Nursing, 100 Church St. South, New Haven, CT
06536-0740, United States] - METAB. CLIN. EXP. 2003 52/11
(1393-1399) - summ in ENGL
When stimulated with 6 mmol/L glucose, a minimal, transient
insulin secretory response was observed from perifused rat islets.
The inclusion of 5 mol/L nateglinide significantly amplified release. Elevating glucose to 8 or 10 mmol/L resulted in an increasing
insulin secretory response that was again markedly potentiated by
the further inclusion of nateglinide. The calcium channel antagonist,
nitrendipine, abolished secretion to 8 mmol/L glucose plus nateglinide. Unlike nateglinide, rosiglitazone (5 mol/L), troglitazone (1
to 10 mol/L), or darglitazone (10 mol/L), 3 peroxisome proliferator-activated receptor gamma (PPAR ) agonists, were without
any acute stimulatory effect on insulin release in the simultaneous
presence of 6 to 10 mmol/L glucose. Glucose (8 to 10 mmol/L) significantly increased inositol phosphate accumulation. Nateglinide
amplified this response. Nitrendipine reduced inositol phosphate
(IP) accumulation in response to the combination of 8 mmol/L
glucose plus 5 mol/L nateglinide. Rosiglitazone had no effect on
IP accumulation. These results confirm the efficacy of nateglinide
as a potent glucose-dependent insulin secretagogue that exerts its
stimulatory effect, at least in part, through the activation of phospholipase C (PLC). No acute potentiating effect of rosiglitazone
on either insulin secretion or IP accumulation could be detected in
isolated rat islets. © 2003 Elsevier Inc. All rights reserved.
569. Milrinone, a selective phosphodiesterase 3 inhibitor, stimulates lipolysis, endogenous glucose production, and insulin
secretion - Cheung P., Yang G. and Boden G. [Dr. G. Boden,
Temple University Hospital, 3401 N Broad St., Philadelphia, PA
19140, United States] - METAB. CLIN. EXP. 2003 52/11 (14961500) - summ in ENGL
In vivo effects of milrinone, a selective phosphodiesterase 3
(PDE-3) inhibitor, on plasma free fatty acids (FFA), glucose, and
insulin levels were examined in alert rats. In dose response
studies, intravenous injection of 1, 5 or 25 mol/kg of milrinone provoked an immediate increase in plasma concentrations
of FFA and insulin, while glucose levels rose only in response
to the 5- and 25-mol/kg doses. During euglycemic-hyperinsulinemic (450 pmol/L) clamps, intravenous injection of milrinone
(25 mol/kg) completely inhibited insulin suppression of lipolysis
and of endogenous glucose production, while having no effect on
insulin-stimulated glucose uptake (ISGU). To explore the reason
why ISGU was not affected, we performed reverse-transcriptase
polymerase chain reaction (RT-PCR) with RNA from skeletal muscle, fat, and liver. The results showed that PDE-3B mRNA was
expressed in adipose tissue and liver, but it was not detected in
skeletal muscle. We conclude that PDE-3 plays a major role in
the inhibitory action of insulin on lipolysis in fat and on glucose
production in liver and, in addition, seems to be involved in insulin
secretion in pancreatic cells. © 2003 Elsevier Inc. All rights
reserved.
570. Effect of tetramethylpyrazine on exocrine pancreatic and
bile secretion - Zhao W.-C., Zhu J.-X., Tang N. et al. [Prof. H.C. Chan, Department of Physiology, Faculty of Medicine, Chinese
University of Hong Kong, Shatin, NT, Hong Kong] - WORLD J.
GASTROENTEROL. 2003 9/11 (2505-2508) - summ in ENGL
Aim: To investigate the effect of tetramethylpyrazine (ligustrazine, TMP) on the secretion of exocrine pancreas (and biliary).
Methods: In in vivo study, we investigated the effect of TMP on
the secretion of pancreatic-bile juice (PBJ) in rats. Using human
pancreatic duct cell line, CAPAN-1, combined with the short-circuit
current (Isc ) technique we further studied the effect of TMP on the
pancreatic anion secretion. Results: Administration of TMP (80
mg/kg, ip) significantly increased the secretion of PBJ (P<0.05),
but the pH of PBJ and the secretion of pancreatic protein were
not significantly affected. Basolateral addition of TMP produced
a dose-dependent increase in Isc (EC50 =1.56 mmol/L), which contained a fast transient Isc response followed by a slow decay. Apical
application of CI- channel blockers, DPC (1 mmol/L), decreased
the response by about 67.1 % (P<0.001), whereas amiloride (100
mol/L), a epithelial sodium channel blockers, had no effect. Removal of extracellular HC0-3 abolished TMP-induced increase in Isc
by about 74.4 % (P<0.001), but the removal of external CI- did not.
Pretreatment with phosphodiesterase inhibitor, IBMX(0.5 mmol/L),
decreased the TMP-induced Isc by 91 % (P<0.001). Conclusion:
TMP could stimulate the secretion of PBJ, especially pancreatic
ductal HCO-3 secretion via cAMP or cGMP-dependent pathway. It
need further study to investigate the roles of cAMP or cGMP in the
effect of TMP on the secretion of exocrine pancreas.
571. Therapeutic efficacy of high-dose vitamin C on acute pancreatitis and its potential mechanisms - Du W.-D., Yuan Z.-R.,
Sun J. et al. [Dr. W.-D. Du, Department of Surgery, Huadong
Hospital, No. 221 Yanan Xilu, Shanghai 200040, China] - WORLD
J. GASTROENTEROL. 2003 9/11 (2565-2569) - summ in ENGL
Aim: To observe the therapeutic efficacy of high-dose Vitamin
C (Vit. C) on acute pancreatitis (AP), and to explore its potential
mechanisms. Methods: Eighty-four AP patients were divided into
treatment group and control group, 40 healthy subjects were taken
as a normal group. In the treatment group, Vit. C (10 g/day) was
given intravenously for 5 days, whereas in the control group, Vit.
111
C (1 g/day) was given intravenously for 5 days. Symptoms, physical signs, duration of hospitalization, complications and mortality
rate were monitored. Meanwhile, serum amylase, urine amylase
and leukocyte counts were also determined. The concentration of
plasma vitamin C (P-VC), plasma lipid peroxide (P-LPO), plasma
vitamin E (P-VE), plasma -carotene (P- -CAR), whole blood
glutathione (WB-GSH) and the activity of erythrocyte surperoxide
dimutase (E-SOD) and erythrocyte catalase (E-CAT) as well as T
lymphocyte phenotype were measured by spectrophotometry in the
normal group and before and after treatment with Vit. C in the
treatment and the control group. Results: Compared with the normal group, the average values of P-VC, P-VE, P- -CAR, WB-GSH
and the activity of E-SOD and E-CAt in AP patients were significantly decreased and the average value of P-LPO was significantly
increased, especially in severe acute pancreatitis (SAP) patients
(P<0.05. P-VC, P=0.045; P-VE, P=0.038; P=0.041; P- -CAR,
P=0.046; WB-GSH, P=0.039; E-SOD, P=0.019; E-CAT, P=0.020;
P-LPO, P=0.038). Compared with the normal group, CD3 and CD4
positive cells in AP patients were significantly decreased. The ratio
of CD4 /CD8 and CD4 positive cells were decreased, especially in
SAP patients (P<0.05. CD4 /CD8 , P=0.041; CD4 , P=0.019). Fever
and vomiting disappeared, and leukocyte counts and amylase in
urine and blood become normal quicker in the treatment group than
in the control group. Moreover, patients in treatment group also
had a higher cure rate, a lower complication rate and a shorter
in-ward days compared with those in he control group. After treatment, the average value of P-VC was significantly higher and the
values of SIL-2R, TNF-, IL-6 and IL-8 were significantly lower
in the treatment group than in the control group (P<0.05 P-VC,
P=0.045; SIL-2R, P=0.012; TNP-, P=0.030; IL-6, P=0.015; and
IL-8, P=0.043). In addition, the ratio of CD4 /CD8 and CD4 positive cells in the patients of treatment group were significantly higher
than that of the control group after treatment (P<0.05. CD4 /CD8 ,
P=0.039; CD4 , P=0.024). Conclusion: High-dose vitamin C has
therapeutic efficacy on acute pancreatitis. The potential mechanisms include promotion of anti-oxidizing ability of AP patients,
blocking of lipid peroxidation in the plasma and improvement of
cellular immune function.
572. Primary sensory neuronal rescue with systemic acetylL-carnitine following peripheral axotomy. A dose-response
analysis - Wilson A.D.H., Hart A., Brannstrom T. et al. [Dr. G. Terenghi, Blond McIndoe Research Laboratory, Plastic/Reconstructive
Surgery Res., University of Manchester, Stopford Building, Oxford
Road, Manchester M13 9PT, United Kingdom] - BR. J. PLAST.
SURG. 2003 56/8 (732-739) - summ in ENGL
The loss of a large proportion of primary sensory neurons after
peripheral nerve axotomy is well documented. As a consequence of
this loss, the innervation density attained on completion of regeneration will never be normal, regardless of how well the individual
surviving neurons regenerate. Acetyl-L-carnitine (ALCAR), an endogenous peptide in man, has been demonstrated to protect sensory
neurons, thereby avoiding loss after peripheral nerve injury. In this
study we examined the dose-response effect of ALCAR on the primary sensory neurons in the rat dorsal root ganglia (DRG) 2 weeks
after sciatic nerve axotomy. Six groups of adult rats (n = 5) underwent unilateral sciatic nerve axotomy, without repair, followed
by 2 weeks systemic treatment with one of five doses of ALCAR
(range 0.5-50 mg/kg/day), or normal saline. L4 and L5 dorsal
root ganglia were then harvested bilaterally and sensory neuronal
cell counts obtained using the optical disector technique. ALCAR
eliminated neuronal loss at higher doses (50 and 10 mg/kg/day),
while lower doses did result in loss (12% at 5 mg/kg/day, p <
0.05; 19% at 1 mg/kg/day, p < 0.001; 23% at 0.5 mg/kg/day, p <
0.001) compared to contralateral control ganglia. Treatment with
normal saline resulted in a 25% (p < 0.001) loss, demonstrating
no protective effect in accordance with previous studies. ALCAR
preserves the sensory neuronal cell population after axotomy in a
dose-responsive manner and as such, has potential for improving
the clinical outcome following peripheral nerve trauma when doses
in excess of 10 mg/kg/day are employed. © 2003 The British
Association of Plastic Surgeons. Published by Elsevier Ltd. All
rights reserved.
112
6.1. Anesthetics
573. Effects of Lidocaine on Shock-Induced Vulnerability - Li
L., Nikolski V. and Efimov I.R. [Dr. I.R. Efimov, Department of
Biomedical Engineering, Case Western Reserve University, 10900
Euclid Avenue, Cleveland, OH 44106-7207, United States] - J.
CARDIOVASC. ELECTROPHYSIOL. 2003 14/10 SUPPL. (S237S248) - summ in ENGL
Introduction: Lidocaine is known to increase the defibrillation
threshold (DFT) of monophasic shocks (MS) and have no effect on
DFT of biphasic shocks (BS). The aim of this study was to enhance
our understanding of the mechanisms of vulnerability and defibrillation through the investigation of this difference. Methods and
Results: We studied the effect of 15 M lidocaine on shock-induced
vulnerability using fluorescent imaging of Langendorff-perfused
rabbit hearts. Vulnerability was assessed as vulnerable window
with shock strengths of 15 to 150 V and vulnerable period (VP) with
shock delivery phase of 0% to 100% of action potential duration
(% APD). With MS, lidocaine caused a significant increase in both
the upper limit of vulnerability (ULV, 71 17 V vs 120 1.5 V, P
< 0.01) and upper limit of VP (91 8. 0% APD vs 110 4.2%
APD, P < 0.01). With BS, lidocaine had no effect on ULV (40
3.4 V vs 45 4.5 V) and did not increase the upper limit of
VP (78 8.9% APD vs 96 12% APD, P < 0.01). Lidocaine
caused reduction of the conduction velocity during pacing (0.58
0.08 m/s vs 0.44 0.05 m/s, P < 0.01), shock-induced break
excitation (0.82 0.17 m/s vs 0.30 0.07 m/s, P < 0.01), and
postshock reentry (0.34 0.07 m/s vs 0.19 0.08 m/s, P < 0.01).
Lidocaine had no effect on shock-induced virtual electrode polarization. Conclusion: Lidocaine increased MS ULV due to slowing
of shock-induced break-excitation wavefronts, which resulted in
enhanced probability of survival of virtual electrode induced phase
singularity. Lidocaine had no effect on BS ULV because no break
excitation was induced by BS. Reduction of conduction velocity by
lidocaine resulted in increased dispersion of repolarization and led
to upper limit of VP increase for both MS and BS.
574. GABAA receptor modulation by the novel intravenous general anaesthetic E-6375 - Pau D., Belelli D., Callachan H. et al.
[J.J. Lambert, Neuroscience Institute, Dept. of Pharmacol. and
Neuroscience, University of Dundee, Dundee DD1 9SY, United
Kingdom] - NEUROPHARMACOLOGY 2003 45/8 (1029-1040) summ in ENGL
E-6375 (4-butoxy-2-[4-(2-cyanobenzoyl)-1-piperazinyl] pyrimidine hydrochloride) is a new intravenous general anaesthetic with
an anaesthetic potency, in mice, comparable to propofol, or etomidate. Here, we examined the effect of E-6375 upon the GABAA
receptor, a putative target of intravenous anaesthetic action. E-6375
reversibly enhanced GABA-evoked currents mediated by recombinant GABAA (1 2 2L ) receptors expressed in Xenopus laevis
oocytes, with little effect on NMDA- and kainate-evoked currents
mediated by NR1a/NR2A and GluR1o/GluR2o glutamate receptors,
respectively. E-6375 prolonged the decay of GABA-evoked miniature inhibitory postsynaptic currents recorded from rat Purkinje
neurones demonstrating the anaesthetic also enhanced the activity
of synaptic GABAA receptors. The GABA enhancing action of
E-6375 on recombinant GABAA receptors was unaffected by the
subtype of the isoform (i.e. x 2 2L ; x=1-3) within the receptor,
but was increased by the omission of the 2L subunit. Receptors
incorporating 2 , or 3 , subunits were more sensitive to modulation
by E-6375 than those containing the 1 subunit. The selectivity of
E-6375 was largely governed by the identity (serine or asparagine)of a single amino acid residue within the second transmembrane
domain of the -subunit. The various in vivo actions of general
anaesthetics may be mediated by GABA A receptor isoforms that
have a differential distribution within the CNS. The identification of
agents, such as E-6375, that discriminate between GABAA receptor
subtypes may augur the development of general anaesthetics with
an improved therapeutic profile. © 2003 Elsevier Ltd. All rights
reserved.
575. A Comparison of a Triple-Injection Axillary Brachial
Plexus Block with the Humeral Approach - March X., Pardina
B., Torres-Bahı́ S. et al. [Dr. X. March, Servei d’Anestesia i
Reanimacio, Hosp. Univ. Girona Dr. Josep Trueta, Av. de França
s/n, 17007 Girona, Spain] - REG. ANESTH. PAIN MED. 2003 28/6
Background and Objectives: This prospective, randomized, and
single-blind study compared effectiveness, performance, onset, and
total anesthetic time and complications of the multiple axillary block
(median, radial, and musculocutaneous nerves) with the humeral
approach. Methods: One hundred patients were randomly assigned
to 2 groups. In group A (axillary) median, radial, and musculocutaneus nerves were located by a nerve stimulator and injections were
made. In group H (humeral) all 4 terminal nerves of the brachial
plexus were located and injections were made. A total of 40 mL
mepivacaine of 1% was used. Results: Complete sensory block
of all 6 peripheral nerves occurred in 94% and 79% of patients in
groups A and H, respectively (P < .05). The time to perform the
block was shorter in group A (8 4 minutes 11 4 minutes; P
< .001); onset time was shorter in group A (16 8 minutes 21
9 minutes; P < .05); total anesthetic time was shorter in group
A (24 8 minutes 33 10 minutes; P < .0001). Complete
motor block was greater in group A (88% 66%; P < .05). More
vascular punctures occurred in group A (22% 8%, P < .05).
Conclusion: The triple-injection axillary block was more effective
than the humeral approach as it was associated with more cases of
sensory and complete motor block and gave shorter performance
and onset times.
576. Lateral Approach to the Sciatic Nerve in the Popliteal
Fossa: A Comparison between 1.5% Mepivacaine and 0.75%
Ropivacaine - Taboada M., Cortés J., Rodrı́guez J. et al. [Dr.
M. Taboada, Department of Anesthesiology, Hosp. Clin. Univ.
de Santiago, Travesı́a da Choupana s/n, 15706 Santiago de Compostela, Spain] - REG. ANESTH. PAIN MED. 2003 28/6 (516-520) summ in ENGL
Background and Objectives: Ropivacaine and mepivacaine are
commonly used local anesthetics for peripheral nerve blockade. The
purpose of the present study was to compare onset time, quality of
anesthesia, and duration of analgesia with ropivacaine 0.75% and
mepivacaine 1.5% for lateral popliteal nerve block. Methods: Fifty
American Society of Anesthesiologists (ASA) physical status I or
II patients scheduled for foot and ankle surgery with calf tourniquet
under lateral popliteal sciatic nerve block were randomly assigned
to receive 30 mL of either ropivacaine 0.75% or mepivacaine 1.5%.
Time required for onset of sensory and motor block, resolution of
motor blockade, onset of postsurgical pain, and time of first analgesic medication were recorded. Results: The 2 groups were similar
with regard to demographic variables and duration of surgery. Onset
of sensory and motor block was significantly shorter in the mepivacaine group (9.9 3.3 min and 14.7 3.6 min, respectively) than
in the ropivacaine group (18.1 6.1 min and 23.6 5.5 min,
respectively) (P < 0.001). Resolution of motor block occurred
later in the ropivacaine group than in the mepivacaine group (P <
0.001), and duration of postoperative analgesia was significantly
longer in the ropivacaine group (19 3.4 h) compared with the
mepivacaine group (5.9 1.1 h) (P < 0.001). Analgesic requirements were higher in mepivacaine group than in the ropivacaine
group (P < 0.001). There were 2 failed blocks, one in each group.
Conclusions: Both ropivacaine and mepivacaine provided effective
sciatic nerve blockade. Mepivacaine 1.5% displayed a significantly
shorter onset time than ropivacaine 0.75%. Postoperatively, ropivacaine 0.75% resulted in longer-lasting analgesia and less need for
oral pain medication.
6.2. Opiates and other analgesics
577. The burden of acute postoperative pain and the potential role of the COX-2-specific inhibitors - Stephens J., Laskin
B., Pashos C. et al. [J. Stephens, Abt Associates Clinical Trials, HERQuLES Group, 4800 Montgomery Lane, Bethesda, MD
20814, United States] - RHEUMATOLOGY (UK) 2003 42/SUPPL.
3 (iii40-iii52) - summ in ENGL
Pain has been recognized as a problem of global proportions,
and postoperative pain is one of the most common types of pain.
Postoperative pain is acute and, although it is preventable and/or
treatable, it is often undertreated. Lack of appropriate analgesic
management has significant impact on clinical and economic outcomes. Negative clinical outcomes of inadequately managed acute
postoperative pain include extended hospitalization, compromised
prognosis, higher morbidity and mortality, and the development of
a chronic pain state as a result of neuronal plasticity. Although
estimating the economic burden of postoperative pain is difficult,
this burden is considerable and results from direct costs due to
excess health-care resource use, as well as indirect costs due to
reduced patient functionality and productivity. These latter factors
also have a significant adverse impact on patients’ quality of life
and may be associated with the development of depression and
anxiety. Thus, improved clinical outcomes are dependent not only
on the availability of effective drugs but also on their appropriate
utilization. A multimodal approach incorporating different drugs
and techniques is effective in reducing postoperative pain but is
limited by the currently available therapies. The efficacy of opioids is well established, but there are concerns about dependency,
respiratory depression and side-effects, which patients often find
intolerable. Non-steroidal anti-inflammatory drugs (NSAIDs) are
effective as adjunctive medication in a multimodal regimen but are
associated with side-effects, such as platelet dysfunction and renal
and gastrointestinal toxicity, that have special clinical significance
in patients undergoing surgical procedures. Cyclooxygenase-2-specific inhibitors such as celecoxib, rofecoxib and valdecoxib, were
developed to provide the efficacy of non-specific NSAIDs while
limiting associated toxicity. These agents have demonstrated analgesic efficacy and an opioid-sparing effect in a variety of surgical
procedures, suggesting their value as an alternative to non-specific
NSAIDs. Further studies are needed to determine the impact of
these drugs on clinical and economic outcomes when used in a
programme of postsurgical pain management.
578. Liver Enzyme Modification in Undernourished Rats
Treated with Acetaminophen (Span) - MODIFICACIÓN DE ENZIMAS
HEPÁTICAS EN RATAS DESNUTRIDAS TRATADAS CON ACETAMINOFÉN González-Mendoza M. and Vicuña-Fernández N. [M. GonzálezMendoza, Avenida Principal de La Pedregosa, Mérida-Mérida,
Venezuela] - GAC. MED. MEX. 2003 139/5 (429-433) - summ
in ENGL, SPAN
Acetaminophen is used as an analgesic and antipyretic. Due
to its relative safety at therapeutic dose, it is frequently used in
children and in pregnant women. We evaluated the effect of a
dose equivalent to the therapeutic dose of Acetaminophen in undernourished rats; 72 Wistar male rats of 18 weeks of age, with
weight between 270 and 280 g, were distributed randomly in four
groups: A, normal without food restriction; B, normal without food
restriction treated with Acetaminophen (100 mg/kg); C; undernourished by food restriction and D, undernourished by food restriction
treated with Acetaminophen (100 mg/kg). The results showed decreasing of body and hepatic weight in undernourished rats and in
undernourished treated with Acetaminophen, significant decrease of
serum albumin concentration (p<0.001). It was demonstrated that
activity of the enzymes alanine aminotransferase (ALT), aspartate
aminotransferase (AST) and alkaline phosphatase significantly decreased (p<0.001) in the group of undernourished rats treated with
Acetaminophen compared with the other groups. We concluded that
the Acetaminophen induces hepatic lesions in undernourished rats
treated with a single non toxic dose of 100 mg/kg of weight, probably
as a consequence of the inherent susceptibility to malnutrition.
579. Spinal muscarinic receptors are activated during low or
high frequency TENS-induced antihyperalgesia in rats - Radhakrishnan R. and Sluka K.A. [K.A. Sluka, Grad. Prog. Phys.
Ther./Rehab. Sci., Pain Research Program, University of Iowa,
Iowa City, IA 52242-1190, United States] - NEUROPHARMACOLOGY 2003 45/8 (1111-1119) - summ in ENGL
Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological modality used clinically to relieve pain. Central
involvement of serotonin and endogenous opioids are implicated in
TENS-induced analgesia. Activation of spinal cholinergic receptors is antinociceptive and these receptors interact with opioid and
serotonin receptors. In the current study, the possible involvement
of spinal cholinergic receptors in TENS analgesia was investigated
in rats. Hyperalgesia was induced by inflaming one knee joint with
3% kaolin-carrageenan and assessed by measuring paw withdrawal
113
latency (PWL) to heat before and 4 h after injection. The non-selective nicotinic antagonist mecamylamine (50 g), non-selective
muscarinic antagonist atropine (30 g) or one of the muscarinic
subtype antagonists: pirenzepine (M1 , 10 g), methoctramine (M2 ,
10 g), 4-DAMP (M3 , 10 g), or saline was administered intrathecally just prior to TENS treatment. Low or high frequency TENS
was then applied to the inflamed knee and PWL was determined
again. Atropine, pirenzepine and 4-DAMP significantly attenuated the antihyperalgesic effects of low and high frequency TENS
while mecamylamine and methoctramine had no effects, compared
to saline control. The results show that TENS-induced antihyperalgesia is mediated partially by activation of spinal muscarinic
receptors but not spinal nicotinic receptors. Further, the results
also indicate that spinal M1 and M3 muscarinic receptor subtypes
mediate the muscarinic component of TENS antihyperalgesia. ©
2003 Elsevier Ltd. All rights reserved.
580. Participation of the opioid system in cannabinoid-induced
antinociception and emotional-like responses - Maldonado R.
and Valverde O. [R. Maldonado, Laboratori de Neurofarmacologia,
Dept. Ciences Experimentals la Salut, Universitat Pompeu Fabra,
C/Doctor Aiguader, s/n, 08003 Barcelona, Spain] - EUR. NEUROPSYCHOPHARMACOL. 2003 13/6 (401-410) - summ in ENGL
Several anatomical, biochemical and pharmacological evidence support the existence of bidirectional interactions between
cannabinoid and opioid systems. The present review is focused on
the participation of the endogenous opioid system in the antinociceptive and emotional-like responses induced by cannabinoids, and
the development of tolerance to cannabinoid pharmacological effects. Cannabinoid and opioid agonists produce antinociception by
acting on similar structures within the central nervous system, and a
peripheral mechanism has been also proposed for both compounds.
Pharmacological studies have suggested that the endogenous opioid system could be involved in cannabinoid antinociception and the
development of cannabinoid tolerance. Recent studies using knockout mice have also demonstrated the role of the opioid system in
cannabinoid antinociception and tolerance, although some discrepancies with the previous pharmacological results have been reported
when using knockout mice. On the other hand, cannabinoid administration can induce anxiolytic-like responses that are mediated at
least in part by an endogenous opioid activity on - and -opioid
receptors. © 2003 Elsevier B.V./ECNP. All rights reserved.
581. Drug dependence and the endogenous opioid system Gerrits M.A.F.M., Lesscher H.B.M. and Van Ree J.M. [M.A.F.M.
Gerrits, Rudolf Magnus Inst. of Neuroscience, Dept. of
Pharmacology and Anatomy, University Medical Center Utrecht,
Universiteitsweg 100, 3584 CG Utrecht, Netherlands] - EUR. NEUROPSYCHOPHARMACOL. 2003 13/6 (424-434) - summ in ENGL
The discovery of endogenous opioids has markedly influenced
the research on the biology of drug dependence. Evidence has
been presented that these brain substances are self-administered
by laboratory animals. This finding, among others, has led to
the hypothesis that endogenous opioids are involved in reinforcing habits, including dependence on drugs of abuse. The course of
drug dependence is presented as a continuum from no drug use via
controlled use to an actual dependence on the drug. Specific brain
opioid systems belonging to four conceptualized brain circuits are
described to be involved during the different phases of the drug
dependence continuum. More recent research to delineate the role
of endogenous opioid systems in drug dependence has focussed
on genetic research in humans and animals. Among others, the
findings obtained from studies of opioid receptor and opioid peptide precursor knockout mice provided further support for a role of
endogenous opioid systems in drug dependence, in agreement with
previous pharmacological studies. © 2003 Elsevier B.V./ECNP. All
rights reserved.
582. Analgesic properties of Capraria biflora leaves aqueous
extract - Acosta S.L., Muro L.V., Sacerio A.L. et al. [S.L. Acosta,
Pharmacy Department, Chemical and Pharmacy School, Central
University of Las Villas, Carretera a Camajuanı́ Km. 5.5, Santa
Clara, Villa Clara, Cuba] - FITOTERAPIA 2003 74/7-8 (686-688) summ in ENGL
114
The analgesic properties of dried leaves of Capraria biflora were
investigated. The aqueous extract (50-200 mg kg-1 ) produced moderate inhibition of acetic acid-induced writhing in mice. At the same
doses, a better analgesic effect was observed on the hot plate test.
583. The Use of Clinical Trial Simulation to Support Dose Selection: Application to Development of a New Treatment for
Chronic Neuropathic Pain - Lockwood P.A., Cook J.A., Ewy
W.E. and Mandema J.W. [P.A. Lockwood, Clin. Pharmacokin. and
Pharmacodyn., Pfizer Global R. and D., Ann Arbor, MI, United
States] - PHARM. RES. 2003 20/11 (1752-1759) - summ in ENGL
Purpose. Pregabalin is being evaluated for the treatment of neuropathic pain. Two phase 2 studies were simulated to determine how
precisely the dose that caused a one-point reduction in the pain score
could be estimated. The likelihood of demonstrating at least a onepoint change for each available dose strength was also calculated.
Methods. A pharmacokinetic-pharmacodynamic (PK/PD) model
relating pain relief to gabapentin plasma concentrations was derived from a phase 3 study. The PK component of the model was
modified to reflect pregabalin PK. The PD component was modified by scaling the gabapentin concentration-effect relationship to
reflect pregabalin potency, which was based on preclincal data.
Uncertainty about the potency difference and the steepness of the
concentration-response slope necessitated simulating a distribution
of outcomes for a series of PK/PD models. Results. Analysis of the
simulated data suggested that after accounting for the uncertainty,
there was an 80% chance that the dose defining the clinical feature
was within 45% of the true value. The likelihood of estimating
a dose that was within an acceptable predefined precision range
relative to a known value approximated 60%. The minimum dose
that should be studied to have a reasonable chance of estimating
the dose that caused a one-point change was 300 mg. Conclusions. Doses that identify predefined response may be imprecisely
estimated, suggesting that replication of a similar outcome may be
elusive in a confirmatory study. Quantification of this precision
provides a rationale for phase 2 trial design and dose selection for
confirmatory studies.
See also: 606, 744.
6.3. Antiinflammatory agents
584. Inhibition of Mg2+ -dependent adhesion of polymorphonuclear leukocytes by serum hemopexin: Differences in
divalent-cation dependency of cell adhesion in the presence and
absence of serum - Suzuki K., Kobayashi N., Doi T. et al. [Dr.
K. Suzuki, Department of Biology, School of Education, Waseda
University, Shinjuku-ku, Tokyo 169-0051, Japan] - CELL STRUCT.
FUNCT. 2003 28/4 (243-253) - summ in ENGL
Circulating and nonadherent polymorphonuclear leukocytes
(PMNs) become activated to attain adhesive state in an integrindependent manner by various stimuli, and perform a variety of
microbicidal functions such as phagocytosis and superoxide production. We found that, in the absence of serum, a physiological
concentration of hemopexin has a strong inhibitory action on Mg2+ dependent adhesion of PMA-activated PMNs to fibrinogen- and
serum-coated surfaces. Under these conditions, Ca2+ had no effect
on Mg2+ -dependent adhesion or the adhesion-inhibitory activity of
hemopexin. In contrast, PMNs suspended in serum containing sufficient amounts of hemopexin to inhibit adhesion showed marked
adherence, which was inhibited by EGTA. Next, we prepared a
small-molecule fraction of serum by ultrafiltration followed by boiling. PMA-activated PMNs was found to adhere in the presence of
both hemopexin and the small-molecule fraction, and the adhesion
was enhanced by exogenous Ca2+ . EGTA abolished the effect of
the small molecule fraction. The data suggest that serum contains
adhesion-promoting factor(s) which allows PMNs to adhere despite
the presence of hemopexin and that Ca2+ is required for adhesionpromoting activity. Further study of hemopexin may provide clues
for new therapeutic strategies aimed at interfering with PMN adhesion to control inflammation and tissue injury.
585. Channelling of patients taking NSAIDs or cyclooxygenase2-specific inhibitors and its effect on interpretation of outcomes
- MacDonald T.M., Pettitt D., Lee F.H. and Schwartz J.S. [T.M.
MacDonald, Medicines Monitoring Unit, Dept. of Clin. Pharmacol./Therapeut., Ninewells Hospital/Medical School, Dundee DD1
9SY, United Kingdom] - RHEUMATOLOGY (UK) 2003 42/SUPPL.
3 (iii3-iii10) - summ in ENGL
When new drugs with improved safety or efficacy are introduced,
they may be preferentially prescribed to specific populations of
patients. Safety and efficacy may be underestimated if such channelling effects are not recognized. Meloxicam and cyclooxygenase
(COX)-2-specific inhibitors were developed as safer alternatives to
non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment
of osteoarthritis and rheumatoid arthritis. Studies of the use of
meloxicam and COX-2-specific inhibitors demonstrate that both of
these drugs are being prescribed to patients at increased risk of
gastrointestinal adverse drug events. In the case of COX-2-specific
inhibitors, this channelling appears to represent a prescribing pattern
consistent with current recommendations. Subsequent analysis of
the data, after adjusting for channelling bias, showed that the risk
of gastrointestinal toxicity for meloxicam was similar to that for
other NSAIDs, while COX-2-specific inhibitors reduced the risk of
developing gastrointestinal adverse drug events by approximately
60%. These studies serve as examples of observed channelling
bias and highlight the need for adjusting for channelling in order to
provide a valid assessment of relevant outcomes for drugs likely to
be preferentially prescribed to specific populations.
586. Drug utilization review of celecoxib in Ontario - LeLorier J.,
Fitzsimon C., Keresteci M. et al. [F. Lavoie, 17300 Trans-Canada
Highway, Kirkland, Que. H9J 2M5, Canada] - RHEUMATOLOGY
(UK) 2003 42/SUPPL. 3 (iii11-iii16) - summ in ENGL
Cyclooxygenase (COX)-2-specific inhibitors were developed to
circumvent the gastrointestinal toxicity of non-specific non-steroidal anti-inflammatory drugs while maintaining, efficacy. However,
the higher acquisition cost of COX-2-specific inhibitors has resulted
in the implementation of a programme for cost containment in the
Ontario public drug program. This programme consists of limited
use (LU) criteria that need to be met for drug reimbursement of
patients with osteoarthritis (OA) or rheumatoid arthritis (RA). Determining the proportion of patients eligible for reimbursement for
celecoxib according to the LU criteria (based on prior treatment
failure and the presence or history of serious ulcer-related gastrointestinal complications) can provide an indication of the extent of
adherence to suggested guidelines. Using a patient-based survey
and an analysis of the Ontario Drug Benefit Program database, the
proportion of patients prescribed celecoxib who met rigorous or
pragmatic definitions of the LU criteria was determined. The extent
of coprescription of gastroprotective agents among patients taking
celecoxib was also determined. Using the pragmatic definition, the
majority of patients in the patient-based survey (53% for OA and
81% for RA) met the LU criteria. Similarly, in the database analysis,
the majority of patients (76% for OA and 78% for RA) met the LU
criteria. These data suggest that physician prescribing of celecoxib
is consistent with the LU criteria. Concomitant prescription of gastroprotective agents in patients taking celecoxib was approximately
40%. It is recommended that further investigations be performed to
determine the long-term impact of LU criteria on clinical and economic outcomes, since these criteria may also serve to restrict use
in patients who may benefit from taking COX-2-specific inhibitors.
587. Persistency of use of COX-2-specific inhibitors and nonspecific non-steroidal anti-inflammatory drugs (NSAIDs) in
Quebec - Moride Y., Ducruet T., Rochon S. and Lavoie F. [Y.
Moride, Faculty of Pharmacy, Université de Montréal, C.P. 6128
succ. Centre-Ville, Montréal, Que. H3T 3J7, Canada] - RHEUMATOLOGY (UK) 2003 42/SUPPL. 3 (iii17-iii22) - summ in ENGL
The effectiveness of pharmacological therapies is dependent in
part on patient persistency with the prescribed therapeutic regimen. In the case of non-specific non-steroidal anti-inflammatory
drugs (NSAIDs), effectiveness is often compromised by undesirable side-effects, poor compliance or discontinuation of therapy.
While patterns of utilization of non-specific NSAIDs have been
investigated, few data are available on the patterns of persistency
for cyclooxygenase (COX)-2-specific inhibitors. This study used
a provincial health-care system database in Quebec, Canada, to
determine the duration of treatment in new users of COX-2-specific inhibitors and non-specific NSAIDs over the first 3 months of
treatment, and to characterize the factors associated with treatment
persistency. Results demonstrate that the median duration of treatment was longer among patients initially prescribed COX-2-specific
inhibitors (30 days and 23 days for celecoxib and rofecoxib respectively) than in those prescribed non-selective NSAIDs (10 days).
Although the percentage of patients remaining on COX-2-specific
drugs declined over the course of treatment, few patients on either
celecoxib or rofecoxib switched drugs, either to the other COX-2specific inhibitor or to non-specific NSAIDs. Factors associated
with persistent drug use were: COX-2-specific inhibitors, age, and
the use of gastroprotective agents either at treatment initiation or
during follow-up. Dosage, chronic disease score and prescriber’s
speciality were only marginally associated with persistency. Prior
use of gastroprotective agents was associated with lower persistency. Although the limitations of this study, which included lack
of information on the indication for the prescription and the reason
for switch or discontinuation, preclude definite conclusions regarding patterns of use of these drugs, the data suggest that the use of
COX-2-specific inhibitors may result in increased persistency with
treatment.
588. Inhibitory effects of anti-rheumatic agent T-614 on immunoglobulin production by cultured B cells and rheumatoid
synovial tissues engrafted into SCID mice - Tanaka K., Yamamoto
T., Aikawa Y. et al. [K. Tanaka, Research Laboratories, Toyama
Chemical Co. Ltd., Shimookui 2-4-1, Toyoma 930-8508, Japan] RHEUMATOLOGY (UK) 2003 42/11 (1365-1371) - summ in ENGL
Objective.
To clarify the pharmacological action of an
anti-rheumatic agent T-614, we investigated its effects on immunoglobulin (Ig) production by cultured B cells and Ig secretion from
synovial tissues of patients with rheumatoid arthritis (RA) using
SCID mice engrafted with human RA tissue (SCID-HuRAg). Methods. Murine B cells were prepared from mouse spleen by a T-cell
depletion method. The cells were cultured with lipopolysaccharide
(LPS) and/or interleukin 4 (IL-4) in the absence or presence of T614. Human B cells were isolated from peripheral blood of healthy
donors and the Ig production was induced by co-culture with autologous T cells and anti-CD3 antibody. SCID-HuRAg was prepared
according to our previous method. T-614 was orally administered
to the mice once daily for 4 weeks starting on the fourth week
after the implantation. Then, peripheral blood was obtained and the
implanted tissues were removed. Igs in the culture media or the sera
were determined by enzyme-linked immunosorbent assay (ELISA).
Results. In murine B-cell cultures, T-614 significantly decreased
not only the IgM production stimulated with LPS but IgG1 production induced by LPS and IL-4. Regarding human B cells stimulated
with T cells, it also inhibited IgM and IgG production. In SCIDHuRAg mice, high concentrations of polyclonal human IgG were
detectable in the sera of all mice. A significant decrease in the IgG
level was observed in the T-614-treated group compared with the
control group. Conclusions. We showed that T-614 inhibited Ig
production by the cultured B cells and also decreased the high level
of human IgG observed in SCID-HuRAg mice. These results may
support its effect on plasma Ig in RA atients and provide insights
into the mechanisms of its anti-rheumatic effect.
589. The effects of Zintona EC (a ginger extract) on symptomatic
gonarthritis - Wigler I., Grotto I., Caspi D. and Yaron M. [Prof. M.
Yaron, Department of Rheumatology, Tel Aviv Sourasky Medical
Center, Weizmann Street 6, Tel Aviv 64239, Israel] - OSTEOARTHRITIS CARTILAGE 2003 11/11 (783-789) - summ in ENGL
Objective: Evaluation of the effect of a ginger extract (Zintona
EC) on patients suffering from gonarthritis. Material and methods:
Twenty-nine patients (6 men and 23 women) with symptomatic
gonarthritis (ACR criteria), in the age range 42-85 years, were
included after randomization in a double blind, placebo controlled,
crossover study of 6 months’ duration. The treatment group was
given a ginger extract (250 mg of Zingiberis Rhizoma per capsule, qid), while the placebo group received the same number of
identical looking capsules per day. The crossover occurred after
3 months of therapy. Results were evaluated by a 100 mm visual
analog scale (VAS) of pain on movement and of handicap. Results:
Eight patients dropped out because of inefficacy, three from group
115
1 (ginger extract first) and five from group 2 (placebo first). One
patient from group 1 and one from group 2 dropped out because
of heartburn (while they were on ginger extract). Twenty patients
completed the study period of 24 weeks and 19 that of 48 weeks
follow-up. By the end of 24 weeks there was a highly statistically
significant difference between the VAS of pain and handicap of the
two groups (P<0.001). However, at crossover both groups showed
a statistically significant decrease in VAS of pain on movement and
of handicap, but the differences between the groups did not reach
statistical significance. Conclusions: Zintona EC was as effective
as placebo during the first 3 months of the study, but at the end of 6
months, 3 months after crossover, the ginger extract group showed
a significant superiority over the placebo group. © 2003 OsteoArthritis Research Society International. Published by Elsevier Ltd.
590. Weight bearing as a measure of disease progression and
efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis - Bove S.E., Calcaterra
S.L., Brooker R.M. et al. [K.S. Kilgore, Pfizer Global Research/Development, 2800 Plymouth Road, Ann Arbor, MI 48105, United
States] - OSTEOARTHRITIS CARTILAGE 2003 11/11 (821-830) summ in ENGL
Objective: To describe an in vivo model in the rat in which change
in weight distribution is used as a measure of disease progression and
efficacy of acetaminophen and two nonsteroidal anti-inflammatory
drugs (NSAIDs) in a model of monosodium iodoacetate (MIA)induced osteoarthritis (OA). Methods: Intra-articular injections of
MIA and saline were administered to male Wistar rats (175-200 g)into the right and left knee joints, respectively. Changes in hind
paw weight distribution between the right (osteoarthritic) and left
(contralateral control) limbs were utilized as an index of joint discomfort. Acetaminophen and two archetypal, orally administered
NSAIDs, naproxen and rofecoxib, were examined for their ability
to decrease MIA-induced change in weight distribution. Results:
A concentration-dependent increase in change in hind paw weight
distribution was noted after intra-articular injection of MIA. Both
naproxen and rofecoxib demonstrated the capacity to significantly
(P<0.05) decrease hind paw weight distribution in a dose-dependent fashion, indicating that the change in weight distribution
associated with MIA injection is susceptible to pharmacological
intervention. Conclusion: The determination of differences in hind
paw weight distribution in the rat MIA model of OA is a technically straightforward, reproducible method that is predictive of
the effects of anti-inflammatory and analgesic agents. This system
may be useful for the discovery of novel pharmacologic agents in
human OA. © 2003 OsteoArthritis Research Society International.
Published by Elsevier Ltd. All rights reserved.
591. Effects of aspirin and indomethacin on endothelial cell proliferation in vitro - Pearce H.R., Kalia N., Bardhan K.D. and Brown
N.J. [Dr. N. Kalia, Department of Biomedical Science, Alfred
Denny Building, University of Sheffield, Western Bank, Sheffield
S10 2TN, United Kingdom] - J. GASTROENTEROL. HEPATOL.
2003 18/10 (1180-1187) - summ in ENGL
Background and Aim: Non-steroidal anti-inflammatory drugs
(NSAID) are associated with delayed peptic ulcer healing. Ulcer
healing is dependent on angiogenesis, which requires endothelial
cell (EC) proliferation. The present study aimed to determine
whether NSAID and prostaglandin E2 (PGE 2 ) inhibited EC proliferation in vitro. Methods: Effects of 50 L aspirin (10 M-1
mM), indomethacin (10 M-1 mM) and PGE2 (1 M-0.1 mM) on
the proliferation, viability and cell cycle of human dermal microvascular (HuDMEC) and human umbilical vein (HUVEC) EC were
assessed using dual staining cell viability, 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H- tetrazolium bromide and flow cytometry
assays. Results: Proliferation of HuDMEC and HUVEC was significantly inhibited by 0.1 mM/1 mM indomethacin, 1 mM aspirin
and 100 M PGE2 , with a significant (P < 0.05) increase in EC
necrosis with 1 mM indomethacin and 100 M PGE2 . No effects
on cell cycle were demonstrated. Conclusions: High concentrations
of NSAID inhibit both HuDMEC and HUVEC proliferation in vitro
by cytotoxic (indomethacin) or cytostatic (aspirin and indomethacin) mechanisms. Interestingly, PGE 2 was also antiproliferative.
Inhibition of EC proliferation may prevent angiogenesis at the ulcer
116
site, which may in part explain the delayed ulcer healing associated
with NSAID. © 2003 Blackwell Publishing Asia Pty Ltd.
592. Flow amperometric determination of pharmaceuticals with
on-line electrode surface renewal - Catarino R.I.L., Conceição
A.C.L., Garcia M.B.Q. et al. [M.B.Q. Garcia, REQUIMTE/Depto.
de Quim.-Fis., Faculdade de Farmácia, Universidade do Porto, Rua
Anı́bal Cunha, 164, 4050-047 Porto, Portugal] - J. PHARM. BIOMED. ANAL. 2003 33/4 (571-580) - summ in ENGL
In this article, a flow system developed for the amperometric
determination of a great variety of pharmaceuticals that are known
to lead the rapid poisoning of the working electrode surface is
described. The referred system was made up of two parallel flow
channels that shared the voltammetric detector of tubular configuration, whose movement in the manifold followed the concept of
multi-site location of detector. In this way, after each measurement,
the conditioning of the working electrode was possible through the
passage by its surface of a regeneration solution without implying
the alteration of the carrier that flowed in the analytical channel of
the manifold. The methodology proposed was evaluated through
the determination of two drugs belonging to two distinct therapeutic
groups: an antihypertensive (diltiazem) and a non-steroid antiinflammatory (nimesulide). The results obtained after evaluation
of various pharmaceutical formulations on the Portuguese market
were in the case of diltiazem compared with those supplied by the
reference US Pharmacopoeia XXIV method, with no statistically
significant differences having been observed for a confidence interval of 95%. In the case of nimesulide, since no official reference
method exists, a series of recovery experiments were proceeded with
and a mean value of 101.1% with a R.S.D. of 0.7% was obtained.
593. Comparison of UV and tandem mass spectrometric
detection for the high-performance liquid chromatographic determination of diclofenac in microdialysis samples - Mayer
B.X., Namiranian K., Dehghanyar P. et al. [B.X. Mayer, Department of Clinical Pharmacology, Div. of Clinical Pharmacokinetics,
Vienna University School of Medicine, Währinger Gürtel 18-20,
1090 Vienna, Austria] - J. PHARM. BIOMED. ANAL. 2003 33/4
High-performance liquid chromatography (HPLC) was used to
analyze microdialysis samples obtained in vivo from human subcutaneous adipose tissue after topical application of the nonsteroidal
anti-inflammatory drug diclofenac. For the reliable determination
of diclofenac two different detection principles were applied in two
different laboratories. One HPLC method utilized UV-detection
at 280 nm, the other one used selected reaction monitoring mass
spectrometry (MS). The HPLC-UV and -MS methods offered low
limits of quantification of 10 and 1 ng/ml and an accuracy between
94.0-126.7 and 89.3-110.9%, respectively. However, a comparison
showed that the HPLC-UV method failed to determine diclofenac
in biological matrices, as both false negative and positive values
were found. HPLC-MS is clearly superior to HPLC-UV due to a
much more selective detection, increased sensitivity and shorter run
times. © 2003 Elsevier B.V. All rights reserved.
594. 4-(5-Chloro-2(3H)-benzoxazolon-3-yl) Butanoic Acid
Derivatives: Synthesis, Antinociceptive and Anti-inflammatory
Properties - Gulcan H.O., Kupeli E., Unlu S. et al. [M.F. Sahin,
Dept. of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi
University, 06330, Etiler, Ankara, Turkey] - ARCH. PHARM. 2003
336/10 (477-482) - summ in ENGL
In this study, 4-(5-chloro-2(3H)-benzoxazolone-3-yl)butanoic
acid and its ethyl ester as well as its ten new amide derivatives
have been synthesized. Their structures have been elucidated by
IR, 1 H-NMR spectra and elemental analysis. The compounds were
screened for antinociceptive and anti-inflammatory activities. The
highest antinociceptive and anti-inflammatory activities were exhibited by Compound 11 which has carboxylic acid structure. A
various decrease in antinociceptive and anti-inflammatory activity
was observed by amidation of the carboxylic acid moiety of this
compound.
595. Receptor density dictates the behavior of a subset of steroid
ligands in glucocorticoid receptor-mediated transrepression Section 30 vol 126.2
Zhao Q., Pang J., Favata M.F. and Trzaskos J.M. [Q. Zhao, Department of Immunology, Bristol-Myers Squibb, Route 206 and
Province Line Road, Princeton, NJ 08540, United States] - INT. IMMUNOPHARMACOL. 2003 3/13-14 (1803-1817) - summ in ENGL
By co-expressing glucocorticoid receptor (GR) and transcriptional reporter systems in GR-deficient Cos-7 cells, we profiled
potency and efficacy of a panel of GR ligands as a function of
GR expression levels (density). Our results show that potency
and efficacy for GR full agonists, such as dexamethasone, in these
transrepression assays are affected by receptor density. Intriguingly,
receptor density dramatically influenced the behavior of the GR
antagonist RU486 or the GR agonist medroxyprogesterone acetate
(MPA). At high receptor density, both MPA and RU486 behaved
as full agonists in transrepression: reducing GR density, however,
resulted in conversion of these ligands from full agonist to full
antagonists. In contrast, varying GR density could not convert
cortisol and budesonide from GR agonists to antagonists. These
results have clearly demonstrated, for the first time, an effect of
receptor density on the agonist and antagonist properties of RU486
and MPA in GR-mediated transrepression. © 2003 Elsevier B.V.
596. Effects of tramadol on synovial fluid concentrations of substance P and interleukin-6 in patients with knee osteoarthritis:
Comparison with paracetamol - Bianchi M., Broggini M., Balzarini P. et al. [M. Bianchi, Department of Pharmacology, University
of Milan, Via Vanvitelli, 32, 20129 Milano, Italy] - INT. IMMUNOPHARMACOL. 2003 3/13-14 (1901-1908) - summ in ENGL
Both the analgesic drugs tramadol and paracetamol are widely
used for the symptomatic therapy of osteoarthritis (OA). The aim
of this double-blind, randomised study in patients with knee OA
was to compare their effects on synovial fluid concentrations of
interleukin (IL)-6 and substance P (SP). Moreover, we evaluated
plasma and synovial fluid concentrations of tramadol and its active
metabolite (O-desmethyl-tramadol, M1) after oral treatment with
this drug. Twenty patients were enrolled. A group of 10 patients
received tramadol (50 mg three times a day), and another group
of 10 patients were treated with paracetamol (500 mg three times
a day) for 7 days. Both drugs significantly reduced the intensity
of joint pain. The synovial fluid concentrations of SP were significantly reduced only by the treatment with tramadol. In this
group of patients, IL-6 synovial fluid concentrations were slightly,
but not significantly, decreased. Paracetamol did not significantly
change the synovial fluid concentrations of SP and IL-6. After oral
administration, a considerable amount of tramadol was measurable
in synovial fluid. Both in plasma and synovial fluid the concentrations of M1 were markedly lower than those of tramadol, with
a T/M1 ratio of 14.74.6 and 9.33.9, respectively. These data
demonstrate that the activity of tramadol may involve the modulation of inflammatory mediators. Moreover, they indicate that after
oral treatment with tramadol, both the parent drug and its active
metabolite can penetrate into synovial fluid. © 2003 Elsevier B.V.
597. A new flavonoid derivative, dosmalfate, attenuates the development of dextran sulphate sodium-induced colitis in mice Villegas I., De La Lastra C.A., Orjales A. and La Casa C. [C.A. De
La Lastra, Department of Pharmacology, Faculty of Pharmacy, University of Seville, Calle Profesor Garcia Gonzalez, 41012 Seville,
Spain] - INT. IMMUNOPHARMACOL. 2003 3/13-14 (1731-1741) summ in ENGL
In this study, we have evaluated the efficacy of dosmalfate, a
new flavonoid derivative compound, for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice
received 5% dextran sulphate sodium (DSS) in their drinking water continuously for 7 days. Colitis was quantified by a clinical
damage score, colon lenght, weight loss, stool consistency and
rectal bleeding. Inflammatory response was assessed by neutrophil
infiltration, determined by histology and myeloperoxidase (MPO)activity. Interleukin (IL)-1 , prostaglandins (PG)E2 and (PG)D2
concentrations in colonic tissue, histological and histochemical analysis of the lesions were also measured. Dosmalfate (400-800
mg/kg body weight, p.o.) ameliorated severe colitis reduced the
degree of inflammation through reduction of neutrophil infiltration
and IL-1 levels. (PG)E2 and (PG)D2 synthesis were significantly
reduced in colitis control group and treatment with dosmalfate abolished the decrease in PG synthesis in colon mucosa. We conclude
that dosmalfate is protective in acute DSS-induced colitis. The
beneficial effects seem to be related to a decrease of neutrophil
infiltration, absence of up-regulation of IL-1 and increase of PG
production in colon mucosa. © 2003 Published by Elsevier B.V.
598. Mometasone furoate degradation and metabolism in human biological fluids and tissues - Teng X.W., Cutler D.J. and
Davies N.M. [N.M. Davies, Dept. of Pharmaceutical Sciences, College of Pharmacy, Washington State University, PO Box 646534,
Pullman, WA 99164-6534, United States] - BIOPHARM. DRUG
DISPOS. 2003 24/8 (321-333) - summ in ENGL
The in vitro metabolic and non-metabolic degradation kinetics of mometasone furoate (MF) was investigated in selected
human biological fluids and subcellular fractions of tissues.
Qualitative and quantitative differences in transformation profiles of MF were observed among human biological media.
Degradation was the major event in plasma and urine with
four new degradation products identified; A: 17-(2-furoate), B: 9,21 -dichloro-11 ,21-dihydroxy-16-methylpregna1,4,17,20-tetraen-3-one 21-(2-furoate), C: 21 -chloro-21-hydroxy-16-methyl-9 ,11 -oxidopregna-1,4,17,20- tetraen-3-one
21-(2-furoate), and D: 21-chloro-17-hydroxy-16-methyl9 ,11 -oxidopregna-1,4-diene-3,20-dione. A, B and C were
predominant and D was minor in plasma while A and C were predominant in urine. Hydrolysis of the 17-ester bond of MF was
not a major event in plasma. The turnover of MF in plasma was
faster than that in phosphate buffers of pH 7.4. Metabolism of MF
occurred primarily and rapidly in liver, appreciably in intestine, but
negligibly in in vitro lung tissue. While 6 -hydroxylation was a
major metabolic pathway for MF in microsomes of both human liver
and intestine, other parallel and subsequent metabolism pathways
could also be involved. If these degradation and metabolic products
are also formed and active in humans in vivo, both MF and its ’active’ products need to be taken into account when determining the
systemic bioavailability of MF and in establishing concentrationeffect relationships with this drug. Copyright © 2003 John Wiley
& Sons, Ltd.
599. Effects of a single arthrocentesis and a COX-2 inhibitor on
disorders of temporamandibular joints. A preliminary clinical
study - Ishimaru J.-I., Ogi N., Mizui T. et al. [Dr. J.-I. Ishimaru, Gifu Prefectural Gifu Hospital, Dept. of Oral/Maxillofacial
Surgery, 4-6-1 Noishiki, Gifu 500-8717, Japan] - BR. J. ORAL
MAXILLOFAC. SURG. 2003 41/5 (323-328) - summ in ENGL
Our aim was to examine the short-term effect of combined treatment with single arthrocentesis and a COX-2 inhibitor on 26 patients
with severe symptoms of temporomandibular joint (TMJ) disorders.
The severity of the disorders was graded according to the degree of
restriction of mouth opening and pain score on a visual analogue
scale. Synovial fluid was collected from the superior joint space of
the affected TMJ, and arthrocentesis was done with isotonic saline,
200 ml. Subsequently, etodolac, 400 mg/day, was given for 2 weeks.
At 14 days, patients were re-examined and further specimens of synovial fluid were collected. Patients generally lost their symptoms
and the severity of the disorders improved significantly (P < 0.01).
The concentrations of total protein and albumin in synovial fluid
decreased with no statistical significance. However, the concentration of matrix metalloproteinase-3 and its ratios to total protein and
albumin did decrease significantly (P < 0.05). Our results suggest
that a larger controlled study is necessary to clarify the contributory
effect of arthrocentesis and etodolac for patients with severe symptoms of TMJ disorders. © 2003 The British Association of Oral
and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights
reserved.
600. Pharmacokinetics of E5564, a Lipopolysaccharide Antagonist, in Patients with Impaired Hepatic Function - Liang E.,
Wong N., Allen I. et al. [Dr. E. Liang, Eisai Research Institute, 100
Research Drive, Wilmington, MA 01887, United States] - J. CLIN.
E5564 is a structural analog of the Lipid A portion of lipopolysaccharide (LPS). E5564 has been tested in several in vitro and in
vivo models and has demonstrated its effectiveness against LPS. It
117
is intended to be an antagonist of LPS to reduce the morbidity and
mortality associated with sepsis syndrome. This study assessed the
pharmacokinetics (PK) of E5564 in patients with impaired hepatic
function. E5564 was administered via intermittent intravenous infusion every 12 hours for six times to 24 hepatic-impaired patients
(12 each to Child-Pugh Classifications A and B) and 24 matching
healthy volunteers. Plasma samples were analyzed by LC/MS/MS.
A one-compartment model resulted in good and comparable fits for
all volunteers. Regardless of liver disease state, none of the PK parameters compared (i.e., Cmax(0-12) , tmax(0-12) , CL, t1/21 , V ss , AUC
0 12 , AUC0 last , AUC0-∞ , Css,min , C ss,max and Css,av ) exhibited
any difference between these two groups. This suggested that the
exposure of E5564 in volunteers was independent of hepatic function. Thus, no dose adjustment is needed in patients with hepatic
impairment classified as Child-Pugh A and B.
601. Different in vitro activity of flurbiprofen and its enantiomers on human articular cartilage - Panico A.M., Cardile V.,
Vittorio F. et al. [A.M. Panico, Dept. of Pharmaceutical Sciences,
Faculty of Pharmacy, University of Catania, V.le A. Doria 6, 95125
Catania, Italy] - FARMACO 2003 58/12 (1339-1344) - summ in
ENGL
The 2-arylpropionic acid derivatives or ’profens’ are an important
group of non-steroidal anti-inflammatory drugs that have been used
for the symptomatic treatment of various forms of arthritis. These
compounds are chiral and the majority of them are still marketed
as racemate although it is known that the (S)- form is the principal
effective in the cyclooxygenase inhibition. However, recent findings suggest that certain pharmacological effect of 2-arylpropionic
acids cannot be attributed exclusively to the (S)-(+) enantiomer.
To obtain further insights into the pharmacological effect of profens, the present study investigated the influence of racemic and
pure enantiomers of flurbiprofen on the production of nitric oxide and glycosaminoglycans, key molecules involved in cartilage
destruction. The culture of human articular cartilage stimulated
by interleukin-1 (IL-1 ), which plays an important role in the
degradation of cartilage, has been established, as a profit experimental model, for reproducing the mechanisms involved in the
pathophysiology of arthritic diseases. Our results show that mainly
(S)-(+)-flurbiprofen decreases, at therapeutically concentrations, the
IL-1 induced cartilage destruction. © 2003 Éditions scientifiques
602. Colchicine induces membrane-associated activation of
matrix metalloproteinase-2 in osteosarcoma cells in an S100A4independent manner - Loennechen T., Mathisen B., Hansen J.
et al. [J.-O. Winberg, Department of Biochemistry, Institute of
Medical Biology, University of Tromsø, 9037 Tromsø, Norway]
- BIOCHEM. PHARMACOL. 2003 66/12 (2341-2353) - summ in
ENGL
Like the metastasis-associated protein S100A4, matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are
important in physiological and pathological conditions. Previously,
we showed that S100A4 is involved in the regulation of MMPs and
TIMPs, and in the present work we have investigated whether the
anti-inflammatory and microtubule-disrupting drug colchicine has
an effect on the expression of these proteins in osteosarcoma cell
lines (OHS) with high and low levels of S100A4. Colchicine treatment of the various OHS cells resulted in an increased expression of
MT1-MMP and TIMP-2 mRNA, and a corresponding increase of
these two proteins in isolated cell membranes. Colchicine-treated
cells produced more of the activated form of MMP-2 than control
cells. However, the drug did not affect the amount of MMP-2
and TIMP-1 mRNA or protein, and it reduced the S100A4 mRNA
expression. Isolated cell membranes from the colchicine-treated
cells were more effective in activating exogenous proMMP-2 than
membranes from control cells, and inhibitory studies indicated that
it was the colchicine-induced increase in MT1-MMP that caused the
increased activation of endogenous MMP-2. A peptide inhibitor of
nuclear factor B nuclear translocation, SN50, blocked the colchicine-induced activation of proMMP-2 and reduced the synthesis of
MMP-2 in colchicine-treated cells, but not in control cells. It can be
concluded that colchicine modulates the expression of MT1-MMP
and TIMP-2 and hence the activation of proMMP-2 independently
118
of the S100A4 level in osteosarcoma cells. © 2003 Elsevier Inc.
603. Ameliorative effects of sodium ferulate on experimental
colitis and their mechanisms in rats - Dong W.-G., Liu S.-P., Yu
B.-P. et al. [Prof. W.-G. Dong, Department of Gastroenterology,
Renmin Hospital, Wuhan University, 238 Jiefang Road, Wuhan
430060, Hubei Province, China] - WORLD J. GASTROENTEROL.
2003 9/11 (2533-2538) - summ in ENGL
AIM: To investigate the ameliorative effects of sodium ferulate
(SF) on acetic acid-induced colitis and their mechanisms in rats.
METHODS: The colitis model of Sprague-Dawley rats was induced by intracolon enema with 8 % (V/V) of acetic acid. The
experimental animals were randomly divided into model control,
5-aminosalicylic acid therapy group and three dose of SF therapy
groups. The 5 groups were treated intracolonically with normal
saline, 5-aminosalicylic acid (100 mg.kg1 ), and SF at the doses of
200, 400 and 800 mg.kg1 respectively and daily (8: 00 am) for
7 days 24 h following the induction of colitis. A normal control group of rats clystered with normal saline instead of acetic
acid was also included in the study. Pathological changes of the
colonic mucosa were evaluated by the colon mucosa damage index (CMDI) and the histopathological score (HS). The insulted
colonic mucosa was sampled for a variety of determinations at the
end of experiment when the animals were sacrificed by decapitation. Colonic activities of myeloperoxidase (MPO) and superoxide
dismutase (SOD), and levels of malondialdehyde (MDA) and nitric oxide (NO) were assayed with ultraviolet spectrophotometry.
Colonic contents of prostaglandin E2 (PGE2 ) and thromboxane
B2 (TXB2 ) were determined by radioimmunoassay. The expressions of inducible nitric oxide synthase (iNOS), cyclo-oxygenase-2
(COX-2) and nuclear factor kappa B (NF-B) p65 proteins in
the colonic tissue were detected with immunohistochemistry. RESULTS: Enhanced colonic mucosal injury, inflammatory response
and oxidative stress were observed in the animals clystered with
acetic acid, which manifested as the significant increase of CMDI,
HS, MPO activities, MDA and NO levels, PGE2 and TXB2 contents, as well as the expressions of iNOS, COX-2 and NF-B p65
proteins in the colonic mucosa, although the colonic SOD activity was significantly decreased compared with the normal control
(CMDI: 2.90.6 vs 0.00.0; HS: 4.30.9 vs 0.71.1; MPO:
98.126.9 vs 24.811.5; MDA: 57.5312.36 vs 9.213.85; NO:
0.3310.092 vs 0.1760.045; PGE2 : 186.296.2 vs 42.832.8;
TXB2 : 34.2613.51 vs 8.833.75; iNOS: 0.3650.026 vs
0.0530.015; COX-2: 0.2960.028 vs 0.0340.013; NF-B p65:
0.3140.026 vs 0.0390.012; SOD: 28.331.17 vs 36.141.91;
P<0.01). However, these parameters were found to be significantly ameliorated in rats treated locally with SF at the
given dose protocols, especially at 400 mg.kg1 and 800 mg.kg1
doses (CMDI: 1.80.8, 1.60.9; HS: 3.30.9, 3.11.0; MPO:
63.830.5, 36.214.2; MDA: 41.8410.62, 37.348.58; NO:
0.2470.042; 0.2160.033; PGE2 : 77.226.9, 58.423.9;TXB2 :
18.0714.83; 15.528.62; iNOS:0.1750.018, 0.1060.019;
COX-2: 0.0640.018,0.0560.014; NF-Bp65: 0.2150.019,
0.1890.016; SOD: 32.154.26, 33.243.69; P<0.05-0.01). Moreover, a therapeutic dose protocol of 800 mg.kg1 SF was
observed as effective as 100 mg.kg1 of 5-ASA in the amelioration
of colonic mucosal injury as evaluated by CMDI and HS. CONCLUSION: Administration of SF intracolonically may have significant
therapeutic effects on the rat model of colitis induced by acetic acid
enema, which was probably due to the mechanism of antioxidation,
inhibition of arachidonic acid metabolism and NF-B expression.
604. Thalidomide inhibits UVB-induced mouse keratinocyte
apoptosis by both TNF--dependent and TNF--independent
pathways - Lu K.Q., Brenneman S., Burns Jr. R. et al. [Dr. A.
Gaspari, Department of Dermatology, Univ. of Maryland School
of Medicine, 405 W. Redwood St., Baltimore, MD 21201, United
States] - PHOTODERMATOL. PHOTOIMMUNOL. PHOTOMED.
2003 19/6 (272-280) - summ in ENGL
Background: Thalidomide is an anti-inflammatory pharmacologic agent that has been utilized as a therapy for a number of
dermatologic diseases. Its anti-inflammatory properties have been
attributed to its ability to antagonize tumor necrosis factor-alfa
(TNF-) production by monocytes. However, its mechanism of
action in the skin is not known. Purpose: To test our hypothesis that
thalidomide may antagonize TNF- production in the skin, we used
a mouse model for acute ultraviolet-B (UVB) exposure, a known
stimulus for inducing this cytokine. Results: A single bolus dose
of thalidomide (either 100 or 400 mg/kg) given immediately before
UVB exposure (40-120 mJ/cm2 ) inhibited, in a dose-dependent
manner, sunburn cell formation (i.e. keratinocyte (KC) apoptosis as defined by histologic appearance and confirmed by terminal
transferase mediated biotinylated dUTP nick end labelling staining) in mouse skin biopsy specimens. However, this agent did not
affect the formation of cyclobutane pyrimidine dimers, a measure
of UVB-induced DNA damage, which is an early event associated
with apoptosis. RNase protection assays confirmed that high (400
mg/kg), but not low (100mg/kg), doses of thalidomide inhibited
the UVB-induced increase in steady-state TNF- mRNA. Additionally, our in vitro data using neonatal mouse KCs showed that
thalidomide prevented UVB-induced cell death (JAM assay). The
antiapoptotic effects of thalidomide can be reversed by the addition
of exogenous recombinant mouse TNF- and hence reconstituting
UVB-induced programmed cell death. The inhibition of sunburn
cell formation by low-dose thalidomide in the absence of TNF-
inhibition suggests that other, unidentified mechanisms of apoptosis
inhibition are active. Conclusions: These data suggest that the antiinflammatory effects of thalidomide can affect UVB injury, and
may, in part, explain its action in photosensitivity diseases such as
cutaneous lupus erythematosus.
605. Design of PEGylated soluble tumor necrosis factor receptor type I (PEG sTNF-RI) for chronic inflammatory diseases Edwards III C.K., Martin S.W., Seely J. et al. [Dr. C.K. Edwards
III, RBA Dermatology U.S.A., Berlex Biosciences, Richmond, CA
94804, United States] - ADV. DRUG DELIV. REV. 2003 55/10 (13151336) - summ in ENGL
A recombinant C-terminal truncated form of the human soluble
tumor necrosis factor receptor type I (sTNF-RI) was produced in
E. coli. This soluble receptor contains the first 2.6 of the 4 domains of the intact sTNF-RI molecule. A monoPEGylated form of
this molecule was produced using a 30 kD methoxyPEG aldehyde
with approximately 85% selectivity for the N-terminal amino group.
This molecule was shown to be less immunogenic in primates than
the full length (4.0 domain) molecule or other versions of sTNFRI which were either PEGylated at different sites or with different
molecular weight PEGs. The 30 kD PEG also has a longer serum
half-life to the molecule than lower molecular weight PEGs. This
molecule markedly blunts the inflammatory response in a number
of rheumatoid arthritis animal models. In addition, phase I/II and
early phase II data in humans indicate that PEG sTNF-RI is nonimmunogenic and that weekly dosing with this drug can reduce the
number of tender and swollen joints in rheumatoid arthritis patients.
PEG sTNF-RI has comparable American College of Rheumatology
(ACR) efficacy scores as other anti-TNF molecules currently used
to treat rheumatoid arthritic patients. © 2003 Elsevier B.V. All
rights reserved.
606. Thiophenes and furans derivatives: A new class of potential pharmacological agents - Meotti F.C., Silva D.O., Dos Santos
A.R.S. et al. [C.W. Nogueira, Departamento de Quimica, Centro de
Ciencias Naturais e Exatas, Universidade Federal de Santa Maria,
Santa Maria, CEP 97105-900, RS, Brazil] - ENVIRON. TOXICOL.
A new class of potential pharmacological thiophenes and furans
compounds has been prepared. The obtained thiophenes and furans
derivatives were screened for anti-inflammatory, antinociceptive
and antioxidant activity in rats. In vitro hepatic ALA-D activity was
also evaluated. Thiophene 2 exhibited higher anti-inflammatory effect than thiophenes 1 and 3. However, compound 1 demonstrated
lower IC50 for lipid peroxidation than 2 and 3 in liver and brain.
Furan compounds 4-6 presented similar anti-inflammatory activity.
The acetylenic furans 4 and 5 inhibited scarcely lipid peroxidation
at low concentration as 10 M. Conversely, furan compound 6 was
the most effective against lipid peroxidation in liver. Furans 4 and
5 inhibited lipid peroxidation, in brain, only in high concentrations.
In contrast, furan 6 protected (90%) against lipid peroxidation at 10
M. Thiophene 1 was devoid of anti-inflammatory activity but was
efficient in reducing acetic acid-induced constriction. Conversely, it
analogue furan 4 presented anti-inflammatory and antinociceptive
activity. Thiophene and furan inhibited hepatic ALA-D only at
high concentrations. All compounds displayed antioxidant activity
however the anti-inflammatory activity is not related to antioxidant
potential. © 2003 Elsevier B.V. All rights reserved.
See also: 703, 714, 729.
6.4. Antineoplastic agents
607. Characterization of cell death induced by ethacrynic acid
in a human colon cancer cell line DLD-1 and suppression
by N-acetyl-L-cysteine - Aizawa S., Ookawa K., Kudo T. et
al. [S. Tsuchida, Second Department of Biochemistry, Hirosaki
Univ. School of Medicine, 5 Zaifucho, Hirosaki, Aomori 036-8562,
Japan] - CANCER SCI. 2003 94/10 (886-893) - summ in ENGL
Since ethacrynic acid (EA), an SH modifier as well as glutathione S-transferase (GST) inhibitor, has been suggested to induce
apoptosis in some cell lines, its effects on a human colon cancer
cell line DLD-1 were examined. EA enhanced cell proliferation
at 20-40 M, while it caused cell death at 60-100 M. Caspase
inhibitors did not block cell death and DNA ladder formation was
not detected. Poly(ADP-ribose) polymerase, however, was cleaved
into an 82-kDa fragment, different from an 85-kDa fragment that
is specific for apoptosisis. The 82-kDa fragment was not recognized by antibody against PARP fragment cleaved by caspase
3. N-Acetyl-L-cysteine (NAC) completely inhibited EA-induced
cell death, but 3(2)-t-butyl-4-hydroxyanisole or pyrrolidinedithiocarbamate ammonium salt did not. Glutathione (GSH) levels were
dose-dependently increased in cells treated with EA and this increase was hardly affected by NAC addition. Mitogen-activated
protein kinase (MAPK) kinase (MEK) 1, extracellular signal-regulated kinase (ERK) 1 and GST P1-1 were increased in cells treated
with 25-75 M EA, while c-Jun N-terminal kinase (JNK 1 and p38
MAPK were markedly decreased by 100 M EA. NAC repressed
EA-induced alterations in these MAPKs and GST P1-1. p38 MAPK
inhibitors, SB203580 and FR167653, dose-dependently enhanced
EA-induced cell death. An MEK inhibitor, U0126, did not affect
EA-induced cell death. These studies revealed that EA induced
cell death concomitantly with a novel PARP fragmentation, but
without DNA fragmentation. p38 MAPK was suggested to play an
inhibitory role in EA-induced cell death.
608. Fenretinide: A prototype cancer prevention drug - Malone
W., Perloff M., Crowell J. et al. [J. Crowell, National Cancer
Institute, Division of Cancer Prevention, Chemoprev. Agent Devmt. Res. Group, Bethesda, MD, United States] - EXPERT OPIN.
INVEST. DRUGS 2003 12/11 (1829-1842) - summ in ENGL
Fenretinide (N-4-hydroxyphenylretinamide [4-HPR]) is a synthetic retinoid that has been examined in in vitro assays, preclinical
animal models and clinical trials as a cancer chemopreventive agent.
Its pharmacology, toxicity and mechanisms of action initially suggested an increased therapeutic index relative to native retinolds for
the control of tumours of the breast, prostate, bladder, colon, cervix
and head and neck. Although fenretinide at the doses and schedules
used in several pivotal Phase II and III clinical trials has not been
proven to be efficacious in reducing the incidence of cancer or in
retarding the development of preneoplastic lesions, encouraging observations regarding unanticipated preventative activity, such as for
ovarian cancer control, have arisen from these studies. Research in
cancer therapy and the elucidation of molecular pathways activated
by fenretinide have also yielded clues about how this agent might
be better used in a prevention setting. Current trials are underway to
re-examine both dose and schedule of fenretinide administration as
well as the target tissues of interest. Investigations of potential synergism between fenretinide and other candidate chemopreventative
molecules with complementary mechanisms of action may support
future assessments of this prototype cancer prevention drug or its
newer analogues.
609. Preclinical and clinical results with the natural marine
product ET-743 - D’Incalci M. and Jimeno J. [M. D’Incalci, Department of Oncology, Ist. Ric. Farmacologiche Mario Negri, Via
119
Eritrea 62, 20157 Milan, Italy] - EXPERT OPIN. INVEST. DRUGS
2003 12/11 (1843-1853) - summ in ENGL
ET-743 (Yondelis™, trabectedin) is a natural marine product
with antitumour properties derived from the tunicate Ecteinascidia
turbinata. ET-743 binds to the N2 position of guanine in the minor
groove of DNA with some degree of sequence specificity, altering the transcription regulation of induced genes. Cells that are
deficient in nucleotide excision repair, hypersensitive to UV rays,
cisplatin and conventional alkylating agents, are resistant to ET743. This is a unique property of ET-743 and is of potential
importance for the drug activity when administered alone or in
combination with other drugs. ET-743 showed striking antitumour
activity against sensitive and resistant human xenografts. The doselimiting toxicities in animal models, hepatobiliary events, were of
concern, but the pattern of the reversibility noted in monkeys and
the evidence of a positive therapeutic index in tumour-bearing nude
mice prompted its clinical development. The Phase I programme
investigated different schedules of administration, with the doselimiting toxicities being neutropenia and fatigue. As anticipated
in the preclinical models, reversible non-cumulative transaminitis
was a prevalent finding from one-third of the maximum tolerated
dose level; long-lasting objective responses in pretreated resistant
patients were noted, including consistent efficacy data in mesenchymal tumours. The Phase II data for ET-743 administered as
a single agent has established a clinical role for the compound in
advanced pretreated soft tissue sarcoma and a promising potential in
pretreated ovarian and breast cancer. ET-743 combined with other
drugs (i.e., cisplatin, paclitaxel or doxorubicin) showed more than
additive effects in several preclinical systems and initial clinical
results (e.g., a combination of ET-743 with cisplatin) appear to
confirm the preclinical findings. In summary, ET-743 is a new drug
with a novel mode of action, which has demonstrated activity in
human tumours resistant to the available anticancer drugs. Further
comparative studies are needed to define the role of ET-743 alone
or in combination in cancer chemotherapy.
610. Synthesis, in vitro and in vivo Evaluation of a Delivery
System for Targeting Anticancer Drugs to the Brain - El-Sherbeny M.A., Al-Salem H.S., Sultan M.A. et al. [H.I. El-Subbagh,
Dept. of Pharmaceutical Chemistry, College of Pharmacy, King
Saud University, P. O. Box 2457, Riyadh 11451, Saudi Arabia] ARCH. PHARM. 2003 336/10 (445-455) - summ in ENGL
A 1,4-dihydropyridine *
) pyridinium salt type redox system
is described as a general and flexible method for site-specific
and sustained delivery of drugs to the brain. This concept
was used in the present investigation as a model to deliver
an alkylating antitumor agent into the brain. A bis-(chloroethyl)amine drug was hooked to 1,4-dihy-dropyridine chemical
delivery system (CDS) through an amide linkage. Five new
target compounds (23-27) of the 1,4-dihydropyridine CDS type
were synthesized through the reduction of five new pyridinium
quaternary intermediates (18-22). The synthesized 1,4-dihydropyridines were subjected to various chemical and biological
investigations to evaluate their ability to cross the blood-brain
barrier (BBB), and to be oxidized biologically into their corresponding quaternary compounds. The in vitro oxidation studies
showed that 1-benzyl-3-fN-[2-bis(2-chloroethyl)aminoethyl]-carbamoylg-1,4-dihydropyridine (23) and 1-(4-nitrobenzyl)-3-f
N-[2-bis(2-chloroethyl)aminoethyl]carbamoylg-1, 4-dihydropyridine (27) could be oxidized into their corresponding quaternary
compounds 18 and 22, respectively, at an adequate rate, which ensure the release of the carried anticancer drug. The in vivo studies
showed that compound 23 was able to cross the BBB at detectable
concentrations. On the other hand, the in vitro alkylation activity
studies revealed that 1-(4-nitrobenzyl)-3-fN-[2-bis(2-chloroethyl)aminoethyl]carbamoylgpyridinium bromide (22) is an alkylating
agent with activity comparable to the known drug chlorambucil.
611. Bisphosphonate Actions on Cancer - Yoneda T., Hashimoto
N. and Hiraga T. - CALCIF. TISSUE INT. 2003 73/4 (315-318) summ in ENGL
Bisphosphonates (BPs) suppress cancer cell colonization in bone
associated with cancers such as breast cancer and multiple myeloma.
The mechanism of the suppressive action of BPs is thought to be
due to an inhibition of osteoclastic bone resorption which releases
120
bone-stored growth factors that feed cancer cells colonizing bone.
Recently, data are accumulating that BP suppresses growth and
induces apoptosis in cancer cells in culture, suggesting that BP
directly influences survival of cancer cells in an osteoclast-independent manner. These results raise the possibility that BP inhibits
cancer growth in organs other than bone. However, evidence is
limited that BP reduces tumor growth in non-bone sites in cancer patients. In this review, we discuss the effectiveness of BP
on breast cancer colonization in non-bone sites and our results in
animal models with metastases. With currently available clinical
and in vivo experimental data, BPs are definitely beneficial for the
treatment of cancer patients who manifest clinically detectable bone
metastases. However, it is not recommended that BP be given as a
preventative to patients with visceral metastases and of no evidence
of bone metastases. Whether individual BP with different chemical
structure has unique biological or biochemical action is an intriguing
question but open at the moment.
612. Use of mathematical derivatives (time-domain differentiation) on chromatographic data to enhance the detection and
quantification of an unknown ’rider’ peak - Ford S.J., Elliott
M.A. and Halbert G.W. [S.J. Ford, Cancer Research UK Formulation Unit, Dept. of Pharmaceutical Sciences, University of
Strathclyde, 204 George Street, Glasgow, G1 1XW, United Kingdom] - J. PHARM. BIOMED. ANAL. 2003 33/4 (563-570) - summ
in ENGL
Two samples of an anticancer prodrug, AQ4N, were submitted
for HPLC assay and showed an unidentified impurity that eluted as a
’rider’ on the tail of the main peak. Mathematical derivatization of
the chromatograms offered several advantages over conventional
skimmed integration. A combination of the second derivative
amplitude and simple linear regression gave a novel method for
estimating the true peak area of the impurity peak. All the calculation steps were carried out using a widely available spreadsheet
program. © 2003 Elsevier B.V. All rights reserved.
613. Growth factor receptor tyrosine kinase inhibitors; clinical development and potential for prostate cancer therapy Blackledge G., Sellers W.R. and Smith M.R. [Dr. G. Blackledge,
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire
SK10 4TG, United Kingdom] - J. UROL. 2003 170/6 II (S77-S83) summ in ENGL
Purpose: The development of effective, novel, targeted cancer
therapies with minimal side effects has long been a goal in cancer
research. A key group of targets identified for drug development
consists of the receptor tyrosine kinases, which have pivotal roles
in the growth factor signaling that is subverted in carcinogenesis
and in the host processes, such as angiogenesis, involved in tumor
progression. Materials and Methods: A literature review of the role
of receptor tyrosine kinases in human malignancies is followed by
a discussion of the potential use of inhibitors of receptor tyrosine
kinases as anticancer therapy, focusing on the epidermal growth
factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839,
AstraZeneca, Macclesfield, United Kingdom). Results: Several
small molecule inhibitors that are specific to individual receptor
tyrosine kinases have been developed and a number of these potential anticancer agents are progressing through clinical trials. Various
surrogate end points are being assessed to demonstrate the activity of
these inhibitors against their targets. Results from studies of gefitinib alone and with the antiandrogen bicalutamide in both hormone
dependent and independent prostate tumor xenografts suggested
that gefitinib may have potential as monotherapy and combination
therapy in the treatment of both forms of the disease. Gefitinib is
currently undergoing further preclinical and clinical evaluation for
the treatment of prostate cancer. Conclusions: A number of tyrosine kinase inhibitors, including gefitinib, are progressing through
clinical development and are beginning to provide new treatment
options for a range of malignancies.
614. Apoptosis-mediated selective killing of malignant cells by
cardiac steroids: Maintenance of cytotoxicity and loss of cardiac
activity of chemically modified derivatives - Daniel D., Süsal C.,
Kopp B. et al. [C. Süsal, Dept. of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Im Neuenheimer
Feld 305, 69120 Heidelberg, Germany] - INT. IMMUNOPHARMACOL. 2003 3/13-14 (1791-1801) - summ in ENGL
Cardiac glycosides are commonly used drugs in clinical medicine.
We analyzed the cytotoxic effect of six steroids belonging to
the bufadienolide family on malignant T lymphoblasts and normal peripheral blood mononuclear cells (PBMC). One compound
was a natural bufadienolide glycoside (hellebrin) with cardiac
activity. The other five compounds were chemically modified
derivatives that did not contain cardioactive groups. We found
that these steroids were able to cause time-dependent apoptosis
in Jurkat T lymphoblasts, whereas they only minimally affected
PBMC. Preferential killing of malignant cells was induced by
the natural cardioactive substance hellebrin and by three of the
five chemically modified non-cardioactive derivatives. The substances caused mitochondrial transmembrane potential disruption
and internucleosomal DNA fragmentation in tumor cells. The cytoplasmic and nuclear events of bufadienolide-induced apoptosis
were strongly inhibited in the presence of caspase 8, caspase 9,
or caspase 3 inhibitors, as well as in the presence of the broadspectrum caspase inhibitor Z-VAD-FMK. Overexpression of Bcl-2
significantly protected bufadienolide-treated cells from phosphatidylserine translocation, transmembrane potential disruption, and
internucleosomal DNA fragmentation. Our results show that the
analyzed bufadienolide derivatives preferentially kill malignant
human lymphoblasts by initiating apoptosis via the classical caspase-dependent pathway. Apoptosis-inducing agents specific for
tumor cells might be ideal anti-tumor drugs. The therapeutic use
of bufadienolides has been hampered by their concomitant cardiac
activity. The description of compounds without cardiac activity
but with tumor-specific cytotoxicity suggests the potential of using
them in cancer therapy. © 2003 Elsevier B.V. All rights reserved.
615. Classification of anticancer drugs - A new system based on
therapeutic targets - Espinosa E., Zamora P., Feliu J. and González
Barón M. [E. Espinosa, Servicio de Oncologia Medica, Hospital La
Paz, Po de la Castellana, 28046 Madrid, Spain] - CANCER TREAT.
REV. 2003 29/6 (515-523) - summ in ENGL
The arrival of a great number of new antineoplastic agents has
made it necessary to reclassify all of them. Anticancer drugs may act
at different levels: cancer cells, endothelium, extracellular matrix,
the immune system or host cells. The tumour cell can be targeted at
the DNA, RNA or protein level. Most classical chemotherapeutic
agents interact with tumour DNA, whereas monoclonal antibodies
and small molecules are directed against proteins. The endothelium
and extracellular matrix may be affected also by specific antibodies
and small molecules. © 2003 Elsevier Ltd. All rights reserved.
616. Oesophageal cancer: New developments in systemic therapy - Ilson D.H. [Dr. D.H. Ilson, Gastrointestinal Oncology
Service, Department of Medicine, Mem. Sloan-Kettering Cancer
Center, 1275 York Avenue, New York, NY 10011, United States] CANCER TREAT. REV. 2003 29/6 (525-532) - summ in ENGL
Oesophageal cancer is a rare but highly virulent malignancy in
the United States and Western countries, and adenocarcinoma of
the oesophagus has had the most rapid rate of increase of any
solid tumour malignancy. Systemic metastatic disease is present in
50% of patients at diagnosis, and in the remaining 50% of patients
presenting initially with loco-regional disease, systemic metastatic
disease will develop in the vast majority of these patients. Combined chemotherapy and radiotherapy is the standard of care in
the nonsurgical management of oesophageal cancer. Preoperative
chemoradiotherapy followed by surgery continues to be actively
studied in the surgical management of locally advanced oesophageal cancer. Pathologic complete responses are seen in 20-40% of
patients, with five-year survival achieved in 25-35% of patients.
The limited efficacy and substantial toxicity of conventional 5-FUcisplatin-based chemotherapy combined with radiation, or used to
treat advanced disease, has prompted the evaluation of newer agents,
including the taxanes and irinotecan. These trials have indicated
promising antitumour activity and therapy tolerance in both advanced disease and in combined modality therapy trials, depending
on the dose and schedule of therapy administered. The advent of
newer, targeted therapies, including agents directed against growth
factor receptor pathways, tumour angiogenesis, and tumour invasion and metastasis, is leading to a new generation of clinical trials
combining these agents with conventional cytotoxic chemotherapy
and radiation. © 2003 Elsevier Ltd. All rights reserved.
617. Cellular pH regulators: Potentially promising molecular
targets for cancer chemotherapy - Izumi H., Torigoe T., Ishiguchi
H. et al. [K. Kohno, Department of Molecular Biology, Univ. of
Occup./Environmental Health, School of Medicine, 1-1 Iseigaoka,
Yahatanishi-ku, Fukuoka 807-8555, Japan] - CANCER TREAT. REV.
2003 29/6 (541-549) - summ in ENGL
One of the major obstacles to the successful treatment of cancer
is the complex biology of solid tumour development. Although
regulation of intracellular pH has been shown to be critically important for many cellular functions, pH regulation has not been fully
investigated in the field of cancer. It has, however, been shown
that cellular pH is crucial for biological functions such as cell proliferation, invasion and metastasis, drug resistance and apoptosis.
Hypoxic conditions are often observed during the development of
solid tumours and lead to intracellular and extracellular acidosis.
Cellular acidosis has been shown to be a trigger in the early phase
of apoptosis and leads to activation of endonucleases inducing DNA
fragmentation. To avoid intracellular acidification under such conditions, pH regulators are thought to be up-regulated in tumour cells.
Four major types of pH regulator have been identified: the proton
pump, the sodium-proton exchanger family (NHE), the bicarbonate transporter family (BCT) and the monocarboxylate transporter
family (MCT). Here, we describe the structure and function of pH
regulators expressed in tumour tissue. Understanding pH regulation
in tumour cells may provide new ways of inducing tumour-specific
apoptosis, thus aiding cancer chemotherapy. © 2003 Elsevier Ltd.
618. HA14-1 selectively induces apoptosis in Bcl-2-overexpressing leukemia/lymphoma cells, and enhances cytarabine-induced
cell death - Lickliter J.D., Wood N.J., Johnson L. et al. [Dr. J.D.
Lickliter, Queensland Inst. of Medical Research, Royal Brisbane
Hospital, Post Office, Herston, QLD 4006, Australia] - LEUKEMIA
2003 17/11 (2074-2080) - summ in ENGL
The Bcl-2 oncoprotein is commonly overexpressed in hematogical malignancy, where it promotes the survival of neoplastic cells.
Recently, a small molecule (HA14-1) was reported to bind the
surface pocket of Bcl-2 that mediates antiapoptotic interactions,
triggering apoptosis in a Bcl-2-transfected cell line. We investigated
the activity of this compound in a panel of malignant hematopoietic
cell lines. Consistent with its proposed role as a Bcl-2 inhibitor,
HA14-1 was most cytotoxic in lines expressing high levels of Bcl2. In addition, at lower concentrations (5-12.5M), the compound
predominantly triggered apoptosis. However, at concentrations
two-fold higher than this and above, increasing primary necrosis
was observed, suggesting the onset of interactions supplementary
to Bcl-2 inhibition. In experiments on primary cells, 25 M HA141 induced extensive apoptosis in acute leukemic blasts, but also
suppressed normal hematopoietic colony formation to <50% of
baseline. Importantly, low-concentration HA14-1 (5 M) was
nontoxic to normal colony-forming cells, whereas it enhanced the
cytotoxicity of the antileukemia drug cytarabine in Bcl-2-positive
lymphoblastic leukemia cells. In conclusion, our results indicate
that HA14-1 at low concentration selectively triggers apoptosis in
malignant hematopoietic cells that over-express Bcl-2. Agents of
this class may have particular utility in combination with cytotoxic
chemotherapy drugs.
619. Regulation and targeting of antiapoptotic XIAP in acute
myeloid leukemia - Carter B.Z., Milella M., Tsao T. et al. [Dr. M.
Andreeff, Sect. of Molec. Hematology/Therapy, The University
of Texas, MD Anderson Cancer Ctr., 1515 Holcombe Boulevard,
Houston, TX 77030, United States] - LEUKEMIA 2003 17/11
(2081-2089) - summ in ENGL
XIAP is a member of the inhibitors-of-apoptosis family of proteins, which inhibit caspases and block cell death, with prognostic
importance in AML. Here we demonstrate that cytokines regulate
the expression of XIAP in leukemic cell lines and primary AML
blasts. Inhibition of phosphatidylinositol-3 kinase (PI3K) with
LY294002 and of the mitogen-activated protein kinase (MAPK)cascade by PD98059 resulted in decreased XIAP levels (348.7
and 235.7%, respectively). We then generated OCI-AML3 cells
121
with constitutively phosphorylated Akt (p473-Akt) by retroviral
gene transfer. Neither these nor Akt inhibitor-treated OCI-AML3
cells showed changes in XIAP levels, suggesting that XIAP expression is regulated by PI3K downstream effectors other than Akt. The
induction of XIAP expression by cytokines through PI3K/MAPK
pathways is consistent with its role in cell survival. Exposure of
leukemic cells to chemotherapeutic agents decreased XIAP protein levels by caspase-dependent XIAP cleavage. Targeting XIAP
by XIAP antisense oligonucleotide resulted in downregulation of
XIAP, activation of caspases and cell death, and sensitized HL60 cells to Ara-C. Our results suggest that XIAP is regulated by
cytokines through PI3K, and to a lesser degree through MAPK
pathways. Selective downregulation of XIAP expression might be
of therapeutic benefit to leukemic patients.
620. Sustained activation of c-jun-terminal kinase (JNK) is
closely related to arsenic trioxide-induced apoptosis in an acute
myeloid leukemia (M2)-derived cell line, NKM-1 - Kajiguchi
T., Yamamoto K., Hossain K. et al. [Dr. N. Emi, First Dept. of
Internal Medicine, Nagoya Univ. Grad. Sch. of Medicine, 65
Turumai-cho, Showa-ku, Nagoya 466-8550, Japan] - LEUKEMIA
2003 17/11 (2189-2195) - summ in ENGL
High concentrations (greater than 5 M) of arsenic trioxide
(As2 O3 ) have been reported to be able to induce apoptosis in several malignant cells. We explored cell lines in which apoptosis was
induced with a therapeutic concentration (1-2 M) of As2 O3 , and
found that 1 M of As2 O3 induced apoptosis in the NKM-1 cell line,
which was established from a patient with acute myelold leukemia
(M2). Apoptosis induced by 1 M of As2 O3 in NKM-1 cells was
accompanied by an increased cellular content of H2 O2 , a decreased
mitochondrial membrane potential ( m), and activation of caspase-3. C-Jun-terminal kinase (JNK was activated only in NKM-1
cells and arsenic-sensitive NB4 cells, but not in arsenic-insensitive
HL-60 cells. Activation of JNK in NKM-1 was sustained from 6 to
24 h after As2 O3 treatment, and preceded changes in cellular H2 O2 ,
m, and caspase-3 activation. Moreover, addition of a JNK
inhibitor reduced the percentage of apoptotic cells after the As2 O3
treatment. Taken together, in the M2 cell line NKM-1, 1 M of
As2 O3 induced sustained activation of JNK and apoptosis. This
finding may provide a basis to select a subgroup other than acute
promyplocytic leukemia, which can benefit from As2 O3 treatment.
621. Synthesis and antitumor evaluation of some new
substituted amidino-benzimidazolyl-furyl-phenyl-acrylates and
naphtho[2,1-b]furan- carboxylates - Hranjec M., Grdiša M.,
Pavelic K. et al. [G. Karminski-Zamola, Department of Organic
Chemistry, Fac. of Chem. Eng. and Technology, University of
Zagreb, Marulicev trg 20, HR-10000 Zagreb, Croatia] - FARMACO
2003 58/12 (1319-1324) - summ in ENGL
The multistep synthesis of a series of substituted amidinobenzimidazolyl- furyl-phenyl-acrylic acid’s esters and substituted
amidino-benzimidazolyl- naphtho[2,1-b]furan-carboxylic acid’s
esters is described starting from corresponding 3-(2-furyl)-2-phenyl-acrylic acids. The new compounds were tested on the
cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma
(HeLa), laryngeal carcinoma (Hep2), colon carcinoma (HT 29),
melanoma (HBL), and human fibroblasts cell line (WI38). All
compounds inhibited the proliferation of tumor cell lines. Inhibitory effect of examined compounds depended on concentration,
but without significant difference among the type of tumor cells.
The compounds 2 and 5 exerted very low inhibitory effect on the
growth of human fibroblasts. Unsubstituted derivative 8 has not
inhibited any tested cell lines. © 2003 Éditions scientifiques et
médicales Elsevier SAS. All rights reserved.
622. Pharmacokinetic study of oxaliplatin iv chronomodulated
infusion combined with 5-fluorouracil iv continuous infusion
in the treatment of advanced colorectal cancer - Cattel L., La
Grotta G., Infante L. et al. [L. Cattel, Dipto. di Sci. e Tecn. del
Farmaco, Università di Torino, Via Petro Giuria 9, I-10125 Turin,
Italy] - FARMACO 2003 58/12 (1333-1338) - summ in ENGL
We investigated the pharmacokinetics (PK), preliminary clinical
results and toxicity of chronomodulated oxaliplatin (OHP) plus 5fluorouracil (5-FU) without folinic acid (FA) in 13 patients with
122
metastatic colorectal cancer. 5-FU (200 mg/m2 /day as 14-day continuous iv infusion for six cycles) plus OHP at increasing doses
(25-30-35 mg/m2 /day, as 12 h chronomodulated iv infusion on days
1-2-3-4, every 14 days for six cycles) were administered to reach
maximum tolerated dose (MTD). At MTD (30 mg/m 2 /day), a PK
study of 5-FU and OHP (in total and ultrafiltered-UF plasma) was
performed. 5-FU plasma levels were fairly stable, below that reported in similar studies and closely related to the lack of the most
typical 5-FU toxicities. OHP Cmax occurred 7 h after infusion
start; a progressive accumulation of free Pt and ultrafiltered Pt (UFOHP) through cycles 1-6 was noted. A marked difference between
total plasma and UF Pt was seen in the elimination phase. OHP
plasma clearance decrease was related to Vz (volume of distribution of late elimination phase), whereas in UF-OHP was due to a
change in Ke or t1/2 . In conclusion, the association of 5-FU with
chronomodulated OHP do not seem to influence PK parameters of
either drugs. Toxicity was modest/acceptable and clinical efficacy
good: preliminary data showed a threshold neurotoxicity at total
plasma Pt concentrations >1500 ng/ml and UF plasma Pt concentrations >150 ng/ml. © 2003 Published by Éditions scientifiques
et médicales Elsevier SAS.
623. Cobalt chloride and low oxygen tension trigger differentiation of acute myeloid leukemic cells: Possible mediation of
hypoxia-inducible factor-1 - Huang Y., Du K.-M., Xue Z.-H.
et al. [Dr. G.-Q. Chen, 280 Chong-Qing South Road, Shanghai
200025, China] - LEUKEMIA 2003 17/11 (2065-2073) - summ in
ENGL
Cellular and systemic O2 concentrations are tightly regulated
to maintain delicate oxygen homeostasis. Although the roles of
hypoxia in solid tumors have been widely studied, few studies were
reported regarding the possible effects of hypoxia on leukemic cells.
Here, we showed for the first time that low concentrations of cobalt
chloride (CoCl2 ) a hypoxia-mimicking agent, and 2-3% O2 triggered differentiation of various subtypes of human acute myeloid
leukemic (AML) cell lines, including NB4, U937 and Kasumi-1
cells, respectively, from M3, M5 and M2b-type AML, but CoCl2
did not modulate AML subtype-specific fusion proteins promyelocytic leukema-retinoic acid receptor alpha (PML-RAR) and
AML1-ETO. Treatment with CoCl2 also induced primary leukemic
cells from some AML patients to undergo differentiation. Similar
to what occurs in solid tumor cells, CoCl2 -mimicked hypoxia also
increased the level of hypoxia-inducible factor (HIF)-1 protein
and its DNA-binding activity in leukemic cells. The CoCl2 induction of HIF-1 protein and its DNA-binding activity were inhibited
by 3-morpholinosydnonimine, which also blocked CoCl2 -induced
cell differentiation in leukemic cells. These results provide an insight into a possible link of hypoxia or HIF-1 and leukemic cell
differentiation, and are possibly of significance to explore clinical potentials of hypoxia or hypoxia-mimicking agents and novel
target-based drugs for differentiation therapy of leukemia.
624. Transferrin receptor ligand-targeted toxin conjugate (TfCRM107) therapy of malignant gliomas - Weaver M. and Laske
D.W. [Dr. D.W. Laske, Department of Neurosurgery, Temple University, School of Medicine, 3401 N. Broad St., Philadelphia, PA
19140-5103, United States] - J. NEURO-ONCOL. 2003 65/1 (313) - summ in ENGL
The authors review the preclinical and clinical results of the ligand-targeted toxin conjugate Transferrin-CRM107 (Tf-CRM107),
for the treatment of malignant gliomas. Tf-CRM107 is a conjugate
protein of diphtheria toxin with a point mutation (CRM107)linked by a thioester bond to human transferrin (Tf). This
conjugate exhibits potent cytotoxicity in vitro against mammalian
cells expressing the transferrin receptor with activity at picomolar concentrations. Phase I clinical trial results demonstrated that
Tf-CRM107, delivered via a high-flow convection method utilizing stereotactically placed catheters, produced tumor response in
patients with malignant brain tumors refractory to conventional
therapy without severe neurologic or systemic toxicity. The results
of a Phase II study are also summarized. Tf-CRM107 treatment results in complete and partial tumor response without severe toxicity
in 35% of the evaluable patients. These data warrant a Phase III
study as well as continued research in the field of targeted toxin therapy. Future directions of research include optimizing Tf-CRM107
delivery to targeted brain regions, and improving the treatment efficacy by combining with other toxin conjugates targeted to different
receptors.
lines of experimental evidence strongly suggested that the inhibition
of SK-Mel-2 cell proliferation by salmosin was due to the induction
of apoptosis via the blocking of integrin v -mediated cell survival.
625. Interleukin-13 receptor-directed cytotoxin for malignant
glioma therapy: From bench to bedside - Husain S.R. and
Puri R.K. [R.K. Puri, Center for Biologics Eval./Research, Food
and Drug Administration, National Institutes of Health, 29 Lincoln
Drive MSC 4555, Bethesda, MD 20892, United States] - J. NEUROONCOL. 2003 65/1 (37-48) - summ in ENGL
Central nervous system malignant neoplasias, in particular, glioblastoma multiforme (GBM) have defied all current therapeutic
modalities. New therapies involving tumor targeting approach are
being explored. This approach relies on the identification of unique
or over-expressed cell surface receptors or antigens on tumor cells.
In that regard, we have identified receptor for an immune regulatory cytokine, interleukin-13 (IL-13), which is over-expressed on
human malignant glioma cell lines and primary tumor cell cultures.
To target IL-13 receptors (IL-13R) for cancer therapy, we have
developed a recombinant fusion protein composed of IL-13 and a
mutated form of Pseudomonas exotoxin (IL13-PE38QQR or IL-13
cytotoxin). The IL-13 cytotoxin was found to be highly selective
and potent in killing human GBM cells in vitro while normal cells
including immune cells, endothelial cells and normal brain cells
were generally spared the cytotoxic effect of IL-13 cytotoxin. This
is because these cells either expressed none or expressed low levels
of IL-13R. Consistent with in vitro cytotoxic activity, IL-13 cytotoxin mediated remarkable anti-tumor activity to human glioma
in animal xenograft models. The direct injection of IL-13 cytotoxin into subcutaneous human GBM tumors grown in nude mice
produced complete and durable regression of established tumors.
Intravenous and intraperitoneal administration of IL-13 cytotoxin
also reduced tumor burden significantly with fewer complete responders. All animals tolerated therapy well with minimal toxicity
to vital organs. Pre-clinical safety and toxicity studies were performed in mice, rats and monkeys. Systemic administration of
IL-13 cytotoxin appeared to be well tolerated at high doses (up to
50 g/kg). Intrabrain parenchyma administration of IL-13 cytotoxin at doses up to 100 g/ml was very well tolerated without any
evidence of gross or microscopic necrosis, whereas at 500 g/ml
dose, localized necrosis was observed in normal rat brain. Based
on these encouraging pre-clinical studies, three Phase I/II clinical
trials in adults with malignant glioma have been initiated. The first
clinical trial involves convection-enhanced delivery (CED) of IL13 cytotoxin into recurrent malignant glioma. This route of IL-13
cytotoxin administration appears to be fairly well tolerated with no
neurotoxicity. The second clinical trial involves infusion of IL-13
cytotoxin by CED following tumor resection. The initial stage of
the second study assessed histologic effect of drug administered
prior to resection. In third one, IL-13 cytotoxin is infused by CED
followed by tumor resection. All three clinical trials are currently
ongoing.
627. Yeast recombination pathways triggered by topoisomerase
II-mediated DNA breaks - Sabourin M., Nitiss J.L., Nitiss K.C.
et al. [N. Osheroff, Department of Biochemistry, Vanderbilt Univ.
School of Medicine, Nashville, TN 37232-0146, United States] NUCLEIC ACIDS RES. 2003 31/15 (4373-4384) - summ in ENGL
Topoisomerase II is a ubiquitous enzyme that removes knots and
tangles from the genetic material by generating transient doublestrand DNA breaks. While the enzyme cannot perform its essential
cellular functions without cleaving DNA, this scission activity is
inherently dangerous to chromosomal integrity. In fact, etoposide
and other clinically important anticancer drugs kill cells by increasing levels of topoisomerase II-mediated DNA breaks. Cells rely
heavily on recombination to repair double-strand DNA breaks, but
the specific pathways used to repair topoisomerase II-generated
DNA damage have not been defined. Therefore, Saccharomyces
cerevisiae was used as a model system to delineate the recombination pathways that repair DNA breaks generated by topoisomerase
II. Yeast cells that expressed wild-type or a drug-hypersensitive
mutant topoisomerase II or over-expressed the wild-type enzyme
were examined. Based on cytotoxicity and recombination induced
by etoposide in different repair-deficient genetic backgrounds, double-strand DNA breaks generated by topoisomerase II appear to
be repaired primarily by the single-strand invasion pathway of homologous recombination. Non-homologous end joining also was
triggered by etoposide treatment, but this pathway was considerably less active than single-strand invasion and did not con ribute
significantly to cell survival in S.cerevisiae.
626. Inhibitory effect of salmosin, a Korean snake venom-derived disintegrin, on the integrin v -mediated proliferation of
SK-Mel-2 human melanoma cells - Chung K.-H., Kim S.-H.,
Han K.-Y. et al. [I.-C. Kang, Biotechnology Research Institute,
Chungbuk National University, 48 San, Gashin-dong, Chungju
361-763, South Korea] - J. PHARM. PHARMACOL. 2003 55/11
(1577-1582) - summ in ENGL
We have investigated the inhibitory effect of salmosin on integrin-mediated human tumour cell proliferation. SK-Mel-2 human
melanoma cell adhesion to denatured collagen or vitronectin was
found to be significantly and statistically inhibited by salmosin in a
dose-dependent manner (P<0.05). Moreover, the binding of SKMel-2 cells to salmosin-coated plates was specifically disrupted by
anti-integrin v monoclonal antibody at 8 g mL-1 , but not by
anti-integrin monoclonal antibody. These findings indicated that
salmosin inhibited the adhesion of SK-Mel-2 cells to denatured
collagen by specifically blocking integrin v . The proliferation of
SK-Mel-2 cells on a denatured collagen-coated plate was statistically and significantly inhibited by salmosin induced apoptosis in
a dose-dependent manner (P<0.05). Anti-integrin v monoclonal
antibody, anti-integrin v 3 monoclonal antibody, and synthetic
RGD peptide also suppressed SK-Mel-2 cell proliferation. Several
628. Hydropathic analysis of the free energy differences in anthracycline antibiotic binding to DNA - Cashman D.J., Scarsdale
J.N. and Kellogg G.E. [G.E. Kellogg, Department of Medicinal
Chemistry, Virginia Commonwealth University, 800 East Leigh
Street, Richmond, VA 23219-1540, United States] - NUCLEIC
ACIDS RES. 2003 31/15 (4410-4416) - summ in ENGL
Molecular models of six anthracycline antibiotics and their complexes with 32 distinct DNA octamer sequences were created and
analyzed using HINT (Hydropathic INTeractions) to describe binding. The averaged binding scores were then used to calculate the free
energies of binding for comparison with experimentally determined
values. In parsing our results based on specific functional groups of
doxorubicin, our calculations predict a free energy contribution of
-3.6 1.1 kcal mol-1 (experimental -2.5 0.5 kcal mol-1 ) from the
groove binding daunosamine sugar. The net energetic contribution
of removing the hydroxyl at position C9 is -0.7 0.7 kcal mol-1 (-1.1
0.5 kcal mol-1 ). The energetic contribution of the 3 amino group
in the daunosamine sugar (when replaced with a hydroxyl group) is
-3.7 1.1 kcal mol-1 (-0.7 0.5 kcal mol-1 ). We propose that this
large discrepancy may be due to uncertainty in the exact protonation
state of the amine. The energetic contribution of the hydroxyl group
at C14 is +0.4 0.6 kcal mol-1 (-0.9 0.5 kcal mol-1 ), largely
due to unfavorable hydrophobic interactions between the hydroxyl
oxygen and the methylene groups of the phosphate backbone of
the DNA. Also, there appears to be considerable conformational
uncertainty in this region. This computational procedure calibrates
our methodology for future analyses where experimental data are
unavailable.
629. Vanillins - A novel family of DNA-PK inhibitors - Durant
S. and Karran P. [S. Durant, Mammalian DNA Repair, Cancer Research UK, Clare Hall Laboratories, Blanche Lane, South Mimms,
Potters Bar, Herts EN6 3LD, United Kingdom] - NUCLEIC ACIDS
RES. 2003 31/19 (5501-5512) - summ in ENGL
Non-homologous DNd end-joining (NHEJ) is a major pathway
of double strand break (DSB) repair in human cells. Here we
show that vanillin (3-methoxy-4-hydroxybenzaldehyde) - a naturally occurring food component and an acknowledged antimutagen,
anticlastogen and anticarcinogen-is an inhibitor of NHEJ. Vanillin
blocked DNA end-joining by human cell extracts by directly inhibiting the activity of DNA-PK, a crucial NHEJ component. Inhibition
was selective and vanillin had no detectable effect on other steps of
123
the NHEJ process, on an unrelated protein kinase or on DNA mismatch repair by cell extracts. Subtoxic concentrations of vanillin
did not affect the ATM/ATR-dependent phosphorylation of Chk2
or the S-phase checkpoint response after ionising radiation. They
significantly potentiated the cytotoxicity of cisplatin, but did not
affect sensitivity to UVC. A limited screen of structurally related
compounds identified two substituted vanillin derivatives that were
100- and 50-fold more potent than vanillin as DNA-PK inhibitors.
These compounds also sensitised cells to cisplatin. The inhibition
of NHEJ is consistent with the antimutagenic and other biological
properties of vanillin, possibly altering the balance between DSB
repair by NHEJ and homologous recombination.
630. Divergent synthetic nucleotide motif recognition pattern:
Design and development of potent immunomodulatory oligodeoxyribonucleotide agents with distinct cytokine induction
profiles - Kandimalla E.R., Bhagat L., Wang D. et al. [S. Agrawal,
Hybridon, Inc., 345 Vassar Street, Cambridge, MA 02139, United
States] - NUCLEIC ACIDS RES. 2003 31/9 (2393-2400) - summ in
ENGL
Unmethylated CpG dinucleotides present within certain specific
sequence contexts in bacterial and synthetic DNA stimulate innate
immune responses and induce cytokine secretion. Recently, we
showed that CpG DNAs containing two 5 -ends, immunomers,
are more potent in both regards. In this study, we show that an
immunomer containing a synthetic CpR motif (R = 2 -deoxy-7deazaguanosine) is a potent immunostimulatory agent. However,
the profile of cytokine induction is different from that with immunomers containing a natural CpG motif. In general, a CpR
immunomer induced higher interleukin (IL)-12 and lower IL-6
secretion. Compared with conventional CpG DNAs, both types
of immunomers showed a rapid and enhanced activation of the
transcription factor NF-B in J774 cells. NF-B activation by
CpG DNA corresponded to degradation of IBa in J774 cells. All
three immunostimulatory oligonucleotides activated the p38 mitogen-activated protein kinase pathway as expected. Immunomers
containing CpG and CpR motifs showed potent reversal of the
antigen-induced Th2 immune response towards a Th1 type in antigen-sensitized mouse spleen cell cultures. Immunomers containing
a CpR motif showed significant antitumor activity in nude mice
bearing MCF-7 human breast cancer and U87MG glioblastoma xenografts. These studies suggest the ability for a divergent synthetic
nucleotide motif recognition pattern of the receptor involved in the
immunostimulatory pathway and the possibility of using synthetic
nucleotides to elicit different cytokine response patterns.
631. Advanced breast cancer: An update and controversies on
diagnosis and therapy - Nicolini A. and Carpi A. [A. Nicolini,
Department of Internal Medicine, University of Pisa, via Roma
67, 56126 Pisa, Italy] - BIOMED. PHARMACOTHER. 2003 57/10
This review on advanced breast cancer considered important
differences in the actual definition of this condition. Advanced
breast cancer includes locally advanced, locoregionally recurrent
and metastatic disease, which have different diagnosis, prognosis
and therapy; their actual definitions are relatively uncertain. Differently from the common opinion that metastatic breast cancer
(MBC) is a very severe incurable disease, recently it has been reported that a small but not irrelevant fraction of MBC patients can
be cured or remain in long-term survival with complete remission.
The type of metastases of the population studied in these reports was
analysed and the authors hypothesised that the particularly high DFS
reported mainly was attributable to the high proportion of patients
with locoregional metastases only. Furthermore, the options and
associations of the drug therapy available for treatment of advanced
breast cancer have been reviewed. © 2003 Éditions scientifiques et
632. Estrogen/EGF receptor interactions in breast cancer: Rationale for new therapeutic combination strategies - Lichtner
R.B. [R.B. Lichtner, Belzigerstrasse 39, 10823 Berlin, Germany]
- BIOMED. PHARMACOTHER. 2003 57/10 (447-451) - summ in
ENGL
In the therapy of estrogen receptor (ER) positive human mammary
carcinomas, the treatment with the antiestrogen tamoxifen has been
124
well established. However, the development of hormone resistance
is an important factor in breast cancer progression against endocrine
therapy. The presence of the receptor for EGF (EGFR) correlates
with lack of response towards antiestrogen therapy. The EGFR
is not only involved in tumor cell growth, survival signaling, cell
migration, metastasis formation and angiogenesis, but also seems
to confer reduced responses of tumor cells towards anti-hormones.
Concomitant inhibition of both, the receptors for estrogen and EGF
may be necessary to improve breast cancer therapy. © 2003 Éditions
633. Intracrine mechanism of estrogen synthesis in breast cancer
- Suzuki T., Moriya T., Ishida T. et al. [T. Suzuki, Department of Pathology, Tohoku University, School of Medicine, 2-1
Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan] - BIOMED.
PHARMACOTHER. 2003 57/10 (460-462) - summ in ENGL
It has been demonstrated that biologically active estrogens are
locally produced from circulating inactive steroids in an intracrine
mechanism in the breast carcinoma. The in situ production of
estrogens is considered to play an important role in the proliferation
of breast cancer cells, especially in the postmenopausal women.
Therefore, the total blockade of this pathway may lead to an improvement in the prognosis in breast cancer patients due to the
inhibition of estrogenic actions. In this review, we describe the recent studies of enzymes related to intracrine mechanism of estrogen
synthesis, including aromatase, steroid sulfatase (STS), and 17 hydroxysteroid dehydrogenase, in human breast carcinoma tissues,
and discuss the biological significance of local production of estrogens in human breast cancer. © 2003 Éditions scientifiques et
634. Anti-angiogenic therapy in breast cancer - Rahman M.A.
and Toi M. [M. Toi, Breast Cancer Research Program, Tokyo
Metropol. Cancer Infect. D., Komagome Hospital, 3-18-22,
Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan] - BIOMED.
PHARMACOTHER. 2003 57/10 (463-470) - summ in ENGL
Breast cancer is a worldwide epidemic among women, and one
of the most rapidly increasing cancers. Not only the incidence rate
but also the death rate is increasing. Despite enthusiastic efforts
in early diagnosis, aggressive surgical treatment and application
of additional non-operative modalities, its prognosis is still dismal. This emphasizes the necessity to develop new measures and
strategies for its prevention. The understanding of the biology of
angiogenesis is improving rapidly, offering the hope for more specific vascular targeting of tumor neovasculature. Anti-angiogenic
therapy is a promising, relatively new form of cancer treatment
using drugs called angiogenesis inhibitors that specifically inhibit
new blood vessel growth. Extensive studies conducted over the past
few years have recognized that overexpression of COX-2, VEGF
in the cancer might be the leading factors, can induce angiogenesis
via induction of multiple pro-angiogenic regulators. Breast tumor
growth and metastasization are both hormone-sensitive and angiogenesis-dependent. A single angiogenic inhibitor is not capable to
inhibit angiogenesis. Therefore, we should select a combination of
angiogenesis inhibitors targeting COX-2, VEGF, and bFGF pathway. This article reviews the background and implementation of the
current use of angiogenesis inhibitors and discusses the likely therapeutic roles in the early and advanced breast cancer together with
its potential for chemoprevention. © 2003 Éditions scientifiques et
635. How does interleukin-6 affect the membrane expressions
of interleukin-6 receptor and gp130 and the proliferation of the
human myeloma cell line OPM-2? - Kovacs E. [E. Kovacs, Society of Cancer Research, Kirschweg 9, 4144 Arlesheim, Switzerland]
- BIOMED. PHARMACOTHER. 2003 57/10 (489-494) - summ in
ENGL
Interleukin-6 (IL-6) is a potent growth factor for the proliferation
of multiple myeloma (MM), which accounts for 1-2% of all human
cancers. In this study we investigated the effects of IL-6 in various
doses on the following parameters in the human myeloma cell line
OPM-2: membrane expression of IL-6 receptor (IL-6R) and gp130,
proliferation of the tumour cells and the amount of the soluble IL-6
receptor (sIL-6R) in the supernatant. Additionally, we tested the
same parameters with the immunomodulator Viscum album (VA)extract. The expression of surface IL-6R and gp130 was analysed
by FACS, the measurements of proliferation using the BrdU incorporation during DNA synthesis, and the determination of sIL-6R in
the supernatant by ELISA. OPM-2 cells proliferate spontaneously
(doubling time: 48 h), IL-6-production was not detectable. The
exogenous IL-6 upregulated its own receptor up to a mean of 180%
of controls at 5 ng/ml (P < 0.001), higher or lower doses were less
effective. The membrane expression of gp130 was downregulated
to 1-2%. IL-6 led to increase of the sIL-6R in the supernatant
(P < 0.001) and raised the proliferation of the myeloma cells up
to a mean of 124% (P < 0.001). These results indicate that the
human myeloma cell line OPM-2 has an autocrine IL-6 regulation
mechanism, with an additional paracrine signalling by exogenous
IL-6. This is the first report that IL-6 inhibits the membrane expression of gp130, although the proliferation of the myeloma cells
increases. VA extract did not affect survival, the expression of
surface receptors IL-6 and gp130 or the amount of sIL-6R in the
supernatant. However, the proliferation of the tumour cells was
inhibited significantly (P < 0.05) suggesting a possible arrest in
the cell cycle. © 2003 Éditions scientifiques et médicales Elsevier
SAS. All rights reserved.
636. Synthesis, structural characterization and in vitro
antitumor activity of 4-dimethylaminopyridinium (6-chloro1,1-dioxo-1,4,2-benzodithiazin-3-yl) methanides - Brzozowski
Z., Sa̧czewski F. and Gdaniec M. [F. Sa̧czewski, Dept. of Chem.
Technology of Drugs, Medical University of Gdańsk, 80-416
Gdańsk, Poland] - EUR. J. MED. CHEM. 2003 38/11-12 (991999) - summ in ENGL
Previously, we have described a novel series of low molecular
weight cancer-specific antitumor agents with aminium N-(1,1-dioxo-1,4,2-benzodithiazin- 3-yl)arylsulfonamidate structure. In an
attempt to determine some of the structural features that account
for the cytotoxic activity of such aminium salts, a novel series
of 4-dimethylaminopyridinium (1,1-dioxo-1,4,2- benzodithiazin3-yl)methanides (6-19) has been synthesized by the reactions of
3-methylthio-1,4,2-benzodithiazine1,1-dioxides with 4-DMAP and
some active methylene compounds. The in vitro antitumor activity
of these compounds has been tested in the National Cancer Institute
(NCI), and relationships between structure and antitumor activity
are discussed. Among the aminium salts 4-dimethylamino-pyridinium 4-chlorobenzoyl cyano (6-chloro-7-methyl-1,1-dioxo-1,
4,2-benzodithiazin-3-yl)methanide (9) was superior to other pyridinium salts in terms of both remarkable activity (logGI50 and
logTGI<-8.00) and high selectivity for the lung HOP-92 and
melanoma UACC-257 cell lines. © 2003 Éditions scientifiques
637. Synthesis and antineoplastic activity of 2-alkylaminoethyl
derivatives of various steroidal oximes - Jindal D.P., Chattopadhaya R., Guleria S. and Gupta R. [R. Gupta, Univ. Inst. of
Pharmaceutical Sci., Panjab University, Chandigarh 160014, India]
- EUR. J. MED. CHEM. 2003 38/11-12 (1025-1034) - summ in
ENGL
Various steroidal oxime ether derivatives in androstene and
estrane series have been synthesized and evaluated for the antineoplastic activity at National Cancer Institute, Bethesda, Maryland,
USA. O-Alkylation of the oximes by various alkylaminoethyl
halides gave the oxime ether derivatives. The 17-ethynylandrostene derivatives 29 (DPJ-684), 30 (DPJ-685), 31 (DPJ-686) and
estrane derivatives 35 (DPJ-531) and 36 (DPJ-532) were among the
small percentage of compounds, which have been screened by NCI
for in vivo hollow fiber assay by virtue of their activity against one
or more human tumour cell lines in 60 cell line in vitro prescreen.
The preliminary in vivo reports of hollow fiber assays have been
referred to the Biological Evaluation Committee for Cancer Drugs
for considering these compounds for further detailed in vivo testing.
reserved.
638. Phase II trial combining docetaxel and doxorubicin as neoadjuvant chemotherapy in patients with operable breast cancer
- Ganem G., Tubiana-Hulin M., Fumoleau P. et al. [Dr. G. Ganem,
Centre Jean Bernard, 9 Rue Beauverger, 72000 Le Mans, France] ANN. ONCOL. 2003 14/11 (1623-1628) - summ in ENGL
Background: This study was conducted to assess the antitumour
activity of docetaxel in combination with doxorubicin for neoadjuvant therapy of patients with breast cancer. Patients and methods:
Forty-eight women were treated with intravenous doxorubicin 50
mg/m2 over 15 min followed by a 1-h infusion of docetaxel 75
mg/m2 every 3 weeks for six cycles. Dexamethasone or prednisolone premedication was allowed. Granulocyte colony-stimulating
factor was not allowed as primary prophylaxis. The primary end
point was the pathologically documented complete response rate
(pathological response). Results: The mean relative dose intensity
calculated for four or more cycles was 0.99 for doxorubicin and 0.99
for docetaxel. Overall, the pathological response rate was 13%.
There were 11 complete and 29 partial clinical responses for an
overall response rate of 85% [95% confidence interval (CI) 75% to
95%] in the evaluable population (n = 47). Disease-free and overall
survival rates were 85% (95% CI 71% to 94%) and 96% (95% CI
85% to 99%), respectively, after a median follow-up of 36.6 months.
Grade 3/4 neutropenia was observed in 65% of patients and 17%
reported grade 4 febrile neutropenia. Conclusions: Docetaxel and
doxorubicin is an effective and well-tolerated combination in the
neoadjuvant therapy of breast cancer. Future controlled trials are
warranted to investigate the best schedules and to correlate response
with biological factors.
639. Apoptotic action of 17 -estradiol in raloxifene-resistant
MCF-7 cells in vitro and in vivo - Liu H., Lee E.-S., Gajdos C. et
al. [Dr. V.C. Jordan, R. H. Lurie Comprehen. Cancer Ctr., Feinberg
School of Medicine, Northwestern University, 303 E. Chicago Ave.,
Chicago, IL 60611, United States] - J. NATL. CANCER INST. 2003
95/21 (1586-1597) - summ in ENGL
Background: Resistance to tamoxifen., a selective estrogen receptor modulator (SERM), involves changes that prevent apoptosis
and enhance cell proliferation and survival. Paradoxically, estrogen
treatment inhibits the growth of long-term tamoxifen-treated breast
tumors. Because of the increasing use of raloxifene, another SERM,
to prevent osteoporosis and potentially reduce breast cancer risk,
some women will develop raloxifene-resistant breast cancer. We developed a raloxifene-resistant MCF-7 cell model (MCF-7/Ral) and
investigated the nature of raloxifene-resistant breast cancer and its
response to estradiol. Methods: Raloxifene resistance and hormone
responsiveness were assessed by proliferation assays and cell cycle
analysis in parental MCF-7 and MCF-7/Ral cells. Nuclear factor
B (NF-B) activity was investigated with a transient transfection
assay. Apoptosis was investigated by annexin V staining, mRNA
was measured by real-time polymerase chain reaction, and protein
was measured by western blotting. Tumorigenesis was studied by
injecting MCF-7 or MCF-7/Ral cells into ovariectomized athymic
mice (10 per group) and monitoring tumor size weekly. All statistical tests were two-sided. Results: Basal NF-B activity was higher
in MCF-7/Ral cells (1.6 U, 95% confidence interval [CI] = 1.2 to
2.0 U) than in MCF-7 cells (0.8 U, 95% CI = 0.4 to 1.1 U; P = .004).
When cultured with 1 M raloxifene, MCF-7/Ral cells grew statistically significantly (P<.001) faster than MCF-7 cells. Estradiol
treatment of MCF-7/Ral cells arrested cells in G2 /M phase of the
cell cycle, decreased NF-B activity (0.2 U, 95% CI = 0.2 to 0.3 U;
P<.001), increased expression of Fas protein and mRNA (4.5-fold,
95% CI = 2.8- to 6.3-fold versus 0.5-fold, 95% CI = 0.3- to 0.8-fold
for control treatment; P<.001), and induced apoptosis. Treatment
with either raloxifene or tamoxifen stimulated MCF-7/Ral tumor
growth, suggesting that such tumors were resistant to both drugs.
When a 9-week raloxifene or tamoxifen treatment was followed
by a 5-week estradiol treatment, estradiol statistically significantly
reduced the size of tumors stimulated by raloxifene or tamoxifen
(at week 14, P = .004 for raloxifene and P<.001 for tamoxifen).
Conclusions: Growth of raloxifene-resistant MCF-7/Ral cells in
vitro and in vivo is repressed by estradiol treatment by a mechanism involving G2 /M-phase arrest, decreased NF-B activity, and
increased Fas expression to induce apoptosis.
640. Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer - Osipo C.,
Gajdos C., Liu H. et al. [Dr. V.C. Jordan, R. H. Lurie Comprehen.
Cancer Ctr., Feinberg School of Medicine, Northwestern University,
125
303 E. Chicago Ave., Chicago, IL 60611, United States] - J. NATL.
CANCER INST. 2003 95/21 (1597-1608) - summ in ENGL
Background: Long-term tamoxifen treatment of breast cancer
can result in tamoxifen-stimulated breast cancer, in which estrogen
inhibits tumor growth after tamoxifen withdrawal. We investigated
the molecular mechanism(s) of estradiol-induced tumor regression by using an in vivo model of tamoxifen-stimulated human
breast cancer. Methods: Growth of parental estradiol-stimulated
MCF-7E2 and long-term tamoxifen-stimulated MCF-7TAMLT xenografts in athymic mice was measured during treatment with
vehicle, estradiol, estradiol plus tamoxifen, tamoxifen alone, estradiol plus fulvestrant, or fulvestrant alone. Apoptosis was detected
by the terminal deoxynucleotidyltransferase-mediated deoxyuridine
triphosphate nick-end labeling (TUNEL) assay. Protein expression
was assessed by western blot analysis. mRNA expression was
assessed by real-time reverse transcription-polymerase chain reaction. All statistical tests were two-sided. Results: MCF-7E2 tumor
growth was stimulated by estradiol (cross-sectional area at week
13 = 1.06 cm2 , 95% confidence interval [CI] = 0.82 to 1.30 cm2 ;
P<.001) compared with control (0.06 cm2 , 95% CI = -0.02 to 0.14
cm2 ) , but tumor growth was inhibited by tamoxifen or fulvestrant.
MCF-7TAMLT tumor growth was stimulated by tamoxifen) crosssectional area at week 10 = 0.60 cm2 , 95% CI = 0.50 to 0.70 cm2 ;
P<.001) compared with control (0.02 cm2 , 95% CI = 0.00 to 0.04
cm2 ) . For MCF-7TAMLT tumors that were initially 0.35 cm2 ,
estradiol-induced regression to 0.18 cm2 (95% CI = 0.15 to 0.21
cm2 ; P<.001), and tamoxifen or estradiol plus fulvestrant enhanced
tumor growth to 1.00 cm2 (95% CI = 0.88 to 1.22 cm2 ). Estradiol
increased the number of apoptotic cells in tumors by 23% (95%
CI = 20% to 26%; P<.001) compared with all other treatments,
decreased estrogen receptor (ER) protein expression, increased
the expression of Fas mRNA and protein, decreased the expression
of HER2/neu mRNA and protein and nuclear factor B (NF-B)protein but did not affect Fas ligand protein expression compared
with control. Paradoxically, fulvestrant reversed this effect and
stimulated MCF-7TAMLT tumor growth apparently through ERmediated regulation of Fas, HER2/neu, and NF-B. Conclusion:
Physiologic levels of estradiol induced regression of tamoxifenstimulated breast cancer tumors, apparently by inducing the death
receptor Fas and suppressing the antiapoptotic/prosurvival factors
NF-B and HER2/neu.
641. Magnetic resonance spectroscopic pharmacodynamic
markers of the heat shock protein 90 inhibitor 17-allylamino,17demethoxygeldanamycin (17AAG) in human colon cancer
models - Chung Y.-L., Troy H., Banerji U. et al. [Dr. Y.-L.
Chung, Cancer Research UK, Biomed. Magnetic Resonance Res.
Grp., Department of Basic Medical Sciences, Cranmer Terrace,
London SW17 0RE, United Kingdom] - J. NATL. CANCER INST.
2003 95/21 (1624-1633) - summ in ENGL
Background:
17-Allylamino,17-demethoxygeldanamycin
(17AAG) is a novel anticancer drug that inhibits heat shock
protein 90 (Hsp90), resulting in proteasomal degradation of
several oncogenic proteins. We used phosphorus magnetic
resonance spectroscopy (31 P-MRS) to determine whether 17AAG
treatment leads to alterations in phospholipids that could serve
as pharmacodynamic markers for tumor response to 17AAG.
Methods: HCT116, HT29, and SW620 colon cancer cells were
treated with 17AAG, and extracts were examined by 31 P-MRS.
HT29 cells were also treated with the active metabolite of 17AAG,
17-amino,17-demethoxygeldanamycin (17AG), or the inactive
17AAG analog NSC683666. MF-1 nude mice carrying HT29
xenografts were examined using in vivo 31 P-MRS before and
after 17AAG treatment; xenograft tumor extracts were examined
by 31 P-MRS and proton MRS (1 H-MRS). Hsp90 client protein
expression was determined by using western blots. Two-tailed t
tests were used to compare metabolite concentrations and ratios,
and a Mann-Whitney U test was used to compare proportions.
All statistical tests were two-sided. Results: 17AAG treatment
led to statistically significantly increased phosphocholine levels
in all three cell lines (P = .02). 17AG treatment also increased
phosphocholine levels in HT29 cells, whereas NSC683666 had
no effect.
The phosphomonoester/phosphodiester ratio was
statistically significantly increased in the HT29 xenografts after
17AAG treatment relative to the pretreatment ratio (P = .02),
126
whereas no statistically significant change was observed after
vehicle treatment (P = .62). Statistically significant increases in
phosphocholine, phosphoethanolamine, and valine levels were
also observed in tumor extracts treated with 17AAG. Conclusions:
Inhibition of Hsp90 by 17AAG resulted in altered phospholipid
metabolism in cultured tumor cells and in tumor xenografts. The
increases observed in phosphocholine and phosphomonoester
levels suggest that these metabolites may have the potential to act
as noninvasive pharmacodynamic markers for analyzing tumor
response to treatment with 17AAG or other Hsp90 inhibitors.
642. Anticancer antifolates: Current status and future directions - McGuire J.J. [J.J. McGuire, Grace Cancer Drug Center,
Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo,
NY 14263, United States] - CURR. PHARM. DES. 2003 9/31 (25932613) - summ in ENGL
Antifolates are the oldest of the antimetabolite class of anticancer
agents and were one of the first modern anticancer drugs. The first
clinically useful antifolate, described in 1947, was 2,4-diaminopteroylglutamate (4-amino-folic acid; aminopterin; AMT) which
yielded the first-ever remissions in childhood leukemia. AMT was
soon superseded by its 10-methyl congener, methotrexate (MTX),
based on toxicity considerations; MTX remains, with one limited
exception, the only antifolate anticancer agent in clinical use to this
date. Because of the safety and utility of MTX, considerable effort has been invested in attempting to design more therapeutically
selective antifolates or antifolates with a wider tumor spectrum.
Initially, the design was based on the burgeoning knowledge of
folate-dependent pathways and the determinants of the mechanism of action of MTX. These determinants include transport, the
tight-binding inhibition of its target (the folate-dependent enzyme
dihydrofolate reductase (DHFR)), and metabolism of MTX to poly -glutamate (Glun ) metabolites. These early studies led to the
development of other antifolate DHFR inhibitors of two types: (1)"classical" analogs that use the same cellular transport systems as
MTX and are also metabolized to Glun ; and (2) "nonclassical" (i.e.,
lipophilic) analogs that do not require transport systems and that
are not metabolized to Glun . Although several of these analogs
have undergone clinical trial, none is proved superior to MTX.
Detailed examination of the mechanisms of cytotoxicity and selectivity of MTX showed that inhibition of both dTMP synthesis and
de novo purine synthesis, secondary to DHFR inhibition, led to
DNA synthesis inhibition and subsequent cell death; inhibition of
other folate-dependent pathways did not appear necessary for cell
death. Further studies showed that the contribution of inhibition
of dTMP or purine synthesis to cell death varied in different cell
types. These data suggested that inhibition of one of these pathways
individually might (at least in some cases) be therapeutically superior to the dual inhibition induced by MTX. Thus in rational design
and in structure-based design studies, two new classes of antifolate
enzyme inhibitors were elaborated-direct inhibitors of thymidylate
synthase (TMPS) and direct inhibitors of one or both of the two
folate-dependent enzymes of de novo purine synthesis. Members
of each class included both classical and nonclassical types. After
preclinical evaluation, several of these have moved into clinical
trials. To date only one new TMPS inhibitor has successfully completed clinical trials and been approved for routine use; this drug,
Tomudex (D1694, raltitrexed) is currently approved only in Europe
and only for the treatment of colon cancer. This still represents a
step forward for antifolates, however, since MTX is well-known
to be ineffective in colon cancer; thus Tomudex extends the tumor
range of antifolates. Antifolate development continues. Based on
the immense body of knowledge now extant on antifolates, specific
aspects of the mechanism of action have been the focus. Newer
antifolates have been described that inhibit more than one pathway
in folate metabolism, that have improved delivery, or that inhibit
other targets in folate metabolism. These new analogs are in various
stages of preclinical and clinical development.
643. Deaza analogs of folic acid as antitumor agents - Kisliuk
R.L. [R.L. Kisliuk, Department of Biochemistry, Tufts University
School of Medicine, 136 Harrison Avenue, Boston, MA 02111,
United States] - CURR. PHARM. DES. 2003 9/31 (2615-2625) summ in ENGL
Derivatives of the vitamin folic acid function in the body for
the synthesis of thymidylate, purines and amino acids and are necessary for normal metabolism and growth. Methotrexate (MTX),
an inhibitor of dihydrofolate reductase (DHFR) is the outstanding
example of an antitumor antifolate. MTX is clinically useful in
the treatment of childhood leukemia, choriocarcinoma and psoriasis, where it corrects abnormal growth, and in rheumatoid arthritis
and other autoimmune diseases where it corrects abnormal immune
function. Since 1949, when the chemical synthesis of MTX was
reported by workers at the Lederle Laboratories of the American
Cyanamid Company, much has been learned about the basis of antifolate cytotoxicity and selectivity. This review will focus on deaza
antifolates which are: 1) presently under clinical development and
2) less developed compounds which represent novel approaches.
Compounds will be grouped according to their enzyme targets;
DHFR, thymidylate synthase (TS) and glycinamide ribonucleotide
formyltransferase (GARFT). In addition to inhibition of target enzymes, antifolate membrane transport into cells and conversion
to poly-L- -glutamate forms are important considerations in drug
design along with the reverse processes, cellular hydrolysis of antifolate poly-L- -glutamates to monoglutamates and the extrusion of
the monoglutamates through the cell membrane. These processes
can be modulated by competition with folates.
644. Thioguanine, mercaptopurine: Their analogs and nucleosides as antimetabolites - Elgemeie G.L. [G.H. Elgemeie,
Chemistry Department, Faculty of Science, Helwan University,
Ain-Helwan, Cairo, Egypt] - CURR. PHARM. DES. 2003 9/31
(2627-2642) - summ in ENGL
6-Mercaptopurine (6MP) and 6-thioguanine (6TG) are analogs
of the natural purines: hypoxanthine and guanine.
Both
mercaptopurine and thioguanine are substrates for hypoxanthineguanine phosphoribosyltransferase and are converted into the
ribonucleotides 6-thioguanosine monophosphate (6-thioGMP) and
6-thioinosine monophosphate (T-IMP) respectively. The accumulation of these monophosphates inhibits several vital metabolic
reactions. Today, these thiopurine bases remain valuable agents
for the induction and maintenance of remissions in patients with
myelocytic and acute lymphocytic leukemia. Despite their proved
clinical importance, 6MP and 6TG have certain therapeutic disadvantages, which have continued to stimulate the search for purine
derivatives enhancing therapeutic efficacy. Considerable efforts
have been made to prepare other novel mercaptopurine and thioguanine analogs and their nucleosides to improve the antitumor
efficacy. The effectiveness of these thiopurines against certain tumor cell lines suggested that some of these mercaptopurine analogs
and their nucleosides would be worthy of consideration in order
to determine whether they exert a more selective effect against
neoplastic cells than against normal cells or they might be useful in
patients whose disease has become resistant to 6MP or 6TG. This
review will focus on mercaptopurine analogs and their nucleosides
as antimetabolite agents.
645. Immunomodulatory activity of resveratrol: Discrepant in
vitro and in vivo immunological effects - Gao X., Deeb D.,
Media J. et al. [S.C. Gautam, Division of Hematology/Oncology,
Department of Medicine, Henry Ford Health System, 2799 West
Grand Boulevard, Detroit, MI 48202, United States] - BIOCHEM.
trans-Resveratrol is a dietary polyphenolic compound present in
grapes, which has been shown to exhibit strong anti-inflammatory, antioxidant, and chemopreventive activities. In this study
we have compared the in vitro and in vivo effects of resveratrol
on the development of various cell-mediated immune responses,
including mitogen/antigen-induced T cell proliferation, induction
of cytotoxic T lymphocytes (CTLs), interleukin-2 (IL-2) induced
lymphokine activated killer cells, and cytokine production. We
found significant suppression (>90%) of the mitogen/antigen-induced T cell proliferation and development of allo-antigen specific
CTLs in vitro with resveratrol at a concentration of 25M. Intragastric administration of resveratrol (2mg daily) to mice for 4 weeks
showed no effect on age-related gain in body weight, peripheral
blood cell counts (WBC, RBC, or platelets), or the cellularity of
bone marrow or spleen. The CD4+ and CD8+ T cells in spleen or
colony-forming units-total in the marrow also remained unaffected
by treatment with resveratrol. Spleen cells, which were stimulated
in vitro after being removed from mice which had been administered resveratrol for 2 or 4 weeks, showed no significant change
in IL-2 or concanavalin A induced proliferation of T cells or production of IL-2 induced lymphokine activated killer cells. Further,
the production of in interferon-gamma and IL-12 was not affected
by administration of resveratrol, but production of tumor necrosis
factor-alpha was reduced. Even when conducted entirely in vivo,
treatment with resveratrol was found to only marginally reduce alloantigen induced T cell proliferation and the generation of CTLs in
the draining lymph nodes. Thus, even though resveratrol strongly
inhibits T cell proliferation and production of cytolytic cells in
vitro, oral administration of resveratrol for 4 weeks does not induce
hematologic or hematopoietic toxicity, and only marginally reduces
the T cell-mediated immune responses. © 2003 Elsevier Inc. All
rights reserved.
646. Induction of the mitochondrial permeability transition by
selenium compounds mediated by oxidation of the protein thiol
groups and generation of the superoxide - Kim T.-S., Yun B.Y.
and Kim I.Y. [I.Y. Kim, Lab. of Cell./Molecular Biochemistry, Sch.
of Life Sci. and Biotechnology, Korea University, 15-Ka, AnamDong, Sungbuk-ku, Seoul 136-701, South Korea] - BIOCHEM.
The cancer chemopreventive effect of selenium compounds cannot be fully explained by the role of selenium as a component
of antioxidant enzymes, suggesting that other mechanisms, such
as thiol oxidation or free radical generation, also underlie this effect. The toxicities of six different selenium compounds (selenite,
selenate, selenocystine, selenocystamine, selenodioxide, and selenomethionine) have now been compared in HepG2 human hepatoma
cells and isolated rat liver mitochondria. Selenite, selenocystine,
and selenodioxide induced apoptosis in HepG2 cells and mediated
oxidation of protein thiol groups in both HepG2 cells and isolated
mitochondria. Selenocystamine oxidized protein thiol groups in
isolated mitochondria and crude extracts of HepG2 cells but not in
intact HepG2 cells, suggesting that this compound is not able to cross
the cell membrane. The selenium compounds capable of oxidizing
thiol groups also induced the mitochondrial permeability transition
(MPT) in isolated mitochondria. Furthermore, they generated the
superoxide (O2 - ) on reaction with glutathione in the presence of
mitochondria, and an O2 - scavenger inhibited their induction of the
MPT. These results suggest that the pro-apoptotic action of selenium
compounds is mediated by both thiol oxidation and the generation
of O2 - , both of which contribute to opening of the MPT pore. ©
2003 Elsevier Inc. All rights reserved.
647. Ecteinascidin-743 drug resistance in sarcoma cells: Transcriptional and cellular alterations - Shao L., Kasanov J.,
Hornicek F.J. et al. [L. Weissbach, Orthopaedic Research Laboratories, Massachusetts General Hospital, Harvard Medical School,
55 Fruit Street, Boston, MA 02114, United States] - BIOCHEM.
A human chondrosarcoma cell line, CS-1, was treated
successively with increasing concentrations of the marine chemotherapeutic Ecteinascidin-743 (ET-743), yielding a variant cell line
displaying a significant degree of resistance to the cytotoxic action of this drug. Various experiments were performed to discern
molecular aberrations between the parent and resistant cell line, and
also identify potential molecular markers indicative of drug resistance. Although no significant differences in the levels of membrane
transporters such as P-glycoprotein or multidrug resistance protein
1 (MRP1) were detected, the cell migratory ability of the ET-743resistant cell variant was reduced, as was its attachment capability to
gelatin-coated cell culture dishes. Staining of the actin-containing
cytoskeleton with fluorescent-labeled phalloidin revealed marked
differences in the cytoskeleton architecture between the parent and
ET-743-resistant CS-1 cell lines. Comparison of serum-free conditioned medium from both cell lines showed conspicuous differences
in the levels of several proteins, including a quartet of high molecular weight proteins (140kDa). The protein sequences of two of
these high molecular weight proteins, present at significantly higher
concentrations in conditioned medium obtained from the parent
cell line, corresponded to subunits of types I and IV collagen. Analysis of type I collagen 1 chain mRNA revealed a significantly
127
lower level in the ET-743-resistant CS-1 cell line. Thus, prolonged
exposure to ET-743 may cause changes in cell function through
cytoskeleton rearrangement and/or modulation of collagen levels.
648. Serum from rabbit orally administered cobra venom inhibits growth of implanted hepatocellular carcinoma cells in
mice - Sun P., Ren X.-D., Zhang H.-W. et al. [X.-K. Li, Biopharmaceutical R and D Center, Jinan University, Guangzhou 510632,
Guangdong Province, China] - WORLD J. GASTROENTEROL.
2003 9/11 (2441-2444) - summ in ENGL
Aim: To investigate the inhibitory effect of serum preparation
from rabbits orally administered cobra venom (SRCV) on implanted
hepatocellular carcinoma (HCC) cells in mice. Methods: An HCC
cell line, HepA, was injected into mice to prepare implanted tumors.
The animals (n=30) were divided randomly into SRCV, 5-fluorouracil (5-FU), and distilled water (control) groups. From the second
day after transplantation, 20 mg/kg 5-FU was administered intraperitoneally once a day for 9 days. SRCV (1 000 mg/kg) or distilled
water (0.2 ml) was given by gastrogavage. Tumor growth inhibition
was described by the inhibitory rate (IR). Apoptosis was detected by
transmission electron microscopy (TEM), flow cytometry (FCM),
and terminal deoxynucleotidyl transferase-mediated dUTP-biotin
nick end labeling (TUNEL). Student’s f-test was performed for statistical analysis. Results: The tumor growth was inhibited markedly
by SRCV treatment compared to that in the control group (P<0.01).
The treatment resulted in a significant increase in the apoptotic rate
of cancer cells by the factors of 10.52.4 % and 20.653.2 %
as demonstrated through TUNEL and FCM assays, respectively
(P<0.01). The apoptotic cells were also identified by characteristic
ultrastructural features. Conclusion: SRCV can inhibit the growth
of implanted HepA cells in mice, and the apoptosis rate appears to
elevate during the process.
649. Programmed cell death protein 4 (pdcd4): A novel target
for antineoplastic therapy? - Lankat-Buttgereit B. and Göke
R. [B. Lankat-Buttgereit, Clin. Res. U Gastrointest. Endocr.,
University of Marburg, 35037 Marburg, Germany] - BIOL. CELL
2003 95/8 (515-519) - summ in ENGL
Pdcd4 is a novel gene first identified as a differentially expressed
protein during apoptosis. In the meantime not only the impact of
Pdcd4 in programmed cell death but also an implication in transformation suppression by inhibition of protein translation is discussed.
These features implicate a potential value of Pdcd4 as a molecular target in cancer therapy. This review summarizes the current
knowledge about expression, structure and function of Pdcd4. ©
2003 Éditions scientifiques et médicales Elsevier SAS. All rights
reserved.
650. In children and adolescents, the pharmacodynamics of
high-dose busulfan is dependent on the second alkylating agent
used in the combined regimen (melphalan or thiotepa) - Bouligand J., Boland I., Valteau-Couanet D. et al. [Prof. G. Vassal,
UPRES EA3535, Pharmacol./New Treatments of Cancers, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif 94800,
France] - BONE MARROW TRANSPLANT. 2003 32/10 (979-986) summ in ENGL
A strong relationship has been demonstrated between high
systemic exposure to busulfan and the occurrence of hepatic
veno-occlusive disease (HVOD) after a busulfan-cyclophosphamide regimen (BU CY). We report a prospective study aimed at
exploring the pharmacodynamics of high-dose busulfan combined
with either melphalan (BU MEL) or thiotepa (BU TTP) followed
by autologous stem cell transplantation in children and adolescents
with a malignant solid tumor. Busulfan was given orally at a total
dose of 600 mg m-2 . In all, 45 patients with a median age of 6.3
years were included in the study: 25 received BU MEL and 20
received BU TTP. The incidence of HVOD was 44% (CI 95% [2365%]) in the BU MEL group and 25% (CI95% [9-49%]) in the
BU TTP group. In the BU TTP group, patients who developed
HVOD had a significantly higher AUC 0-6 h after the 13th dose
(6201607 h ng ml-1 ) than those who did not (5024978 h ng
ml-1 ) (P < 0.05). In the BU MEL group, there was no difference in
terms of systemic exposure to busulfan between patients who developed HVOD and those who did not. In conclusion, the guidelines
128
established for monitoring BU CY cannot be extrapolated when
busulfan is combined with another drug.
651. Pegaspargase: A review of clinical studies - Graham M.L.
[M.L. Graham, Univ. of AZ Health Sciences Center, Department
of Pediatrics, 1501 N. Campbell Avenue, Tucson, AZ 85724-5073,
United States] - ADV. DRUG DELIV. REV. 2003 55/10 (1293-1302) summ in ENGL
The chemotherapy agent L-asparaginase has been an important
part of acute lymphoblastic leukemia therapy for over 30 years. Two
of the main disadvantages of the drug are (1) the need for frequent
intramuscular injection and (2) a very high rate of allergic reactions. Because of this, L-asparaginase seemed like an ideal target
for pegylation and PEG-L-asparaginase was developed in the 1970s
and 1980s. The drug has undergone extensive testing and appears
to retain its antileukemic effectiveness while allowing less frequent
administration than the native compound. While the actual cost
to patients for PEG-L-asparaginase is greater than that of multiple
injections of other L-asparaginases, the reduced need for physician
visits and treatment of complications of therapy may make overall
treatment costs considerably less than that of the conventional Lasparaginases. In the review below, we outline the history of therapy
with L-asparaginase, the development of PEG-L-asparaginase, and
clinical trials in which it has been administered. © 2003 Elsevier
652. Effect of the antidepressant desipramine on cytosolic Ca2+
movement and proliferation in human osteosarcoma cells Jan C.-R., Lu Y.-C., Tseng L.-L. et al. [J.-K. Huang, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung
813, Taiwan] - PHARMACOLOGY 2003 69/4 (190-196) - summ in
ENGL
In human osteosarcoma MG63 cells, the effect of desipramine, an
antidepressant, on intracellular Ca2+ concentration ([Ca 2+ ]i ) was
measured by using fura-2. Desipramine (>10 mol/l) caused a
rapid and sustained rise of [Ca2+ ]i in a concentration-dependent
manner (EC50 = 200 mol/l). Desipramine-induced [Ca2+ ]i rise
was prevented by 80% by removal of extracellular Ca2+ but was
not altered by voltage-gated Ca2+ channel blockers. In Ca2+ -free
medium, thapsigargin, an inhibitor of the endoplasmic reticulum
(ER) Ca2+ -ATPase, caused a monophasic [Ca2+ ]i rise, after which
the increasing effect of desipramine on [Ca2+ ]i was abolished; also,
pretreatment with desipramine partly reduced thapsigargin-induced
[Ca 2+ ]i increase. U73122, an inhibitor of phospholipase C, did not
affect desipramine-induced [Ca2+ ]i rise. Overnight incubation with
10 mol/l desipramine did not alter cell proliferation, but killed 32
and 89% of cells at concentrations of 100 and 200 mol/l, respectively. These findings suggest that desipramine rapidly increases
[Ca2+ ]i in osteoblasts by stimulating both extracellular Ca2+ influx
and intracellular Ca2+ release, and is cytotoxic at high concentrations. Copyright © 2003 S. Karger AG, Basel.
653. Inhibition of adenovirus-mediated p27kip1 gene on growth
of esophageal carcinoma cell strain - Wu Q.-M., Yu J.-P., Tong
Q. et al. [Dr. Q.-M. Wu, Department of Gastroenterology, Taihe
Hosp. of Yunyang Med. College, 29 Renmin Road, Shiyan 442000,
Hubei Province, China] - WORLD J. GASTROENTEROL. 2003 9/11
(2404-2408) - summ in ENGL
AIM: To investigate the inhibition of p27kip1 gene on the growth
of esophageal carcinoma cell strain (EC9706). METHODS: Recombinant adenovirus Ad-p27kip1 was constructed and transfected
into esophageal carcinoma cell EC-9706, and its effect on p27kip1
expression, the growth of esophageal carcinoma cell, DNA replication, protein synthesis, cell multiplication and apoptosis were
explored by means of cell growth count, 3 H-TdR, 3 H-Leucine incorporation, flow cytometry, DNA fragment analysis and TUNEL.
RESULTS: Recombinant adenovirus Ad-p27kip1 was successfully
constructed with a virus titer of 1.241012 pfu/ml. p27kip protein
expression increased markedly after EC-9706 transfection, while
incorporation quantity of 3 H-TdR and 3 H-Leucine decreased significantly. The growth of esophageal carcinoma cell was inhibited
obviously. Testing of flow cytometry displayed a typical apoptosis peak, and DNA gel electrophoresis showed a typical apoptosis
ladder. TUNEL showed the apoptosis rate of Ad-p27kip1 group
and control group to be 37.3 % and 1.26 % (P<0.001) respectively.
CONCLUSION: Ad-p27kip1 can inhibit the growth and multiplication of esophageal carcinoma cells and induce apoptosis. Therefore,
enhanced p27kip1 expression may be a new way to treat esophageal
carcinoma.
See also: 697, 704, 712, 735, 737, 748.
tuberculosis. Mechanism-of-action studies revealed that the immediate inhibitory effects of 2-methyl-adenosine were associated with
protein and DNA synthesis and not RNA synthesis. Conclusions:
Results indicate that 2-methyl-adenosine, or similar derivatives,
might be effective against M. tuberculosis infections during latency. This information should be helpful in understanding purine
metabolism of M. tuberculosis and also the metabolic activity of
this important human pathogen in the persistent state.
6.5. Antiinfective agents
654. Cyrmenins, new -methoxyacrylate inhibitors of the electron transport. Production, isolation, physico-chemical and
biological properties - Sasse F., Leibold T., Kunze B. et al. [F.
Sasse, GBF, German Research Center Biotechnology, Dept. of Natural Product Biology, Mascheroder Weg 1, D-38124 Braunschweig,
Germany] - J. ANTIBIOT. 2003 56/10 (827-831) - summ in ENGL
New antibiotic compounds, named cyrmenins, were isolated from
the culture broth of strains of the myxobacteria Cystobacter armeniaca and Archangium gephyra. The compounds belong to the
group of -methoxyacrylate (MOA) inhibitors and are the first naturally occuring nitrogen-linked MOAs. The cyrmenins show nearly
the same antifungal activity as strobilurin A, but are less toxic in a
growth inhibition assay with L929 mouse cells. Cyrmenins inhibit
NADH oxidation by submitochondrial particles from beef heart.
Investigations by difference spectroscopy showed that cyrmenin B1
blocks the electron transport within the cytochrome bc1 -segment
(complex III) of the respiratory chain.
655. Synthesis and biological activity of AM-112 and related
oxapenem analogues - Simpson I., Urch C.J., Hagen G. et al. [I.N.
Simpson, Micron Research Ltd., Ely CB7 4JY, United Kingdom] J. ANTIBIOT. 2003 56/10 (838-847) - summ in ENGL
Thirty five oxapenem analogues substituted with a range of
tertiary groups at C-2 have been synthesised and evaluated as
broad-spectrum -lactamase inhibitors. All analogues enhanced
the activity of ceftazidime against bacterial isolates producing Class
A and Class C -lactamases. Compounds with cyclic substituents
at C-1 (attached to C-6) were associated with enhanced antibacterial activity against Staphylococcus aureus. (R) Stereochemistry
at C-1 led to synergistic activity against -lactamase negative
enterococci. (S) Stereochemistry at C-1 was associated with
enhanced inhibition of Class A -lactamases and lack of synergistic activity against enterococci. AM-113 was unstable in serum
and not detectable following subcutaneous or oral dosing in mice.
AM-112 and AM-115 achieved good serum levels following subcutaneous dosing. AM-114 exhibited 30% bioavailability following
oral dosing. AM-112 [(1 R,5R,6R)-2-(4-ammonio-1,1-dimethylbutyl -6-(1 -hydroxyethyl) oxapenem-3-carboxylate] achieved the
greatest protection of ceftazidime against Gram-negatives producing Class A or C -lactamases.
656. Antimycobacterial activity of 2-methyl-adenosine - Barrow
E.W., Westbrook L., Bansal N. et al. [W.W. Barrow, Mycobacteriology Research Unit, Dept. of Veterinary Pathobiology, Oklahoma
State University, 250 McElroy Hall, Stillwater, OK 74078, United
States] - J. ANTIMICROB. CHEMOTHER. 2003 52/5 (801-808) summ in ENGL
Objectives: The aims of this study were to assess the in vitro
activity of 2-methyl-adenosine against Mycobacterium tuberculosis and evaluate, and to intracellular efficacy, and to evaluate its
effectiveness against M. tuberculosis in a persistent state model
and examine its potential mechanism of action. Methods: In vitro
activity was determined by means of a colorimetric microdilution
broth assay. Intracellular activity was assessed with a Mono Mac 6
human monocytic cell line. A hypoxic shift-down model was used
to evaluate the effect of 2-methyl-adenosine on M. tuberculosis in
a persistent state. Mechanism-of-action studies were conducted
by examining the effect of 2-methyl-adenosine on the uptake of
appropriate radiolabelled precursors into respective mycobacterial
macromolecular components. Results: Studies confirmed the in
vitro activity of 2-methyl-adenosine against M. tuberculosis and
demonstrated intracellular efficacy against M. tuberculosis within
macrophages. 2-Methyl-adenosine was able to significantly affect
the viability of M. tuberculosis in a hypoxic shift-down model previously described to simulate the persistent state that results during
657. Hypertrophy of Vascularized Bone Isograft in Rats Treated
with Cyclosporine A - Tsubone T., Shigetomi M., Ihara K. et
al. [M. Shigetomi, Department of Orthopedic Surgery, Yamaguchi
Univ. School of Medicine, 1-1-1 Minamikogushi, Yamaguchi 7558505, Japan] - CALCIF. TISSUE INT. 2003 73/4 (393-399) - summ
in ENGL
The aim of this study was to investigate the effects of cyclosporine
A (CsA) on vascularized tibiofibula isograft between 12-week-old
male Lewis rats. After transplantation, 45 rats were randomly allocated to one of the following 7 treatment groups: (1) 4-week vehicle
(n = 5), (2) 4-week CsA (n = 5), (3) 8-week vehicle (n = 10), (4) 8week CsA (n = 10), (5) 4-week CsA followed by 4-week vehicle
(n = 5), (6) 16-week vehicle (n = 5), or (7) 4-week CsA followed
by 12-week vehicle (n = 5). In soft X-ray and micro-computed
tomography examination, hypertrophic change of the grafted bones
was apparent in the 4- and 8-week CsA groups. Mineral apposition
rate and bone formation rate of the grafted bones in the 4-week
CsA group were markedly higher than those in the 4-week vehicle
group. In the 4- and 8-week CsA groups, however, bone mineral
density (BMD) of the grafted bones was lower and strength of the
reconstructed bones was weaker than the 4- and 8-week vehicle
groups. Urinary deoxypyridinoline (DPD) level was higher in the
4- and 8-week CsA groups than in the 4- and 8-week vehicle groups.
The group of 4-week CsA followed by 4-week vehicle had a level
of urinary DPD equal to the 8-week vehicle group, but their BMD
of the grafted bones was lower and strength of the reconstructed
bones was weaker than the 8-week vehicle group. By contrast, the
group of 4-week CsA followed by 12-week vehicle had BMD of the
grafted bones and strength of the reconstructed bones similar to the
16-week vehicle group. These findings demonstrate that short-term
CsA treatment induces hypertrophic change of vascularized bone
graft with high-turnover bone loss, and strength of the reconstructed
bone is gradually restored after the cessation of CsA treatment.
658. Semi-synthetic glycopeptide antibacterials - Judice J.K.
and Pace J.L. [J.L. Pace, 35 Indian Rock Court, San Anselmo, CA
94960, United States] - BIOORG. MED. CHEM. LETT. 2003 13/23
(4165-4168) - summ in ENGL
Studies leading to the discovery of TD-6424 and their relevance to
other hydrophobically-substituted glycopeptides are reviewed along
with a brief comparison of properties for related agents currently
undergoing clinical evaluation. © 2003 Elsevier Ltd. All rights
reserved.
659. Influence of ethylene-oxy spacer group on the activity of
linezolid: Synthesis of potent antibacterials possessing a thiocarbonyl group - Selvakumar N., Raheem M.A., Khera M.K. et
al. [N. Selvakumar, Anti-infectives Discovery Group, Discovery
Research, Dr. Reddy’s Laboratories Ltd., Miyapur, Hyderabad 500
049, India] - BIOORG. MED. CHEM. LETT. 2003 13/23 (41694172) - summ in ENGL
The influence of an ethylene-oxy spacer element between the
heterocycle and the aromatic ring in linezolid is reported. The introduction of such spacer group generated compounds with inferior
antibacterial activity. However, the conversion of the acetamide
group present in the linezolid analogues to either thiocarbamate
or thioacetamide functionality restored the activity. The synthesis
of linezolid analogues possessing the ethylene-oxy spacer group
along with SAR studies with different heterocycles and preparation
of some thiocarbonyl compounds possessing potent antibacterial
property are presented. © 2003 Elsevier Ltd. All rights reserved.
660. Synthesis and antibacterial activity of pyrroloaryl-substituted oxazolidinones - Paget S.D., Foleno B.D., Boggs C.M. et
al. [S.D. Paget, Johnson/Johnson Pharmaceutical R., L.L.C., Route
129
202, Raritan, NJ 08869, United States] - BIOORG. MED. CHEM.
LETT. 2003 13/23 (4173-4177) - summ in ENGL
A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative
panel of susceptible and resistant Gram-positive bacteria. Several
members of this series were found to have antibacterial activity
comparable to or better than linezolid. © 2003 Elsevier Ltd. All
rights reserved.
661. New classes of antibacterial oxazolidinones with C-5, methylene O-linked heterocyclic side chains - Gravestock M.B., Acton
D.G., Betts M.J. et al. [M.B. Gravestock, AstraZeneca R and D
Boston, Infection Discovery, 35 Gatehouse Park, Waltham, MA
(4179-4186) - summ in ENGL
Exploration of the structure-activity relationships of the traditional C-5 acetamidomethyl side chain of the oxazolidonone
antibacterials has yielded new, potent series of compounds of which
the first examples, the O-linked iosoxazoles are described in detail,
leading to the selection of the pre-clinical candidate AZD2563. ©
662. Synthesis and biological activity of N-acylated ornithine
analogues of daptomycin - Hill J., Siedlecki J., Parr I. et al. [I.
Parr, Cubist Pharmaceuticals Inc., 65 Hayden Ave, Lexington, MA
(4187-4191) - summ in ENGL
N-Acylated ornithine analogues of daptomycin were synthesized
and tested for their antibacterial efficacy. © 2003 Elsevier Ltd. All
rights reserved.
663. The synthesis and antibacterial activity of 1,3,4-thiadiazole phenyl oxazolidinone analogues - Thomasco L.M.,
Gadwood R.C., Weaver E.A. et al. [L.M. Thomasco, Discov.Chem./Discov.-Infect. Dis., Pharmacia Corporation, 7000 Portage
Road, Kalamazoo, MI 49001, United States] - BIOORG. MED.
CHEM. LETT. 2003 13/23 (4193-4196) - summ in ENGL
Replacement of the morpholine C-ring of linezolid 1 with a 1,3,4thiadiazolyl ring leads to oxazolidinone analogues 5 having potent
antibacterial activity against both gram-positive and gram-negative
organisms. Conversion of the C5 acetamide group to a thioacetamide further increases the potency of these compounds. © 2003
Elsevier Ltd. All rights reserved.
664. Synthesis and biological evaluation of benzazepine oxazolidinone antibacterials - Johnson P.D., Aristoff P.A., Zurenko G.E.
et al. [P.D. Johnson, Discovery-Chemistry, Pharmacia Corporation, 7000 Portage Road, Kalamazoo, MI 49001, United States] BIOORG. MED. CHEM. LETT. 2003 13/23 (4197-4200) - summ in
ENGL
Novel benzazepine oxazolidinone antibacterials were synthesized
and evaluated against clinically relevant susceptible and resistant
organisms. The effect of ring nitrogen position and N-substitution
on antibacterial activity is examined. © 2003 Elsevier Ltd. All
rights reserved.
665. MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: Discovery and early strategies for
lead optimization - Nakayama K., Ishida Y., Ohtsuka M. et al. [K.
Nakayama, Med. Chemistry Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 1-16-13, Kitakasai, Edogawa, Tokyo 134-8630,
Japan] - BIOORG. MED. CHEM. LETT. 2003 13/23 (4201-4204) summ in ENGL
The identification of a series of compounds that specifically inhibit efflux by the MexAB-OprM pump system in Pseudomonas
aeruginosa is described. Synthesis and in vitro structure-activity
relationships (SARs) are outlined. Early leads lacked activity in
animal models, and efforts to improve solubility and reduce serum
protein binding by the introduction of polar groups are discussed.
© 2003 Elsevier Ltd. All rights reserved.
666. MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 2: Achieving activity in vivo through
the use of alternative scaffolds - Nakayama K., Ishida Y., Ohtsuka
M. et al. [K. Nakayama, Med. Chemistry Research Laboratory,
130
Daiichi Pharmaceutical Co., Ltd., 1-16-13, Kitakasai, Edogawa,
Tokyo 134-8630, Japan] - BIOORG. MED. CHEM. LETT. 2003
13/23 (4205-4208) - summ in ENGL
Problems of low solubility, high serum protein binding, and lack
of efficacy in vivo in first generation MexAB-OprM specific efflux
pump inhibitors were addressed. Through the use of pharmacophore
modelling, the key structural elements for pump inhibition were defined. Use of alternative scaffolds upon which the key elements
were arrayed gave second generation leads with greatly improved
physical properties and activity in the potentiation of antibacterial
quinolones (levofloxacin and sitafloxacin) versus Pseudomonas aeruginosa in vivo. © 2003 Elsevier Ltd. All rights reserved.
667. New antibacterial tetrahydro-4(2H)-thiopyran and thiomorpholine S-oxide and S,S-dioxide phenyloxazolidinones Singh U., Raju B., Lam S. et al. [M.F. Gordeev, Vicuron Pharmaceuticals Inc., 34790 Ardentech Court, Fremont, CA 94555, United
States] - BIOORG. MED. CHEM. LETT. 2003 13/23 (4209-4212) summ in ENGL
Combinatorial libraries of N-acylated 5-(S)-aminomethyloxazolidinone derivatives of S-oxide and S,S-dioxide tetrahydro-4(2H)thiopyranyl and thiomorpholine phenyloxazolidinone series have
been synthesized on a solid phase and evaluated for antimicrobial
activity. Several novel potent leads have been identified, including orally active oxazolidinones with enhanced activity against
respiratory tract infection pathogens Haemophilus influenzae and
Moraxella catarrhalis. © 2003 Elsevier Ltd. All rights reserved.
668. Novel oxazolidinone-quinolone hybrid antimicrobials Gordeev M.F., Hackbarth C., Barbachyn M.R. et al. [M.F. Gordeev,
Vicuron Pharmaceuticals Inc., 34790 Ardentech Ct., Fremont, CA
(4213-4216) - summ in ENGL
Antimicrobial compounds incorporating oxazolidinone and quinolone pharmacophore substructures have been synthesized and
evaluated. Representative analogues 2, 5, and 6 display an
improved potency versus linezolid against gram-positive and fastidious gram-negative pathogens. The compounds are also active
against linezolid- and ciprofloxacin-resistant Staphylococcus aureus and Enterococcus faecium strains. The MOA for these new
antimicrobials is consistent with a combination of protein synthesis
and gyrase A/topoisomerase IV inhibition, with a structure-dependent degree of the contribution from each inhibitory mechanism. ©
669. Iclaprim, a novel diaminopyrimidine with potent activity
on trimethoprim sensitive and resistant bacteria - Schneider P.,
Hawser S. and Islam K. [P. Schneider, Arpida Ltd., Dammstrasse 36,
CH-4142 Muenchenstein, Switzerland] - BIOORG. MED. CHEM.
LETT. 2003 13/23 (4217-4221) - summ in ENGL
Iclaprim, a new selective dihydrofolate inhibitor was synthesized
based on rational drug design. Iclaprim’s interaction with a resistant
Staphylococcus aureus dihydrofolate reductase (DHFR) is outlined
in comparison to trimethoprim (TMP). This compound is active
against methicillin, TMP and vancomycin resistant strains. Arpida
Ltd. is developing Iclaprim for serious hospital infections from
Gram-positive pathogens and respiratory tract infections. © 2003
Elsevier Ltd. All rights reserved.
670. -substituted hydroxamic acids as novel bacterial deformylase inhibitor-based antibacterial agents - Jain R., Sundram
A., Lopez S. et al. [Z. Yuan, Vicuron Pharmaceuticals, 34790
Ardentech Court, Fremont, CA 94555, United States] - BIOORG.
MED. CHEM. LETT. 2003 13/23 (4223-4228) - summ in ENGL
We report the synthesis and biological activity of analogues
of VRC3375 (N-hydroxy-3-R-butyl-3-[(2-S-(tert-butoxycarbonyl)pyrrolidin-1-ylcarbonyl] propionamide), an orally active peptide
deformylase inhibitor. This study explores the structure-activity
relationship of various chelator groups, alpha substituents, P2 and
P3 substituents in order to achieve optimal antibacterial activity
with minimal toxicity liability. © 2003 Elsevier Ltd. All rights
reserved.
671. Structure-activity relationship in the oxazolidinone-quinolone hybrid series: Influence of the central spacer on the
antibacterial activity and the mode of action - Hubschwerlen
C., Specklin J.-L., Baeschlin D.K. et al. [C. Hubschwerlen, Morphochem AG, Schwarzwaldallee 215, CH 4058 Basel, Switzerland]
- BIOORG. MED. CHEM. LETT. 2003 13/23 (4229-4233) - summ
in ENGL
Oxazolidinone-quinolone hybrids, which combine the pharmacophores of a quinolone and an oxazolidinone, were synthesised
and shown to be active against a variety of susceptible and resistant
Gram-positive and Gram-negative bacteria. The nature of the spacer
greatly influences the antibacterial activity by directing the mode
of action, that is quinolone- and/or oxazolidinone-like activity. The
best compounds in this series have a balanced dual mode of action
and overcome all types of resistance, including resistance to quinolones and linezolid, in clinically relevant Gram-positive pathogens.
© 2003 Elsevier Ltd. All rights reserved.
672. The effect of remote chirality on the antibacterial activity of indolinyl, tetrahydroquinolyl and dihydrobenzoxazinyl
oxazolidinones - Ciske F.L., Barbachyn M.R., Genin M.J. et
al. [M.R. Barbachyn, Pfizer, 7000 Portage Road, Kalamazoo, MI
(4235-4239) - summ in ENGL
The oxazolidinones are promising agents for the treatment of
infections caused by gram-positive bacteria, including multidrugresistant strains. In ongoing studies we have discovered that a
strategically placed chiral center of appropriate absolute configuration improves the antibacterial activity of indolinyl oxazolidinone
analogues (gram-positive MIC’s<0.5 g/mL for the most potent
congeners). The design, synthesis, antibacterial activity and pharmacokinetic profile of a selected series of -methylated indoline
derivatives and a related set of tetrahydroquinolyl and dihydrobenzoxazinyl analogues are discussed. © 2003 Published by Elsevier
Ltd.
673. The relationship between physicochemical properties, in
vitro activity and pharmacokinetic profiles of analogues of
diamine-containing efflux pump inhibitors - Watkins W.J., Landaverry Y., Léger R. et al. [W.J. Watkins, Essential Therapeutics,
Inc., 850 Maude Ave., Mountain View, CA 94043, United States] BIOORG. MED. CHEM. LETT. 2003 13/23 (4241-4244) - summ in
ENGL
Following the optimization of diamine-containing efflux pump
inhibitors with respect to in vitro potentiation activity, in vivo stability and acute toxicity, we addressed the question of how to control
the pharmacokinetic properties of the series. Upon intravenous
administration in the rat, tissue levels of MC-04,124 (the lead compound) were high and prolonged compared to those in the serum.
The lipophilicity and basicity of analogues of this compound were
systematically varied, and effects on potency and pharmacokinetics
explored. The ratio of drug levels in tissue versus serum was not
significantly reduced in any of the active analogues examined. ©
2003 Published by Elsevier Ltd.
674. Array synthesis of novel lipodepsipeptide - Siedlecki J.,
Hill J., Parr I. et al. [I. Parr, Cubist Pharmaceuticals Inc., 65
Hayden Ave., Lexington, MA 02421, United States] - BIOORG.
MED. CHEM. LETT. 2003 13/23 (4245-4249) - summ in ENGL
Synthetic array technology was utilized to rapidly synthesize and
analyze a diverse set of reductive alkylation analogues of daptomycin. Analysis of the array suggested the use of polar functionality
such as sulfonamides or amide or polar spaces such as piperazine
would beneficially affect activity. © 2003 Elsevier Ltd. All rights
reserved.
675. Square wave adsorptive stripping voltammetric determination of piromidic acid. Application in urine - Guiberteau
Cabanillas A., Ortiz Burguillos J.M., Martı́nez Cañas M.A. et al.
[A. Guiberteau Cabanillas, Department of Analytical Chemistry,
Faculty of Sciences, University of Extremadura, Avda. Elvas s/n,
06071 Badajoz, Spain] - J. PHARM. BIOMED. ANAL. 2003 33/4
A simple procedure for the determination of piromidic acid by
square wave adsorptive stripping voltammetry (SW-AdSV) at a
hanging mercury drop electrode has been developed. The variables
affecting to accumulation process such as concentration of perchloric acid, accumulation potential and accumulation time have
been optimised (0.025 mol L-1 , -0.25 V and 140 s, respectively) by
using response surface methodology. A linear relationship between
concentration of piromidic acid and peak intensity has been found
in the range 2.2210-9 to 3.3310-8 mol L-1 . The detection limit
(1.6510-9 mol L-1 ) has been calculated by the method proposed
by Clayton et al. so that protection against both false positive and
false negative errors is assured. The procedure was successfully
applied to determine piromidic acid in spiked urine samples. The
obtained recovery values were in the range 97.3-103.3% at different
levels of concentration of piromidic acid. © 2003 Elsevier B.V. All
rights reserved.
676. Binding of Pediocin PA-1 with Anionic Lipid Induces Model
Membrane Destabilization - Gaussier H., Lefèvre T. and Subirade
M. [M. Subirade, Inst. Nutraceut./Aliments Fonct., Université Laval, Dept. Sci. des Aliments et des Nutr., Sainte-Foy, Que. G1K
7P4, Canada] - APPL. ENVIRON. MICROBIOL. 2003 69/11 (67776784) - summ in ENGL
To obtain molecular insights into the action mode of antimicrobial
activity of pediocin PA-1, the interactions between this bacteriocin
and dimyristoylphosphatidylcholine (DMPC) or dimyristoylphosphatidylglycerol (DMPG) model membranes have been investigated
in D2 O at pD 6 by Fourier transform infrared spectroscopy. The
interactions were monitored with respect to alteration of the secondary structure of pediocin, as registered by the amide I band, and
phospholipid conformation, as revealed by the methylene vs (CH2 )and carbonyl v(C=O) stretching vibrations. The results show that
no interaction between pediocin and DMPC occurs. By contrast,
pediocin undergoes a structural reorganization in the presence of
DMPG. Upon heating, pediocin self-aggregates, which is not observed for this pD in aqueous solution. The gel-to-crystalline phase
transition of DMPG shifts to higher temperatures with a concomitant dehydration of the interfacial region. Our results indicate that
pediocin is an extrinsic peptide and that its action mechanism may
lie in a destabilization of the cell membrane.
677. The effects of fruit juices on drug disposition: A new model
for drug interactions - Dresser G.K. and Bailey D.G. [Dr. G.K.
Dresser, Department of Medicine, London Health Sciences Centre,
Victoria Campus, 370 South Street, London, Ont., Canada] - EUR.
J. CLIN. INVEST. SUPPL. 2003 33/2 (10-16) - summ in ENGL
Grapefruit juice produces mechanism-based inhibition of intestinal drug metabolism when consumed in normal quantities. This
can produce clinically important increases in oral drug bioavailability when coadministered with substrates of cytochrome P450 3A4
(CYP3A4) that undergo high presystemic metabolism. Furanocoumarins such as bergamottin and 6 ,7 - dihydroxybergamottin have
been identified as probable active constituents. Grapefruit juice
may also inhibit intestinal P-glycoprotein-mediated efflux transport
of drugs such as cyclosporine to increase its oral bioavailability.
However, grapefruit juice does not enhance the absorption of digoxin, a prototypical P-glycoprotein substrate, likely because it has
high inherent oral bioavailability. Grapefruit and other fruit juices
have recently been shown to be potent in vitro inhibitors of a number
of organic anion-transporting polypeptides (OATPs). These juices
were also found to decrease the absorption of the nonmetabolized
OATP substrate, fexofenadine. Taken together, the data support inhibition of intestinal uptake transporters by fruit juices to decrease
drug bioavailability. This would represent a new mechanism for
food-drug interactions. These findings with grapefruit and other
fruit juices continue to enhance our understanding of the complex
nature of food-drug interactions, and their possible influence on the
clinical effects of medications.
678. Pharmacokinetic characterization of a human immunodeficiency virus protease inhibitor, saquinavir, during ethanol
intake in rats - Shibata N., Kageyama M., Kishida T. et al. [N.
Shibata, Department of Pharmacokinetics, Kyoto Pharmaceutical
University, 5 Nakauchi-cho Misasagi, Yamashina-ku, Kyoto 6078414, Japan] - BIOPHARM. DRUG DISPOS. 2003 24/8 (335-344) summ in ENGL
Throughout therapeutic drug monitoring of human immunodeficiency virus (HIV) protease inhibitors in HIV-infected patients,
131
it was found that plasma concentrations of saquinavir (SQV) were
reduced in patients who had a habit of alcohol intake during double
protease therapy with SQV and ritonavir (RTV). This study confirmed the pharmacokinetic profiles of SQV during ethanol intake
in rats. After oral administration of SQV alone (20mg/kg) in rats
prepared by free access to 15% ethanol solution for 14 days (day
14 rats), the area under the concentration vs time curves (AUC)showed a significant decrease (p<0.01) in comparison with control
rats from 0.78 0.10 to 0.38 0.03 g h/ml. For intravenous
administration of SQV alone (5mg/kg) to day 14 rats, the total body
clearance increased significantly by 1.4-fold (p < 0.05), whereas
for intracolonic administration of SQV alone, no significant differences in the values of pharmacokinetic parameters were found
between control and day 14 rats. With RTV, which has the strongest
inhibitory effect on the CYP3A enzyme of the current HIV protease
inhibitors, the AUC values of SQV at RTV doses of 2 and 20 mg/kg
in day 14 rats also decreased significantly (p < 0.01) from 1.30 0.06 to 0.57 0.05 g h/ml and from 17.63 1.66 to 4.18 0.94
g h/ml, respectively, indicating that the degree of the decrease of
AUC values after oral administration with RTV after ethanol intake
was larger than the mono-therapy with SQV. This study showed
that ethanol-intake decreases the bioavailability of SQV after oral
administration alone or with RTV. These observations provide useful information for the treatment of HIV-infected patients when
they receive a combination therapy with SQV and RTV, and arouse
attention for the effects of alcohol intake. Copyright © 2003 John
Wiley & Sons, Ltd.
679. A simple and sensitive assay for cefepime in human plasma
using high performance liquid chromatography - Kim Y.-S.,
Yim D.-S., Lee D.-G. and Lee S.-B. [D.-S. Yim, Department of
Pharmacology, College of Medicine, The Catholic University of
Korea, 505 Banpo-dong, Soncho-gu, Seoul 137-701, South Korea]
- KOREAN J. PHYSIOL. PHARMACOL. 2003 7/4 (247-250) - summ
in ENGL
A simple and sensitive assay method was developed for cefepime
in human plasma using high performance liquid chromatography
(HPLC). Cefepime and cefadroxil (the internal standard) were extracted from heparinized human plasma by simple deproteination
with perchloric acid. The extract was injected into an Atlantis dC18
column (250 4.6 mm; particle size 5 m, Waters) and the column
was eluted with methanol and 0.01 M dihydrogen phosphate at pH
3.0 (15 : 85 v : v) as a mobile phase at a flow rate of 0.7 mL/min.
Linearity was confirmed for the range 0.25 to 200 L/mL and the
limit of quantitation was 0.25 L/mL. The retention times were
10.2 min and 13.4 min for cefepime and cefadroxil, respectively.
This method was successfully applied to a pharmacokinetic study
of cefepime in plasma from bone marrow transplant patients.
680. Daptomycin: A novel lipopeptide antibiotic for the treatment of resistant gram-positive infections - Sun H.K., Kuti J.L.,
Nicolau D.P. and Quercla R.A. [H.K. Sun, Ctr. for Anti-Infective Res./Devmt., Hartford Hospital, Hartford, CT, United States] FORMULARY 2003 38/11 (634-645) - summ in ENGL
The continuing rise of resistance rates among bacteria today has
led to the need for the development of new antibiotics with the
ability to circumvent current resistance mechanisms. Daptomycin
(Cubicin, Cubist Pharmaceuticals) is an injectable novel lipopeptide antibiotic shown to have excellent in vitro bactericidal activity
against gram-positive organisms, including resistant isolates. First
in the new class of lipopeptide antibiotics, daptomycin possesses a
unique mechanism of action. Clinical studies in patients with complicated skin and skin structure infections have shown daptomycin
to be similar in clinical cure rates compared to standard therapy.
Daptomycin was recently approved by FDA for the treatment of
complicated skin and skin structure infections caused by susceptible strains of specific gram-positive microorganisms. Daptomycin
may offer an alternative in the treatment of gram-positive infections,
especially when resistance is suspected.
681. Lack of Enzyme-Inducing Effect of Rifampicin on the Pharmacokinetics of Enfuvirtide - Boyd M.A., Zhang X., Dorr A. et al.
[Dr. M.A. Boyd, HIV-NAT, 104 Ratchadumri Road, Pathumwan,
Bangkok 10330, Thailand] - J. CLIN. PHARMACOL. 2003 43/12
(1382-1391) - summ in ENGL
132
The primary objective was to determine whether rifampicin influences the pharmacokinetics of enfuvirtide in HIV-1-infected
patients. In a single-center, open-label, one-sequence crossover,
clinical pharmacology study, 12 HIV-1-infected adults received enfuvirtide (90 mg, twice daily) on days 1 to 3 and days 11 to 13
(morning dose only on days 3 and 13) and rifampicin (600 mg, once
daily) from days 4 to 13. Plasma concentrations were measured
for enfuvirtide and its metabolite (days 3 and 13) and rifampicin
(day 13 only). The ratios of least squares means (LSM) and 90%
confidence intervals for enfuvirtide and enfuvirtide metabolite pharmacokinetic parameters (AUC 12h , Cmax , Ctrough ) were estimated in
the presence and absence of rifampicin. Treatments were compared
using an analysis of variance for natural log-transformed variables,
with factors patient and treatment. Efficacy and safety were also
monitored. Steady-state rifampicin had no appreciable effect on any
of the pharmacokinetic parameters assessed for either enfuvirtide or
its metabolite. The ratio of LSM for AUC12h , Cmax , and Ctrough for
enfuvirtide was 97.5%, 103%, and 84.9%, respectively, and 108%,
112%, and 92.9%, for the enfuvirtide metabolite. Rifampicin did
not affect the t1/2 of enfuvirtide or its metabolite. There were no
unexpected effects of rifampicin on the short-term antiviral effect
or safety of the administered antiretroviral treatment. The pharmacokinetics of enfuvirtide are not induced by a 10-day pretreatment
with rifampicin.
682. Synthesis and anti-measles virus activity of new isoquinolin-4-one derivatives - Santagati N.A., Bousquet E., Garozzo A.
et al. [N.A. Santagati, Dipto. di Scienze Farmaceutiche, Facolta
di Farmacia, Univ. degli Studi di Catania, Viale Andrea Doria, 6,
95125 Catania, Italy] - FARMACO 2003 58/12 (1217-1225) - summ
in ENGL
Despite intense efforts to increase vaccine coverage, measles
virus (MV) still causes significant morbidity and mortality in the
world sometimes as a results of severe, chronic and lethal diseases. In an effort to develop therapies to supplement immunization
strategies a number of 1-oxo-2-f[(1E)- phenylmethylene]aminog
-1,2-dihydroisoquinoline-4-carboxylic acid derivatives were synthesized and evaluated for anti-measles activity. The substituents
on the aromatic ring were chosen in order to evaluate the influence of
electron-withdrawing or electron-donating effects on the electronic
density of the aromatic moiety. We also evaluated the introduction of a vinyl chain between the exocyclic nitrogen and phenyl
moiety. The biological results allow to outline some preliminary
considerations on structure-activity relationship. © 2003 Éditions
683. Functionalized alkyl and aryl diselenides as antimicrobial
and antiviral agents: Synthesis and properties - Wójtowicz H.,
Chojnacka M., Młochowski J. et al. [J. Młochowski, Inst. Organ. Chem., Biochem./B., Wrocław Univ. of Technology, Wyb.
Wyspiańskiego 27, 50-375 Wrocław, Poland] - FARMACO 2003
58/12 (1235-1242) - summ in ENGL
The different dialkyl and diaryl diselenides with carbamoyl and
sulfamoyl moieties 2, 3, 5 and other substituents in the ortho position
of benzene ring 4, 7, 8 as well as derivatives of 1,2,4-benzoselenadiazine (6) were designed as antiviral and antimicrobial agents and
synthesized. Some of them, particularly 8a and 8b, were found in
the antiviral assay in vitro to be strong inhibitors of cytopathic activity encephalomyocarditis virus (EMCV). The compound 4a and
8a were found to have a broad spectrum of acivity against bacteria,
yeasts and pathogenic fungi in vitro. © 2003 Éditions scientifiques
684. Synthesis of styrylbenzofuran derivatives as styrylquinoline analogues for HIV-1 integrase inhibitor - Yoo H., Lee J.Y.,
Park J.H. et al. [Y.S. Lee, Medicinal Chemistry Research Center,
Life Sciences Division, Korea Inst. of Sci. and Technology, P.O.
Box 131, Cheongryang, Seoul 130-650, South Korea] - FARMACO
2003 58/12 (1243-1250) - summ in ENGL
A series of styrylbenzofuran derivatives (8a-i) as styrylquinoline
isosters were efficiently prepared by Wittig reaction and evaluated for inhibitory activity against HIV-1 integrase. In this series,
compounds 8g, 8h and 8i containing a free catechol ring showed
moderate inhibitory activities (IC50 =40 M) against HIV-1 integrase, while less than the corresponding styrylquinoline compound
(I). © 2003 Éditions scientifiques et médicales Elsevier SAS. All
rights reserved.
685. Quinoxalin-2-ones: Part 5. Synthesis and antimicrobial
evaluation of 3-alkyl-, 3-halomethyl- and 3-carboxyethylquinoxaline-2-ones variously substituted on the benzo-moiety - Carta
A., Loriga M., Zanetti S. and Sechi L.A. [A. Carta, Dipto. Farmaco
Chimico Tossicologico, via Muroni 23/a, 07100 Sassari, Italy] FARMACO 2003 58/12 (1251-1255) - summ in ENGL
A new series of 3-alkyl-, 3-trifluoromethyl-, 3-carboxyethyl- and
3-bromomethylquinoxaline-2-ones and 2,3-bis(bromomethyl)quinoxalines bearing Cl, CF3 , morpholine on the benzo-moiety, were
synthesised and submitted to a preliminary in vitro evaluation for
antibacterial and anticandida activities. Results of the screening
showed that compounds 9b, 14b and 19b (MIC=62.5 g/ml) and
10b (MIC=15.6 g/ml) were the most active against Vibrio alginolyticus. © 2003 Éditions scientifiques et médicales Elsevier SAS.
686. Synthesis and antimicrobial activities of some new benzimidazole derivatives - Ayhan-Kilcigil G. and Altanlar N. [G.
Ayhan-Kilcigil, Dept. of Pharmaceutical Chemistry, Faculty of
Pharmacy, Ankara University, 06100 Tandoǧan, Ankara, Turkey] FARMACO 2003 58/12 (1345-1350) - summ in ENGL
Some benzimidazolylbenzamides were synthesized and their antimicrobial activities against Staphylococcus aureus, Streptococcus
faecalis, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Candida albicans evaluated. It was shown that the
compound 14 exhibited the best activity against B. subtilis, P. aeruginosa and C. albicans. © 2003 Éditions scientifiques et médicales
Elsevier SAS. All rights reserved.
687. Cynthichlorine: A bioactive alkaloid from the tunicate
Cynthia savignyi - Abourriche A., Abboud Y., Maoufoud S. et al.
[A. Abourriche, Lab. Chim. Organique Biomoleculaire, Fac. des
Sciences Ben M’Sik, BP 7955, Casablanca, Morocco] - FARMACO
2003 58/12 (1351-1354) - summ in ENGL
From ether extracts of the tunicate Cynthia savignyi, collected
in Morocco, a new alkaloid-cynthichlorine-has been isolated. The
structure of cynthichlorine has been characterized by extensive 2DNMR data. Cynthichlorine possesses antifungal activity against two
tomato pathogenic fungi: Botrytis cinerea and Verticillium albo
atrum and antibacterial activity against Agrobacterium radiobacter, Escherichia coli and Pseudomonas aeruginosa and cytotoxicity
against Artemia salina larvae. © 2003 Éditions scientifiques et
688. Effect of polyamines on the inhibition of peptidyltransferase by antibiotics: Revisiting the mechanism of
chloramphenicol action - Xaplanteri M.A., Andreou A., Dinos
G.P. and Kalpaxis D.L. [D.L. Kalpaxis, Laboratory of Biochemistry, School of Medicine, University of Patras, GR-26500 Patras,
Greece] - NUCLEIC ACIDS RES. 2003 31/17 (5074-5083) - summ
in ENGL
Chloramphenicol is thought to interfere competitively with the
binding of the aminoacyl-tRNA 3 -terminus to ribosomal A-site.
However, noncompetitive or mixed-noncompetitive inhibition, often observed to be dependent on chloramphenicol concentration
and ionic conditions, leaves some doubt about the precise mode of
action. Here, we examine further the inhibition effect of chloramphenicol, using a model system derived from Escherichia coli in
which a peptide bond is formed between puromycin and AcPhetRNA bound at the P-site of poly(U -programmed ribosomes, under
ionic conditions (6 mM Mg2+ , 100 mM NH+4 , 100 M spermine)more closely resembling the physiological status. Kinetics reveal
that chloramphenicol (I) reacts rapidly with AcPhe-tRNA-poly(U)70S ribosomal complex (C) to form the encounter complex CI which
is then isomerized slowly to a more tight complex, CI. A similar
inhibition pattern is observed, if complex C modified by a photoreactive analogue of spermine, reacts in buffer free of spermine.
Spermine, either reversibly interacting with or covalently attached to
ribosomes, enhances the peptidyltransferase activity and increases
the chloramphenicol potency, without affecting the isomerization
step. As indicated by photoaffinity labeling, the peptidyltransferase center at which chloramphenicol binds, is one of the preferred
cross-linking sites for polyamines. This fact may explain the effect
of spermine on chloramphenicol binding to ribosomes.
689. Determination of DNA minor groove width in distamycinDNA complexes by solid-state NMR - Olsen G.L., Louie E.A.,
Drobny G.P. and Sigurdsson S.Th. [S.Th. Sigurdsson, Department
of Chemistry, University of Washington, Seattle, WA 98195-1700,
United States] - NUCLEIC ACIDS RES. 2003 31/17 (5084-5089) summ in ENGL
We have performed solid-state 31 P-19 F REDOR nuclear magnetic resonance (NMR) experiments to monitor changes in minor
groove width of the oligo-nucleotide d(CGCAAA2 F UTGGC
d(GCCAAT(pS)TTGCG) (A3 T2 ) upon binding of the drug distamycin A at different stoichiometries. In the hydrated solid-state
sample, the minor groove width for the unbound DNA, measured as
the 2 F U7-pS19 inter-label distance, was 9.4 0.7 Å, comparable
to that found for similar A:T-rich DNAs. Binding of a single drug
molecule is observed to cause a 2.4 Å decrease in groove width.
Subsequent addition of a second drug molecule results in a larger
conformational change, expanding this minor groove width to 13.6
Å, consistent with the results of a previous solution NMR study
of the 2:1 complex. These 31 P-19 F REDOR results demonstrate
the ability of solid-state NMR to measure distances of 7-14 Å in
DNA-drug complexes and provide the first example of a direct
spectroscopic measurement of minor groove width in nucleic acids.
690. Cationic phosphoramidate -oligonucleotides efficiently
target single-stranded DNA and RNA and inhibit hepatits C
virus IRES-mediated translation - Michel T., Martinand-Mari C.,
Debart F. et al. [F. Debart, Lab. Chim. Organ. Biomolec. Synthese,
UMR 5625 CNRS-UMII, Université Montpellier II, Place Eugène
Bataillon, 34095 Montpellier Cedex 05, France] - NUCLEIC ACIDS
RES. 2003 31/18 (5282-5290) - summ in ENGL
A potential means to improve the efficacy of steric-blocking antisense oligonucleotides (ON) is to increase their affinity for a target
RNA. The grafting of cationic amino groups to the backbone of
the ON is one way to achieve this, as it reduces the electrostatic
repulsion between the ON and its target. We have examined the
duplex stabilising effects of introducing cationic phosphoramidate
internucleoside linkages into ON with a non-natural -anomeric
configuration. Cationic -ON bound with high affinity to single-stranded DNA and RNA targets. Duplex stabilisation was
proportional to the number of cationic modifications, with fully
cationic ON having particularly high thermal stability. The average stabilisation was greatly increased at low ionic strength. The
duplex formed between cationic -ON and their RNA targets were
not substrates for RNase H. The penalty in Tm inflicted by a single
mismatch, however, was high; suggesting that they are well suited
as sequence-specific, steric-blocking, antisense agents. Using a
well-described target sequence in the internal ribosome entry site
of the human hepatitis C virus, we have confirmed this potential
in a cell-free translation assay as well as in a whole cell assay.
Interestingly, no vectorisation was necessary for the cationic -ON
in cell culture.
691. Functional dissection of the C-terminal domain of type
II DNA topoisomerase from the kinetoplastid hemoflagellate
Leishmania donovani - Sengupta T., Mukherjee M., Mandal C.
et al. [H.K. Majumder, Department of Molecular Parasitology, Development and Molecular Modeling, Indian Institute of Chemical
Biology, Kolkata 700032, India] - NUCLEIC ACIDS RES. 2003
31/18 (5305-5316) - summ in ENGL
The amino acid sequences of the C-terminal domain (CTD) of
the type II DNA topoisomerases are divergent and species specific as compared with the highly conserved N-terminal and central
domains. A set of C-terminal deletion mutants of Leishmania donovani topoisomerase II was constructed. Removal of more than 178
amino acids out of 1236 amino acid residues from the C-terminus
inactivates the enzyme, whereas removal of 118 amino acids or
less has no apparent effect on the ability of the parasite enzyme to
complement a temperature-sensitive mutation of the Saccharomyces
133
cerevisiae topoisomerase II gene. Deletion analysis revealed a potent nuclear localization signal (NLS) within the amino acid residues
998-1058. Immunomicroscopy results suggest that the removal of
an NLS in the CTD is likely to contribute to the physiological
dysfunction of these proteins. Modeling of the LdTOP2 based on
the crystal structure of the yeast type II DNA topoisomerase showed
that the parasite protein assumes a structure similar to its yeast counterpart harboring all the conserved residues in a structurally similar
position. However, a marked difference in electrostatic potential
was found in a span of 60 amino acid residues (998-1058), which
also do not have any homology with topoisomerase II sequences.
Such significant differences can be exploited by the structure-based
design of selective inhibitors using the structure of the Leishmania
enzyme as a template.
692. Antifungal therapy - State of the art at the beginning of
the 21st century - Polak A. [Dr. A. Polak, Spitzenrainweg 45,
CH-4147 Aesch, Switzerland] - PROG. DRUG RES. 2003 2/SPEC.
ISS. (59-190) - summ in ENGL
The most relevant information on the present state of the art of
antifungal chemotherapy is reviewed in this chapter. For dermatomycoses a variety of topical antifungals are available, and safe and
efficacious systemic treatment, especially with the fungicidal drug
terbinafine, is possible. The duration of treatment can be drastically
reduced. Substantial progress in the armamentarium of drugs for
invasive fungal infections has been made, and a new class of antifungals, echinocandins, is now in clinical use. The following drugs
in oral and/or intravenous formulations are available: the broad
spectrum polyene amphotericin B with its new "clothes"; the sterol
biosynthesis inhibitors fluconazole, itraconazole, and voriconazole;
the glucan synthase inhibitor caspofungin; and the combination
partner flucytosine. New therapy schedules have been studied;
combination therapy has found a significant place in the treatment
of severely compromised patients, and the field of prevention and
empiric therapy is fast moving. Guidelines exist nowadays for the
treatment of various fungal diseases and maintenance therapy. New
approaches interfering with host defenses or pathogenicity of fungal
cells are being investigated, and molecular biologists are looking
for new targets studying the genomics of pathogenic fungi.
693. Single-Dose Azithromycin for Acute Otitis Media: A Pharmacokinetic/ Pharmacodynamic Rationale - Rothermel C.D. [Dr.
C.D. Rothermel, Clinical Research, Anti-Infectives, Pfizer Inc., 235
East 42nd Street, New York, NY 10017, United States] - CURR.
THER. RES. CLIN. EXP. 2003 64/SUPPL. A (A4-A15) - summ in
ENGL
The pharmacokinetic (PK) and pharmacodynamic (PD) properties of the azalide azithromycin distinguish it from other antibiotics.
The PK profile of azithromycin features high tissue-to-serum ratios,
including high concentrations in the middle ear, and a prolonged
elimination half-life. These characteristics result from the accumulation of drug within cells and its subsequent slow, sustained release
from cells and tissues into the bloodstream. The PD properties
of azithromycin include bactericidal activity against key respiratory tract pathogens and a prolonged postantibiotic, or persistent,
effect. In addition, white blood cells deliver the drug to infected
foci, thereby enhancing local tissue concentrations and improving in
vivo efficacy. Recent PK studies in mice suggest that a single, large
dose of azithromycin achieves higher tissue concentrations than do
multidose regimens. Other studies in animal infection models, in
particular, a gerbil model of acute otitis media, have demonstrated
improved bacterial eradication when azithromycin is administered
as a single dose rather than divided over 2 or 3 days. Taken together,
the results from these preclinical studies provide a PK/PD rationale
for the use of single-dose azithromycin in the treatment of acute
otitis media. Clinical data on the efficacy and safety of single-dose
azithromycin for the treatment of acute otitis media in children are
presented in 2 accompanying articles in this supplement. Copyright
© 2003 Excerpta Medica, Inc.
694. A Pilot Study of Single-Dose Azithromycin Versus
Three-Day Azithromycin or Single-Dose Ceftriaxone for Uncomplicated Acute Otitis Media in Children - Arguedas A.,
Loaiza C., Perez A. et al. [Dr. A. Arguedas, Inst. de Atencion
134
Pediat., San José, Costa Rica] - CURR. THER. RES. CLIN. EXP.
2003 64/SUPPL. A (A16-A29) - summ in ENGL
Background: The pharmacokinetic profile of azithromycin supports its use as single-dose therapy for uncomplicated acute otitis
media (AOM) in children. Objective: This study was designed
to (1) compare the safety of single-dose oral azithromycin, 3 daily
doses of oral azithromycin, and a single dose of intramuscular ceftriaxone for the treatment of uncomplicated AOM in children, and
(2) provide preliminary efficacy data to support initiation of a larger,
comparative trial of single-dose azithromycin for the treatment of
uncomplicated AOM in children. Methods: In this single-center
pilot study, children with uncomplicated AOM were randomly assigned to receive single-dose oral azithromycin (30 mg/kg), 3-day
oral azithromycin (10 mg/kg once daily), or single-dose intramuscular ceftriaxone (50 mg/kg). Tympanocentesis was performed before
administration of the first dose, and clinical response was assessed
on days 14-15 and 28-30. Results: Between September 1995 and
May 1997, 198 children (mean age, 2.5 years) were enrolled. All
of the patients were evaluable for the safety and clinical intent-totreat (ITT) analyses, and 98 were evaluable for the microbiologic
ITT analysis. On day 14-15, rates of clinical success (cure or
improvement) for the 3 treatment groups were: 62/64 (97%) for
single-dose azithromycin, 60/63 (95%) for 3-day azithromycin, and
61/62 (98%) for single-dose ceftriaxone. On day 28-30, the corresponding clinical success rates were 61/65 (94%), 61/66 (92%),
and 62/64 (97%). For the 98 microbiologically evaluable patients,
clinical success rates at day 14-15 were 28/30 (93%) for singledose azithromycin, 31/35 (89%) for 3-day azithromycin, and 33/33
(100%) for single-dose ceftriaxone. On day 28-30, the corresponding clinical success rates were 27/30 (90%), 30/35 (86%), and 32/33
(97%). Treatment-related adverse event rates for single-dose azithromycin, 3-day azithromycin, and single-dose ceftriaxone were
10.6%, 9.1%, and 9.1%, respectively. Conclusion: In this pilot
study comparing single-dose azithromycin, 3-day azithromycin, and
single-dose ceftriaxone for the treatment of uncomplicated AOM
in children, no differences were detected among the 3 regimens.
Copyright © 2003 Excerpta Medica, Inc.
695. Single-Dose (30 mg/kg) Azithromycin Compared with
10-Day Amoxicillin/Clavulanate (45 mg/kg per day) for the
Treatment of Uncomplicated Acute Otitis Media - Block S.L.,
Arrieta A., Seibel M. et al. [Dr. S.L. Block, Kentucky Pediatric
Research, 201 South Fifth Street, Bardstown, KY 40004, United
States] - CURR. THER. RES. CLIN. EXP. 2003 64/SUPPL. A (A30A42) - summ in ENGL
Background: The long half-life of azithromycin allows for singledose oral therapy for acute otitis media (AOM). Objective: This
study was designed to compare the efficacy and safety of singledose azithromycin with 10-day, twice-daily amoxicillin/clavulanate
for the treatment of new-onset, uncomplicated AOM in children.
Methods: Children aged 6 months to 12 years with new-onset AOM
were randomly assigned to receive either a single 30-mg/kg dose
of azithromycin or standard-dose amoxicillin/clavulanate (45 mg/kg
per day divided BID for 10 days) in a double-blind, double-placebo,
multicenter clinical trial. The diagnosis of AOM was based on specific clinical signs and symptoms, and was confirmed by pneumatic
otoscopy and acoustic reflectometry (level 3). Clinical response
was assessed on days 12-16 and 28-32. Results: Mean (SD) age of
children receiving azithromycin (n = 173) or amoxicillin/clavulanate (n = 173) was 2.7 (2.3) years and 3.4 (2.8) years, respectively,
with 43% and 36% 2 years of age. Clinical success rates (intentto-treat) for azithromycin and amoxicillin/clavulanate, respectively,
were 87% and 88% (95% CI, -9.2 to 6.5) on day 12-16 and 75%
and 75% (95% CI, -10.2 to 10.5) on day 28-32. The incidences of
treatment-related adverse events for azithromycin and amoxicillin/clavulanate were 16.8% and 22.5%, respectively. Corresponding
rates of diarrhea were 6.4% and 12.7%, respectively. Vomiting,
which was generally mild, occurred in 7 children in each group.
One azithromycin patient and 5 amoxicillin/clavulanate patients
discontinued treatment because of adverse events. The compliance rate for azithromycin was significantly higher than that for
amoxicillin/clavulanate (99% vs 83%; P < 0.001). Conclusions:
In this trial comparing the efficacy of single-dose azithromycin (30
mg/kg) with amoxicillin/clavulanate (45 mg/kg per day) for the
treatment of new-onset, uncomplicated AOM, no differences were
detected between the 2 regimens. Single-dose azithromycin was
generally well tolerated and provides an alternative to conventional
oral regimens for AOM. Copyright © 2003 Excerpta Medica, Inc.
696. Synthesis and in vitro anti-protozoal activity of a series
of benzotropolone derivatives incorporating endocyclic hydrazines - Ren H., Grady S., Banghart M. et al. [G. Moyna, Dept. of
Chemistry and Biochemistry, Univ. of the Sci. in Philadelphia, 600
South 43rd Street, Philadelphia, PA 19104, United States] - EUR.
J. MED. CHEM. 2003 38/11-12 (949-957) - summ in ENGL
The preparation and evaluation as potential anti-protozoal agents
of molecules bearing an endocyclic hydrazine moiety is presented.
The synthetic route to this new series of compounds is straightforward, involving a hetero Diels-Alder reaction between different
benzotropolone esters and diethyl azodicarboxylate (DEAD). While
they show limited or no in vitro activity against Leishmania donovani, Plasmodium falciparum and Trypanosoma brucei rhodesiense,
several of the compounds have activities against Trypanosoma cruzi
in the 15.8-41.0 M range. These activities are comparable to that
of benznidazole (IC50 6.0 M), the main chemotherapy employed
in the treatment of T. cruzi infections. In addition, all but one of
the new bicyclic hydrazine esters are virtually non-toxic, one of
the most important drawbacks of currently available trypanocidal
drugs. © 2003 Éditions scientifiques et médicales Elsevier SAS.
697. Polysubstituted pyrazoles, part 5.1 .
Synthesis
of new 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic
acid hydrazide analogs and some derived ring systems. A novel
class of potential antitumor and anti-HCV agents - Rostom
S.A.F., Shalaby M.A. and El-Demellawy M.A. [S.A.F. Rostom,
Department of Medicinal Chemistry, Fac. of Medicine and Allied
Sciences, King Abdul-Aziz University, P.O. Box 80205, Jeddah
21589, Saudi Arabia] - EUR. J. MED. CHEM. 2003 38/11-12 (959974) - summ in ENGL
A novel series of 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid hydrazide analogs and some derived
4-substituted-1,2,4-triazolin-3-thiones, 2-substituted-1,3,4-thiadiazole and 2-substituted-1,3,4-oxadiazoles has been synthesized.
Ten of the newly synthesized compounds were selected by the
National Cancer Institute (NCI)-in vitro-disease oriented antitumor
screening to be evaluated for their antitumor activity. Seven compounds, namely 7a-c, 9, 11, 13 and 14, exhibited potential and broad
spectrum antitumor activity against most of the tested subpanel tumour cell lines (GI50 <100 M). Compounds 14 (GI50 , TGI, and
LC50 MG-MID values of 0.08, 15.8 and 64.6 M, respectively) and
11 (GI50 , TGI, and LC50 MG-MID values of 0.20, 11.7 and 87.1
M, respectively) proved to be the most active members in this
study with potential activity against all the tested subpanel tumour
cell lines and particular effectiveness on the leukaemia subpanel at
both the GI50 (0.03 and 0.09 M, respectively) and the TGI levels
(35.2 and 28.1 M, respectively). Moreover, compound 14 exhibited a super sensitivity profile towards about 26 different cancer
cell lines with GI50 values lying in the nanomolar concentration
range (GI50 values<0.01 M). In addition, compounds 2-5, 6a-d,
7a, 8-11, 12a, 13, 14 were investigated for their in vitro effect on
the replication of hepatitis-C virus (HCV) in HepG2 hepatocellular carcinoma cell line infected with the virus using the reverse
transcription-polymerase chain reaction (RT-PCR) technique. The
results revealed that compounds 2 and 5 were capable of inhibiting
the replication of both the HCV RNA (+) and (-) strands at 10-100
g mL-1 concentration range. © 2003 Éditions scientifiques et
698. Synthesis of 6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives as potential antimicrobial agents Rameshkumar N., Ashokkumar M., Subramanian E.H. et al. [N.
Rameshkumar, Dept. Pharmaceutical Chem. P., C. L. Baid Metha
College of Pharmacy, Jyothi Nagar, Chennai 600096, Tamilnadu,
India] - EUR. J. MED. CHEM. 2003 38/11-12 (1001-1004) - summ
in ENGL
In the present study, a series of 1-ethyl/benzyl-6-fluoro-7-(substituted piperazin-1-yl)1,4-dihydro-4-oxo-quinoline-3-carboxylic
acid were synthesized and characterized by IR, 1 H-NMR, mass
spectral and elemental analysis. The in vitro antibacterial and
antifungal activities of the compounds were evaluated by paper
disc diffusion method. The minimum inhibitory concentrations
(MIC) of the compounds were also determined by agar streak
dilution method. The in vivo antibacterial activity of the compounds against Escherichia coli was also evaluated by mouse
protection test. All the compounds exhibited significant antibacterial and weak antifungal activities. The in vivo antibacterial
activity (ED50 ) against E. coli was 50-160 mg kg -1 in the order
of 7<9<8<10. 1-Ethyl-6-fluoro-7-(2,5-dioxo- piperazin-1-yl)1,4dihydro-4-oxo-quinoline-3-carboxylic acid (7) was found to exhibit
the most potent in vitro antimicrobial activity with MIC of 4.1, 3.1,
3.1, 2.4, 1, 1, 25 and >100 g mL-1 against Staphylococcus aureus,
Staphylococcus epidermidis, Micrococcus luteus, Bacillus cereus,
E. coli, Klebsiella pneumoniae, Candida albicans and Aspergillus
niger. © 2003 Éditions scientifiques et médicales Elsevier SAS. All
rights reserved.
699. Synthesis and biological activities of diflunisal hydrazidehydrazones - Küçükgüzel S.G., Mazi A., Sahin F. et al. [S.G.
Küçükgüzel, Dept. of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Istanbul 81010, Turkey] - EUR. J. MED.
CHEM. 2003 38/11-12 (1005-1013) - summ in ENGL
Several diflunisal hydrazide-hydrazone derivatives namely
2 ,4 -difluoro-4-hydroxybiphenyl-3-carboxylic acid [(5-nitro-2furyl/substitutedphenyl)methylene] hydrazide (3a-o) have been
synthesised.
Methyl 2 ,4 -difluoro-4-hydroxybiphenyl-3-carboxylate (1) and 2 ,4 -difluoro-4-hydroxybiphenyl-3-carboxylic
acid hydrazide (2) were also synthesised and used as intermediate compounds. All synthesised compounds were screened for their
antimycobacterial activity against Mycobacterium tuberculosis H37
Rv, antimicrobial activities against various bacteria, fungi and yeast
species. Compound 3a have shown activity against Staphylococcus epidermis HE-5 and Staphylococcus aureus HE-9 at 18.75 and
37.5 g mL-1 , respectively. Compound 3o have exhibited activity
against Acinetobacter calcoaceticus IÖ-16 at a concentration of 37.5
g mL-1 , whereas Cefepime, the drug used as standard, have been
found less active against the microorganisms mentioned above. The
synthesised compounds were found to provide 12-34% inhibition
of mycobacterial growth of M. tuberculosis H37 Rv in the primary
screen at 6.25 g mL -1 . Anticonvulsant activity of the compounds
were also determined by maximal electroshock (MES) and subcutaneous metrazole (scMET) tests in mice and rats following the
procedures of antiepileptic drug development (ADD) program of
the National Institutes of Health (NIH). Compound 3k showed 25%
protection against MES induced seizures in p.o. rat screening at a
dose level of 30 mg kg-1 whereas 3n and 3o showed neurotoxicity
after 4 and 0.5 h at a dose level of 100 and 300 mg kg-1 , respectively.
reserved.
700. Synthesis and anti-microbial activities of choline-like quaternary ammonium chlorides - Pernak J. and Chwała P. [J. Pernak,
Poznań Univ. of Technology, pl. M. Skłodowskiej-Curie 2, 60-965
Poznań, Poland] - EUR. J. MED. CHEM. 2003 38/11-12 (10351042) - summ in ENGL
New choline-like quaternary ammonium chlorides were obtained.
The work-up procedure of synthesis was quick and efficient. The
obtained chlorides showed anti-microbial activities. Quaternary
ammonium chlorides derivatives of deanol esters exhibited strong
activity and wide anti-bacterial spectra, similar to the activity of
benzalkonium chloride. The relationship between chemical structure and anti-microbial activity was analyzed by the QSAR method.
reserved.
701. A quantum chemical and statistical study of flavonoid compounds (flavones) with anti-HIV activity - Souza Jr. J., De
Almeida Santos R.H., Ferreira M.M.C. et al. [A.B.F. Da Silva,
Depto. de Quim. e Fis. Molecular, Inst. de Quim. de São Carlos,
Universidade de São Paulo, CP 780, 13560-970 São Carlos, SP,
Brazil] - EUR. J. MED. CHEM. 2003 38/11-12 (929-938) - summ
in ENGL
135
The molecular orbital semi-empirical method AM1 was employed to calculate a set of molecular properties (variables) of
22 flavonoid compounds (flavones) with anti-HIV-1 activity and
nine new compounds were proposed for anti-HIV-1 activity prediction. Pattern recognition techniques, principal component analysis
(PCA), hierarchical cluster analysis (HCA), stepwise discriminant
analysis (SDA) and K-nearest neighbor (KNN), were employed
in order to reduce dimensionality and investigate which subset of
variables could be more effective for classifying the flavones according to their degree of anti-HIV-1 activity. The PCA, HCA,
SDA and KNN studies showed that the variables logP (partition
coefficient), molecular volume (VOL) and electron affinity (EA)are responsible for the separation between anti-HIV-1 active and
inactive compounds. The prediction study was done with a new
set of nine analog compounds by using the PCA, HCA, SDA and
KNN methods and only one of them was predicted as active against
HIV-1. © 2003 Éditions scientifiques et médicales Elsevier SAS.
702. Antivirals interacting with hepatitis B virus core protein and core mutations may misdirect capsid assembly in a
similar fashion - Hacker H.J., Deres K., Mildenberger M. and
Schröder C.H. [H.J. Hacker, Dept. of Virus-Host Interactions, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, 69120
Heidelberg, Germany] - BIOCHEM. PHARMACOL. 2003 66/12
(2273-2279) - summ in ENGL
Recently, heteroarylpyrimidines (HAP) have been identified as
potent inhibitors of capsid maturation. Here we discuss the HAP
mode of action comparing the aggregation phenotype of wild-type
and mutant core proteins with the respective phenotype imposed by
HAP or other agents interacting with core protein. Pertinent tests
include core fusion protein-mediated transactivation in a two-hybrid system and capsid formation. The finding that transactivation
appeared to be unaffected by HAP, or by mutations preventing
assembly, is surprising and raises the question for the structure of
the interacting hybrid core proteins: Are they monomers, dimers
or even oligomers? A direct activity of core fusion monomers
is not excluded but considered to be highly unlikely due to rapid
homodimerisation. A role of core fusion dimers in transactivation
would indicate distinct interactions with a differential sensitivity
to HAP. Regarding significance of data gained in two-hybrid systems, caution is necessary, since the site of transactivation is the
nucleus, whereas the real site of the core protein interactions during
replication is the cytoplasm. Apparently, HAP leave the monomermonomer interface of HBV core protein unaffected but prevent
capsid maturation by interacting with a region known to be crucial
for dimer multimerisation and formation of stable capsids. It is
suggested to use antivirals as tools for the elucidation of early steps
in genome replication and capsid assembly. A frame for this could
be the hypothesis that the virus uses soluble core protein, namely
intracellular maturation intermediates of HbeAg for a core targeted
self-restriction of replication. © 2003 Elsevier Inc. All rights
reserved.
703. Involvement of tumor suppressor protein p53 and p38
MAPK in caffeic acid phenethyl ester-induced apoptosis of C6
glioma cells - Lee Y.-J., Kuo H.-C., Chu C.-Y. et al. [T.-H. Tseng,
Department of Applied Chemistry, Chung Shan Medical University, No. 110, Sect. 1, Chien Kuo N. Road, Taichung, Taiwan]
- BIOCHEM. PHARMACOL. 2003 66/12 (2281-2289) - summ in
ENGL
Caffeic acid phenethyl ester (CAPE), an active component of
propolis, has many biological and pharmacological activities including antioxidant, anti-inflammation, antiviral action, and anticancer
effect. Our previous studies showed that CAPE exhibited significant
cytotoxicity in oral cancer cells. Herein we further investigated the
cytotoxicity potential of CAPE and the mechanism of its action in
C6 glioma cells. The data exhibited that C6 glioma cells underwent internucleosomal DNA fragmentation 24hr after the treatment
of CAPE (50M). The proportion of C6 glioma cells with hypodiploid nuclei was increased to 24% at 36hr after the exposure.
Further results showed that CAPE induced the release of cytochrome c from mitochondria into cytosol, and the activation of
CPP32. CAPE application also enhanced the expression of p53,
136
Bax, and Bak. Finally, the potential signaling components underlying CAPE induction of apoptosis were elucidated. We found that
CAPE activated extracellular signal-regulated kinase (ERKs) and
p38 mitogen-activated protein kinase (p38 MAPK) in C6 glioma
cells. More importantly, p38 kinase formed a complex with p53
after the treatment of CAPE for 0.5hr. The expression of p53,
phospho-serine 15 of p53, and Bax, and inactivate form of CPP32
was suppressed by a pretreatment of a specific p38 MAPK inhibitor,
SB203580. The resultant data suggest that p38 MAPK mediated
the CAPE-induced p53-dependent apoptosis in C6 glioma cells. ©
2003 Elsevier Inc. All rights reserved.
704. Mechanism underlying cytotoxicity of thialysine, lysine
analog, toward human acute leukemia Jurkat T cells - Jun D.Y.,
Rue S.W., Han K.H. et al. [Y.H. Kim, Department of Microbiology, College of Natural Sciences, Kyungpook National University,
Taegu 702-701, South Korea] - BIOCHEM. PHARMACOL. 2003
66/12 (2291-2300) - summ in ENGL
We first report the mechanism for the inhibitory effect of the
lysine analog, thialysine on human acute leukemia Jurkat T cells.
When Jurkat T cells were treated with thialysine (0.32-2.5mM),
apoptotic cell death along with several biochemical events such as
mitochondrial cytochrome c release, caspase-9 activation, caspase3 activation, degradation of poly (ADP-ribose) polymerase, and
DNA fragmentation was induced in a dose- and time-dependent
manner. However, these thialysine-induced apoptotic events were
significantly abrogated by an ectopic expression of Bcl-xL, which
is known to block mitochondrial cytochrome c release. Decylubiquinone, a mitochondrial permeability transition pore inhibitor, also
suppressed thialysine-induced apoptotic events. Comparison of the
thialysine-induced alterations in the cell cycle distribution between
Jurkat T cells transfected with Bcl-xL gene (J/Bcl-xL) and Jurkat
T cells transfected with vector (J/Neo) revealed that the apoptotic
cells were mainly derived from the cells accumulated in S and G2/M
phases following thialysine treatment. The interruption of cell cycle progression in the presence of thialysine was accompanied by a
significant decline in the protein level of cdk4, cdk6, cdc2, cyclin A,
cyclin B1, and cyclin E. These results demonstrate that the cytotoxic
activity of thialysine toward Jurkat T cells is attributable to not only
apoptotic cell death mediated by a mitochondria-dependent death
signaling pathway, but also interruption of cell cycle progression by
a massive down-regulation in the level of cdks and cyclins. © 2003
Elsevier Inc. All rights reserved.
705. Highly active antiretroviral therapy and the cardiovascular
system: The heart of the matter - Barbaro G. [Dr. G. Barbaro,
Viale Anicio Gallo 63, IT-00174 Rome, Italy] - PHARMACOLOGY
2003 69/4 (177-179) - summ in ENGL
Highly active antiretroviral therapy (HAART) has prolonged
many patients’ lives, but many cardiac sequelae of HIV are not
affected by HAART and continue to develop even with treatment.
In addition, HAART itself causes in a high proportion of patients
a metabolic syndrome, characterized by lipodystrophy/lipoatrophy,
dyslipidemia and insulin resistance that may be associated with an
increase in coronary artery disease and stroke. Careful cardiovascular evaluation in the course of HIV disease can identify cardiac
complications early enough to treat. All HIV-infected patients are
candidates for antiretroviral therapy and patients already under treatment should undergo an assessment that includes the evaluation of
the cardiovascular risk according to the available guidelines. Copyright © 2003 S. Karger AG, Basel.
706. Therapeutic drug monitoring of the HIV/AIDS drugs
abacavir, zidovudine, efavirenz, nevirapine, indinavir, lopinavir, and nelfinavir - Donnerer J., Kronawetter M., Kapper A. et
al. [J. Donnerer, Inst. of Exp./Clinical Pharmacology, University
of Graz, Universitätsplatz 4, AT-8010 Graz, Austria] - PHARMACOLOGY 2003 69/4 (197-204) - summ in ENGL
Combination therapy with antiretroviral drugs is used for the
treatment of patients infected with the human immunodeficiency
virus. To achieve optimal drug concentrations for viral suppression
and avoidance of drug toxicity, monitoring of drug levels has been
considered essential. We set up an analytical procedure for monitoring the plasma concentrations of a total of seven drugs: abacavir,
zidovudine, efavirenz, nevirapine, indinavir, lopinavir, and nelfinavir. The plasma samples were liquid/liquid extracted and subjected
to high-performance liquid chromatography (HPLC) analysis. The
compounds were monitored by ultraviolet detection: indinavir, lopinavir, and nelfinavir at 215 nm; efavirenz at 254 nm, and abacavir,
zidovudine, and nevirapine at 266 nm. Two different extraction
procedures and two different HPLC eluents on a C 8 reversed-phase
HPLC column were used to monitor all seven compounds. Under steady state conditions, the plasma concentrations of antiviral
drugs in 175 patients were correlated with the time after the last
dosing to define the peak or trough levels. Due to the short plasma
elimination half-life of abacavir and zidovudine, only peak levels
could be determined for these compounds, whereas both peak and
trough levels could be assessed for the other compounds because
of a longer plasma elimination half-life. The mean peak concentrations (g/ml) were 0.69 for abacavir and 0.57 for zidovudine; the
mean peak/trough concentrations (g/ml) were 2.07/1.32 for efavirenz, 2.43/2.23 for nevirapine, 5.48/1.08 for indinavir, 4.69/3.51
for lopinavir, and 3.54/ 1.45 for nelfinavir. The described analytical
method offers a broad-spectrum monitoring of plasma levels of
antiretroviral drugs. Copyright © 2003 S. Karger AG, Basel.
See also: 741, 742, 743, 745, 747, 749.
6.6. Immunologic agents
707. The contralateral effect conferred by intra-articular adenovirus-mediated gene transfer of viral IL-10 is specific to the
immunizing antigen - Lechman E.R., Keravala A., Nash J. et al.
[Dr. P.D. Robbins, Dept. of Molec. Genet./Biochemistry, Univ.
of Pittsburgh Sch. of Medicine, E1240 Biomedical Science Tower,
Pittsburgh, PA 15261, United States] - GENE THER. 2003 10/24
(2029-2035) - summ in ENGL
We have demonstrated previously that local, adenoviral-mediated
gene transfer of vIL-10 to a single joint of rabbits and mice with
experimental arthritis can suppress disease in both the treated and
untreated contralateral joints. These therapeutic effects observed in
distant untreated joints following local intra-articular gene delivery
have been termed the ’contralateral effect’. To begin to understand
the underlying immunologic mechanism that confers this effect, a
dual-antigen model of antigen-induced arthritis (AIA) in rabbit knee
joints was utilized. Rabbits were immunized against two antigens,
ovalbumin and keyhole limpet hemocyanin, and AIA generated by
intra-articular injection of each antigen into contralateral knees.
Intra-articular adenovirus-mediated gene transfer of vIL-10 significantly reduced intra-articular leukocytosis and cartilage matrix
degradation, while preserving near normal levels of cartilage matrix
synthesis within treated joints. However, no antiarthritic effect was
conferred in the contralateral control joints that received only a
marker gene, in contrast to the results seen in a single-antigen AIA
model. These results suggest that the distant antiarthritic effects
associated with local gene delivery to joints are antigen-specific,
and not due to vIL-10-induced generalized immunosuppression of
the animal.
708. Comparative sequence analysis of the P-, M- and L-coding region of the measles virus CAM-70 live attenuated vaccine
strain - Santos P.R., Azevedo M.L.B., Borges M.B.J. et al. [M.T.B.
Moraes, Bio-Manguinhos, FIOCRUZ, Av. Brasil, 4365 Rio de
Janeiro, RJ, Brazil] - BRAZ. J. MED. BIOL. RES. 2003 36/11 (14751484) - summ in ENGL
Measles virus is a highly contagious agent which causes a major
health problem in developing countries. The viral genomic RNA is
single-stranded, nonsegmented and of negative polarity. Many live
attenuated vaccines for measles virus have been developed using either the prototype Edmonston strain or other locally isolated measles
strains. Despite the diverse geographic origins of the vaccine viruses
and the different attenuation methods used, there was remarkable
sequence similarity of H, F and N genes among all vaccine strains.
CAM-70 is a Japanese measles attenuated vaccine strain widely
used in Brazilian children and produced by Bio-Manguinhos since
1982. Previous studies have characterized this vaccine biologically
and genomically. Nevertheless, only the F, H and N genes have been
sequenced. In the present study we have sequenced the remaining P,
M and L genes (approximately 1.6, 1.4 and 6.5 kb, respectively) to
complete the genomic characterization of CAM-70 and to assess
the extent of genetic relationship between CAM-70 and other current vaccines. These genes were amplified using long-range or
standard RT-PCR techniques, and the cDNA was cloned and automatically sequenced using the dideoxy chain-termination method.
The sequence analysis comparing previously sequenced genotype
A strains with the CAM-70 Bio-Manguinhos strain showed a low
divergence among them. However, the CAM-70 strains (CAM-70
Bio-Manguinhos and a recently sequenced CAM-70 submaster seed
strain) were assigned to a specific group by phylogenetic analysis
using the neighbor-joining method. Information about our product at the genomic level is important for monitoring vaccination
campaigns and for future studies of measles virus attenuation.
709. Effects of the Anti-ICAM-1 Monoclonal Antibody, Allopurinol, and Methylene Blue on Intestinal Reperfusion Injury
- Ilhan H., Alatas Ö., Tokar B. et al. [Dr. H. Ilhan, Osmangazi
Universitesi, Cocuk Cerrahisi AD, Meselik. 26480-TR, Eskisehir,
Turkey] - J. PEDIATR. SURG. 2003 38/11 (1591-1595) - summ in
ENGL
Purpose: The aim of this study was to evaluate the effect of
allopurinol, methylene blue, and a monoclonal antibody to the adhesion molecule ICAM-1 in intestinal ischemia and reperfusion
injury, Methods: The rats were divided into 5 groups. CG (n =
8) was untreated controls, SISG (n = 11) received sterile isotonic
saline solution, ICAMG (n = 12) received a monoclonal antibody
to rat ICAM-1, ALLOG (n = 12) received allopurinol, and MBG (n
= 14) received methylene blue. Intestinal ischemia was performed
for 60 minutes followed by 60 minutes of reperfusion, The agents
were injected 10 minutes before the reperfusion to animals. After
60 minutes of reperfusion, the plasma samples for myeloperoxidase
(MPO) activity, tumor necrosis factor alpha (TNF-) and uric acid
levels, and the intestinal biopsies of ileum and jejunum for histopathologic examination were taken. Results: The mucosal damage
was attenuated, and TNF- level significantly decreased in ALLOG
and ICAMG compared with SISG. The MPO activity was the lowest
in ICAMG, and uric acid level was significantly decreased in ALLOG compared with the other groups. Methylene blue decreased
TNF- response to reperfusion injury but significantly increased the
grade of the mucosal damage and the MPO activity. Conclusions:
This study shows that prereperfusion application of allopurinol and
monoclonal antibody to the adhesion molecule ICAM-1 may attenuate the damage caused by intestinal ischemia and reperfusion,
but the different time-points for application, the effects observed in
the different ischemia and reperfusion durations, and the long-term
results also should be investigated in the same experimental model
before the final conclusion. Methylene blue was not effective to
prevent or attenuate the intestinal tissue injury, but because this was
the first study examining the effect of methylene blue on intestinal
reperfusion injury, further studies with the different doses, ischemic
duration, and application times will be needed. 2003 Elsevier
Inc. All rights reserved.
710. Hypotension with intravenous immunoglobulin therapy:
Importance of pH and dimer formation - Kroez M., Kanzy
E.-J., Gronski P. and Dickneite G. [G. Dickneite, Aventis Behring
GmbH, Emil von Behring Strasse 76, 35041, Marburg, Germany] BIOLOGICALS 2003 31/4 (277-286) - summ in ENGL
Therapy with intravenous immunoglobulin preparations has been
used effectively in a wide range of conditions. Although generally
well tolerated, intravenous immunoglobulin preparations may be
associated with transient hypotension in some patients. This study
examined the role of different immunoglobulin G fractions in the
development of intravenous immunoglobulin-induced hypotension
in an anaesthetized rat model and assessed the effects of a new
liquid immunoglobulin prepared at a low pH on both the formation
of immunoglobulin G dimers and the development of hypotension.
The effects of this new preparation in an experimental autoimmune
encephalomyelitis model were also evaluated. Results from the
haemodynamic studies indicated that immunoglobulin G dimers in
polyclonal immunoglobulin G are responsible for the hypotensive
events associated with some immunoglobulin preparations. They
also showed that adjustment to an acidic pH results in the rapid
137
dissociation of immunoglobulin G dimers and prevents the development of hypotension. Additional experiments demonstrated that
only immunoglobulin G dimers with a functional Fc fragment can
bind to Fc receptors on macrophages to induce the release of blood
pressure-lowering mediators. Moreover, essentially monomeric Fc
fragments can block the blood pressure-lowering effects of immunoglobulin G dimers. Preparation of a new liquid intravenous
immunoglobulin with the pH adjusted to 4.3 prevents the formation of immunoglobulin G dimers even over long-term storage and
does not significantly affect blood pressure in a rat model. This
preparation is as effective as other intravenous immunoglobulin
preparations in ameliorating symptoms of experimental autoimmune encephalomyelitis. These results, like those from previous
studies, indicate that preparation of intravenous immunoglobulin
at a low pH substantially reduces immunoglobulin G dimerization;
this effect significantly decreases the potential for intravenous immunoglobulin to induce hypotension without reducing its clinically
relevant biological activity. © 2003 The International Assocation
for Biologicals. Published by Elsevier Ltd. All rights reserved.
711. Stability of murine, chimeric and humanized antibodies
against pre-S2 surface antigen of hepatitis B virus - Park S.S.,
Kim J., Brandts J.F. and Hong H.J. [S.S. Park, Korea Res. Inst.
of Biosci./Biotech., 52 Oun-dong, Yusong, Taejon 305-333, South
Korea] - BIOLOGICALS 2003 31/4 (295-302) - summ in ENGL
We have constructed a humanized antibody with specificity for
the pre-S2 surface antigen of hepatitis B virus (HBV) by grafting the complementarity determining regions (CDRs) of parental
murine monoclonal antibody (mAb) into human anti-Sm antibody
framework regions. The humanized antibody has a substitution
at position 94 in a framework region of the heavy chain variable
region, and exhibits the same antigen binding affinity as the parental
murine monoclonal and chimeric antibodies. In order to assess the
stability of these antibodies, thermal inactivation of the parental,
chimeric and humanized antibodies was analyzed. Fifty percent inactivation of the chimeric and humanized antibodies was observed
at 63.7°C and 68.7°C, respectively, compared to 55.0°C for murine
antibody. The humanized antibody also exhibited increased stability
against denaturant. Guanidine-induced unfolding monitored by the
changes in fluorescence intensity at 360 nm showed that midpoints
of the transition of the chimeric and humanized antibodies were 2.47
M and 2.56 M, respectively, whereas that of the murine antibody
was 1.36 M. © 2003 The International Association for Biologicals.
Published by Elsevier Ltd. All rights reserved.
712. The immunopharmacology of paclitaxel (Taxol®), docetaxel (Taxotere®), and related agents - Fitzpatrick F.A. and
Wheeler R. [F.A. Fitzpatrick, Depts. Oncological Sci./Med. Chem.,
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
84103, United States] - INT. IMMUNOPHARMACOL. 2003 3/1314 (1699-1714) - summ in ENGL
Paclitaxel (Taxol®) and docetaxel (Taxotere®) are among the
most unique, and successful, chemotherapeutic agents used for the
treatment of breast and ovarian cancer. Both agents have antimitotic properties derived from binding to tubulin and excessive
stabilization of microtubules. Their anti-neoplastic effects derive
from this mechanism. Distinct from their effects on microtubule
stabilization, paclitaxel, docetaxel, and related taxanes display
immunopharmacological traits. In this review, we discuss their
induction of pro-inflammatory genes and proteins; the current hypotheses on the molecular mechanism for this induction, especially
its relationship to the lipopolysaccharide (LPS) signaling pathway.
We also discuss the structure-activity relationships (SAR) that govern gene induction, especially the striking differences between the
SAR for murine and human cells in vitro. Lastly, we discuss the
immunopharmacological traits of paclitaxel and docetaxel in terms
of their relevance to human clinical pharmacology and toxicology
and their activity in animal models of autoimmune disorders. ©
713. Laser scanning confocal fluorescence microscopy: An overview - Földes-Papp Z., Demel U. and Tilz G.P. [G.P. Tilz, Clin.
Immunol./Jean Dausset Lab., Graz University M.S. and Hospital,
Auenbruggerplatz 8, A-8036, Graz, LKH, Austria] - INT. IMMUNOPHARMACOL. 2003 3/13-14 (1715-1729) - summ in ENGL
138
Innovative and important aspects of laser scanning confocal fluorescence imaging (LSCFI) are presented here as a general overview.
We have described and discussed the technology of the procedure
in some detail. We also report some of our original work with
transmembraneous uptake of 5S gamma-globulin on living human
leukocytes as an example of one specific application of LSCFI.
These original data and results are presented, as well as citing
other uses and applications, to show the power of LSCFI technique.
The article will hopefully be useful for those not familiar with the
methodology and utility of laser scanning confocal fluorescence
microscopy. Applications of LSCFI are very diverse, and there
are new applications of this technology constantly being developed.
Interest is growing in LSCFI, particularly in the pharmacologic and
therapeutic areas, as demonstrated in this article. © 2003 Elsevier
714. Differing effects of two iron compounds on experimental arthritis, TNF- levels and immune response in mice Poljak-Blaži M., Hrvačić B., Županović Z. et al. [M. Poljak-Blaži,
Division of Molecular Medicine, Rudjer Bošković Inst., Bijenička
54, 10002, Zagreb, Croatia] - INT. IMMUNOPHARMACOL. 2003
3/13-14 (1743-1749) - summ in ENGL
The effects of ferric-sorbitol-citrate and ferric-citrate on the severity of experimental arthritis, TNF- secretion and the immune status
were examined in mice. Arthritis was induced by footpad injection of methylated BSA and intraperitoneal injection of Bordetella
pertussis. Joint and footpad swelling were measured weekly by
a caliper. TNF- serum levels were measured by ELISA. The
immune status was determined by the response of mouse lymphocytes to ConA in vitro and by the antigen-presenting cell assay.
Experimental arthritis was aggravated by ferric-citrate, whereas
ferric-sorbitol-citrate did not promote it. If applied to normal
(non-arthritic) mice three times a week for 4 weeks, ferric-sorbitol-citrate stimulated isolated splenocytes to increase production of
TNF-, the function of antigen-presenting cells and lymphocyte
proliferation in response to ConA in vitro. TNF- production by
cultured splenocytes was also stimulated. In mice with antigeninduced arthritis, iron compounds did not additionally stimulate
TNF- production. Thus, we have shown that ferric-sorbitol- citrate stimulated TNF- production, antigen-presenting cell activity
and cellular immune response. Development of antigen-induced arthritis and TNF- production in arthritic mice were not stimulated.
715. Effect of endosulfan and malathion on lipid peroxidation,
nitrite and TNF- release by rat peritoneal macrophages - Ayub
S., Verma J. and Das N. [N. Das, Department of Biochemistry, All
India Inst. of Medical Sciences, Ansari Nagar, New Delhi 110029,
India] - INT. IMMUNOPHARMACOL. 2003 3/13-14 (1819-1828) summ in ENGL
Endosulfan and malathion are organochlorine and organophosphate insecticides, respectively. The toxicity of both the insecticides
are well known on non-target organisms. Both endosulfan and
malathion are reported to suppress humoral as well as cellular immune responses. We investigated the possible effect of both these
insecticides on lipid peroxidation, nitrite production and TNF-
generation in rat peritoneal macrophages under in vitro conditions.
Rat peritoneal cells were collected and cultured with or without insecticides and relevant stimulants for lipid peroxidation, generation
of nitric oxide and TNF-. FeSO4 was used as an inducer for lipid
peroxidation and LPS was used to induce nitric oxide synthase and
release of TNF-. Lipid peroxidation was assayed by estimating
MDA; nitric oxide was determined by estimating nitrite and TNF-
by using an assay kit in culture supernatants. Both endosulfan and
malathion had no effect on lipid peroxidation. Endosulfan did not
have any influence on nitrite production, but suppressed the LPSinduced TNF- generation. Malathion, however, showed a direct
suppression on nitrite production and suppression of LPS-induced
TNF- generation. This study suggests that functional aberrations
of macrophages may contribute significantly to the immunomodulation reported for these insecticides. © 2003 Elsevier B.V. All
rights reserved.
716. Polyphenolic antioxidants inhibit peptide presentation by
antigen-presenting cells - Gong J. and Chen S.-S. [S.-S. Chen,
Division of Allergy, La Jolla Inst. for Allerg./Immunol., San Diego,
CA, United States] - INT. IMMUNOPHARMACOL. 2003 3/13-14
(1841-1852) - summ in ENGL
Antigen-presenting cells (APC) provide two essential signals,
e.g., antigenic peptides as well as costimulatory molecules for
T-cell activation. Small molecules of smoke tobacco extracts (SMSTE) inhibited antigen presentation of A20 to OVAp-specific T-cell
hybridomas. Pretreatment of A20 but not T hybridomas abrogates
the APC function. Viability of APC and levels of MHCII, CD40
and B7 of APC were not affected by this treatment. The active
principle, inhibiting APC was reproduced with pure tobacco polyphenols, quercetin and its glycoside, rutin. Antioxidant activity
of rutin is relevant since rutin downregulated levels of reactive
oxygen species (ROS) in phorbol ester-stimulated A20; moreover,
another antioxidant, N-acetyl cysteine (NAC) also inhibited antigen presentation, albeit at a higher concentration. Other types
of APC, such as bone marrow-derived mast cells (BMMC), MHCII-transfected fibroblast, and splenocytes are affected by tobacco
polyphenols. We propose that polyphenols may affect redox-sensitive signal transduction pathway since APC function of PD 98059,
MEK inhibitor-pretreated A20 were similarly abrogated. Taken
together, we propose that maintaining appropriate intracellular redox of APC is crucial for its antigen-presenting function. © 2003
717. In vivo modulation of the circulating lymphocyte subsets
and monocytes by androgen - Yao G., Liang J., Han X. and
Hou Y. [Y. Hou, Immunol./Repro. Biology Laboratory, Medical
School, Nanjing University, Nanjing 210093, China] - INT. IMMUNOPHARMACOL. 2003 3/13-14 (1853-1860) - summ in ENGL
Androgens influence some immunological processes, including
alternation of the number and function of the circulating lymphocytes and monocytes. In the present study, the effects of three
different doses of testosterone on the numbers and percentages of
the peripheral blood cells were investigated; the lymphocyte subsets
were determined and the proliferation of lymphocyte was detected.
Groups of Sprague-Dawley rats were treated with 0.5, 2.5, 12.5
mg/kg or only vehicle, respectively. Compared with controls, the results of complete blood counts showed that the absolute and relative
numbers of monocytes decreased. The lymphocyte subpopulations
determined by flow cytometry indicated an increase in CD8+ T
cells, whereas the CD3+, CD4+ and CD4+CD8+ T cells remained
unchanged. Thus, the immunoregulatory index (CD4+/CD8+ ratio) decreased. The proliferative activities determined by MTT
assay were down-regulated. In conclusion, the immunosuppressive
effects of testosterone may be attributed to a decline in number of
monocytes, CD4+/CD8+ ratio and proliferative activities together
with an increase of CD8+ T cells in Sprague-Dawley rats. © 2003
718. Neuropeptides (SP and CGRP) augment pro-inflammatory
cytokine production in HSV-infected macrophages - Yaraee R.,
Ebtekar M., Ahmadiani A. and Sabahi F. [R. Yaraee, Department of
Immunology, School of Medicine, Shahed University, Tehran, Iran]
- INT. IMMUNOPHARMACOL. 2003 3/13-14 (1883-1887) - summ
in ENGL
Neuropeptides are able to modulate cytokine production by macrophages in response to various stimulators. In this study, the
effects of neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) on production of pro-inflammatory cytokines
TNF and IL-1 by macrophages were considered. Mouse peritoneal
macrophages were infected with herpes simplex virus type-1 (HSV1), or remained unstimulated, and cytokine assays were performed
after 12 h. IL-1 and TNF secretion by unstimulated macrophages
have been significantly increased in the presence of SP and CGRP.
Each neuropeptide, alone or in coordination with the other, caused
significant increase in IL-1 and TNF production by HSV-infected
mouse peritoneal macrophages. It was concluded that the macrophage-mediated inflammatory response to HSV-1 is enhanced in the
presence of these neuropeptides. © 2003 Elsevier B.V. All rights
reserved.
719. Concentration-dependent bifunctional effect of TGF- 1 on
immunoglobulin production: A role for Smad3 in IgA production in vitro - McKarns S.C., Letterio J.J. and Kaminski N.E. [N.E.
Kaminski, Dept. of Pharmacology and Toxicology, 315 Natl. Food
Safety/Toxicol. Ctr., Michigan State University, East Lansing, MI
48824, United States] - INT. IMMUNOPHARMACOL. 2003 3/1314 (1761-1774) - summ in ENGL
Injury to the liver results in rapid induction of transforming
growth factor-beta1 (TGF- 1 ) consistent with a role for TGF-
1 in repairing damaged tissue. In addition to its ubiquitous role in
injury repair, TGF- 1 is also well established as a critical regulator
of immune homeostasis; however, its mechanisms of action remain
enigmatic. We have previously demonstrated that the hepatotoxic
chlorinated hydrocarbon, carbon tetrachloride, suppresses helper
T-lymphocyte function in a TGF- 1 -dependent manner. Here,
we report that, in opposition to its immunosuppressive effects at
picomolar concentrations, femtomolar concentrations of TGF- 1
augment T cell-dependent anti-sRBC IgM antibody forming cell
(AFC) and T cell-independent DNP-Ficoll-induced AFC responses.
These data support a concentration-dependent bifunctional effect
by TGF- 1 on humoral immune responses in vitro. We further
investigated a putative mechanistic role for Smad3, an intracellular
mediator of TGF- 1 signaling, in propagating the inhibitory effects
of TGF- 1 on humoral immune responses. Relative to wild type
littermates, splenocytes from mice homologous for a null mutation in the gene encoding the TGF- receptor-activated Smad3
(Smad3Exon8-/- ) were less sensitive to inhibition by TGF- 1 following anti-sRBC- and LPS-sensitization in vitro. In agreement,
inhibition of IgM protein production by TGF- 1 was also dampened in LPS-sensitized Smad3Exon8-/- splenic B cells. Moreover,
stimulation of IgA by TGF- 1 was abrogated in LPS-sensitized
Smad3Exon8-/- splenocytes suggesting an additional role for Smad3
in regulating IgA production in vitro. Our results suggest that the
effects of TGF- 1 on humoral immune responses fundamentally
differ in a concentration-dependent manner and are mediated, in
part, through Smad3 signaling. © 2003 Elsevier B.V. All rights
reserved.
720. Differential inhibition of receptor activation by two mouse
monoclonal antibodies specific for the human leukotriene B4
receptor, BLT 1 - Sabirsh A., Pettersson A., Boketoft Å. et al. [A.
Sabirsh, Molecular Neurobiology, Lund University, BMC A12, Tornavägen 10, 224 81 Lund, Sweden] - INT. IMMUNOPHARMACOL.
2003 3/13-14 (1829-1839) - summ in ENGL
The inflammatory mediator leukotriene B4 (LTB4 ) binds to and
activates a G-protein-coupled receptor named BLT1 . We have
previously produced two monoclonal antibodies, named 7B1 and
14F11, that bind specifically to this receptor. Using a HeLa cell line
expressing human BLT1 , we find that both antibodies inhibit LTB4 induced calcium release, and activation of a MAP-kinase-sensitive
luciferase reporter system. The normal chemotactic movement
of polymorphonuclear cells towards higher LTB4 concentrations
was also strongly inhibited by both antibodies. Neither antibody
was found to activate BLT1 , and experiments using cyclic peptide
fragments of the BLT1 n-terminal and extracellular loops showed
that these antibodies bind only to complex epitopes in the tertiary,
membrane bound, conformation of the receptor protein. In ligand
binding experiments, 7B1 was found to be a competitive antagonist,
while 14F11 was a noncompetitive antagonist that inhibited receptor
activation, but not agonist (LTB4 ) binding. 14F11 will be a useful
tool for studying the mechanisms of receptor activation. © 2003
721. Cholera toxin activates dendritic cells through dependence
on MG1-ganglioside which is mediated by NF-B translocation - Kawamura Y.I., Kawashima R., Shirai Y. et al. [T. Dohi,
Department of Gastroenterology, Research Institute, International
Medical Ctr. of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 1628655, Japan] - EUR. J. IMMUNOL. 2003 33/11 (3205-3212) - summ
in ENGL
Cholera toxin (CT) is a potent adjuvant; however, the mechanism
for its ability to enhance mucosal immunity has not been fully
elucidated. We report here that CT exerts its adjuvant properties by
signaling through the GM1 ganglioside receptor. When gangliosidedefective mice were given the antigen (Ag) ovalbumin (OVA) with
CT by the oral route, CT failed to support either OVA-specific antibody or CD4+ T cell responses. In vitro treatment of murine bone
139
marrow-derived dendritic cells (DC) with CT induced full maturation as evidenced by upregulation of the costimulatory molecules,
as well as by an enhanced ability to effectively present OVA for Agspecific T cell responses. On the other hand, ganglioside-defective
DC failed to differentiate to full function as Ag-presenting cells in
response to CT. Since ganglioside-defective DC showed a mature
phenotype after stimulation with lipopolysaccharide (LPS), the effects of CT on DC was independent of signal transduction through
adjuvant receptor for LPS, the Toll-like receptor 4. Furthermore, CT
also induced nuclear translocation of nuclear factor (NF)-B in DC
in a GM1-dependent fashion. These results highlight gangliosides
expressed by DC for recognition of the non-self protein bacterial
enterotoxin, which employ a unique signaling pathway to induce
both innate and adaptive immunity.
722. Considerations for the treatment of multiple sclerosis in
the managed care setting - Morrow T., Brown J., Smith C. and
Thrower B. [Dr. T. Morrow, Matria Healthcare, Inc., Marietta, GA,
United States] - FORMULARY 2003 38/11 (646-655) - summ in
ENGL
The direct and indirect healthcare costs associated with multiple
sclerosis are high. In the managed care setting, before treatment is
initiated, these costs must be reconciled with other factors such
as the epidemiological and clinical features of MS and current
recommendations for pharmacologic management. Managed care
organizations (MCOs) have the opportunity to improve the outcomes of MS through a system of care. MCOs can also manage
the costs of the 2 first-line therapies (glatiramer and agents from
the interferon class) used to treat MS by using stepped care and
preferred formulary designations. In addition, improved outcomes
can be achieved by establishing a disease management approach to
treat MS.
723. Nadroparine inhibits the hypersensitivity response in the
conjunctiva - Giannoulaki V., Papathanassiou M., Sitaras N.M.
and Tiligada E. [E. Tiligada, Dept. of Experimental Pharmacology,
Medical School, University of Athens, M. Asias 75, GR-11527
Athens, Greece] - EUR. J. PHARMACOL. 2003 481/1 (119-124) summ in ENGL
This study sought to investigate the effects of nadroparine on an
in vivo experimental model of type I hypersensitivity response in
the rat conjunctiva. Following drug application onto the eye, either
before or after challenge with the mast cell degranulator, basic polyamine compound 48/80, the conjunctival histamine content and the
nitrite levels in the conjunctival lavage fluid were quantified fluorometrically and spectrophotometrically, respectively. Instillation
into the eye of nadroparine inhibited the C48/80-induced decreases
in conjunctival histamine and the delayed increases in nitrite levels,
without influencing basal mediator levels. Protamine did not induce
histamine release and only partially reversed the effects of nadroparine post-challenge, yet it had no effect on the protective action
of the drug when administered prior to degranulation. The results
showed that nadroparine was equally effective in attenuating the
effects of compound 48/80 in the eye when administered topically
either before or after challenge. © 2003 Elsevier B.V. All rights
reserved.
724. Pharmacokinetics of daclizumab and mycophenolate mofetil with cyclosporin and steroids in renal transplantation Pescovitz M.D., Bumgardner G., Gaston R.S. et al. [Dr. M.D. Pescovitz, Dept. Surgery/Microbiology/Immunol., Indiana University,
550 N. University Blvd., Indianapolis, IN 46202, United States] CLIN. TRANSPLANT. 2003 17/6 (511-517) - summ in ENGL
Daclizumab and mycophenolate mofetil (MMF) decrease the
incidence of acute allograft rejection. This double-blind, randomized, placebo-controlled trial was performed primarily to assess
the pharmacokinetics of MMF in an immunosuppressive regimen
incorporating daclizumab. At five centers, 75 renal transplant recipients were randomized 2 : 1 to receive either daclizumab 1 mg/kg
or placebo pre-transplantation and every other week, for a total of
five doses. All patients received cyclosporine, steroids, and MMF.
Levels of mycophenolic acid (MPA), its glucuronide metabolite,
and daclizumab were measured after dosing on days 28 and 56.
Safety parameters evaluated included: adverse events, laboratory
140
abnormalities, infections, patient/graft survival, incidence of lymphoproliferative disorders, and incidence of acute rejection at 12
months. The concomitant administration of daclizumab and MMF
had no effect on the pharmacokinetics of MPA: AUC0-8 values (g
h/mL SD) on day 28 were 30.1 13.3 for daclizumab-treat
patients vs. 31.1 12.4 for placebo and on day 56, 37.7 18.2 for
daclizumab-treated patients vs. 35.7 14.0 for placebo. Adverse
events were similar between the two groups. Acute rejection at 12
months occurred in 14% of patients receiving daclizumab and 20%
of patients receiving placebo. The coadministration of daclizumab
did not result in a pharmacokinetic interaction with MPA, the active
metabolite of MMF.
725. Molecular mechanisms of cis-urocanic acid and permethrin-induced alterations in cutaneous immunity - Prater
M.R., Blaylock B.L. and Holladay S.D. [M.R. Prater, E. Via VA College Osteopathic Med., 2265 Kraft Drive, Blacksburg, VA 24060,
United States] - PHOTODERMATOL. PHOTOIMMUNOL. PHOTOMED. 2003 19/6 (287-294) - summ in ENGL
Background/Purpose: Cutaneous cis-urocanic acid (cUCA) or ultraviolet B exposure has been shown to cause diminished cutaneous
contact hypersensitivity (CH) and to induce systemic tolerance (increased regulatory T lymphocytes) in mice. Permethrin is also a
known CH inhibitor, but the molecular mechanisms are currently
poorly understood. In this study, CH was evaluated in four strains
of mice: an immunosensitive strain (C57BL/6N), an immunoresistant strain (SvImJ), a strain developed from C57BL/6N mice but
genetically altered at both the tumor necrosis factor-alpha receptors
(TNFp55R and p75R), and a strain developed from C57BL/6N but
genetically deleted at the interferon-gamma (IFN ) locus. Methods: CH was evaluated in each group via oxazolone challenge
following a 5-day exposure to intradermal (ID) cUCA or a single
exposure to topical permethrin, or co-exposure to both chemicals
in 5-week-old female C57BL/6N, SvImJ, and C57BL/6N mice genetically altered at the TNF or IFN locus. Results: A 5-day
exposure to ID cUCA or a single exposure to topical permethrin
resulted in diminished CH response in C57BL/6N mice, and this
effect was exacerbated with concurrent exposure to both chemicals.
CH in SvImJ was both cUCA- and permethrin-resistant relative to
C57BL/6N mice, as 5-day cUCA or a single exposure to permethrin
did not diminish CH, nor did concurrent exposure to cUCA and
permethrin. Mice deleted at both TNFR loci displayed similar
but somewhat blunted diminished CH responses to cUCA or permethrin. This trend became significant with combined chemical
exposure. IFN knockout mice displayed similar diminished CH
responses to cUCA or permethrin alone. Unlike C57BL/6N mice,
the IFN knockout mice did not show a further reduction in CH
with combined chemical exposure. Conclusions: These results suggest the following: (1) Mouse strains show variable susceptibility
to permethrin- and cUCA-induced immunomodulation. (2) TNF
may be involved in the immunomodulatory effects of cUCA and
permethrin. (3) IFN may be required for the more than additive
depression of CH caused by cUCA + permethrin.
6.7. Emetics and antiemetics
726. Neural, hormonal and genetic mechanisms for the activation of brain and behavior - Mong J., Easton A., Kow L.-M. and
Pfaff D. [D. Pfaff, Lab. of Neurobiology and Behavior, Rockefeller
University, Box 275, 1230 York Avenue, New York, NY 10021,
United States] - EUR. J. PHARMACOL. 2003 480/1-3 (229-231) summ in ENGL
Underlying all motivated behavior is the concept of brain arousal,
the generalized activation of forebrain and behavior. A concrete
expression of this would be sexual arousal and behavior. The
sex behavior whose mechanisms are best understood is the lordosis response, a vertebral dorsiflexion by the female permitting
fertilization. Estrogenic facilitation of this behavior requires new
transcription and protein synthesis. The genes which are turned
on by estrogens and whose products facilitate the behavior are
organized in modules. Some exert direct effects, e.g. genes coding for neurotransmitter receptors in hypothalamic neurons. Other
modules exert indirect effects: through neuronal growth, through
facilitation of transcription from the progesterone receptor gene,
and even through other preparative behaviors. An unexpected result deriving from a microarray study was the estrogenic effect
on prostaglandin-D synthetase, important because of the marked
actions of prostaglandin-D on arousal and sleep. © 2003 Published
by Elsevier B.V.
6.8. Autacoids and prostaglandins
727. Improved hemostasis with superactive analogs of factor
VIIa in a mouse model of hemophilia A - Tranholm M., Kristensen K., Kristensen A.T. et al. [M. Tranholm, Pharmacology,
Research and Development, A/S Novo Nordisk Park, DK-2760
Måløv, Denmark] - BLOOD 2003 102/10 (3615-3620) - summ in
ENGL
It is currently debated whether the mechanism of action of therapeutic doses of recombinant factor VIIa (rFVIIa, Novo-Seven) relies
on the tissue factor (TF)-independent activity of the enzyme. The
present study was conducted to investigate the in vivo hemostatic
effects of rFVIIa and 3 analogs thereof with superior intrinsic activity (FVIIaIIa , K337A-FVIIa IIa , and M298Q-FVIIa) in mice with
antibody-induced hemophilia A. A highly significant dose response
was observed for the bleeding time and blood loss for each of the
rFVIIa variants. The bleeding time and blood loss were normalized
after administration of 10 mg/kg rFVIIa, 3 mg/kg K337A-FVIIa IIa ,
and 3 mg/kg M298Q-FVIIa, indicating a potency of these FVIIa
analogs 3-4 times above that of rFVIIa in FVIII-depleted mice. The
different in vivo potencies of the various forms of FVIIa could not
be explained by the pharmacokinetics. Histopathological evaluation of kidneys revealed no signs of treatment-related pathological
changes even after treatment with the superactive variants. The
fact that FVIIa analogs with enhanced intrinsic activity are more
efficacious in the murine hemophilia A model strongly suggests
that the TF-independent procoagulant activity of FVIIa contributes
to its clinical hemostatic effect. © 2003 by The American Society
of Hematology.
728. Bilirubin and S-nitrosothiols interaction: Evidence for a
possible role of bilirubin as a scavenger of nitric oxide - Mancuso C., Bonsignore A., Di Stasio E. et al. [C. Mancuso, Institute
of Pharmacology, Catholic University, School of Medicine, Largo
Francesco Vito, 1, 00168 Rome, Italy] - BIOCHEM. PHARMACOL.
2003 66/12 (2355-2363) - summ in ENGL
Bilirubin (BR), the final product of heme catabolism, plays a crucial role in the defense against reactive oxygen species in various
cell types. In this study, we addressed the hypothesis that BR can
act as a physiological scavenger of nitric oxide (NO), a gaseous
mediator involved in many cellular functions and able to trigger
the formation of reactive nitrogen species with pro-oxidant activity.
We found that S-nitrosocysteine (SNOC) and S-nitrosoglutathione
(GSNO), which have a half-life of 0.520.07hr and 385hr and
release NO at a constant rate of 1.420.2hr-1 and 0.0180.002hr-1 ,
respectively, were able to decrease BR half-life in a concentration-dependent manner under physiological conditions. This effect
appears to be dependent on NO formation as L-cysteine and GSH
did not affect BR consumption and nitrite was four to five times less
efficient than SNOC in reducing BR half-life. Oxyhemoglobin, a
well-known scavenger of NO, protected BR from SNOC-mediated
degradation. In addition, the reaction between SNOC/GSNO and
BR modified the absorption spectrum of the bile pigment showing
a gradual increase in the absorbance at 316nm. This change in
the BR spectrum indicates that the bile pigment could be a target
for N-nitrosation reactions, since it resembles the modifications occurred when other molecules such as di-peptides and uric acid are
nitrosated. Taken together, these data suggest that BR should not be
considered only as an endogenous antioxidant but also as a molecule
with the potential ability to counteract intracellular nitrosative stress
reactions. © 2003 Elsevier Inc. All rights reserved.
729. Endogenous glucocorticoids inhibit scratching behavior
induced by the administration of compound 48/80 in mice Hirayama K., Sudo N., Sueyasu M. et al. [N. Sudo, Hlth. Care
Admin. and Management, Graduate School of Medical Sciences,
Kyushu University, 3-1-1 Maidashi, Higashi, Fukuoka 812-8582,
Japan] - EUR. J. PHARMACOL. 2003 481/1 (59-65) - summ in
ENGL
In this study, we investigated the effects of endogenous glucocorticoids on the compound 48/80 (a condensation product of
N-methyl-p- methoxyphenethylamine with formaldehyde)-induced
mouse scratching behavior using either RU-486 (mifepristone), a
glucocorticoid receptor antagonist, or a surgical resection of the
adrenal glands. Subcutaneous injection of compound 48/80 induced not only a corticosterone elevation in the plasma but also
an enhanced expression of corticotropin releasing hormone (CRH)mRNA in the paraventricular nucleus, which thus suggests that
hypothalamic-pituitary- adrenal axis is activated by the compound
48/80-induced cutaneous reaction. Inhibition of such an endogenous glucocorticoid activity by RU-486 significantly increased the
degree of scratching behavior at not only the early-phase (<60 min)but also the late-phase (>60 min) time course after the injection of
compound 48/80. Since the elevation of the histamine levels in the
plasma in the RU-486-treated mice was no longer found in latephase scratching behavior, these results thus indicate that histamine
is a dominant mediator responsible for early-phase scratching behavior, while different mediators other than histamine may be also
involved in the induction of late-phase scratching behavior. Moreover, surgical removal of adrenal glands also significantly increased
the compound 48/80-induced scratching behavior without affecting anxiety and locomotor parameters, indicating that endogenous
glucocorticoids exert their anti-pururitogenic effects independently
of changes in behavioral performance. In conclusion, endogenous
glucocorticoid activity was found to suppress the compound 48/80induced scratching behavior in mice. © 2003 Elsevier B.V. All
rights reserved.
730. In vivo coronary effects of endothelin-1 after ischemiareperfusion. Role of nitric oxide and prostanoids - Fernández
N., Martı́nez M.A., Climent B. et al. [G. Diéguez, Departamento
de Fisiologı́a, Facultad de Medicina, Universidad Autónoma, Arzobispo Morcillo 2, 28029, Madrid, Spain] - EUR. J. PHARMACOL.
2003 481/1 (109-117) - summ in ENGL
To examine the effects of reperfusion after short and prolonged
ischemia on the coronary action of endothelin-1, left circumflex
coronary artery flow was electromagnetically measured, and 15or 60-min occlusion of this artery followed by reperfusion was
induced in anesthetized goats. In non-treated animals, during
reperfusion after 15-min occlusion, the duration but not the peak
of endothelin-1-induced coronary effects (0.01-0.3 nmol) was increased, and the effects of acetylcholine (3-100 ng) were unchanged.
During reperfusion after 60-min occlusion, the peak and duration
of endothelin-1-induced effects were increased whereas those of
acetylcholine were decreased. N w -nitro-L-arginine methyl esther
(L-NAME) treatment did not modify the peak and duration of the
coronary effects of endothelin-1 during reperfusion after both durations of occlusion. This treatment inhibited the effects of the two
higher doses but not those of the two lower doses of acetylcholine
during reperfusion after 15-min occlusion, and it did not modify
the effects of any dose of this drug during reperfusion after 60-min
occlusion. Meclofenamate treatment did not modify the coronary
effects of endothelin-1 and acetylcholine during reperfusion after
both durations of occlusion. These results suggest that ischemiareperfusion increases the coronary response to endothelin-1, which
is more pronounced during reperfusion after prolonged than after
brief ischemia, and that this increased response is probably related
to inhibition of nitric oxide release, without involvement of prostanoids. © 2003 Elsevier B.V. All rights reserved.
6.9. Medicinal plants and herbal medicines
731. Modulation of B lymphocyte function by an aqueous fraction of the ethanol extract of Cissampelos sympodialis Eichl
(Menispermaceae) - Alexandre-Moreira M.S., Piuvezam M.R.
and Peçanha L.M.T. [L.M.T. Peçanha, Departamento de Imunologia, Instituto de Microbiologia, Univ. Federal do Rio de Janeiro,
Bloco I, Ilha do Fundão, 21944-570 Rio de Janeiro, RJ, Brazil] BRAZ. J. MED. BIOL. RES. 2003 36/11 (1511-1522) - summ in
ENGL
141
Cissampelos sympodialis Eichl species are used in folk medicine
for the treatment of asthma, arthritis and rheumatism. In the present
study, we investigated the immunomodulatory effect of an aqueous
fraction of a 70% (v/v) ethanol extract of C sympodialis leaves on
B lymphocyte function. The hydroalcoholic extract inhibited the
in vitro proliferative response of resting B cells induced by LPS
(IC50 = 17.2 g/ml), anti-delta-dextran (IC50 = 13.9 g/ml) and
anti-IgM (IC50 = 24.3 g/ml) but did not affect the anti-MHC
class II antibody-stimulated proliferative response of B cell blasts
obtained by stimulation with IL-4 and anti-IgM. Incubation with the
hydroalcoholic extract used at 50 g/ml induced a 700% increase
in intracellular cAMP levels. IgM secretion by resting B cells
(obtained from normal mice) and polyclonally activated B cells
(obtained from Trypanosonza cruzi-infected animals) was inhibited
by the hydroalcoholic extract. The latter were more sensitive to the
hydroalcoholic extract since 6.5 g/ml induced a 20% inhibition
in the response of cells from normal mice while it inhibited the
response of B cells from infected animals by 75%. The present
data indicate that the alcoholic extract of C. sympodialis inhibited B
cell function through an increase in intracellular cAMP levels. The
finding that the hydroalcoholic extract inhibited immunoglobulin
secretion suggests a therapeutic use for the extract from C. sympodialis in conditions associated with unregulated B cell function
and enhanced immunoglobulin secretion. Finally, the inhibitory
effect of the hydroalcoholic extract on B cells may indicate an antiinflammatory effect of this extract.
732. Quality control of liquid herbal drug preparations: Ethanol content and test on methanol and 2-propanol - Apers S., Van
Meenen E., Pieters L. and Vlietinck A. [S. Apers, Dept. of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1,
2610 Wilrijk, Belgium] - J. PHARM. BIOMED. ANAL. 2003 33/4
In the quality control of liquid herbal drug preparations, i.e. tinctures and liquid extracts, the ethanol content is determined and the
test on methanol and 2-propanol is performed. Capillary headspace
GC/MS methods for both analyses were developed and fully validated. These specific, selective, accurate and precise methods are
a fast and fully automated alternative for the laborious methods of
the European Pharmacopoeia, since they need no or only simple
sample preparation. © 2003 Elsevier B.V. All rights reserved.
733. Determination of hamamelitannin, catechins and gallic acid
in witch hazel bark, twig and leaf by HPLC - Wang H., Provan
G.J. and Helliwell K. [H. Wang, R and D Department, William
Ransom and Son plc, Hitchin, Herts SG5 1LY, United Kingdom]
- J. PHARM. BIOMED. ANAL. 2003 33/4 (539-544) - summ in
ENGL
An HPLC method for the determination of hamamelitannin,
catechins and gallic acid in witch hazel bark, twig and leaf has been
developed. The separation system consisted of a C18 reversedphase column, a gradient elution system of methanol/water and
orthophosphoric acid, and a photodiode array detector. The concentrations of hamamelitannin, gallic acid, (+)-gallocatechin and
(+)-catechin were 4.77, 0.59, 0.22 and 0.39% (w/w), respectively,
in the bark. Hamamelitannin and catechins were also detected in
the leaves at concentration less than 0.04% (w/w). This method is
simple, sensitive and reproducible, ideally suited for rapid, routine
analysis. © 2003 Elsevier B.V. All rights reserved.
734. Effects of the Herbal Medicine Inchinko-to on Liver Function in Postoperative Patients with Biliary Atresia - A Pilot
Study - Iinuma Y., Kubota M., Yagi M. et al. [Dr. Y. Iinuma,
Division of Pediatric Surgery, Niigata University, Grad. Sch. of
Med. and Dent. Sci., 1-757 Asahimachi-dori, Niigata-City, Niigata
951-8510, Japan] - J. PEDIATR. SURG. 2003 38/11 (1607-1611) summ in ENGL
Background/Purpose: A continuation of liver fibrosis after undergoing successful Kasai operation has become the important
clinical issue in the long-term follow-up of patients with biliary
atresia (BA). The aim of this study is to evaluate the efficacy
of the herbal medicine Inchinko-to (TJ-135) on the treatment of
liver fibrosis in patients with BA without jaundice, especially from
the viewpoint of the long-term effects of TJ-135. Methods: Six
postoperative patients with BA ranging between 3 and 13 years
142
of age with normal serum total bilirubin levels (total bilirubin <
1.0 mg/dL [17 mol/L]) received TJ-135 from 2 to 4 years. The
liver enzyme (glutamic oxaloacetic transaminase [GOT], glutamic
pyruvic transaminase [GPT], gamma glutamyl transpeptidase[ GTP]transpeptidase[ -GTP] levels and hyaluronic acid (HA) levels
were compared before and after the administration of TJ-135. The
monthly collected data were averaged on a 1-year basis. The record
of one postoperative patient with BA and a normal serum total
bilirubin level was incorporated as a control. This patient showed
portal hypertension and did not receive TJ-135. Results: Five of
the six patients who showed abnormal values for liver enzymes, exhibited a significant decrease in serum GOT, -GTP, or GPT levels
after a 1 to 3-year administration of TJ-135, and the improvement
in these parameters persisted thereafter. Furthermore, one patient
who had an abnormally high value of HA also showed a significant
decrease in the serum level of HA. In the remaining patient with
normal liver enzyme values, no significant change was observed
during the administration of TJ-135. The control patient exhibited
a chronological decrease in the serum GOT and GPT levels by 5
years of age, but the serum -GTP and HA levels remained stable
throughout the postoperative period. Conclusions: The long-term
effectiveness of TJ-135 was only found in those patients with abnormal liver enzyme levels and HA, thereby suggesting that TJ-135
has a protective and antifibrotic effect on the liver. © 2003 Elsevier
Inc. All rights reserved.
!
!
735. The -(1 6)-branched -(1 3) glucohexaose and its
analogues containing an -(1 3)-linked bond have similar
stimulatory effects on the mouse spleen as Lentinan - Yan J.,
Zong H., Shen A. et al. [J. Gu, Gene Research Center, Shanghai
Medical Center, Fudan University, Shanghai 200032, China] - INT.
IMMUNOPHARMACOL. 2003 3/13-14 (1861-1871) - summ in
ENGL
The stimulatory effects of the synthetic -(1!6)-branched
-(1!3) glucohexaose and its analogues containing an -(1!3)linked bond on the mouse spleen were studied for elucidation of
the mechanism of their antitumor activity, and their stimulatory
effects were compared with Lentinan. The mouse spleen’s weight
was increased after the intraperitoneal (i.p.) injection of the oligosaccharides compared with the saline group. In addition, routinely
hematoxylin and eosin (HE)-stained spleen sections showed that the
injection also changed the spleen’s histopathology. RNA samples
were isolated from splenocytes of oligosaccharides, Lentinan or
saline-injected mice. Reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot showed that the administration
of the oligosaccharides or Lentinan enhanced mouse spleen mRNA
production of TNF- but not IL-2. The injection also enhanced
Concanavalin A (Con A)-induced mouse splenocytes proliferation,
but the in vitro administration of the oligosaccharides did not have
the proliferation-enhancing effect. Taken together, these results suggest that the synthetic -(1!6)-branched -(1!3) glucohexaose
and its analogues containing an -(1!3)-linked bond have similar
stimulatory effects as Lentinan. Additionally, they may exert their
antitumor effects through the induction of splenocytes mediated
immune responses. © 2003 Elsevier B.V. All rights reserved.
!
736. Toll-like receptor 4-dependent activation of macrophages
by polysaccharide isolated from the radix of Platycodon grandiflorum - Yoon Y.D., Han S.B., Kang J.S. et al. [H.M.
Kim, Biopotency Evaluation Laboratory, Korea Res. Inst. Biosci./Biotech., 52 Oun-dong, Yusong-gu, Taejon 305-333, South
Korea] - INT. IMMUNOPHARMACOL. 2003 3/13-14 (1873-1882) summ in ENGL
Platycodon grandiflorum, a traditional oriental herbal medicine,
is known to have immunostimulatory and antitumor effects. PG,
a polysaccharide isolated from P. grandiflorum, has been reported
to activate macrophages and B cells. Here, we investigated the
membrane receptor and intracellular signaling responsible for the
activation of macrophages by PG. PG induced the production of
nitric oxide (NO) and the mRNA expression of iNOS in RAW
264.7 cells. To investigate the membrane receptor involved in the
activation of NO production, we examined the effect of PG on the
production of NO in mouse peritoneal macrophages isolated from
wild type C3H/HeN and functional Toll-like receptor 4 (TLR4)-deficient C3H/HeJ mice. PG induced NO production by macrophages
isolated from C3H/HeN mice, but had no effect on NO production
by macrophages isolated from C3H/HeJ mice. Moreover, monoclonal antibodies directed to TLR4 blocked PG-mediated induction
of NO production. In addition, LBP and sCD14 was also found to
be involved in the activation of NO production by PG. To further
investigate, we examined the effect of PG on the activation of DNA
binding of NF-B, which is a downstream transcriptional regulator
of TLR4. PG caused degradation of IB and activation of DNA
binding of NF-B. In addition, TPCK, a specific NF-B inhibitor,
abolished PG-mediated induction of DNA binding of NF-B, production of NO and mRNA expression of iNOS, demonstrating the
involvement of NF-B in PG-mediated macrophage activation.
Taken together, these results suggest that PG-mediated induction
of NO production and iNOS mRNA expression in macrophages is
mediated, at least in part, by TLR4/NF-B signaling pathway. ©
737. An extract of Uncaria tomentosa inhibiting cell division
and NF-B activity without inducing cell death - Åkesson C.,
Lindgren H., Pero R.W. et al. [F. Ivars, Section for Immunology,
Dept. of Cell and Molecular Biology, Lund University, Lund, SE221 84, Sweden] - INT. IMMUNOPHARMACOL. 2003 3/13-14
(1889-1900) - summ in ENGL
Previous reports have demonstrated that extracts of the plant Uncaria tomentosa inhibit tumor cell proliferation and inflammatory
responses. We have confirmed that C-Med 100®, a hot water extract
of this plant, inhibits tumor cell proliferation albeit with variable
efficiency. We extend these findings by showing that this extract
also inhibits proliferation of normal mouse T and B lymphocytes
and that the inhibition is not caused by toxicity or by induction of
apoptosis. Further, the extract did not interfere with IL-2 production
nor IL-2 receptor signaling. Since there was no discrete cell cycle
block in C-Med 100®-treated cells, we propose that retarded cell
cycle progression caused the inhibition of proliferation. Collectively, these data suggested interference with a common pathway
controlling cell growth and cell cycle progression. Indeed, we provide direct evidence that C-Med 100® inhibits nuclear factor B
(NF-B) activity and propose that this at least partially causes the
inhibition of proliferation. © 2003 Elsevier B.V. All rights reserved.
738. The in-vivo effects of sho-saiko-to, a traditional Chinese
herbal medicine, on two cytochrome P450 enzymes (1A2 and
3A) and xanthine oxidase in man - Saruwatari J., Nakagawa
K., Shindo J. et al. [T. Ishizaki, Div. of Clinical Pharmacology,
Grad. School of Pharmaceut. Sciences, Kumamoto University,
Oe-honmachi 5-1, Kumamoto 862-0973, Japan] - J. PHARM.
The Chinese herbal medicine sho-saiko-to is a mixture of seven
herbal components (Bupleurum root, Pinellia tuber, Scutellaria root,
Jujube fruit. Ginseng root, Glycyrrhiza root and Ginger rhizome)that is widely administered to patients with chronic hepatitis in
Japan. We assessed the effects of sho-saiko-to on the activity
of cytochrome P450 (CYP) 1A2, CYP3A and xanthine oxidase
(XO) in man. Twenty-six healthy subjects were studied to evaluate their baseline activity of CYP1A2 and XO by the respective
urinary metabolic ratios of an 8-h urine sample after an oral 150mg dose of caffeine and of CYP3A by a urinary excretion ratio of
6 -hydroxycortisol (6 -HC) to free cortisol (FC). Thereafter, the
subjects received a twice-daily 2.5-g dose of sho-saiko-to for five
days, and underwent the caffeine test on day 1 and day 5. The mean
activity of CYP1A2 decreased by 16% on both day 1 and day 5
compared with the baseline (P=0.001). The mean activity of XO
also significantly decreased by 25% on day 1 and 20% on day 5
(P < 0.0001) compared with the baseline value. The activity of
CYP3A tended to be lower on day 5 than the baseline (P = 0.146).
It is concluded that sho-saiko-to reduces CYP1A2 and XO activity
in man.
739. Multiple-Dose Administration of Ginkgo biloba Did Not
Affect Cytochrome P-450 2D6 or 3A4 Activity in Normal Volunteers - Markowitz J.S., Donovan J.L., DeVane C.L. et al. [Dr. J.S.
Markowitz, Med. Univ. of SC Inst. of Psychiat., RM 246, N. Lab.
of Drug Dispos./Pharmacogen., 67 President Street, Charleston, SC
29425, United States] - J. CLIN. PSYCHOPHARMACOL. 2003 23/6
Standardized extracts from the Ginkgo biloba tree are purported
to exert positive neurocognitive effects and may also be useful in the
treatment of a variety of vascular and other disorders. This dietary
supplement is among the most commonly used herbal preparations
in the world. The objective of this study was to assess in normal
volunteers (n = 12) the influence of standardized Ginkgo biloba
(GB) on the activity of cytochrome P-450 (CYP) 2D6 and 3A4
normal volunteers phenotyped as CYP2D6 extensive metabolizers.
Probe substrates dextromethorphan (CYP2D6 activity) and alprazolam (CYP 3A4 activity) were co-administered orally at baseline,
and following treatment with GB (120 mg twice daily) for 14 days.
Urinary concentrations of dextromethorphan and dextrorphan were
quantified and dextromethorphan metabolic ratios (DMRs) were
determined at baseline and after GB treatment. Likewise, plasma
samples were collected (0-60 hrs) for alprazolam pharmacokinetics at baseline and after GB treatment to assess effects on CYP
3A4 activity. Validated HPLC methods were used to quantify all
compounds and relevant metabolites. No statistically significant
differences were found between baseline and post-GB treatment
DMRs indicating a lack of effect on CYP2D6. For alprazolam
there was a 17% decrease in the area under the plasma concentration versus time curve (AUC); (P < 0.05). However, the half-life of
elimination was not significantly different after GB administration
indicating a lack of hepatic CYP3A4 induction. We conclude that
standardized extracts of GB at recommended doses are unlikely to
significantly alter the disposition of co-administered medications
primarily dependent on the CYP2D6 or CYP3A4 pathways for
elimination.
740. Antihyperglycemic activity of the aqueous extract of Urtica dioica - Bnouham M., Merhfour F.-Z., Ziyyat A. et al. [M.
Bnouham, Lab. de Physiol./Pharmacologie Cell., UFR de Physiologie et Pharmacologie, Université Mohamed Ier, B.P. 524, Oujda,
Morocco] - FITOTERAPIA 2003 74/7-8 (677-681) - summ in ENGL
When administered 30 min before glucose loading, the aqueous
extract of Urtica dioica (nettle) (250 mg/kg) showed a strong glucose
lowering effect. The decrease of glycemia has reached to 333.4%
of the control value 1 h after glucose loading. This effect was persistent during 3 h. In contrast, nettle did not show hypoglycemic effect
in alloxan-induced diabetic rats. The amount of glucose absorbed in
a segment jejunum in situ was 8.050.68 mg in presence of nettle
extract vs. 11.110.75 mg in control rats during 2 h (P<0.05). The
results indicate that nettle has a significant antihyperglycemic effect
in OGTT model. This effect may be caused in part by the reduction
of intestinal glucose absorption. LD50 is 3.5 g/kg (i.p.). © 2003
741. Antimicrobial activity of Gymnema sylvestre leaf extract
- Satdive R.K., Abhilash P. and Fulzele D.P. [D.P. Fulzele, Plant
Biotech./Secdry. Prod. Section, Nucl. Agric./Biotechnology Division, Bhabha Atomic Research Centre, Mumbai 400 085, India] FITOTERAPIA 2003 74/7-8 (699-701) - summ in ENGL
The ethanolic extract of Gymnema sylvestre leaves demonstrated
antimicrobial activity against Bacillus pumilis, B. subtilis, Pseudomonas aeruginosa and Staphylococcus aureus and inactivity against
Proteus vulgaris and Escherichia coli. © 2003 Elsevier B.V. All
rights reserved.
742. Antimicrobial activity of aqueous extracts and of berberine
isolated from Berberis heterophylla - Freile M.L., Giannini F.,
Pucci G. et al. [R.D. Enriz, Fac. de Quim., Bioquim. y Farmacia, Universidad Nacional de San Luis, Chacabuco 917, San Luis
5700, Argentina] - FITOTERAPIA 2003 74/7-8 (702-705) - summ
in ENGL
The antimicrobial activity of Berberis heterophylla leaves, stems
and root aqueous extracts was studied in vitro on Gram-positive and
Gram-negative bacteria and fungi. The in vitro antifungal activity of
berberine isolated from the same source against different Candida
species was also investigated. © 2003 Elsevier B.V. All rights
reserved.
743. Antimicrobial and cytotoxicity evaluation of Buchholzia
coriacea stem bark - Ajaiyeoba E.O., Onocha P.A., Nwozo S.O.
143
and Sama W. [E.O. Ajaiyeoba, Department of Pharmacognosy, University of Ibadan, Ibadan, Nigeria] - FITOTERAPIA 2003 74/7-8
Fractions prepared from the methanol extract of Buchholzia coriacea stem bark exhibited a high concentration-dependent
antibacterial and antifungal activity compared to the standard antibiotics, ampicillin and tioconazole. In the brine shrimp lethality
(BSL) assay, the methanol extract was found to be non-toxic with
an LC50 of 1031 g/ml. The two main compounds present in
the most active fraction were isolated and identified as lupeol and
-sitosterol. © 2003 Elsevier B.V. All rights reserved.
744. Ethnobotanical knowledge of the Istro-Romanians of
Žejane in Croatia - Pieroni A., Giusti M.E., Münz H. et al. [A.
Pieroni, Department of Pharmacy, School of Life Sciences, University of Bradford, Richmond Road, Bradford, West Yorkshire BD7
1DP, United Kingdom] - FITOTERAPIA 2003 74/7-8 (710-719) summ in ENGL
An ethno-pharmacognostic survey was carried out in one of the
smallest ethnic and linguistic groups in Europe: the Istro-Romanians of the village of Žejane (in Croatia), which has a population
of approximately 140 persons, mainly elderly. Using an intensive
field participant observation methodology, we recorded about 60
remedies of the local folk pharmacopoeia, and mainly derived from
plants. Among them, the uncommon traditions to use homemade
vinegar from wild apple (Malus sylvestris) and Cornelian cherries
(Cornus mas) for diverse medical purposes, and houseleek (Sempervivum tectorum) against ear pains have been briefly discussed.
745. Antinephritis and radical scavenging activity of prenylflavonoids - Fukai T., Satoh K., Nomura T. and Sakagami H. [T.
Fukai, School of Pharmaceutical Sciences, Toho University, 2-2-1
Miyama, Funabashi, Chiba 274-8510, Japan] - FITOTERAPIA 2003
74/7-8 (720-724) - summ in ENGL
Antinephritis activity of 5 prenylflavonoids similar to glabridin
(1-5), isolated from Morus alba, Artocarpus communis, Glycyrrhiza
uralensis and G. inflata, was evaluated in mice with glomerular disease (Masugi-nephritis). Oral administrations of artonin E (2) or
licochalcone A (4) for 10 days (30 mg kg-1 day-1 ) reduced the
amount of urinary protein excretion compared to nephritic mice.
ESR spectroscopy demonstrated that morusin (1) and licorisoflavan
A (5) increased the radical intensity of sodium ascorbate by about
two times. Morusin, licoricidin (3), licochalcone A and licorisoflavan A showed weak scavenging activity against superoxide anion
radical. © 2003 Elsevier B.V. All rights reserved.
746. Spasmolytic activity of several extracts obtained from some
Mexican medicinal plants - Rodrı́guez-López V., Salazar L. and
Estrada S. [S. Estrada, Facultad de Farmacia, Univ. Auton. del Estado de Morelos, Ave. Univ. 1001, Colonia Chamilpa, Cuernavaca
Morelos 62210, Mexico] - FITOTERAPIA 2003 74/7-8 (725-728) summ in ENGL
A total of ten extracts from different parts of eight medicinal
plants that are used in the treatment of gastrointestinal disorders,
were evaluated to determine their spasmolytic action on in vitro
isolated rat ileum. All extracts were less potent than papaverine,
which was used as a positive control. © 2003 Elsevier B.V. All
rights reserved.
747. Antimicrobial activity and constituents of Coccoloba acrostichoides - Barros Cota B., Braga De Oliveira A., Dias De
144
Souza-Filho J. and Castro Braga F. [F. Castro Braga, Faculty of
Pharmacy, UFMG, Av. Olegário Maciel, 2360, Belo Horizonte
CEP 30.180-112, Brazil] - FITOTERAPIA 2003 74/7-8 (729-731) summ in ENGL
The ethanol extract and fractions from Coccoloba acrostichoides
aerial parts were assayed for in vitro antimicrobial activity. The
extract was active against the assayed bacteria while most of the
fractions also inhibited fungal growth, especially the n-hexane and
EtOAc fractions. The isolated -sitosterol and betulin were tested,
being the last one active against Fusarium oxysporum. © 2003
748. Cytotoxic activity of Ozoroa insignis from Zimbabwe - Rea
A.I., Schmidt J.M., Setzer W.N. et al. [E.T. Gwebu, Department
of Chemistry, Oakwood College Huntsville, Huntsville, AL 35896,
United States] - FITOTERAPIA 2003 74/7-8 (732-735) - summ in
ENGL
The crude methanol bark extract of the Zimbabwean medicinal
plant, Ozoroa insignis, showed in-vitro cytotoxic activity against
Hep-G2 (human hepatocellular carcinoma), MDA-MB-231 (human
mammary adenocarcinoma), and 5637 (human primary bladder
carcinoma). Bioactivity-directed chromatographic separation led
to isolation of anacardic acid and ginkgoic acid as the cytotoxic
components. © 2003 Elsevier B.V. All rights reserved.
749. Antibacterial activity of Alstonia scholaris and Leea tetramera - Khan M.R., Omoloso A.D. and Kihara M. [M.R. Khan,
Department of Applied Sciences, Papua New Guinea Univ. of
Technology, P.M.B., Lae, Papua New Guinea] - FITOTERAPIA
2003 74/7-8 (736-740) - summ in ENGL
The crude methanolic extracts of the leaves, stem and root barks
of Alstonia scholaris and Leea tetramera on partitioning (petrol,
dichloromethane, ethyl acetate, butanol) gave fractions exhibiting
improved and broader spectrum of antibacterial activity. Especially
the butanol fractions of A. scholaris and the root bark of L. tetramera.
None of the fractions were active against the fungi tested. © 2003
750. Direct inhibitory effect of curcumin on Src and focal adhesion kinase activity - Leu T.-H., Su S.L., Chuang Y.-C. and Maa
M.-C. [M.-C. Maa, Institute of Biochemistry, Chung Shan Medical
University, Taichung, Taiwan] - BIOCHEM. PHARMACOL. 2003
66/12 (2323-2331) - summ in ENGL
Curcumin (diferuloylmethane) is a well-known agent with antiinflammatory, antioxidant, and anticarcinogenic properties. In this
study, we observed that curcumin inhibited the kinase activity of
v-Src, which led to a decrease in tyrosyl substrate phosphorylation
of Shc, cortactin, and FAK. Our in vitro kinase experiment revealed that the inhibitory effect of curcumin on Src could be direct.
Consistent with the abrogation of Src activity was the reduction
of Src-Tyr-416 phosphorylation, Src-mediated Shc-Tyr-317 phosphorylation, decreased ERK activation, and cell proliferation in
v-Src transformed cells. Remarkably, curcumin not only exerted its
negative effect on FAK via the disappearance of Src-mediated FAK
phosphorylation, but also directly inhibited its enzymatic activity.
Concurrent to reduced cortactin tyrosyl phosphorylation and FAK
kinase activity was the abolishment of v-Src-mediated cell mobility.
To our knowledge, this is the first report indicating that curcumin
can retard cellular growth and migration via downregulation of Src
and FAK kinase activity. © 2003 Elsevier Inc. All rights reserved.
SUBJECT INDEX
(figures refer to item numbers)
abdominal aorta, angiotensin, angiotensin 1 receptor, angiotensin
2 receptor, vasoconstriction, 508
abetalipoproteinemia, alpha tocopherol, drug bioavailability,
microsphere, polyglactin, 386
abortion, mifepristone, misoprostol, 542
acamprosate, alcohol, alcoholism, naltrexone, opiate antagonist,
480
acetic acid derivative, glycerol derivative, heart infarction size,
heart muscle ischemia, reperfusion injury, 501
acetylcysteine, cell death, colon cancer, etacrynic acid, 607
- clopidogrel, thrombocyte aggregation inhibition, 546
- heart muscle ischemia, heart protection, isosorbide 5 nitrate,
reperfusion injury, 500
acetylsalicylic acid, cell proliferation, endothelium cell,
indometacin, 591
acoustic reflex, receptor subtype, startle reflex, 470
acquired immune deficiency syndrome, antivirus agent, Human
immunodeficiency virus, 706
acridine derivative, DNA adduct, DNA base, intercalation
complex, platinum, 420
acute granulocytic leukemia, arsenic trioxide, stress activated
protein kinase, 620
- cobalt chloride, hypoxia inducible factor 1alpha, 623
- inhibitor of apoptosis protein, 619
acute heart failure, 496
acute heart infarction, angiotensin 2 receptor antagonist,
candesartan, dipeptidyl carboxypeptidase inhibitor,
monocyte chemotactic protein 1, perindopril, renin
angiotensin aldosterone system, vasculotropin, 505
acute pancreatitis, ascorbic acid, 571
addiction, amygdaloid nucleus, 478
addition reaction, antiglaucoma agent, carbonate dehydratase I,
carbonate dehydratase II, carbonate dehydratase inhibitor,
carbonate dehydratase IV, glaucoma, sulfonamide, 452
adenine derivative, adenosine A1 receptor, ligand, 429
adenosine A1 receptor, adenine derivative, ligand, 429
adrenal suppression, hydrocortisone release, methylprednisolone
sodium succinate, nefazodone, 534
alcohol, acamprosate, alcoholism, naltrexone, opiate antagonist,
480
- alcoholism, major depression, mood disorder, placebo,
sertraline, 483
- capsaicin, sensory nerve, stomach epithelium, stomach injury,
519
- herbaceous agent, methanol, 2 propanol, quality control, 732
alcoholism, acamprosate, alcohol, naltrexone, opiate antagonist,
480
- alcohol, major depression, mood disorder, placebo, sertraline,
483
alcohol withdrawal, 4 aminobutyric acid A receptor, drug
dependence, drug tolerance, drug withdrawal, 477
alkaloid, 687
alkyl group, antineoplastic activity, oxime derivative, steroid, 637
allergic encephalomyelitis, hypotension, immunoglobulin,
immunotherapy, 710
allopurinol, intercellular adhesion molecule 1 antibody, intestine
injury, intestine perfusion, methylene blue, monoclonal
antibody, 709
alpha 1 adrenergic receptor, alpha 1 adrenergic receptor blocking
agent, carvedilol, 510
- cell subpopulation, noradrenalin, subthalamic nucleus, 463
- cyproterone acetate, vas deferens, 526
alpha 1 adrenergic receptor blocking agent, alpha 1 adrenergic
receptor, carvedilol, 510
alpha tocopherol, abetalipoproteinemia, drug bioavailability,
4 aminobutyric acid A receptor, alcohol withdrawal, drug
dependence, drug tolerance, drug withdrawal, 477
- pyrimidine derivative, receptor binding, 574
4 aminobutyric acid B receptor, desensitization, endocytosis,
forskolin, 439
aminoguanidine, cytokine, down regulation, Fas antigen,
membrane antigen, nitric oxide synthase, pancreas islet
cell, 535
aminopenicillin, amoxicillin, antibiotic agent, degradation
kinetics, 553
amitriptyline, drug solubility, imipramine, mepacrine, promazine,
promethazine, propranolol, solubilization, 387
amoxicillin, aminopenicillin, antibiotic agent, degradation
kinetics, 553
amoxicillin plus clavulanic acid, azithromycin, serous otitis
media, 695
AMPA receptor, AMPA receptor agonist, drug receptor binding,
kainic acid receptor, kainic acid receptor agonist, 438
AMPA receptor agonist, AMPA receptor, drug receptor binding,
amperometry, 592
amphetamine, dopamine, 479
amygdaloid nucleus, addiction, 478
analgesic activity, analgesic agent, plant extract, 582
analgesic agent, analgesic activity, plant extract, 582
analytic method, 402
- piromidic acid, 675
angiogenesis inhibitor, breast cancer, cancer prevention, 634
angiotensin, abdominal aorta, angiotensin 1 receptor, angiotensin
angiotensin 1 receptor, abdominal aorta, angiotensin, angiotensin
angiotensin 2 receptor, abdominal aorta, angiotensin, angiotensin
angiotensin 2 receptor antagonist, acute heart infarction,
candesartan, dipeptidyl carboxypeptidase inhibitor,
- heart muscle cell, olmesartan, 503
aniline derivative, bioassay, dimethylallyltransferase, drug
synthesis, farnesyl diphosphate, transferase inhibitor, 414
anisomycin, heart infarction prevention, heart muscle ischemia,
mitogen activated protein kinase, synaptophysin, 502
anorexia nervosa, bulimia, 457
anovulation, birth rate, female infertility, ovulation induction, 544
ansamycin derivative, antineoplastic agent, colon cancer, heat
shock protein 90, 641
anthracycline antibiotic agent, DNA, 628
antiandrogen, bicalutamide, drug design, epidermal growth factor
receptor kinase, gefitinib, prostate cancer, protein tyrosine
kinase inhibitor, 613
antibacterial activity, antifungal activity, antiinfective agent,
benzimidazole derivative, drug synthesis, 686
- antiinfective agent, bacterial infection, drug synthesis,
oxazolidinone derivative, phenyl group, 1,3,4 thiadiazole
derivative, 663
- antiinfective agent, isoxazole derivative, methyl group,
oxazolidinone derivative, 661
- antiinfective agent, protein inhibitor, 666
- bacterial infection, daptomycin, ornithine derivative, 662
- bacterial infection, glycopeptide, oritavancin, vancomycin, 658
- bacterial infection, oxazolidinone derivative, polycyclic
aromatic hydrocarbon derivative, pyrrole derivative, 660
- carbonyl derivative, ethylene derivative, linezolid, structure
activity relation, 659
- chirality, oxazolidinone derivative, 672
- oxazolidinone derivative, quinolone derivative, structure
- plant extract, 749
antibiotic agent, aminopenicillin, amoxicillin, degradation
kinetics, 553
- Chinese drug, drug bioavailability, glycyrrhizic acid, 558
anticoagulant agent, anticoagulation, 545
anticoagulation, anticoagulant agent, 545
- dalteparin, drug effect, enoxaparin, fondaparinux, heparin,
osteoblast, 450
SUBJECT INDEX
1
anticonvulsive agent, 476
- anxiety disorder, anxiolytic agent, etiracetam, 487
antidepressant agent, calcium ion, desipramine, 652
- corticotropin, depression, 2 dipropylamino 8 hydroxytetralin,
imipramine, serotonin 1A agonist, tetracosactide zinc
phosphate, 488
antidiabetic agent, diabetes mellitus, Urtica dioica extract, 740
antifungal activity, antibacterial activity, antiinfective agent,
benzimidazole derivative, drug synthesis, 686
- Candida albicans, ergosterol, fluconazole, gene expression,
mevinolin, prenylation, 562
antifungal agent, 654
- antiinfective agent, antimicrobial activity, quinoline derivative,
698
- antiinfective agent, antivirus agent, drug synthesis, ebselen,
683
- antiinfective agent, berberine, herbaceous agent, plant extract,
742
- antiinfective agent, cytotoxic agent, herbaceous agent, plant
extract, 743
antigen presenting cell, antioxidant, antioxidant activity, peptide,
polyphenol derivative, 716
antiglaucoma agent, addition reaction, carbonate dehydratase I,
antiinfective agent, 673
- antibacterial activity, antifungal activity, benzimidazole
derivative, drug synthesis, 686
- antibacterial activity, bacterial infection, drug synthesis,
derivative, 663
- antibacterial activity, isoxazole derivative, methyl group,
oxazolidinone derivative, 661
- antibacterial activity, protein inhibitor, 666
- antifungal agent, antimicrobial activity, quinoline derivative,
698
- antifungal agent, antivirus agent, drug synthesis, ebselen, 683
- antifungal agent, berberine, herbaceous agent, plant extract,
742
- antifungal agent, cytotoxic agent, herbaceous agent, plant
extract, 743
- antimicrobial activity, choline derivative, quaternary
ammonium derivative, 700
- benzazepine derivative, drug synthesis, oxazolidinone
derivative, Staphylococcus infection, 664
- daptomycin, 674
- herbaceous agent, plant extract, 741
- membrane protein, 665
- oxazolidinone derivative, quinolone derivative, 668
- oxazolidinone derivative, thiomorpholine derivative, thiopyran
derivative, 667
antiinflammatory activity, antinociception, 2 benzoxazolone
derivative, butyric acid derivative, drug synthesis, 594
antiinflammatory agent, B lymphocyte, lymphocyte function,
plant extract, 731
- flavonoid, glomerulopathy, herbaceous agent, Masugi
nephritis, plant extract, scavenger, 745
antilipemic agent, drug synthesis, phthalimide derivative, 415
- high performance liquid chromatography, ultraviolet
spectrophotometry, 395
- hypercholesterolemia, 495
- probucol, 497
antimicrobial activity, antifungal agent, antiinfective agent,
quinoline derivative, 698
- antiinfective agent, choline derivative, quaternary ammonium
derivative, 700
- plant extract, 747
antimigraine agent, calcium channel, calcium ion, chromaffin
cell, dotarizine, exocytosis, 441
antineoplastic activity, alkyl group, oxime derivative, steroid, 637
- bisphosphonic acid derivative, 611
- pyridinium derivative, 636
antineoplastic agent, 615
- ansamycin derivative, colon cancer, heat shock protein 90, 641
- antivirus agent, pyrazole derivative, 697
2
- apoptosis, apoptosis inducing factor, cancer chemotherapy, 649
- benzimidazole derivative, carboxylic acid derivative, 621
- cell pH, 617
- diphtheria toxin, glioblastoma, 624
- drug delivery system, drug synthesis, drug targeting, 610
- esophagus cancer, 616
- esophagus carcinoma, 653
- folic acid antagonist, 643
- glioblastoma, interleukin 13 receptor, 625
antinociception, antiinflammatory activity, 2 benzoxazolone
derivative, butyric acid derivative, drug synthesis, 594
- cannabinoid, emotion, opiate receptor, 580
- prostaglandin synthase inhibitor, sildenafil, 490
antioxidant, antigen presenting cell, antioxidant activity, peptide,
- antioxidant activity, lipid peroxidation, skin disease, 473
- endothelium derived hyperpolarizing factor, hypertension,
tempol, vasodilatation, 511
- growth inhibition, paraquat, paraquat poisoning, reactive
oxygen metabolite, thiamine, 445
antioxidant activity, antigen presenting cell, antioxidant, peptide,
- antioxidant, lipid peroxidation, skin disease, 473
antiparasitic agent, drug activity, 413
antiprotozoal agent, antitrypanosomal agent, hydrazine
derivative, tropolone derivative, 696
antisense oligonucleotide, Hepatitis C virus, phosphoramidic acid
derivative, RNA, single stranded DNA, 690
antithrombocytic agent, atheroma, atherosclerosis, thrombosis,
514
antitrypanosomal agent, antiprotozoal agent, hydrazine
derivative, tropolone derivative, 696
antiviral activity, antivirus agent, measles, 682
antivirus agent, acquired immune deficiency syndrome, Human
immunodeficiency virus, 706
- antifungal agent, antiinfective agent, drug synthesis, ebselen,
683
- antineoplastic agent, pyrazole derivative, 697
- antiviral activity, measles, 682
- core protein, 702
- flavone derivative, flavonoid, quantum chemistry, 701
anxiety disorder, anticonvulsive agent, anxiolytic agent,
etiracetam, 487
anxiolytic agent, anticonvulsive agent, anxiety disorder,
etiracetam, 487
aorta constriction, artery dilatation, cysteine derivative,
glutathione derivative, iron complex, nitric oxide, nitro
derivative, nitrosation, thiol derivative, 434
apoptosis, antineoplastic agent, apoptosis inducing factor, cancer
chemotherapy, 649
- artery muscle, calphostin C, coronary artery, 506
- ceramide, protein p75, sympathetic nerve cell, 465
- keratinocyte, thalidomide, tumor necrosis factor alpha,
ultraviolet B radiation, 604
apoptosis inducing factor, antineoplastic agent, apoptosis, cancer
chemotherapy, 649
arachidonate 12 lipoxygenase, cocaine, gene disruption,
morphine sulfate, 467
area under the curve, blood sampling, hydrochlorothiazide,
statistical model, telmisartan, 381
arsenic trioxide, acute granulocytic leukemia, stress activated
protein kinase, 620
artery dilatation, aorta constriction, cysteine derivative,
artery injury, blood vessel function, cardiovascular agent,
coronary artery disease, paclitaxel, protein
farnesyltransferase inhibitor, pyranoside, 512
artery muscle, apoptosis, calphostin C, coronary artery, 506
arthritis, enantiomer, flurbiprofen, 601
- ferric citrate, immune response, iron derivative, tumor necrosis
factor, 714
arthrocentesis, etodolac, temporomandibular joint disorder, 599
ascorbic acid, acute pancreatitis, 571
asparaginase, asparaginase macrogol, 651
SUBJECT INDEX
asparaginase macrogol, asparaginase, 651
asthma, beta 2 adrenergic receptor stimulating agent, 517
- bronchodilatation, loratadine, terbutaline, 516
- montelukast, 559
Astragalus membranaceus extract, cell adhesion molecule,
immunoglobulin enhancer binding protein, 548
atheroma, antithrombocytic agent, atherosclerosis, thrombosis,
514
atherosclerosis, antithrombocytic agent, atheroma, thrombosis,
514
- calcium antagonist, cardiovascular system, dihydropyridine,
hypertension, nitric oxide synthase inhibitor, protective
agent, 513
azithromycin, amoxicillin plus clavulanic acid, serous otitis
media, 695
- ceftriaxone, serous otitis media, 694
- serous otitis media, 693
bacterial infection, antibacterial activity, antiinfective agent, drug
synthesis, oxazolidinone derivative, phenyl group, 1,3,4
thiadiazole derivative, 663
- antibacterial activity, daptomycin, ornithine derivative, 662
- antibacterial activity, glycopeptide, oritavancin, vancomycin,
658
- antibacterial activity, oxazolidinone derivative, polycyclic
aromatic hydrocarbon derivative, pyrrole derivative, 660
- daptomycin, skin infection, 680
Barrett esophagus, esomeprazole, gastroesophageal reflux, 549
benzazepine derivative, antiinfective agent, drug synthesis,
oxazolidinone derivative, Staphylococcus infection, 664
benzimidazole derivative, antibacterial activity, antifungal
activity, antiinfective agent, drug synthesis, 686
- antineoplastic agent, carboxylic acid derivative, 621
benzodiazepine receptor affecting agent, drug receptor binding,
flavonoid, receptor affinity, 436
benzofuran derivative, integrase inhibitor, quinoline derivative,
684
benzoporphyrin derivative, photodynamic therapy,
photosensitizing agent, subretinal neovascularization, 451
benzothiazepine derivative, brain mitochondrion, calcium ion,
granule cell, isoprotein, sodium calcium exchange, sodium
ion, 437
2 benzoxazolone derivative, antiinflammatory activity,
antinociception, butyric acid derivative, drug synthesis,
594
benzyl derivative, imipramine, 379
berberine, antifungal agent, antiinfective agent, herbaceous agent,
plant extract, 742
beta 2 adrenergic receptor stimulating agent, asthma, 517
beta adrenergic receptor stimulating agent,
hyperhomocysteinemia, uterus spasmolytic agent, 527
bicalutamide, antiandrogen, drug design, epidermal growth factor
bicuculline methiodide, globus pallidus, jaw movement,
locomotion, tremor, 469
bile duct atresia, herbaceous agent, liver function, 734
bile secretion, pancreas, tetramethylpyrazine, 570
bilirubin, nitric oxide, s nitrosothiol, scavenger, 728
bioassay, aniline derivative, dimethylallyltransferase, drug
biochemical marker, bone turnover, carbamazepine, 449
bioequivalence, drug bioavailability, etiracetam, 475
biopolymer, capillary electrophoresis, high performance liquid
chromatography, membrane protein, 399
bipolar depression, bipolar mania, lithium, schizoaffective
psychosis, serotonin 2A receptor, 404
bipolar mania, bipolar depression, lithium, schizoaffective
birth rate, anovulation, female infertility, ovulation induction, 544
bismuth, cisplatin, nephrotoxicity, 524
bisoprolol, heart failure, 540
bisphosphonic acid derivative, antineoplastic activity, 611
- postmenopause osteoporosis, 418
blood pressure monitoring, circadian rhythm, melatonin, 499
blood sampling, area under the curve, hydrochlorothiazide,
blood vessel function, artery injury, cardiovascular agent,
B lymphocyte, antiinflammatory agent, lymphocyte function,
plant extract, 731
- cell activation, herbaceous agent, macrophage, toll like
receptor 4, 736
body weight, neuroendocrinology, neuropeptide, 530
bone graft, cyclosporin A, hypertrophy, immunosuppressive
treatment, vascularization, 657
bone turnover, biochemical marker, carbamazepine, 449
botulinum toxin, esophagus achalasia, 550
botulinum toxin A, 491
bovine serum albumin, chemoluminescence, flow injection
analysis, microdialysis, terbutaline sulfate, 377
brachial plexus anesthesia, injection site, 575
brain, cholecystokinin, intestine, neuroendocrinology, pancreas,
pancreas secretion, secretin, 536
brain derived neurotrophic factor, dopamine 3 receptor,
Parkinson disease, 458
brain development, brain function, dopaminergic nerve cell,
dopaminergic system, mesencephalon, 394
brain function, brain development, dopaminergic nerve cell,
brain mitochondrion, benzothiazepine derivative, calcium ion,
granule cell, isoprotein, sodium calcium exchange, sodium
ion, 437
brain nerve cell, cell energy, energy balance, hypothalamus,
melanocortin, obesity, proopiomelanocortin, 456
brain tumor, Pseudomonas exotoxin, recombinant protein,
transforming growth factor alpha, 551
breast cancer, angiogenesis inhibitor, cancer prevention, 634
- breast metastasis, recurrent cancer, 631
- docetaxel, doxorubicin, 638
- epidermal growth factor receptor, estrogen receptor, molecular
interaction, 632
- estradiol, fulvestrant, tamoxifen, 640
- estradiol, raloxifene, 639
breast carcinoma, docetaxel, immunopharmacology, ovary
carcinoma, paclitaxel, rheumatoid arthritis, structure
- estrogen, estrogen synthesis, 633
breast metastasis, breast cancer, recurrent cancer, 631
bronchodilatation, asthma, loratadine, terbutaline, 516
bulimia, anorexia nervosa, 457
busulfan, melphalan, solid tumor, thiotepa, 650
butyric acid derivative, antiinflammatory activity,
antinociception, 2 benzoxazolone derivative, drug
synthesis, 594
caffeic acid phenethyl ester, mitogen activated protein kinase,
protein p53, tumor suppressor protein, 703
calcitonin gene related peptide, cytokine production,
macrophage, neuropeptide, substance P, 718
calcitriol, keratinocyte, photodynamic therapy, 444
calcium antagonist, atherosclerosis, cardiovascular system,
dihydropyridine, hypertension, nitric oxide synthase
inhibitor, protective agent, 513
calcium binding protein, colchicine, gelatinase A, 602
calcium channel, antimigraine agent, calcium ion, chromaffin
cell, dotarizine, exocytosis, 441
calcium ion, antidepressant agent, desipramine, 652
- antimigraine agent, calcium channel, chromaffin cell,
dotarizine, exocytosis, 441
- benzothiazepine derivative, brain mitochondrion, granule cell,
isoprotein, sodium calcium exchange, sodium ion, 437
calphostin C, apoptosis, artery muscle, coronary artery, 506
cancer cell, cell killing, cytotoxicity, heart contraction, steroid,
614
cancer chemotherapy, antineoplastic agent, apoptosis, apoptosis
inducing factor, 649
SUBJECT INDEX
3
cancer inhibition, liver cell carcinoma, snake venom, 648
cancer prevention, angiogenesis inhibitor, breast cancer, 634
candesartan, acute heart infarction, angiotensin 2 receptor
antagonist, dipeptidyl carboxypeptidase inhibitor,
Candida albicans, antifungal activity, ergosterol, fluconazole,
gene expression, mevinolin, prenylation, 562
cannabinoid, antinociception, emotion, opiate receptor, 580
capillary electrophoresis, biopolymer, high performance liquid
chromatography, membrane protein, 399
capsaicin, alcohol, sensory nerve, stomach epithelium, stomach
injury, 519
captopril, hypertriglyceridemia, skeletal muscle, 447
carbamazepine, biochemical marker, bone turnover, 449
carbonate dehydratase I, addition reaction, antiglaucoma agent,
carbonate dehydratase II, addition reaction, antiglaucoma agent,
carbonate dehydratase I, carbonate dehydratase inhibitor,
carbonate dehydratase inhibitor, addition reaction, antiglaucoma
agent, carbonate dehydratase I, carbonate dehydratase II,
carbonate dehydratase IV, addition reaction, antiglaucoma agent,
carbonate dehydratase I, carbonate dehydratase II,
carbonate dehydratase inhibitor, glaucoma, sulfonamide,
452
carbonyl derivative, antibacterial activity, ethylene derivative,
linezolid, structure activity relation, 659
carboxylic acid derivative, 618
- antineoplastic agent, benzimidazole derivative, 621
cardiovascular agent, artery injury, blood vessel function,
cardiovascular disease, non insulin dependent diabetes mellitus,
560
cardiovascular system, atherosclerosis, calcium antagonist,
dihydropyridine, hypertension, nitric oxide synthase
- coronary artery disease, heart, highly active antiretroviral
therapy, Human immunodeficiency virus infection, stroke,
705
carvedilol, alpha 1 adrenergic receptor, alpha 1 adrenergic
receptor blocking agent, 510
catechin, gallic acid, herbaceous agent, 733
catechol methyltransferase, catechol methyltransferase inhibitor,
474
catechol methyltransferase inhibitor, catechol
methyltransferase, 474
CD29 antigen, propionic acid derivative, 411
cefepime, high performance liquid chromatography, 679
ceftriaxone, azithromycin, serous otitis media, 694
celecoxib, drug utilization, osteoarthritis, rheumatoid arthritis, 586
cell activation, B lymphocyte, herbaceous agent, macrophage, toll
like receptor 4, 736
cell adhesion molecule, Astragalus membranaceus extract,
cell death, acetylcysteine, colon cancer, etacrynic acid, 607
- cell division, immunoglobulin enhancer binding protein,
Uncaria tomentosa extract, 737
cell differentiation, cell maturation, neutrophil, thrombopoietin,
515
cell division, cell death, immunoglobulin enhancer binding
protein, Uncaria tomentosa extract, 737
cell energy, brain nerve cell, energy balance, hypothalamus,
cell killing, cancer cell, cytotoxicity, heart contraction, steroid, 614
cell maturation, cell differentiation, neutrophil, thrombopoietin,
515
cell membrane permeability, nose mucosa, occludin,
polyarginine, protein dephosphorylation, protein
phosphorylation, protein ZO1, serine, threonine, 427
cell pH, antineoplastic agent, 617
4
cell proliferation, acetylsalicylic acid, endothelium cell,
indometacin, 591
cell subpopulation, alpha 1 adrenergic receptor, noradrenalin,
subthalamic nucleus, 463
ceramide, apoptosis, protein p75, sympathetic nerve cell, 465
cerivastatin, cyclosporin A, kidney transplantation, rapamycin,
522
chemical bond, lentinan, oligosaccharide, spleen, 735
chemoluminescence, bovine serum albumin, flow injection
analysis, microdialysis, terbutaline sulfate, 377
chimeric antibody, recombinant antibody, 711
Chinese drug, antibiotic agent, drug bioavailability, glycyrrhizic
acid, 558
Chinese medicine, cytochrome P450 1A2, cytochrome P450 3A,
xanthine oxidase, xiao chai hu tang, 738
chirality, antibacterial activity, oxazolidinone derivative, 672
chitosan, 552
- drug formulation, drug uptake, 425
chloramphenicol, peptidyltransferase, spermine, 688
chlorpromazine, drug dose regimen, neuroleptic agent, 485
cholecystokinin, brain, intestine, neuroendocrinology, pancreas,
cholera toxin, ganglioside GM1, immunoglobulin enhancer
binding protein, 721
choline derivative, antiinfective agent, antimicrobial activity,
quaternary ammonium derivative, 700
chromaffin cell, antimigraine agent, calcium channel, calcium ion,
dotarizine, exocytosis, 441
chroman derivative, 2 dipropylamino 8 hydroxytetralin,
haloperidol, muscle rigidity, 462
chromatography, 612
chronic inflammation, inflammatory disease, macrogol
derivative, recombinant receptor, rheumatoid arthritis,
tumor necrosis factor receptor 1, 605
chronic pain, dose calculation, neuropathic pain, pregabalin, 583
chymotrypsin, peptide derivative, protein stability, small
intestine, trypsin, 521
circadian rhythm, blood pressure monitoring, melatonin, 499
- diazepam, heart muscle cell, melatonin, 498
cisplatin, bismuth, nephrotoxicity, 524
clobetasol, stratum corneum, 426
clopidogrel, acetylcysteine, thrombocyte aggregation inhibition,
546
clozapine, hebephrenia, insulin, olanzapine, paranoid
schizophrenia, psychosis, schizoaffective psychosis,
schizophreniform disorder, triacylglycerol, 405
- schizophrenia, 455 486
cobalt chloride, acute granulocytic leukemia, hypoxia inducible
factor 1alpha, 623
cocaine, arachidonate 12 lipoxygenase, gene disruption, morphine
sulfate, 467
- drug delivery system, drug determination, drug penetration,
microdialysis, 385
coffee, folic acid, homocysteine, hyperhomocysteinemia,
pyridoxine, 492
colchicine, calcium binding protein, gelatinase A, 602
colitis, dextran sulfate, dosmalfate, 597
- ferulic acid, 603
collagen, collagen metabolism, cross linking, deoxypyridinoline,
drug effect, pamidronic acid, total hip prosthesis, 448
collagen metabolism, collagen, cross linking, deoxypyridinoline,
colon cancer, acetylcysteine, cell death, etacrynic acid, 607
- ansamycin derivative, antineoplastic agent, heat shock protein
90, 641
colorectal cancer, fluorouracil, metastasis, oxaliplatin, 622
confocal laser microscopy, gamma venin, immunoglobulin G,
laser microscopy, 713
conjunctiva disease, hypersensitivity reaction, immediate type
hypersensitivity, nadroparin, 723
contact allergy, permethrin, urocanic acid, 725
contraception, follitropin, medroxyprogesterone acetate,
norethisterone enantate, 528
core protein, antivirus agent, 702
coronary artery, apoptosis, artery muscle, calphostin C, 506
SUBJECT INDEX
coronary artery disease, artery injury, blood vessel function,
cardiovascular agent, paclitaxel, protein
- cardiovascular system, heart, highly active antiretroviral
therapy, Human immunodeficiency virus infection, stroke,
705
corticosteroid, cyclosporin A, daclizumab, kidney allograft
rejection, kidney transplantation, mycophenolic acid 2
morpholinoethyl ester, 724
corticotropin, antidepressant agent, depression, 2 dipropylamino
8 hydroxytetralin, imipramine, serotonin 1A agonist,
tetracosactide zinc phosphate, 488
cost effectiveness analysis, cytochrome P450 2C19, duodenum
ulcer, genetic polymorphism, Helicobacter infection, 408
cross linking, collagen, collagen metabolism, deoxypyridinoline,
curcumin, focal adhesion kinase, protein kinase p60, 750
cyanocobalamin, folic acid, homocysteine,
hyperhomocysteinemia, methylmalonic acid, pyridoxine,
389
cyclic AMP phosphodiesterase, cyclic GMP, heart muscle cell,
509
cyclic GMP, cyclic AMP phosphodiesterase, heart muscle cell,
509
- frontal cortex, serotonin, serotonin 1A receptor, serotonin 2
receptor, 460
cyclooxygenase 2, immunoglobulin enhancer binding protein,
mitogen activated protein kinase 1, salicylate sodium, 416
cyclooxygenase 2 inhibitor, nonsteroid antiinflammatory agent,
osteoarthritis, rheumatoid arthritis, 585 587
- postoperative pain, 577
cyclosporin A, bone graft, hypertrophy, immunosuppressive
- cerivastatin, kidney transplantation, rapamycin, 522
- corticosteroid, daclizumab, kidney allograft rejection, kidney
transplantation, mycophenolic acid 2 morpholinoethyl
ester, 724
cyproterone acetate, alpha 1 adrenergic receptor, vas deferens,
526
cysteine, mesna, 409
cysteine derivative, aorta constriction, artery dilatation,
cytochrome P450 1A1, cytochrome P450 1B1, indirubin, 433
cytochrome P450 1A2, Chinese medicine, cytochrome P450 3A,
cytochrome P450 1B1, cytochrome P450 1A1, indirubin, 433
cytochrome P450 2C19, cost effectiveness analysis, duodenum
ulcer, genetic polymorphism, Helicobacter infection, 408
cytochrome P450 2D6, cytochrome P450 3A4, Ginkgo biloba
extract, 739
cytochrome P450 3A, Chinese medicine, cytochrome P450 1A2,
cytochrome P450 3A4, cytochrome P450 2D6, Ginkgo biloba
extract, 739
cytokine, aminoguanidine, down regulation, Fas antigen,
cell, 535
- immunomodulating agent, nucleotide,
oligodeoxyribonucleotide, 630
cytokine production, calcitonin gene related peptide,
macrophage, neuropeptide, substance P, 718
cytopathogenic effect, plant extract, 748
cytotoxic agent, antifungal agent, antiinfective agent, herbaceous
agent, plant extract, 743
cytotoxicity, cancer cell, cell killing, heart contraction, steroid, 614
daclizumab, corticosteroid, cyclosporin A, kidney allograft
rejection, kidney transplantation, mycophenolic acid 2
dactinomycin, DNA base, oligomer, 421
dalteparin, anticoagulation, drug effect, enoxaparin,
fondaparinux, heparin, osteoblast, 450
daptomycin, antibacterial activity, bacterial infection, ornithine
derivative, 662
- antiinfective agent, 674
- bacterial infection, skin infection, 680
darifenacin, 525
data analysis, 383
daunorubicin, glycoprotein P, lymphatic leukemia, tetrandrine,
556
degradation kinetics, aminopenicillin, amoxicillin, antibiotic
agent, 553
deoxypyridinoline, collagen, collagen metabolism, cross linking,
depression, antidepressant agent, corticotropin, 2 dipropylamino 8
hydroxytetralin, imipramine, serotonin 1A agonist,
- fluoxetine, imipramine, leptin, 482
dermatological agent, rosacea, 563
dermatomycosis, gynecologic infection, onychomycosis, 692
desensitization, 4 aminobutyric acid B receptor, endocytosis,
forskolin, 439
designer drug, DNA sequence, oligonucleotide, polyamide, zinc
finger protein, 422
desipramine, antidepressant agent, calcium ion, 652
desmopressin, intrauterine contraceptive device, menorrhagia,
543
dextran sulfate, colitis, dosmalfate, 597
diabetes mellitus, antidiabetic agent, Urtica dioica extract, 740
diazepam, circadian rhythm, heart muscle cell, melatonin, 498
diclofenac, high performance liquid chromatography,
microdialysis, tandem mass spectrometry, ultraviolet
diflunisal, drug activity, hydrazide, hydrazone derivative, 699
dihydropyridine, atherosclerosis, calcium antagonist,
cardiovascular system, hypertension, nitric oxide synthase
dimethylallyltransferase, aniline derivative, bioassay, drug
dimyristoylphosphatidylcholine,
dimyristoylphosphatidylglycerol, membrane biology,
pediocin, protein lipid interaction, 676
dimyristoylphosphatidylglycerol,
dimyristoylphosphatidylcholine, membrane biology,
pediocin, protein lipid interaction, 676
dipeptidyl carboxypeptidase inhibitor, acute heart infarction,
angiotensin 2 receptor antagonist, candesartan, monocyte
chemotactic protein 1, perindopril, renin angiotensin
aldosterone system, vasculotropin, 505
diphtheria toxin, antineoplastic agent, glioblastoma, 624
2 dipropylamino 8 hydroxytetralin, antidepressant agent,
corticotropin, depression, imipramine, serotonin 1A
agonist, tetracosactide zinc phosphate, 488
- chroman derivative, haloperidol, muscle rigidity, 462
discriminative stimulus, n methyl dextro aspartic acid receptor
blocking agent, phencyclidine, 471
disintegrin, melanoma cell, snake venom, 626
distamycin A, DNA, DNA drug complex, DNA structure, 689
divalent cation, hemopexin, leukocyte adherence, magnesium ion,
neutrophil, 584
diving, emergency treatment, sport injury, 397
dizocilpine, Escherichia coli lipopolysaccharide, immunoglobulin
enhancer binding protein, 7 nitroindazole, 464
DNA, anthracycline antibiotic agent, 628
- distamycin A, DNA drug complex, DNA structure, 689
- DNA repair, DNA strand breakage, protein kinase inhibitor,
vanillin derivative, 629
- drug DNA binding, echinomycin, energy transfer, 423
DNA adduct, acridine derivative, DNA base, intercalation
DNA alkylation, DNA topoisomerase (ATP hydrolysing), gyrase
inhibitor, 419
DNA base, acridine derivative, DNA adduct, intercalation
- dactinomycin, oligomer, 421
DNA drug complex, distamycin A, DNA, DNA structure, 689
SUBJECT INDEX
5
DNA repair, DNA, DNA strand breakage, protein kinase
inhibitor, vanillin derivative, 629
DNA sequence, designer drug, oligonucleotide, polyamide, zinc
finger protein, 422
DNA strand breakage, DNA, DNA repair, protein kinase
inhibitor, vanillin derivative, 629
- DNA topoisomerase (ATP hydrolysing), etoposide, 627
DNA structure, distamycin A, DNA, DNA drug complex, 689
DNA topoisomerase (ATP hydrolysing), DNA alkylation, gyrase
inhibitor, 419
- DNA strand breakage, etoposide, 627
- gyrase inhibitor, kinetoplast DNA, Leishmania donovani, 691
docetaxel, breast cancer, doxorubicin, 638
- breast carcinoma, immunopharmacology, ovary carcinoma,
paclitaxel, rheumatoid arthritis, structure activity relation,
712
dopamine, amphetamine, 479
- frontal cortex, serotonin, serotonin 1A receptor, serotonin
release, 461
dopamine 3 receptor, brain derived neurotrophic factor,
Parkinson disease, 458
dopamine receptor, drug synthesis, indole derivative, ligand,
ligand binding, 454
dopamine receptor stimulating agent, Parkinson disease, 453
dopaminergic nerve cell, brain development, brain function,
dopaminergic system, brain development, brain function,
dopaminergic nerve cell, mesencephalon, 394
dopaminergic transmission, hypothalamus nucleus, metabolic
syndrome X, 531
dose calculation, chronic pain, neuropathic pain, pregabalin, 583
dosmalfate, colitis, dextran sulfate, 597
dotarizine, antimigraine agent, calcium channel, calcium ion,
chromaffin cell, exocytosis, 441
down regulation, aminoguanidine, cytokine, Fas antigen,
cell, 535
doxorubicin, breast cancer, docetaxel, 638
drug activity, antiparasitic agent, 413
- diflunisal, hydrazide, hydrazone derivative, 699
drug bioavailability, abetalipoproteinemia, alpha tocopherol,
- antibiotic agent, Chinese drug, glycyrrhizic acid, 558
- bioequivalence, etiracetam, 475
drug delivery system, antineoplastic agent, drug synthesis, drug
targeting, 610
- cocaine, drug determination, drug penetration, microdialysis,
385
drug dependence, alcohol withdrawal, 4 aminobutyric acid A
receptor, drug tolerance, drug withdrawal, 477
- opiate, opiate receptor, 581
drug design, antiandrogen, bicalutamide, epidermal growth factor
drug determination, cocaine, drug delivery system, drug
penetration, microdialysis, 385
drug disposition, first pass effect, food drug interaction,
furocoumarin derivative, grapefruit juice, 677
drug DNA binding, DNA, echinomycin, energy transfer, 423
drug dose regimen, chlorpromazine, neuroleptic agent, 485
drug effect, anticoagulation, dalteparin, enoxaparin, fondaparinux,
heparin, osteoblast, 450
- collagen, collagen metabolism, cross linking,
deoxypyridinoline, pamidronic acid, total hip prosthesis,
448
drug formulation, chitosan, drug uptake, 425
drug metabolite, plant extract, 417
drug penetration, cocaine, drug delivery system, drug
determination, microdialysis, 385
drug receptor binding, AMPA receptor, AMPA receptor agonist,
- benzodiazepine receptor affecting agent, flavonoid, receptor
affinity, 436
- estrogen receptor, halide, hormone receptor interaction,
imidazole derivative, 532
6
drug solubility, amitriptyline, imipramine, mepacrine, promazine,
drug synthesis, aniline derivative, bioassay,
dimethylallyltransferase, farnesyl diphosphate, transferase
inhibitor, 414
- antibacterial activity, antifungal activity, antiinfective agent,
benzimidazole derivative, 686
- antibacterial activity, antiinfective agent, bacterial infection,
derivative, 663
- antifungal agent, antiinfective agent, antivirus agent, ebselen,
683
- antiinfective agent, benzazepine derivative, oxazolidinone
derivative, Staphylococcus infection, 664
- antiinflammatory activity, antinociception, 2 benzoxazolone
derivative, butyric acid derivative, 594
- antilipemic agent, phthalimide derivative, 415
- antineoplastic agent, drug delivery system, drug targeting, 610
- dopamine receptor, indole derivative, ligand, ligand binding,
454
- furan, furan derivative, thiophene, thiophene derivative, 606
drug targeting, antineoplastic agent, drug delivery system, drug
synthesis, 610
drug tolerance, alcohol withdrawal, 4 aminobutyric acid A
receptor, drug dependence, drug withdrawal, 477
drug transformation, endometrium, tamoxifen, 388
drug uptake, chitosan, drug formulation, 425
drug utilization, celecoxib, osteoarthritis, rheumatoid arthritis,
586
drug withdrawal, alcohol withdrawal, 4 aminobutyric acid A
receptor, drug dependence, drug tolerance, 477
- steroid, tsukubaenolide, 382
duodenum ulcer, cost effectiveness analysis, cytochrome P450
2C19, genetic polymorphism, Helicobacter infection, 408
dutasteride, prostate hypertrophy, urinary tract disease, 523
ebselen, antifungal agent, antiinfective agent, antivirus agent, drug
synthesis, 683
echinomycin, DNA, drug DNA binding, energy transfer, 423
ecteinascidin 743, 609 647
electroanalgesia, hyperalgesia, muscarinic receptor,
transcutaneous nerve stimulation, 579
emergency treatment, diving, sport injury, 397
emotion, antinociception, cannabinoid, opiate receptor, 580
enantiomer, arthritis, flurbiprofen, 601
endocytosis, 4 aminobutyric acid B receptor, desensitization,
forskolin, 439
endometrium, drug transformation, tamoxifen, 388
endosulfan, lipid peroxidation, malathion, nitrite, tumor necrosis
factor alpha, 715
endothelin 1, heart infarction, heart muscle ischemia, heart muscle
reperfusion, nitric oxide, prostanoid, 730
endothelium cell, acetylsalicylic acid, cell proliferation,
indometacin, 591
- hypoxia, isoflavonoid, umbilical vein, 440
endothelium derived hyperpolarizing factor, antioxidant,
hypertension, tempol, vasodilatation, 511
energy balance, brain nerve cell, cell energy, hypothalamus,
- neuropeptide Y, neuropeptide Y receptor, obesity, satiety, 529
energy transfer, DNA, drug DNA binding, echinomycin, 423
enfuvirtide, Human immunodeficiency virus infection, rifampicin,
681
enoxaparin, anticoagulation, dalteparin, drug effect,
fondaparinux, heparin, osteoblast, 450
enzyme activation, insulin, insulin release, nateglinide,
phospholipase C, rosiglitazone, 568
enzyme inhibitor, lanosterol synthase, 390
- protein protein interaction, 401
epidermal growth factor receptor, breast cancer, estrogen
receptor, molecular interaction, 632
epidermal growth factor receptor kinase, antiandrogen,
bicalutamide, drug design, gefitinib, prostate cancer,
protein tyrosine kinase inhibitor, 613
SUBJECT INDEX
ergosterol, antifungal activity, Candida albicans, fluconazole,
gene expression, mevinolin, prenylation, 562
Escherichia coli lipopolysaccharide, dizocilpine,
nitroindazole, 464
esomeprazole, Barrett esophagus, gastroesophageal reflux, 549
esophagus achalasia, botulinum toxin, 550
esophagus cancer, antineoplastic agent, 616
esophagus carcinoma, antineoplastic agent, 653
essential hypertension, homocysteine, 507
estradiol, breast cancer, fulvestrant, tamoxifen, 640
- breast cancer, raloxifene, 639
estrogen, breast carcinoma, estrogen synthesis, 633
- estrogen activity, genetic analysis, sexual arousal, sexual
behavior, 726
estrogen activity, estrogen, genetic analysis, sexual arousal,
sexual behavior, 726
estrogen receptor, breast cancer, epidermal growth factor
receptor, molecular interaction, 632
- drug receptor binding, halide, hormone receptor interaction,
imidazole derivative, 532
estrogen synthesis, breast carcinoma, estrogen, 633
etacrynic acid, acetylcysteine, cell death, colon cancer, 607
ethylene derivative, antibacterial activity, carbonyl derivative,
linezolid, structure activity relation, 659
etiracetam, anticonvulsive agent, anxiety disorder, anxiolytic
agent, 487
- bioequivalence, drug bioavailability, 475
etodolac, arthrocentesis, temporomandibular joint disorder, 599
etoposide, DNA strand breakage, DNA topoisomerase (ATP
hydrolysing), 627
exercise, fitness, 380
exocytosis, antimigraine agent, calcium channel, calcium ion,
chromaffin cell, dotarizine, 441
farnesyl diphosphate, aniline derivative, bioassay,
dimethylallyltransferase, drug synthesis, transferase
inhibitor, 414
Fas antigen, aminoguanidine, cytokine, down regulation,
cell, 535
female infertility, anovulation, birth rate, ovulation induction, 544
fenretinide, 608
- Graves disease, retinoic acid, 567
ferric citrate, arthritis, immune response, iron derivative, tumor
necrosis factor, 714
ferulic acid, colitis, 603
first pass effect, drug disposition, food drug interaction,
fish oil, food intake, health hazard, nutrition, risk assessment,
unsaturated fatty acid, 396
fitness, exercise, 380
flavone derivative, antivirus agent, flavonoid, quantum chemistry,
701
flavonoid, antiinflammatory agent, glomerulopathy, herbaceous
agent, Masugi nephritis, plant extract, scavenger, 745
- antivirus agent, flavone derivative, quantum chemistry, 701
- benzodiazepine receptor affecting agent, drug receptor
binding, receptor affinity, 436
flecainide, heart conduction, heart muscle refractory period, heart
ventricle fibrillation, 504
flow injection analysis, bovine serum albumin,
chemoluminescence, microdialysis, terbutaline sulfate,
377
fluconazole, antifungal activity, Candida albicans, ergosterol, gene
expression, mevinolin, prenylation, 562
fluorouracil, colorectal cancer, metastasis, oxaliplatin, 622
fluoxetine, depression, imipramine, leptin, 482
flurbiprofen, arthritis, enantiomer, 601
flushing, nifedipine, ovariectomy, 442
fluvoxamine maleate, quazepam, 412
focal adhesion kinase, curcumin, protein kinase p60, 750
folic acid, coffee, homocysteine, hyperhomocysteinemia,
pyridoxine, 492
- cyanocobalamin, homocysteine, hyperhomocysteinemia,
methylmalonic acid, pyridoxine, 389
folic acid antagonist, antineoplastic agent, 643
- malignant neoplastic disease, 642
follitropin, contraception, medroxyprogesterone acetate,
fondaparinux, anticoagulation, dalteparin, drug effect,
enoxaparin, heparin, osteoblast, 450
food drug interaction, drug disposition, first pass effect,
food intake, fish oil, health hazard, nutrition, risk assessment,
formaldehyde, glucocorticoid, 4 methoxy n
methylphenethylamine, pruritus, scratching, 729
3 formamido 7 methanesulfonamido 6 phenoxychromone,
rheumatoid arthritis, 588
forskolin, 4 aminobutyric acid B receptor, desensitization,
endocytosis, 439
frontal cortex, cyclic GMP, serotonin, serotonin 1A receptor,
serotonin 2 receptor, 460
- dopamine, serotonin, serotonin 1A receptor, serotonin release,
461
fullerene derivative, 431
fulvestrant, breast cancer, estradiol, tamoxifen, 640
furan, drug synthesis, furan derivative, thiophene, thiophene
derivative, 606
furan derivative, drug synthesis, furan, thiophene, thiophene
derivative, 606
furocoumarin derivative, drug disposition, first pass effect, food
drug interaction, grapefruit juice, 677
gallic acid, catechin, herbaceous agent, 733
gamma venin, confocal laser microscopy, immunoglobulin G,
ganglioside GM1, cholera toxin, immunoglobulin enhancer
binding protein, 721
gastroesophageal reflux, Barrett esophagus, esomeprazole, 549
gefitinib, antiandrogen, bicalutamide, drug design, epidermal
growth factor receptor kinase, prostate cancer, protein
tyrosine kinase inhibitor, 613
gelatin, insulin, microsphere, 538
gelatinase A, calcium binding protein, colchicine, 602
gene disruption, arachidonate 12 lipoxygenase, cocaine,
morphine sulfate, 467
gene expression, antifungal activity, Candida albicans, ergosterol,
fluconazole, mevinolin, prenylation, 562
genetic analysis, estrogen, estrogen activity, sexual arousal, sexual
behavior, 726
genetic polymorphism, cost effectiveness analysis, cytochrome
P450 2C19, duodenum ulcer, Helicobacter infection, 408
genomics, guanylate cyclase, tamoxifen, 557
ghrelin, growth hormone secretagogue receptor, hexarelin, 566
ginger extract, knee osteoarthritis, 589
Ginkgo biloba extract, cytochrome P450 2D6, cytochrome P450
3A4, 739
glatiramer, interferon, multiple sclerosis, 722
glaucoma, addition reaction, antiglaucoma agent, carbonate
dehydratase I, carbonate dehydratase II, carbonate
dehydratase inhibitor, carbonate dehydratase IV,
sulfonamide, 452
glioblastoma, antineoplastic agent, diphtheria toxin, 624
- antineoplastic agent, interleukin 13 receptor, 625
globus pallidus, bicuculline methiodide, jaw movement,
glomerulopathy, antiinflammatory agent, flavonoid, herbaceous
agent, Masugi nephritis, plant extract, scavenger, 745
glucocorticoid, formaldehyde, 4 methoxy n
methylphenethylamine, pruritus, scratching, 729
glucocorticoid receptor, ligand, receptor density, receptor down
regulation, steroid, 595
glucose, insulin, milrinone, 569
glutathione derivative, aorta constriction, artery dilatation,
cysteine derivative, iron complex, nitric oxide, nitro
SUBJECT INDEX
7
glycerol derivative, acetic acid derivative, heart infarction size,
glyceryl trinitrate, 432
glycopeptide, antibacterial activity, bacterial infection,
oritavancin, vancomycin, 658
glycoprotein P, 406
- daunorubicin, lymphatic leukemia, tetrandrine, 556
glycyrrhetinic acid, liver mitochondrion, mitochondrial
membrane, 435
glycyrrhizic acid, antibiotic agent, Chinese drug, drug
bioavailability, 558
granule cell, benzothiazepine derivative, brain mitochondrion,
calcium ion, isoprotein, sodium calcium exchange, sodium
ion, 437
grapefruit juice, drug disposition, first pass effect, food drug
interaction, furocoumarin derivative, 677
Graves disease, fenretinide, retinoic acid, 567
- liothyronine, propylthiouracil, thyroxine, thyroxine deiodinase,
537
growth hormone secretagogue receptor, ghrelin, hexarelin, 566
growth inhibition, antioxidant, paraquat, paraquat poisoning,
reactive oxygen metabolite, thiamine, 445
guanylate cyclase, genomics, tamoxifen, 557
gynecologic infection, dermatomycosis, onychomycosis, 692
gyrase inhibitor, DNA alkylation, DNA topoisomerase (ATP
hydrolysing), 419
- DNA topoisomerase (ATP hydrolysing), kinetoplast DNA,
Leishmania donovani, 691
halide, drug receptor binding, estrogen receptor, hormone receptor
interaction, imidazole derivative, 532
haloperidol, chroman derivative, 2 dipropylamino 8
hydroxytetralin, muscle rigidity, 462
health hazard, fish oil, food intake, nutrition, risk assessment,
heart, cardiovascular system, coronary artery disease, highly
active antiretroviral therapy, Human immunodeficiency
virus infection, stroke, 705
heart conduction, flecainide, heart muscle refractory period, heart
ventricle fibrillation, 504
heart contraction, cancer cell, cell killing, cytotoxicity, steroid,
614
heart failure, bisoprolol, 540
heart infarction, endothelin 1, heart muscle ischemia, heart
muscle reperfusion, nitric oxide, prostanoid, 730
heart infarction prevention, anisomycin, heart muscle ischemia,
mitogen activated protein kinase, synaptophysin, 502
heart infarction size, acetic acid derivative, glycerol derivative,
heart muscle cell, angiotensin 2 receptor antagonist, olmesartan,
503
- circadian rhythm, diazepam, melatonin, 498
- cyclic AMP phosphodiesterase, cyclic GMP, 509
heart muscle ischemia, acetic acid derivative, glycerol derivative,
heart infarction size, reperfusion injury, 501
- acetylcysteine, heart protection, isosorbide 5 nitrate,
reperfusion injury, 500
- anisomycin, heart infarction prevention, mitogen activated
protein kinase, synaptophysin, 502
- endothelin 1, heart infarction, heart muscle reperfusion, nitric
oxide, prostanoid, 730
heart muscle refractory period, flecainide, heart conduction,
heart ventricle fibrillation, 504
heart muscle reperfusion, endothelin 1, heart infarction, heart
muscle ischemia, nitric oxide, prostanoid, 730
heart protection, acetylcysteine, heart muscle ischemia,
isosorbide 5 nitrate, reperfusion injury, 500
heart ventricle fibrillation, flecainide, heart conduction, heart
muscle refractory period, 504
heat shock protein 90, ansamycin derivative, antineoplastic agent,
colon cancer, 641
hebephrenia, clozapine, insulin, olanzapine, paranoid
8
Helicobacter infection, cost effectiveness analysis, cytochrome
P450 2C19, duodenum ulcer, genetic polymorphism, 408
hemodialysis, meropenem, 410
hemopexin, divalent cation, leukocyte adherence, magnesium ion,
neutrophil, 584
hemophilia A, hemostasis, recombinant blood clotting factor 7a,
727
hemostasis, hemophilia A, recombinant blood clotting factor 7a,
727
heparin, anticoagulation, dalteparin, drug effect, enoxaparin,
fondaparinux, osteoblast, 450
Hepatitis C virus, antisense oligonucleotide, phosphoramidic acid
derivative, RNA, single stranded DNA, 690
herbaceous agent, alcohol, methanol, 2 propanol, quality control,
732
- antifungal agent, antiinfective agent, berberine, plant extract,
742
- antifungal agent, antiinfective agent, cytotoxic agent, plant
extract, 743
- antiinfective agent, plant extract, 741
- antiinflammatory agent, flavonoid, glomerulopathy, Masugi
nephritis, plant extract, scavenger, 745
- bile duct atresia, liver function, 734
- B lymphocyte, cell activation, macrophage, toll like receptor 4,
736
- catechin, gallic acid, 733
- plant extract, spasmolytic agent, 746
herbal medicine, 744
hexarelin, ghrelin, growth hormone secretagogue receptor, 566
highly active antiretroviral therapy, cardiovascular system,
coronary artery disease, heart, Human immunodeficiency
virus infection, stroke, 705
high performance liquid chromatography, antilipemic agent,
ultraviolet spectrophotometry, 395
- biopolymer, capillary electrophoresis, membrane protein, 399
- cefepime, 679
- diclofenac, microdialysis, tandem mass spectrometry,
ultraviolet spectrophotometry, 593
high performance thin layer chromatography, tizanidine, 376
homocysteine, coffee, folic acid, hyperhomocysteinemia,
pyridoxine, 492
- cyanocobalamin, folic acid, hyperhomocysteinemia,
methylmalonic acid, pyridoxine, 389
- essential hypertension, 507
hormone receptor interaction, drug receptor binding, estrogen
receptor, halide, imidazole derivative, 532
Human immunodeficiency virus, acquired immune deficiency
syndrome, antivirus agent, 706
Human immunodeficiency virus infection, cardiovascular
system, coronary artery disease, heart, highly active
antiretroviral therapy, stroke, 705
- enfuvirtide, rifampicin, 681
- saquinavir, 678
- tipranavir, 393
hydrazide, diflunisal, drug activity, hydrazone derivative, 699
hydrazine derivative, antiprotozoal agent, antitrypanosomal
agent, tropolone derivative, 696
hydrazone derivative, diflunisal, drug activity, hydrazide, 699
hydrochlorothiazide, area under the curve, blood sampling,
hydrocortisone release, adrenal suppression, methylprednisolone
sodium succinate, nefazodone, 534
hydrogen bond, thromboxane A2 receptor blocking agent, 430
hydroxamic acid derivative, 378 670
3beta hydroxy 5alpha pregnan 20 one, lordosis, mesencephalon,
olanzapine, ventral tegmentum, 468
hyperalgesia, electroanalgesia, muscarinic receptor,
hypercholesterolemia, antilipemic agent, 495
hyperhomocysteinemia, beta adrenergic receptor stimulating
agent, uterus spasmolytic agent, 527
- coffee, folic acid, homocysteine, pyridoxine, 492
- cyanocobalamin, folic acid, homocysteine, methylmalonic
acid, pyridoxine, 389
SUBJECT INDEX
hypersensitivity reaction, conjunctiva disease, immediate type
hypersensitivity, nadroparin, 723
hypertension, antioxidant, endothelium derived hyperpolarizing
factor, tempol, vasodilatation, 511
- atherosclerosis, calcium antagonist, cardiovascular system,
dihydropyridine, nitric oxide synthase inhibitor, protective
agent, 513
- kinesiotherapy, losartan, 494
hypertriglyceridemia, captopril, skeletal muscle, 447
hypertrophy, bone graft, cyclosporin A, immunosuppressive
hypotension, allergic encephalomyelitis, immunoglobulin,
immunotherapy, 710
hypothalamus, brain nerve cell, cell energy, energy balance,
hypothalamus nucleus, dopaminergic transmission, metabolic
syndrome X, 531
hypoxia, endothelium cell, isoflavonoid, umbilical vein, 440
hypoxia inducible factor 1alpha, acute granulocytic leukemia,
cobalt chloride, 623
ibandronic acid, osteoporosis, 565
imidazole derivative, drug receptor binding, estrogen receptor,
halide, hormone receptor interaction, 532
imipramine, amitriptyline, drug solubility, mepacrine, promazine,
- antidepressant agent, corticotropin, depression, 2
dipropylamino 8 hydroxytetralin, serotonin 1A agonist,
- benzyl derivative, 379
- depression, fluoxetine, leptin, 482
- panic, sertraline, 484
immediate type hypersensitivity, conjunctiva disease,
hypersensitivity reaction, nadroparin, 723
immune response, arthritis, ferric citrate, iron derivative, tumor
immunoglobulin, allergic encephalomyelitis, hypotension,
immunotherapy, 710
immunoglobulin A, immunoglobulin production,
immunomodulation, Smad3 protein, transforming growth
factor beta1, 719
immunoglobulin enhancer binding protein, Astragalus
membranaceus extract, cell adhesion molecule, 548
- cell death, cell division, Uncaria tomentosa extract, 737
- cholera toxin, ganglioside GM1, 721
- cyclooxygenase 2, mitogen activated protein kinase 1,
salicylate sodium, 416
- dizocilpine, Escherichia coli lipopolysaccharide, 7
nitroindazole, 464
immunoglobulin G, confocal laser microscopy, gamma venin,
immunoglobulin production, immunoglobulin A,
immunomodulation, Smad3 protein, transforming growth
factor beta1, 719
immunomodulating agent, cytokine, nucleotide,
immunomodulation, immunoglobulin A, immunoglobulin
production, Smad3 protein, transforming growth factor
beta1, 719
- resveratrol, 645
immunopharmacology, breast carcinoma, docetaxel, ovary
carcinoma, paclitaxel, rheumatoid arthritis, structure
immunosuppressive treatment, bone graft, cyclosporin A,
hypertrophy, vascularization, 657
immunotherapy, allergic encephalomyelitis, hypotension,
immunoglobulin, 710
indirubin, cytochrome P450 1A1, cytochrome P450 1B1, 433
indole derivative, dopamine receptor, drug synthesis, ligand,
ligand binding, 454
- phosphodiesterase IV inhibitor, quantitative structure activity
relation, 428
indometacin, acetylsalicylic acid, cell proliferation, endothelium
cell, 591
infertility, recombinant follitropin, 541
inflammatory disease, chronic inflammation, macrogol
derivative, recombinant receptor, rheumatoid arthritis,
tumor necrosis factor receptor 1, 605
inhibition kinetics, leukotriene B4 receptor, monoclonal antibody,
720
inhibitor of apoptosis protein, acute granulocytic leukemia, 619
injection site, brachial plexus anesthesia, 575
insulin, clozapine, hebephrenia, olanzapine, paranoid
- enzyme activation, insulin release, nateglinide, phospholipase
C, rosiglitazone, 568
- gelatin, microsphere, 538
- glucose, milrinone, 569
- insulin resistance, neuroendocrinology, obesity, 533
- iontophoresis, 554
- phenotype, smooth muscle contraction, 518
- proteinase inhibitor, 555
insulin release, enzyme activation, insulin, nateglinide,
insulin resistance, insulin, neuroendocrinology, obesity, 533
integrase inhibitor, benzofuran derivative, quinoline derivative,
684
intercalation complex, acridine derivative, DNA adduct, DNA
base, platinum, 420
intercellular adhesion molecule 1 antibody, allopurinol, intestine
injury, intestine perfusion, methylene blue, monoclonal
antibody, 709
interferon, glatiramer, multiple sclerosis, 722
interleukin 10, knee arthritis, 707
interleukin 13 receptor, antineoplastic agent, glioblastoma, 625
interleukin 6, knee osteoarthritis, paracetamol, substance P,
synovial fluid, tramadol, 596
intestine, brain, cholecystokinin, neuroendocrinology, pancreas,
intestine injury, allopurinol, intercellular adhesion molecule 1
antibody, intestine perfusion, methylene blue, monoclonal
antibody, 709
intestine perfusion, allopurinol, intercellular adhesion molecule 1
antibody, intestine injury, methylene blue, monoclonal
antibody, 709
intracellular transport, membrane lipid, 398
intrauterine contraceptive device, desmopressin, menorrhagia,
543
iodoacetic acid, knee osteoarthritis, nonsteroid antiinflammatory
agent, paracetamol, weight bearing, 590
iontophoresis, insulin, 554
iron complex, aorta constriction, artery dilatation, cysteine
derivative, glutathione derivative, nitric oxide, nitro
iron derivative, arthritis, ferric citrate, immune response, tumor
isoflavonoid, endothelium cell, hypoxia, umbilical vein, 440
isoprotein, benzothiazepine derivative, brain mitochondrion,
calcium ion, granule cell, sodium calcium exchange,
sodium ion, 437
isosorbide 5 nitrate, acetylcysteine, heart muscle ischemia, heart
protection, reperfusion injury, 500
isoxazole derivative, antibacterial activity, antiinfective agent,
methyl group, oxazolidinone derivative, 661
jaw movement, bicuculline methiodide, globus pallidus,
kainic acid receptor, AMPA receptor, AMPA receptor agonist,
drug receptor binding, kainic acid receptor agonist, 438
kainic acid receptor agonist, AMPA receptor, AMPA receptor
agonist, drug receptor binding, kainic acid receptor, 438
keratinocyte, apoptosis, thalidomide, tumor necrosis factor alpha,
- calcitriol, photodynamic therapy, 444
kidney allograft rejection, corticosteroid, cyclosporin A,
SUBJECT INDEX
9
daclizumab, kidney transplantation, mycophenolic acid 2
kidney transplantation, cerivastatin, cyclosporin A, rapamycin,
522
- corticosteroid, cyclosporin A, daclizumab, kidney allograft
rejection, mycophenolic acid 2 morpholinoethyl ester, 724
kinesiotherapy, hypertension, losartan, 494
kinetoplast DNA, DNA topoisomerase (ATP hydrolysing), gyrase
inhibitor, Leishmania donovani, 691
knee arthritis, interleukin 10, 707
knee osteoarthritis, ginger extract, 589
- interleukin 6, paracetamol, substance P, synovial fluid,
tramadol, 596
- iodoacetic acid, nonsteroid antiinflammatory agent,
paracetamol, weight bearing, 590
lacidipine, lercanidipine, systolic hypertension, 561
beta lactamase inhibitor, 655
lanosterol synthase, enzyme inhibitor, 390
laser microscopy, confocal laser microscopy, gamma venin,
immunoglobulin G, 713
lead, lead poisoning, lipocortin 5, thymocyte, 446
lead poisoning, lead, lipocortin 5, thymocyte, 446
Leishmania donovani, DNA topoisomerase (ATP hydrolysing),
gyrase inhibitor, kinetoplast DNA, 691
lentinan, chemical bond, oligosaccharide, spleen, 735
leptin, depression, fluoxetine, imipramine, 482
lercanidipine, lacidipine, systolic hypertension, 561
leukocyte adherence, divalent cation, hemopexin, magnesium
ion, neutrophil, 584
leukotriene B4 receptor, inhibition kinetics, monoclonal
antibody, 720
levacecarnine, 472
- nerve fiber transection, sensory neuropathy, 572
lidocaine, shock, 573
ligand, adenine derivative, adenosine A1 receptor, 429
- dopamine receptor, drug synthesis, indole derivative, ligand
binding, 454
- glucocorticoid receptor, receptor density, receptor down
ligand binding, dopamine receptor, drug synthesis, indole
derivative, ligand, 454
linezolid, antibacterial activity, carbonyl derivative, ethylene
derivative, structure activity relation, 659
liothyronine, Graves disease, propylthiouracil, thyroxine,
thyroxine deiodinase, 537
lipid peroxidation, antioxidant, antioxidant activity, skin disease,
473
- endosulfan, malathion, nitrite, tumor necrosis factor alpha, 715
lipocortin 5, lead, lead poisoning, thymocyte, 446
lipopolysaccharide, thrombocyte aggregation, 547
lipoprotein A, lipoprotein blood level, pravastatin, 493
lipoprotein blood level, lipoprotein A, pravastatin, 493
lithium, bipolar depression, bipolar mania, schizoaffective
liver cell carcinoma, cancer inhibition, snake venom, 648
liver disease, receptor blocking agent, 600
liver enzyme, malnutrition, paracetamol, 578
liver fibrosis, Salvia miltiorrhiza extract, 520
liver function, bile duct atresia, herbaceous agent, 734
liver mitochondrion, glycyrrhetinic acid, mitochondrial
membrane, 435
live vaccine, measles, measles vaccine, nucleotide sequence, 708
locomotion, bicuculline methiodide, globus pallidus, jaw
movement, tremor, 469
loratadine, asthma, bronchodilatation, terbutaline, 516
lordosis, 3beta hydroxy 5alpha pregnan 20 one, mesencephalon,
olanzapine, ventral tegmentum, 468
losartan, hypertension, kinesiotherapy, 494
lymphatic leukemia, daunorubicin, glycoprotein P, tetrandrine,
556
lymphocyte, monocyte, testosterone, 717
lymphocyte function, antiinflammatory agent, B lymphocyte,
plant extract, 731
10
lysine derivative, 704
macrogol derivative, chronic inflammation, inflammatory
disease, recombinant receptor, rheumatoid arthritis, tumor
necrosis factor receptor 1, 605
- physical chemistry, theophylline, theophylline derivative, 384
macrophage, B lymphocyte, cell activation, herbaceous agent, toll
like receptor 4, 736
- calcitonin gene related peptide, cytokine production,
neuropeptide, substance P, 718
magnesium ion, divalent cation, hemopexin, leukocyte adherence,
neutrophil, 584
major depression, alcohol, alcoholism, mood disorder, placebo,
sertraline, 483
- sertraline, 481
malathion, endosulfan, lipid peroxidation, nitrite, tumor necrosis
factor alpha, 715
malignant neoplastic disease, folic acid antagonist, 642
malnutrition, liver enzyme, paracetamol, 578
Masugi nephritis, antiinflammatory agent, flavonoid,
glomerulopathy, herbaceous agent, plant extract,
scavenger, 745
measles, antiviral activity, antivirus agent, 682
- live vaccine, measles vaccine, nucleotide sequence, 708
measles vaccine, live vaccine, measles, nucleotide sequence, 708
medroxyprogesterone acetate, contraception, follitropin,
melanocortin, brain nerve cell, cell energy, energy balance,
hypothalamus, obesity, proopiomelanocortin, 456
melanogenesis, norbornane derivative, prostaglandin E2, protein
p53, tumor necrosis factor alpha, ultraviolet B radiation,
443
melanoma cell, disintegrin, snake venom, 626
melatonin, blood pressure monitoring, circadian rhythm, 499
- circadian rhythm, diazepam, heart muscle cell, 498
melphalan, busulfan, solid tumor, thiotepa, 650
membrane antigen, aminoguanidine, cytokine, down regulation,
Fas antigen, nitric oxide synthase, pancreas islet cell, 535
membrane biology, dimyristoylphosphatidylcholine,
dimyristoylphosphatidylglycerol, pediocin, protein lipid
interaction, 676
membrane lipid, intracellular transport, 398
membrane protein, antiinfective agent, 665
- biopolymer, capillary electrophoresis, high performance liquid
chromatography, 399
menorrhagia, desmopressin, intrauterine contraceptive device,
543
mepacrine, amitriptyline, drug solubility, imipramine, promazine,
mepivacaine, nerve block, ropivacaine, 576
6 mercaptopurine derivative, thioguanine derivative, 644
meropenem, hemodialysis, 410
mesencephalon, brain development, brain function, dopaminergic
nerve cell, dopaminergic system, 394
- 3beta hydroxy 5alpha pregnan 20 one, lordosis, olanzapine,
ventral tegmentum, 468
mesna, cysteine, 409
metabolic syndrome X, dopaminergic transmission,
hypothalamus nucleus, 531
metastasis, colorectal cancer, fluorouracil, oxaliplatin, 622
methanol, alcohol, herbaceous agent, 2 propanol, quality control,
732
4 methoxy n methylphenethylamine, formaldehyde,
glucocorticoid, pruritus, scratching, 729
n methyl dextro aspartic acid receptor blocking agent,
discriminative stimulus, phencyclidine, 471
methylene blue, allopurinol, intercellular adhesion molecule 1
antibody, intestine injury, intestine perfusion, monoclonal
antibody, 709
3,4 methylenedioxymethamphetamine, 489
methyl group, antibacterial activity, antiinfective agent, isoxazole
derivative, oxazolidinone derivative, 661
methylmalonic acid, cyanocobalamin, folic acid, homocysteine,
hyperhomocysteinemia, pyridoxine, 389
SUBJECT INDEX
methylprednisolone sodium succinate, adrenal suppression,
hydrocortisone release, nefazodone, 534
mevinolin, antifungal activity, Candida albicans, ergosterol,
fluconazole, gene expression, prenylation, 562
microdialysis, bovine serum albumin, chemoluminescence, flow
injection analysis, terbutaline sulfate, 377
- cocaine, drug delivery system, drug determination, drug
penetration, 385
- diclofenac, high performance liquid chromatography, tandem
mass spectrometry, ultraviolet spectrophotometry, 593
- protein determination, 400
microsphere, abetalipoproteinemia, alpha tocopherol, drug
bioavailability, polyglactin, 386
- gelatin, insulin, 538
- oxprenolol, 539
mifepristone, abortion, misoprostol, 542
milrinone, glucose, insulin, 569
misoprostol, abortion, mifepristone, 542
mitochondrial membrane, glycyrrhetinic acid, liver
mitochondrion, 435
mitogen activated protein kinase, anisomycin, heart infarction
prevention, heart muscle ischemia, synaptophysin, 502
- caffeic acid phenethyl ester, protein p53, tumor suppressor
protein, 703
mitogen activated protein kinase 1, cyclooxygenase 2,
immunoglobulin enhancer binding protein, salicylate
sodium, 416
molecular interaction, breast cancer, epidermal growth factor
receptor, estrogen receptor, 632
mometasone furoate, 598
monoclonal antibody, allopurinol, intercellular adhesion
molecule 1 antibody, intestine injury, intestine perfusion,
methylene blue, 709
- inhibition kinetics, leukotriene B4 receptor, 720
monocyte, lymphocyte, testosterone, 717
monocyte chemotactic protein 1, acute heart infarction,
angiotensin 2 receptor antagonist, candesartan, dipeptidyl
carboxypeptidase inhibitor, perindopril, renin angiotensin
aldosterone system, vasculotropin, 505
montelukast, asthma, 559
mood disorder, alcohol, alcoholism, major depression, placebo,
sertraline, 483
morphine sulfate, arachidonate 12 lipoxygenase, cocaine, gene
disruption, 467
multiple sclerosis, glatiramer, interferon, 722
muscarinic receptor, electroanalgesia, hyperalgesia,
muscle rigidity, chroman derivative, 2 dipropylamino 8
hydroxytetralin, haloperidol, 462
Mycobacterium tuberculosis, purine derivative, 656
mycophenolic acid 2 morpholinoethyl ester, corticosteroid,
cyclosporin A, daclizumab, kidney allograft rejection,
kidney transplantation, 724
myeloma cell, recombinant interleukin 6, tumor cell, 635
nadroparin, conjunctiva disease, hypersensitivity reaction,
immediate type hypersensitivity, 723
naltrexone, acamprosate, alcohol, alcoholism, opiate antagonist,
480
nateglinide, enzyme activation, insulin, insulin release,
nefazodone, adrenal suppression, hydrocortisone release,
methylprednisolone sodium succinate, 534
nephrotoxicity, bismuth, cisplatin, 524
nerve block, mepivacaine, ropivacaine, 576
nerve fiber transection, levacecarnine, sensory neuropathy, 572
neuroendocrinology, body weight, neuropeptide, 530
- brain, cholecystokinin, intestine, pancreas, pancreas secretion,
secretin, 536
- insulin, insulin resistance, obesity, 533
neuroleptic agent, chlorpromazine, drug dose regimen, 485
neuropathic pain, chronic pain, dose calculation, pregabalin, 583
neuropeptide, body weight, neuroendocrinology, 530
- calcitonin gene related peptide, cytokine production,
macrophage, substance P, 718
neuropeptide Y, energy balance, neuropeptide Y receptor, obesity,
satiety, 529
neuropeptide Y receptor, energy balance, neuropeptide Y,
obesity, satiety, 529
neurotransmission, serotonin, serotonin 2C antagonist,
serotoninergic system, 459
neutrophil, cell differentiation, cell maturation, thrombopoietin,
515
- divalent cation, hemopexin, leukocyte adherence, magnesium
ion, 584
nifedipine, flushing, ovariectomy, 442
nitric oxide, aorta constriction, artery dilatation, cysteine
derivative, glutathione derivative, iron complex, nitro
- bilirubin, s nitrosothiol, scavenger, 728
- endothelin 1, heart infarction, heart muscle ischemia, heart
muscle reperfusion, prostanoid, 730
- paroxetine, 424
nitric oxide synthase, aminoguanidine, cytokine, down regulation,
Fas antigen, membrane antigen, pancreas islet cell, 535
nitric oxide synthase inhibitor, atherosclerosis, calcium
antagonist, cardiovascular system, dihydropyridine,
hypertension, protective agent, 513
nitrite, endosulfan, lipid peroxidation, malathion, tumor necrosis
factor alpha, 715
nitro derivative, aorta constriction, artery dilatation, cysteine
derivative, glutathione derivative, iron complex, nitric
oxide, nitrosation, thiol derivative, 434
7 nitroindazole, dizocilpine, Escherichia coli lipopolysaccharide,
nitrosation, aorta constriction, artery dilatation, cysteine
oxide, nitro derivative, thiol derivative, 434
s nitrosothiol, bilirubin, nitric oxide, scavenger, 728
non insulin dependent diabetes mellitus, cardiovascular disease,
560
nonsteroid antiinflammatory agent, cyclooxygenase 2 inhibitor,
osteoarthritis, rheumatoid arthritis, 585 587
- iodoacetic acid, knee osteoarthritis, paracetamol, weight
bearing, 590
nonviral gene delivery system, 403
noradrenalin, alpha 1 adrenergic receptor, cell subpopulation,
subthalamic nucleus, 463
norbornane derivative, melanogenesis, prostaglandin E2, protein
443
norethisterone enantate, contraception, follitropin,
medroxyprogesterone acetate, 528
nose mucosa, cell membrane permeability, occludin, polyarginine,
protein dephosphorylation, protein phosphorylation,
protein ZO1, serine, threonine, 427
nucleotide, cytokine, immunomodulating agent,
nucleotide sequence, live vaccine, measles, measles vaccine, 708
nutrition, fish oil, food intake, health hazard, risk assessment,
obesity, brain nerve cell, cell energy, energy balance,
hypothalamus, melanocortin, proopiomelanocortin, 456
- energy balance, neuropeptide Y, neuropeptide Y receptor,
satiety, 529
- insulin, insulin resistance, neuroendocrinology, 533
occludin, cell membrane permeability, nose mucosa, polyarginine,
protein dephosphorylation, protein phosphorylation,
olanzapine, clozapine, hebephrenia, insulin, paranoid
- 3beta hydroxy 5alpha pregnan 20 one, lordosis,
mesencephalon, ventral tegmentum, 468
oligodeoxyribonucleotide, cytokine, immunomodulating agent,
nucleotide, 630
SUBJECT INDEX
11
oligomer, dactinomycin, DNA base, 421
oligonucleotide, designer drug, DNA sequence, polyamide, zinc
finger protein, 422
oligosaccharide, chemical bond, lentinan, spleen, 735
olmesartan, angiotensin 2 receptor antagonist, heart muscle cell,
503
onychomycosis, dermatomycosis, gynecologic infection, 692
opiate, drug dependence, opiate receptor, 581
opiate antagonist, acamprosate, alcohol, alcoholism, naltrexone,
480
opiate receptor, antinociception, cannabinoid, emotion, 580
- drug dependence, opiate, 581
oritavancin, antibacterial activity, bacterial infection,
glycopeptide, vancomycin, 658
ornithine derivative, antibacterial activity, bacterial infection,
daptomycin, 662
osteoarthritis, celecoxib, drug utilization, rheumatoid arthritis,
586
- cyclooxygenase 2 inhibitor, nonsteroid antiinflammatory agent,
rheumatoid arthritis, 585 587
osteoblast, anticoagulation, dalteparin, drug effect, enoxaparin,
fondaparinux, heparin, 450
osteoporosis, ibandronic acid, 565
- parathyroid hormone[1-34], 407
ovariectomy, flushing, nifedipine, 442
ovary carcinoma, breast carcinoma, docetaxel,
immunopharmacology, paclitaxel, rheumatoid arthritis,
structure activity relation, 712
ovulation induction, anovulation, birth rate, female infertility, 544
oxaliplatin, colorectal cancer, fluorouracil, metastasis, 622
oxazolidinone derivative, antibacterial activity, antiinfective
agent, bacterial infection, drug synthesis, phenyl group,
1,3,4 thiadiazole derivative, 663
- antibacterial activity, antiinfective agent, isoxazole derivative,
methyl group, 661
- antibacterial activity, bacterial infection, polycyclic aromatic
hydrocarbon derivative, pyrrole derivative, 660
- antibacterial activity, chirality, 672
- antibacterial activity, quinolone derivative, structure activity
relation, 671
- antiinfective agent, benzazepine derivative, drug synthesis,
Staphylococcus infection, 664
- antiinfective agent, quinolone derivative, 668
- antiinfective agent, thiomorpholine derivative, thiopyran
derivative, 667
oxime derivative, alkyl group, antineoplastic activity, steroid, 637
oxprenolol, microsphere, 539
paclitaxel, artery injury, blood vessel function, cardiovascular
agent, coronary artery disease, protein farnesyltransferase
inhibitor, pyranoside, 512
- breast carcinoma, docetaxel, immunopharmacology, ovary
carcinoma, rheumatoid arthritis, structure activity relation,
712
pamidronic acid, collagen, collagen metabolism, cross linking,
deoxypyridinoline, drug effect, total hip prosthesis, 448
pancreas, bile secretion, tetramethylpyrazine, 570
- brain, cholecystokinin, intestine, neuroendocrinology, pancreas
secretion, secretin, 536
pancreas islet cell, aminoguanidine, cytokine, down regulation,
Fas antigen, membrane antigen, nitric oxide synthase, 535
pancreas secretion, brain, cholecystokinin, intestine,
neuroendocrinology, pancreas, secretin, 536
panic, imipramine, sertraline, 484
paracetamol, interleukin 6, knee osteoarthritis, substance P,
synovial fluid, tramadol, 596
- iodoacetic acid, knee osteoarthritis, nonsteroid
antiinflammatory agent, weight bearing, 590
- liver enzyme, malnutrition, 578
paranoid schizophrenia, clozapine, hebephrenia, insulin,
olanzapine, psychosis, schizoaffective psychosis,
paraquat, antioxidant, growth inhibition, paraquat poisoning,
12
paraquat poisoning, antioxidant, growth inhibition, paraquat,
parathyroid hormone[1-34], osteoporosis, 407
Parkinson disease, brain derived neurotrophic factor, dopamine 3
receptor, 458
- dopamine receptor stimulating agent, 453
paroxetine, nitric oxide, 424
pediocin, dimyristoylphosphatidylcholine,
protein lipid interaction, 676
peptide, antigen presenting cell, antioxidant, antioxidant activity,
peptide derivative, chymotrypsin, protein stability, small
peptidyltransferase, chloramphenicol, spermine, 688
perindopril, acute heart infarction, angiotensin 2 receptor
antagonist, candesartan, dipeptidyl carboxypeptidase
inhibitor, monocyte chemotactic protein 1, renin
permethrin, contact allergy, urocanic acid, 725
phencyclidine, discriminative stimulus, n methyl dextro aspartic
acid receptor blocking agent, 471
phenotype, insulin, smooth muscle contraction, 518
phenyl group, antibacterial activity, antiinfective agent, bacterial
infection, drug synthesis, oxazolidinone derivative, 1,3,4
thiadiazole derivative, 663
phosphodiesterase IV inhibitor, indole derivative, quantitative
phospholipase C, enzyme activation, insulin, insulin release,
nateglinide, rosiglitazone, 568
phosphoramidic acid derivative, antisense oligonucleotide,
Hepatitis C virus, RNA, single stranded DNA, 690
photodynamic therapy, benzoporphyrin derivative,
photosensitizing agent, subretinal neovascularization, 451
- calcitriol, keratinocyte, 444
photosensitizing agent, benzoporphyrin derivative, photodynamic
therapy, subretinal neovascularization, 451
phthalimide derivative, antilipemic agent, drug synthesis, 415
physical chemistry, macrogol derivative, theophylline,
theophylline derivative, 384
piromidic acid, analytic method, 675
placebo, alcohol, alcoholism, major depression, mood disorder,
sertraline, 483
plant extract, analgesic activity, analgesic agent, 582
- antibacterial activity, 749
- antifungal agent, antiinfective agent, berberine, herbaceous
agent, 742
- antifungal agent, antiinfective agent, cytotoxic agent,
herbaceous agent, 743
- antiinfective agent, herbaceous agent, 741
- antiinflammatory agent, B lymphocyte, lymphocyte function,
731
- antiinflammatory agent, flavonoid, glomerulopathy,
herbaceous agent, Masugi nephritis, scavenger, 745
- antimicrobial activity, 747
- cytopathogenic effect, 748
- drug metabolite, 417
- herbaceous agent, spasmolytic agent, 746
plasminogen activator, 391
platinum, acridine derivative, DNA adduct, DNA base,
intercalation complex, 420
polyamide, designer drug, DNA sequence, oligonucleotide, zinc
finger protein, 422
polyarginine, cell membrane permeability, nose mucosa,
occludin, protein dephosphorylation, protein
phosphorylation, protein ZO1, serine, threonine, 427
polycyclic aromatic hydrocarbon derivative, antibacterial
activity, bacterial infection, oxazolidinone derivative,
pyrrole derivative, 660
polyglactin, abetalipoproteinemia, alpha tocopherol, drug
bioavailability, microsphere, 386
polyphenol derivative, antigen presenting cell, antioxidant,
antioxidant activity, peptide, 716
postmenopause osteoporosis, bisphosphonic acid derivative, 418
postoperative pain, cyclooxygenase 2 inhibitor, 577
SUBJECT INDEX
pravastatin, lipoprotein A, lipoprotein blood level, 493
pregabalin, chronic pain, dose calculation, neuropathic pain, 583
prenylation, antifungal activity, Candida albicans, ergosterol,
fluconazole, gene expression, mevinolin, 562
probucol, antilipemic agent, 497
prolactin, Sertoli cell, 564
promazine, amitriptyline, drug solubility, imipramine, mepacrine,
promethazine, amitriptyline, drug solubility, imipramine,
mepacrine, promazine, propranolol, solubilization, 387
proopiomelanocortin, brain nerve cell, cell energy, energy
balance, hypothalamus, melanocortin, obesity, 456
2 propanol, alcohol, herbaceous agent, methanol, quality control,
732
propionic acid derivative, CD29 antigen, 411
propranolol, amitriptyline, drug solubility, imipramine,
mepacrine, promazine, promethazine, solubilization, 387
propylthiouracil, Graves disease, liothyronine, thyroxine,
prostaglandin E2, melanogenesis, norbornane derivative, protein
443
prostaglandin synthase inhibitor, antinociception, sildenafil, 490
prostanoid, endothelin 1, heart infarction, heart muscle ischemia,
heart muscle reperfusion, nitric oxide, 730
prostate cancer, antiandrogen, bicalutamide, drug design,
epidermal growth factor receptor kinase, gefitinib, protein
tyrosine kinase inhibitor, 613
prostate hypertrophy, dutasteride, urinary tract disease, 523
protective agent, atherosclerosis, calcium antagonist,
cardiovascular system, dihydropyridine, hypertension,
nitric oxide synthase inhibitor, 513
proteinase inhibitor, insulin, 555
protein dephosphorylation, cell membrane permeability, nose
mucosa, occludin, polyarginine, protein phosphorylation,
protein determination, microdialysis, 400
protein farnesyltransferase inhibitor, artery injury, blood vessel
function, cardiovascular agent, coronary artery disease,
paclitaxel, pyranoside, 512
protein inhibitor, antibacterial activity, antiinfective agent, 666
protein kinase inhibitor, DNA, DNA repair, DNA strand
breakage, vanillin derivative, 629
protein kinase p60, curcumin, focal adhesion kinase, 750
protein lipid interaction, dimyristoylphosphatidylcholine,
pediocin, 676
protein p53, caffeic acid phenethyl ester, mitogen activated
protein kinase, tumor suppressor protein, 703
- melanogenesis, norbornane derivative, prostaglandin E2,
tumor necrosis factor alpha, ultraviolet B radiation, 443
protein p75, apoptosis, ceramide, sympathetic nerve cell, 465
protein phosphorylation, cell membrane permeability, nose
mucosa, occludin, polyarginine, protein
dephosphorylation, protein ZO1, serine, threonine, 427
protein protein interaction, enzyme inhibitor, 401
protein stability, chymotrypsin, peptide derivative, small
protein tyrosine kinase inhibitor, antiandrogen, bicalutamide,
drug design, epidermal growth factor receptor kinase,
gefitinib, prostate cancer, 613
protein ZO1, cell membrane permeability, nose mucosa, occludin,
phosphorylation, serine, threonine, 427
pruritus, formaldehyde, glucocorticoid, 4 methoxy n
methylphenethylamine, scratching, 729
Pseudomonas exotoxin, brain tumor, recombinant protein,
psychosis, clozapine, hebephrenia, insulin, olanzapine, paranoid
schizophrenia, schizoaffective psychosis,
purine derivative, Mycobacterium tuberculosis, 656
pyranoside, artery injury, blood vessel function, cardiovascular
agent, coronary artery disease, paclitaxel, protein
farnesyltransferase inhibitor, 512
pyrazole derivative, antineoplastic agent, antivirus agent, 697
pyridinium derivative, antineoplastic activity, 636
pyridoxine, coffee, folic acid, homocysteine,
hyperhomocysteinemia, 492
- cyanocobalamin, folic acid, homocysteine,
hyperhomocysteinemia, methylmalonic acid, 389
pyrimidine derivative, 4 aminobutyric acid A receptor, receptor
binding, 574
- trimethoprim, 669
pyrrole derivative, antibacterial activity, bacterial infection,
oxazolidinone derivative, polycyclic aromatic
hydrocarbon derivative, 660
quality control, alcohol, herbaceous agent, methanol, 2 propanol,
732
quantitative structure activity relation, indole derivative,
phosphodiesterase IV inhibitor, 428
quantum chemistry, antivirus agent, flavone derivative,
flavonoid, 701
quaternary ammonium derivative, antiinfective agent,
antimicrobial activity, choline derivative, 700
quazepam, fluvoxamine maleate, 412
quinoline derivative, antifungal agent, antiinfective agent,
antimicrobial activity, 698
- benzofuran derivative, integrase inhibitor, 684
quinolone derivative, antibacterial activity, oxazolidinone
derivative, structure activity relation, 671
- antiinfective agent, oxazolidinone derivative, 668
quinoxaline derivative, 685
raloxifene, breast cancer, estradiol, 639
rapamycin, cerivastatin, cyclosporin A, kidney transplantation,
522
reactive oxygen metabolite, antioxidant, growth inhibition,
paraquat, paraquat poisoning, thiamine, 445
receptor affinity, benzodiazepine receptor affecting agent, drug
receptor binding, flavonoid, 436
receptor binding, 4 aminobutyric acid A receptor, pyrimidine
derivative, 574
receptor blocking agent, liver disease, 600
receptor density, glucocorticoid receptor, ligand, receptor down
receptor down regulation, glucocorticoid receptor, ligand,
receptor density, steroid, 595
receptor subtype, acoustic reflex, startle reflex, 470
recombinant antibody, chimeric antibody, 711
recombinant blood clotting factor 7a, hemophilia A, hemostasis,
727
recombinant erythropoietin, 392
recombinant follitropin, infertility, 541
recombinant interleukin 6, myeloma cell, tumor cell, 635
recombinant protein, brain tumor, Pseudomonas exotoxin,
recombinant receptor, chronic inflammation, inflammatory
disease, macrogol derivative, rheumatoid arthritis, tumor
necrosis factor receptor 1, 605
recurrent cancer, breast cancer, breast metastasis, 631
renin angiotensin aldosterone system, acute heart infarction,
angiotensin 2 receptor antagonist, candesartan, dipeptidyl
carboxypeptidase inhibitor, monocyte chemotactic protein
1, perindopril, vasculotropin, 505
reperfusion injury, acetic acid derivative, glycerol derivative,
heart infarction size, heart muscle ischemia, 501
- acetylcysteine, heart muscle ischemia, heart protection,
isosorbide 5 nitrate, 500
resveratrol, immunomodulation, 645
retinoic acid, fenretinide, Graves disease, 567
rheumatoid arthritis, breast carcinoma, docetaxel,
immunopharmacology, ovary carcinoma, paclitaxel,
- celecoxib, drug utilization, osteoarthritis, 586
- chronic inflammation, inflammatory disease, macrogol
SUBJECT INDEX
13
derivative, recombinant receptor, tumor necrosis factor
receptor 1, 605
- cyclooxygenase 2 inhibitor, nonsteroid antiinflammatory agent,
osteoarthritis, 585 587
- 3 formamido 7 methanesulfonamido 6 phenoxychromone, 588
rifampicin, enfuvirtide, Human immunodeficiency virus infection,
681
risk assessment, fish oil, food intake, health hazard, nutrition,
RNA, antisense oligonucleotide, Hepatitis C virus,
phosphoramidic acid derivative, single stranded DNA, 690
ropivacaine, mepivacaine, nerve block, 576
rosacea, dermatological agent, 563
rosiglitazone, enzyme activation, insulin, insulin release,
nateglinide, phospholipase C, 568
salicylate sodium, cyclooxygenase 2, immunoglobulin enhancer
binding protein, mitogen activated protein kinase 1, 416
Salvia miltiorrhiza extract, liver fibrosis, 520
saquinavir, Human immunodeficiency virus infection, 678
satiety, energy balance, neuropeptide Y, neuropeptide Y receptor,
obesity, 529
scavenger, antiinflammatory agent, flavonoid, glomerulopathy,
herbaceous agent, Masugi nephritis, plant extract, 745
- bilirubin, nitric oxide, s nitrosothiol, 728
schizoaffective psychosis, bipolar depression, bipolar mania,
lithium, serotonin 2A receptor, 404
- clozapine, hebephrenia, insulin, olanzapine, paranoid
schizophrenia, psychosis, schizophreniform disorder,
triacylglycerol, 405
schizophrenia, clozapine, 455 486
schizophreniform disorder, clozapine, hebephrenia, insulin,
olanzapine, paranoid schizophrenia, psychosis,
schizoaffective psychosis, triacylglycerol, 405
scratching, formaldehyde, glucocorticoid, 4 methoxy n
methylphenethylamine, pruritus, 729
secretin, brain, cholecystokinin, intestine, neuroendocrinology,
pancreas, pancreas secretion, 536
selenium derivative, superoxide, thiol group, 646
sensory nerve, alcohol, capsaicin, stomach epithelium, stomach
injury, 519
sensory neuropathy, levacecarnine, nerve fiber transection, 572
serine, cell membrane permeability, nose mucosa, occludin,
phosphorylation, protein ZO1, threonine, 427
serotonin, cyclic GMP, frontal cortex, serotonin 1A receptor,
- dopamine, frontal cortex, serotonin 1A receptor, serotonin
release, 461
- neurotransmission, serotonin 2C antagonist, serotoninergic
system, 459
serotonin 1A agonist, antidepressant agent, corticotropin,
depression, 2 dipropylamino 8 hydroxytetralin,
imipramine, tetracosactide zinc phosphate, 488
serotonin 1A receptor, cyclic GMP, frontal cortex, serotonin,
- dopamine, frontal cortex, serotonin, serotonin release, 461
serotonin 2A receptor, bipolar depression, bipolar mania, lithium,
schizoaffective psychosis, 404
serotonin 2C antagonist, neurotransmission, serotonin,
serotoninergic system, 459
serotonin 2 receptor, cyclic GMP, frontal cortex, serotonin,
serotonin 1A receptor, 460
serotoninergic system, neurotransmission, serotonin, serotonin
2C antagonist, 459
serotonin release, dopamine, frontal cortex, serotonin, serotonin
1A receptor, 461
serous otitis media, amoxicillin plus clavulanic acid,
azithromycin, 695
- azithromycin, 693
- azithromycin, ceftriaxone, 694
Sertoli cell, prolactin, 564
sertraline, alcohol, alcoholism, major depression, mood disorder,
placebo, 483
14
- imipramine, panic, 484
- major depression, 481
sexual arousal, estrogen, estrogen activity, genetic analysis,
sexual behavior, 726
sexual behavior, estrogen, estrogen activity, genetic analysis,
sexual arousal, 726
shock, lidocaine, 573
sildenafil, antinociception, prostaglandin synthase inhibitor, 490
single stranded DNA, antisense oligonucleotide, Hepatitis C
virus, phosphoramidic acid derivative, RNA, 690
skeletal muscle, captopril, hypertriglyceridemia, 447
skin disease, antioxidant, antioxidant activity, lipid peroxidation,
473
skin infection, bacterial infection, daptomycin, 680
Smad3 protein, immunoglobulin A, immunoglobulin production,
immunomodulation, transforming growth factor beta1, 719
small intestine, chymotrypsin, peptide derivative, protein stability,
trypsin, 521
smooth muscle contraction, insulin, phenotype, 518
snake venom, cancer inhibition, liver cell carcinoma, 648
- disintegrin, melanoma cell, 626
sodium calcium exchange, benzothiazepine derivative, brain
mitochondrion, calcium ion, granule cell, isoprotein,
sodium ion, 437
sodium ion, benzothiazepine derivative, brain mitochondrion,
calcium ion, granule cell, isoprotein, sodium calcium
exchange, 437
solid tumor, busulfan, melphalan, thiotepa, 650
solubilization, amitriptyline, drug solubility, imipramine,
mepacrine, promazine, promethazine, propranolol, 387
spasmolytic agent, herbaceous agent, plant extract, 746
spermine, chloramphenicol, peptidyltransferase, 688
spleen, chemical bond, lentinan, oligosaccharide, 735
sport injury, diving, emergency treatment, 397
Staphylococcus infection, antiinfective agent, benzazepine
derivative, drug synthesis, oxazolidinone derivative, 664
startle reflex, acoustic reflex, receptor subtype, 470
statistical model, area under the curve, blood sampling,
hydrochlorothiazide, telmisartan, 381
steroid, alkyl group, antineoplastic activity, oxime derivative, 637
- cancer cell, cell killing, cytotoxicity, heart contraction, 614
- drug withdrawal, tsukubaenolide, 382
- glucocorticoid receptor, ligand, receptor density, receptor
down regulation, 595
stomach epithelium, alcohol, capsaicin, sensory nerve, stomach
injury, 519
stomach injury, alcohol, capsaicin, sensory nerve, stomach
epithelium, 519
stratum corneum, clobetasol, 426
stress activated protein kinase, acute granulocytic leukemia,
arsenic trioxide, 620
stroke, cardiovascular system, coronary artery disease, heart,
highly active antiretroviral therapy, Human
immunodeficiency virus infection, 705
structure activity relation, antibacterial activity, carbonyl
derivative, ethylene derivative, linezolid, 659
- antibacterial activity, oxazolidinone derivative, quinolone
derivative, 671
- breast carcinoma, docetaxel, immunopharmacology, ovary
carcinoma, paclitaxel, rheumatoid arthritis, 712
subretinal neovascularization, benzoporphyrin derivative,
photodynamic therapy, photosensitizing agent, 451
substance P, calcitonin gene related peptide, cytokine production,
macrophage, neuropeptide, 718
- interleukin 6, knee osteoarthritis, paracetamol, synovial fluid,
tramadol, 596
subthalamic nucleus, alpha 1 adrenergic receptor, cell
subpopulation, noradrenalin, 463
sulfonamide, addition reaction, antiglaucoma agent, carbonate
dehydratase I, carbonate dehydratase II, carbonate
dehydratase inhibitor, carbonate dehydratase IV,
glaucoma, 452
superoxide, selenium derivative, thiol group, 646
sympathetic nerve cell, apoptosis, ceramide, protein p75, 465
synaptic transmission, ventral tegmentum, 466
SUBJECT INDEX
synaptophysin, anisomycin, heart infarction prevention, heart
muscle ischemia, mitogen activated protein kinase, 502
synovial fluid, interleukin 6, knee osteoarthritis, paracetamol,
substance P, tramadol, 596
systolic hypertension, lacidipine, lercanidipine, 561
tamoxifen, breast cancer, estradiol, fulvestrant, 640
- drug transformation, endometrium, 388
- genomics, guanylate cyclase, 557
tandem mass spectrometry, diclofenac, high performance liquid
chromatography, microdialysis, ultraviolet
telmisartan, area under the curve, blood sampling,
hydrochlorothiazide, statistical model, 381
tempol, antioxidant, endothelium derived hyperpolarizing factor,
hypertension, vasodilatation, 511
temporomandibular joint disorder, arthrocentesis, etodolac, 599
terbutaline, asthma, bronchodilatation, loratadine, 516
terbutaline sulfate, bovine serum albumin, chemoluminescence,
flow injection analysis, microdialysis, 377
testosterone, lymphocyte, monocyte, 717
tetracosactide zinc phosphate, antidepressant agent,
corticotropin, depression, 2 dipropylamino 8
hydroxytetralin, imipramine, serotonin 1A agonist, 488
tetramethylpyrazine, bile secretion, pancreas, 570
tetrandrine, daunorubicin, glycoprotein P, lymphatic leukemia,
556
thalidomide, apoptosis, keratinocyte, tumor necrosis factor alpha,
theophylline, macrogol derivative, physical chemistry,
theophylline derivative, 384
theophylline derivative, macrogol derivative, physical chemistry,
theophylline, 384
1,3,4 thiadiazole derivative, antibacterial activity, antiinfective
agent, bacterial infection, drug synthesis, oxazolidinone
derivative, phenyl group, 663
thiamine, antioxidant, growth inhibition, paraquat, paraquat
poisoning, reactive oxygen metabolite, 445
thioguanine derivative, 6 mercaptopurine derivative, 644
thiol derivative, aorta constriction, artery dilatation, cysteine
oxide, nitro derivative, nitrosation, 434
thiol group, selenium derivative, superoxide, 646
thiomorpholine derivative, antiinfective agent, oxazolidinone
derivative, thiopyran derivative, 667
thiophene, drug synthesis, furan, furan derivative, thiophene
derivative, 606
thiophene derivative, drug synthesis, furan, furan derivative,
thiophene, 606
thiopyran derivative, antiinfective agent, oxazolidinone
derivative, thiomorpholine derivative, 667
thiotepa, busulfan, melphalan, solid tumor, 650
threonine, cell membrane permeability, nose mucosa, occludin,
phosphorylation, protein ZO1, serine, 427
thrombocyte aggregation, lipopolysaccharide, 547
thrombocyte aggregation inhibition, acetylcysteine, clopidogrel,
546
thrombopoietin, cell differentiation, cell maturation, neutrophil,
515
thrombosis, antithrombocytic agent, atheroma, atherosclerosis,
514
thromboxane A2 receptor blocking agent, hydrogen bond, 430
thymocyte, lead, lead poisoning, lipocortin 5, 446
thyroxine, Graves disease, liothyronine, propylthiouracil,
thyroxine deiodinase, Graves disease, liothyronine,
propylthiouracil, thyroxine, 537
tipranavir, Human immunodeficiency virus infection, 393
tizanidine, high performance thin layer chromatography, 376
toll like receptor 4, B lymphocyte, cell activation, herbaceous
agent, macrophage, 736
total hip prosthesis, collagen, collagen metabolism, cross linking,
deoxypyridinoline, drug effect, pamidronic acid, 448
tramadol, interleukin 6, knee osteoarthritis, paracetamol,
substance P, synovial fluid, 596
transcutaneous nerve stimulation, electroanalgesia,
hyperalgesia, muscarinic receptor, 579
transferase inhibitor, aniline derivative, bioassay,
dimethylallyltransferase, drug synthesis, farnesyl
diphosphate, 414
transforming growth factor alpha, brain tumor, Pseudomonas
exotoxin, recombinant protein, 551
transforming growth factor beta1, immunoglobulin A,
immunoglobulin production, immunomodulation, Smad3
protein, 719
tremor, bicuculline methiodide, globus pallidus, jaw movement,
locomotion, 469
triacylglycerol, clozapine, hebephrenia, insulin, olanzapine,
paranoid schizophrenia, psychosis, schizoaffective
psychosis, schizophreniform disorder, 405
trimethoprim, pyrimidine derivative, 669
tropolone derivative, antiprotozoal agent, antitrypanosomal
agent, hydrazine derivative, 696
trypsin, chymotrypsin, peptide derivative, protein stability, small
intestine, 521
tsukubaenolide, drug withdrawal, steroid, 382
tumor cell, myeloma cell, recombinant interleukin 6, 635
tumor necrosis factor, arthritis, ferric citrate, immune response,
iron derivative, 714
tumor necrosis factor alpha, apoptosis, keratinocyte,
thalidomide, ultraviolet B radiation, 604
- endosulfan, lipid peroxidation, malathion, nitrite, 715
protein p53, ultraviolet B radiation, 443
tumor necrosis factor receptor 1, chronic inflammation,
inflammatory disease, macrogol derivative, recombinant
receptor, rheumatoid arthritis, 605
tumor suppressor protein, caffeic acid phenethyl ester, mitogen
activated protein kinase, protein p53, 703
ultraviolet B radiation, apoptosis, keratinocyte, thalidomide,
tumor necrosis factor alpha, 604
protein p53, tumor necrosis factor alpha, 443
ultraviolet spectrophotometry, antilipemic agent, high
performance liquid chromatography, 395
- diclofenac, high performance liquid chromatography,
microdialysis, tandem mass spectrometry, 593
umbilical vein, endothelium cell, hypoxia, isoflavonoid, 440
Uncaria tomentosa extract, cell death, cell division,
unsaturated fatty acid, fish oil, food intake, health hazard,
nutrition, risk assessment, 396
urinary tract disease, dutasteride, prostate hypertrophy, 523
urocanic acid, contact allergy, permethrin, 725
Urtica dioica extract, antidiabetic agent, diabetes mellitus, 740
uterus spasmolytic agent, beta adrenergic receptor stimulating
agent, hyperhomocysteinemia, 527
vancomycin, antibacterial activity, bacterial infection,
glycopeptide, oritavancin, 658
vanillin derivative, DNA, DNA repair, DNA strand breakage,
protein kinase inhibitor, 629
vascularization, bone graft, cyclosporin A, hypertrophy,
immunosuppressive treatment, 657
vasculotropin, acute heart infarction, angiotensin 2 receptor
antagonist, candesartan, dipeptidyl carboxypeptidase
inhibitor, monocyte chemotactic protein 1, perindopril,
renin angiotensin aldosterone system, 505
vas deferens, alpha 1 adrenergic receptor, cyproterone acetate, 526
vasoconstriction, abdominal aorta, angiotensin, angiotensin 1
receptor, angiotensin 2 receptor, 508
vasodilatation, antioxidant, endothelium derived hyperpolarizing
factor, hypertension, tempol, 511
ventral tegmentum, 3beta hydroxy 5alpha pregnan 20 one,
lordosis, mesencephalon, olanzapine, 468
SUBJECT INDEX
15
xiao chai hu tang, Chinese medicine, cytochrome P450 1A2,
cytochrome P450 3A, xanthine oxidase, 738
- synaptic transmission, 466
weight bearing, iodoacetic acid, knee osteoarthritis, nonsteroid
antiinflammatory agent, paracetamol, 590
zinc finger protein, designer drug, DNA sequence,
oligonucleotide, polyamide, 422
xanthine oxidase, Chinese medicine, cytochrome P450 1A2,
cytochrome P450 3A, xiao chai hu tang, 738
16
SUBJECT INDEX
AUTHOR INDEX
(figures refer to item numbers)
Abboud Y. 687
Abhilash P. 741
Abi-Dargham A. 479
Abourriche A. 687
Acosta S.L. 582
Acton D.G. 661
Adami S. 418
Adeagbo A.S.O. 511
Ago Y. 461
Agrawal D.K. 506
Agrawal H. 376
Ahmadiani A. 718
Aikawa Y. 588
Aizawa S. 607
Ajaiyeoba E.O. 743
Akabani G. 551
Akao T. 558
Åkesson C. 737
Al-Salem H.S. 610
Alatas Ö. 709
Alegrı́a Ezquerra E. 540
Alencar J.L. 434
Alexandre-Moreira M.S. 731
Allen I. 600
Almeida L. 474
Alonso M.J. 552
Altanlar N. 686
Amitzur G. 504
Ammar A. 457
Andrade S.S. 392
Andreou A. 688
Andrisano V. 399
Anissimov Y.G. 426
Anton R.F. 483
Apers S. 732
Appleyard R.C. 432
Araki H. 488
Araya J. 507
Archer G.E. 551
Archer S.L. 424
Arcos D. 463
Arguedas A. 694
Aristoff P.A. 664
Arizzi M.N. 469
Armanini D. 435
Arrieta A. 695
Ashokkumar M. 698
Avital A. 559
Ayar A. 527
Ayhan-Kilcigil G. 686
Ayub S. 715
Azas N. 413
Azevedo L.F. 494
Azevedo M.L.B. 708
Baba A. 461
Babu G.J. 508
Baelde H.J. 524
Baeschlin D.K. 671
Bailey D.G. 677
Baker G.B. 424
Baki A. 516
Balster R.L. 471
Balzarini P. 596
Banerji U. 641
Banghart M. 696
Bansal N. 656
Barbachyn M.R. 668, 672
Barbaro G. 705
Bardach E. 559
Bardhan K.D. 591
Barros Cota B. 747
Barrow E.W. 656
Bartolini M. 399
Bartoszyk G.D. 462
Baruah H. 420
Beksinska M.E. 528
Belelli D. 574
Bellastella A. 567
Benthem L. 533
Bergh C. 457
Berkels R. 513
Berkman N. 559
Berman S.R. 481
Berthold H.K. 449
Bertini S. 414
Bertucci C. 399
Betti L. 414
Betts M.J. 661
Bezard E. 458
Bhagat L. 630
Biagi G. 429
Bianchi M. 596
Bierbach U. 420
Biggio F. 477
Biggio G. 477
Binder B.R. 548
Biollaz J. 410
Blackledge G. 613
Blaylock B.L. 725
Block S.L. 695
Bnouham M. 740
Boden G. 569
Boggs C.M. 660
Boketoft Å. 720
Boland I. 650
Bonsignore A. 728
Booker B.M. 409
Booth B.P. 383
Boots J.M.M. 382
Borges M.B.J. 708
Bosco O. 547
Bosi S. 431
Bottazzi C. 564
Bouligand J. 650
Boumakis S. 443
Bousquet E. 682
Bove S.E. 590
Boyd M.A. 681
Bradbury A. 545
Braga De Oliveira A. 747
Brämswig S. 449
Brandts J.F. 711
Brannstrom T. 572
Brenneman S. 604
Brewer E.R. 534
Briganti S. 473
Broekhuizen-van den Berg
T.M. 524
Broggini M. 596
Brooker R.M. 590
Brouwers J.R.B.J. 485
Brown C.T. 523
Brown J. 722
Brown N.J. 591
Brum P.C. 494
Brzozowski Z. 636
Bumgardner G. 724
Burbach J.P.H. 394
Burns Jr. R. 604
Burns K.L. 401
Busch S. 532
Byun J.-O. 416
Cahová M. 447
Cake M.A. 432
Calcaterra S.L. 590
Callachan H. 574
Calvillo L. 500
Campos M. 526
Cardile V. 601
Carpi A. 631
Carson S.W. 534
Carta A. 685
Carter B.Z. 619
Cashman D.J. 628
Casini A. 452
Caspi D. 589
Castro Braga F. 747
Catarino R.I.L. 592
Cateni F. 384
Cattel L. 622
Caviglia D. 564
Celik H. 527
Chadha R. 553
Chae H.-J. 416
Chaires J.B. 423
Chakraborti A.K. 428
Chalupsky K. 434
Chan C.C.W. 542
Chang G.-D. 557
Chanin K. 397
Chattopadhaya R. 637
Chaudhry M.M. 563
Chen F.-M. 421
Chen S.-S. 716
Chen Z.-J. 557
Cheung P. 569
Chin K.-H. 421
Chiu J.-H. 520
Chojnacka M. 683
Chou S.-H. 421
Christiaans M.H.L. 382
Chu C.-Y. 703
Chuang Y.-C. 750
Chung K.-H. 626
Chung Y.-L. 641
Chwała P. 700
Ciske F.L. 672
Climent B. 730
Colantuoni V. 567
Conceição A.C.L. 592
Cook J.A. 583
Correa M. 469
Cortés J. 576
Coupez R. 475
Cowley M.A. 456
Creaven P. 409
Crepaldi G. 418
Crowell J. 608
Curran M.P. 451
Cutler D.J. 598
Czarnecki J. 536
Czock D. 522
Czyz A. 437
Da Ros T. 431
Dahl M.-L. 405
Daniel D. 614
Das N. 715
Das R.G. 491
Davies N.M. 598
AUTHOR INDEX
Dazzi L. 477
De Almeida Santos R.H. 701
De Jong-Van Den Berg L.T.W.
485
De La Lastra C.A. 597
De Simone R. 543
De Vries K. 533
Debart F. 690
Decker M. 454
Decosterd L.A. 410
Deeb D. 645
DeGorordo A. 397
Dehghanyar P. 593
Del Sorbo L. 547
DelCore M.G. 506
Dell’Osso B. 486
Demel U. 713
Derendorf H. 380
Deres K. 702
DeVane C.L. 739
Dey C.S. 554
Di Carlo C. 543
Di Luca G. 384
Di Stasio E. 728
Dias De Souza-Filho J. 747
Dickneite G. 710
Dı́ez J.J. 495
D’Incalci M. 609
Dinos G.P. 688
Dirksen W.P. 508
Disch A. 450
Djekou S. 413
Doggrell S.A. 497
Doi T. 584
Dong W.-G. 603
Donnerer J. 706
Donovan J.L. 739
Dorr A. 681
Dos Santos A.R.S. 606
Dresser G.K. 677
Drobny G.P. 689
Du K.-M. 623
Du W.-D. 571
Ducruet T. 587
Durant S. 629
Eastell R. 448
Easton A. 726
Ebeling P.R. 407
Ebtekar M. 718
Eddington N.D. 380
Edwards III C.K. 605
Efimov I.R. 573
Eijkemans M.J.C. 544
Ejdrup Bredkjæer H. 541
El Zeany B.A. 379
El-Demellawy M.A. 697
El-Sherbeny M.A. 610
Elgemeie G.L. 644
Elliott M.A. 612
Espinosa E. 615
Estrada S. 746
Ewy W.E. 583
Fabris D. 419
Falkner C. 511
Falter U. 487
Fan Y. 440
Farid N.F. 379
Favata M.F. 595
Feliu J. 615
1
Fernández N. 730
Ferreira M.M.C. 701
Filipponi P. 418
Fiore C. 435
Fitzpatrick F.A. 712
Fitzsimon C. 586
Fletcher P.J. 459
Földes-Papp Z. 713
Foleno B.D. 660
Ford S.J. 612
Francis G.S. 496
Franklin P.D. 408
Freile M.L. 742
Friedman E.S. 481
Fromm M.F. 406
Frye C. 468
Fu Z. 377
Fukai T. 745
Fukasawa T. 412
Fulzele D.P. 741
Fumoleau P. 638
Gadwood R.C. 663
Gajdos C. 639, 640
Galvin J.W. 443
Ganem G. 638
Gao X. 645
Garcia M.B.Q. 592
Garcı́a Saavedra V. 540
Garozzo A. 682
Gaston R.S. 724
Gatto B. 419
Gaussier H. 676
Gdaniec M. 636
Genade S. 502
Genin M.J. 672
Gerrits M.A.F.M. 581
Gerson L.B. 549
Geyer M.A. 470
Giannini F. 742
Giannoulaki V. 723
Giorgi I. 429
Giusti M.E. 744
Glezer I. 464
Gobburu J.V.S. 383
Godfrey M. 467
Göke R. 649
Golding M. 534
Gong J. 716
Gong Y.-Q. 440
González Barón M. 615
González-Juanatey J.R. 540
González-Maeso J. 439
González-Mendoza M. 578
Gopalakrishnan B. 428
Gordeev M.F. 668
Gosens R. 518
Gotti R. 399
Gower A.J. 487
Grady S. 696
Graham M.L. 651
Gravestock M.B. 661
Grdiša M. 621
Green A. 439
Greenough A. 561
Griffon N. 458
Gronski P. 710
Grotto I. 589
Guiberteau Cabanillas A. 675
Guillin O. 458
Gulcan H.O. 594
Guleria S. 637
Gupta A.K. 563
Gupta R. 637
Gupta R.C. 395
2
Gust R. 532
Hackbarth C. 668
Hacker H.J. 702
Hagen G. 655
Haisma H.J. 422
Halbert G.W. 612
Halushka P.V. 430
Han K.-Y. 626
Han K.H. 704
Han S.B. 736
Han X. 717
Hansen J. 602
Harada K. 444
Hart A. 572
Hasegawa A. 493
Hashimoto N. 611
Hashimoto T. 386
Hasumi K. 391
Hato F. 515
Hattingh S. 502
Hauger R.L. 470
Hawser S. 669
He J.-X. 558
Helliwell K. 733
Herbert J.-M. 546
Hernández-Guijo J.M. 441
Herzog H. 529
Hiemstra M. 518
Higaki K. 521
Higgins G.A. 459
Hill J. 662, 674
Hiraga T. 611
Hirano T. 556
Hirayama K. 729
Holladay S.D. 725
Holleman S. 562
Hong H.J. 711
Honkakoski P. 403
Horimoto M. 493
Hornicek F.J. 647
Hossain K. 620
Hou Y. 717
Hranjec M. 621
Hrvačić B. 714
Hu W. 391
Huang Y. 623
Hubschwerlen C. 671
Huen M.S.Y. 436
Hufnagl P. 548
Hui K.-M. 436
Hunter III W.J. 506
Husain S.R. 625
Hussain M.M. 433
Iglesias P. 495
Ihara K. 657
Iinuma Y. 734
Ilhan H. 709
Ilson D.H. 616
Imani B. 544
Inano A. 472
Infante L. 622
Ishida T. 633
Ishida Y. 665, 666
Ishiguchi H. 617
Ishimaru J.-I. 599
Islam K. 669
Iwanaga K. 538
Izumi H. 617
Jackson B. 448
Jain D.V.S. 553
Jain N.K. 490
Jain R. 670
Jan C.-R. 652
Jankovic J. 453
Jeenah F.Y. 482
Jensen B.K. 411
Jimeno J. 609
Jindal D.P. 637
Jindal R.D. 481
Joffe B.I. 482
Joh T. 519
Johnson L. 618
Johnson M.S. 438
Johnson P.D. 664
Joshua I.G. 511
Judice J.K. 658
Jun D.Y. 704
Jung I.L. 445
Kageyama M. 678
Kai M. 442
Kajiguchi T. 620
Kakemi M. 538
Kalia N. 591
Kalpaxis D.L. 688
Kamal A. 466
Kaminski N.E. 719
Kanda H. 412
Kandimalla E.R. 630
Kang J.S. 736
Kanzy E.-J. 710
Kapper A. 706
Karran P. 629
Kasanov J. 647
Kashid N. 553
Katz B.H. 433
Kaul N. 376
Kawamoto E.M. 464
Kawamura Y.I. 721
Kawashima R. 721
Keam S.J. 451
Kegeles L.S. 479
Keilitz R. 532
Keinänen K. 438
Kellogg G.E. 628
Kennedy S. 512
Keravala A. 707
Keresteci M. 586
Khamaisi M. 560
Khan M.R. 749
Khera M.K. 659
Kiedrowski L. 437
Kihara M. 749
Kim I.G. 445
Kim I.Y. 646
Kim J. 711
Kim S.-H. 626
Kim T.-S. 646
Kim Y.-S. 679
Kimura T. 521
Kishida T. 678
Kisliuk R.L. 643
Kitamura Y. 488
Kitano Y. 391
Kivilo K.M. 501
Kleinschmidt I. 528
Klöting N. 535
Kobayashi N. 584
Koenig J.A. 439
Konturek J.W. 536
Konturek S.J. 536
Koob G.F. 478
Kopp B. 614
Kotlyar M. 534
Kovacs E. 635
Kow L.-M. 726
Koyama Y. 461
AUTHOR INDEX
Kraus E. 443
Kristensen A.T. 727
Kristensen K. 727
Kroez M. 710
Kronawetter M. 706
Krueger K.D. 506
Kubota M. 734
Küçükgüzel S.G. 699
Kudo T. 607
Kulkarni S.K. 490
Kumar N. 554
Kunapuli S.P. 398
Kunze B. 654
Kunzendorf U. 522
Kuo H.-C. 703
Kupeli E. 594
Kurosaki K. 505
Kuti J.L. 680
Kuttler B. 535
La Casa C. 597
La Grotta G. 622
Lalé A. 546
Lam S. 667
Lamberty Y. 487
Lamy O. 565
Landaas S. 492
Landaverry Y. 673
Lankat-Buttgereit B. 649
Lara N. 424
Laske D.W. 624
Laskin B. 577
Latham P.K. 483
Lavoie F. 587
Lazar M.J. 509
Le Mellédo J.-M. 424
Lechman E.R. 707
Lee D.-G. 679
Lee E.-S. 639
Lee F.H. 585
Lee J.-K. 416
Lee J.Y. 684
Lee S.-B. 679
Lee T.-Y. 520
Lee Y.-J. 703
Lefèvre T. 676
Léger R. 673
Lehmann D.F. 408
Lehmann J. 454
Leibold T. 654
LeLorier J. 586
Leng F. 423
Lesscher H.B.M. 581
Letterio J.J. 719
Leu T.-H. 750
Leucuta S.E. 539
Leung J.W.C. 436
Leung T. 491
Leussink B.T. 524
Lewerin C. 389
Li L. 573
Liang E. 600
Liang J. 717
Liao X. 387
Lichtner R.B. 632
Lickliter J.D. 618
Lim L.-Y. 425
Lima V.L.M. 415
Lin H.-C. 520
Lindgren H. 737
Lip G.Y.H. 514
Liu H. 555, 639, 640
Liu S.-P. 603
Liu Z.-L. 556
Livi O. 429
Loaiza C. 694
Lochner A. 502
Lockwood P.A. 583
Loennechen T. 602
Loft A. 541
Lopez S. 670
Lopez-Kinninger L. 545
Lorenc-Koci E. 462
Loriga M. 685
Louie E.A. 689
Lu K.Q. 604
Lu Y.-C. 652
Lunte C. 385
Luo G.A. 402
Lyons C.N. 562
Młochowski J. 683
Ma Z. 425
Maa M.-C. 750
MacDonald T.M. 585
Maeno T. 427
Mahadik K.R. 376
Mahmood I. 381
Makarova L.A. 499
Malde A. 428
Maldonado R. 580
Malone W. 608
Mancuso C. 728
Mandal C. 691
Mandema J.W. 583
Mansell P. 537
Maoufoud S. 687
March X. 575
Markowitz J.S. 739
Markowitz M. 393
Martin S.W. 605
Martinand-Mari C. 690
Martı́nek J. 550
Martı́nez Cañas M.A. 675
Martinez D. 479
Martı́nez M.A. 730
Mason B.J. 480
Masson S. 500
Matheson P.J. 511
Mathisen B. 602
Mathon D.S. 466
Matousek M. 389
Matsuda T. 461
Matsui K. 505
Matsumoto A. 390
Matsuyama A. 444
Mattos K.C. 494
Matziolis G. 450
Mauri M.C. 486
Mavissakalian M.R. 484
May S.W. 401
Mayer B.X. 593
Mayorgas I. 441
Mazi A. 699
McDonald S. 385
McGuire J.J. 642
McKarns S.C. 719
Media J. 645
Medicis J.J. 408
Mehandru S. 393
Mehrotra N. 395
Meier G.P. 430
Melkersson K.I. 405
Meotti F.C. 606
Mercer J.G. 530
Mercorio F. 543
Merhfour F.-Z. 740
Meshki J. 398
Michel T. 690
Mildenberger M. 702
Milella M. 619
Millar-Carig M. 561
Mincione F. 452
Minutolo F. 414
Miyamae K. 525
Mizui T. 599
Moak D.H. 483
Molina V. 455
Mong J. 726
Monster T.B.M. 485
Montrucchio G. 547
Moosa M.Y.H. 482
Morais P.L. 526
Moride Y. 587
Moriya T. 633
Morrow T. 722
Moustafa A.A. 379
Mueller B. 426
Mueller M. 504
Mukherjee M. 691
Mulders A.G.M.G.J. 544
Munhoz C.D. 464
Münz H. 744
Murakami S. 525
Murakami Y. 505
Muro L.V. 582
Nakagawa K. 738
Nakano H. 444
Nakao H. 446
Nakayama K. 665, 666
Nakazawa T. 417
Namiranian K. 593
Nash J. 707
Nelemans S.A. 518
New D.I. 566
Ng E.H.Y. 542
Nicholson K.L. 471
Nicolau D.P. 680
Nicolini A. 631
Nikaido H. 472
Nikolski V. 573
Nilsson-Ehle H. 389
Nishizaki Y. 446
Nitiss J.L. 627
Nitiss K.C. 627
Nomura T. 745
Norman D. 566
Nuñez A. 463
Nuttall M.C. 523
Nwozo S.O. 743
Obniska J. 476
Ogawara K.-I. 521
Ogi N. 599
Ohki R. 503
Ohsawa K. 417
Ohtake K. 427
Ohtani S. 521
Ohtsuka M. 665, 666
Okimoto K. 442
Olsen G.L. 689
Omoloso A.D. 749
Onocha P.A. 743
Ookawa K. 607
Orhan F. 516
Orjales A. 597
Orkin R.D. 566
Ortiz Burguillos J.M. 675
Oshima T. 519
Osipo C. 640
Osnes J.-B. 510
Ou J.P. 402
Pace J.L. 658
Pache I. 565
Paget S.D. 660
Palmero S. 564
Pan W.-S. 555
Panchal A.R. 501
Pande R. 378
Pandey G.N. 404
Pandey S.C. 404
Pang J. 595
Panico A.M. 601
Panz V.R. 482
Papathanassiou M. 723
Paradkar A.R. 376
Pardina B. 575
Park J.H. 684
Park S.S. 711
Parr I. 662, 674
Pashos C. 577
Pasquali D. 567
Passalacqua W. 507
Patil C.S. 490
Pau D. 574
Pavelic K. 621
Pearce H.R. 591
Peçanha L.M.T. 731
Pelleymounter M.A. 470
Pentikäinen O.T. 438
Perez A. 694
Periasamy M. 508
Perka C. 450
Perloff M. 608
Pernak J. 700
Pero R.W. 737
Persky A.M. 380
Pescovitz M.D. 724
Pettersson A. 720
Pettitt D. 585
Pfaff D. 726
Picardo M. 473
Pieroni A. 744
Pieters L. 732
Pijl H. 531
Pillai O. 554
Piuvezam M.R. 731
Plottová Z. 550
Polak A. 692
Poljak-Blaži M. 714
Popovic-Todorovic B. 541
Posse De Chaves E.I. 465
Prater M.R. 725
Prato M. 431
Preda M. 539
Provan G.J. 733
Pucci G. 742
Punjabi K. 509
Pupo A.S. 526
Puri R.K. 625
Quercla R.A. 680
Qvigstad E. 510
Rabe K.F. 517
Rabin R.A. 460
Radhakrishnan R. 579
Raheem M.A. 659
Rahman M.A. 634
Raju B. 667
Ramakers G.M.J. 466
Rameshkumar N. 698
Ramos A.S. 392
Rathelot P. 413
Rea A.I. 748
Read R.A. 432
Regina M.J. 460
Reig S. 455
AUTHOR INDEX
Ren H. 696
Ren X. 404
Ren X.-D. 648
Renders L. 522
Richter S. 419
Rijcken C.A.W. 485
Risbrough V.B. 470
Robatel C. 410
Roberts M.S. 426
Rochon S. 587
Rodrigo R. 507
Rodrı́guez J. 576
Rodrı́guez-López V. 746
Rönkkö S. 403
Rösen R. 513
Rosenkranz A. 513
Rostom S.A.F. 697
Rothermel C.D. 693
Rots M.G. 422
Rue S.W. 704
Ruiz-Nuño A. 441
Ruponen M. 403
Russell R.G.G. 407
Sabahi F. 718
Sabarinath S. 395
Sabirsh A. 720
Sabourin M. 627
Sacerio A.L. 582
Sa̧czewski F. 636
Sahin F. 699
Sai Y. 472
Sakagami H. 745
Sakamoto C. 515
Sakano Y. 390
Salazar L. 746
Salio M. 500
Salvi M. 435
Sama W. 743
Sampson J.H. 551
Sánchez A. 552
Sandini L. 565
Sandnes D. 510
Santagati N.A. 682
Santos P.R. 708
Saria A. 489
Sarr M. 434
Sarramea F. 455
Sartori L. 418
Saruwatari J. 738
Sasse F. 654
Satdive R.K. 741
Satoh K. 745
Savi P. 546
Scarabelli L. 564
Scarsdale J.N. 628
Schmidt C.A. 392
Schmidt J.M. 748
Schneider P. 669
Schöcklmann H. 522
Schröder C.H. 702
Schwartz J.S. 585
Scott L.J. 451
Scozzafava A. 452
Sechi L.A. 685
Seely J. 605
Sehgal G. 475
Seibel M. 695
Seliga A. 468
Sellers W.R. 613
Selvakumar N. 659
Sena V.L.M. 415
Sengupta T. 691
Sesardic D. 491
Settimo L. 438
3
Setzer W.N. 748
Sha F. 421
Shaffu B. 561
Shah B. 411
Shakarova A.N. 499
Shalaby M.A. 697
Shao L. 647
Sharma M. 388
Shen A. 735
Shenkar N. 504
Shepherdley C.A. 537
Shibata K. 488
Shibata N. 678
Shibuya M. 390
Shigetomi M. 657
Shima Y. 386
Shindo J. 738
Shirai Y. 721
Shubert D.E. 388
Sidhu K.S. 396
Siedlecki J. 662, 674
Sierra A. 463
Sigurdsson S.Th. 689
Silva D.O. 606
Silva R.O. 415
Simpson I. 655
Singh A. 490
Singh S.K. 395
Singh U. 667
Široký M. 550
Sitaras N.M. 723
Skrha J. 560
Sluka K.A. 579
Smidt M.P. 394, 466
Smit J.A. 528
Smith C. 722
Smith M.R. 613
Smith P.F. 409
Smits S.M. 394
Soares-Da-Silva P. 474
Sobhia M.E. 428
Sobue M. 519
Södersten P. 457
Song J.L. 562
Song M.-S. 465
Souza Jr. J. 701
Spalluto G. 431
Specklin J.-L. 671
Spink B.C. 433
Srivastava R.M. 415
Stanley W.C. 501
Stephens J. 577
Steveling A. 535
Straetemans R. 475
Strandhagen E. 492
Sturm K. 489
4
Su S.L. 750
Subirade M. 676
Subramanian E.H. 698
Sudo N. 729
Sueyasu M. 729
Sultan M.A. 610
Sun H.K. 680
Sun J. 571
Sun P. 648
Sundram A. 670
Süsal C. 614
Suzuki K. 584
Suzuki T. 633
Taboada M. 576
Takenaka T. 493
Tan K.T. 514
Tanaka K. 588
Tanaka S. 556
Tang N. 570
Tang O.S. 542
Tang R. 555
Tang W.H.W. 496
Tani T. 558
Taubert D. 513
Taylor D.M. 430
Teng X.W. 598
Terada Y. 515
Tesz G. 568
Thelle D.S. 492
Thomasco L.M. 663
Thrower B. 722
Tiligada E. 723
Tilz G.P. 713
Tintner R. 453
Toi M. 634
Tokar B. 709
Tominaga K. 442
Tong Q. 653
Toninello A. 435
Torigoe T. 617
Torres-Bahı́ S. 575
Tranholm M. 727
Triadafilopoulos G. 549
Troy H. 641
Trzaskos J.M. 595
Tsai T.-H. 400
Tsao T. 619
Tseng L.-L. 652
Tsubone T. 657
Tubiana-Hulin M. 638
Tug N. 527
Tuluc F. 398
Tups A. 530
Tutterova M. 447
Ueda H. 427
Ueno S. 503
Uil T.G. 422
Umebayashi C. 446
Unlu S. 594
Urch C.J. 655
Vallejo-Manzur F. 397
Valteau-Couanet D. 650
Valverde O. 580
Van Dijk G. 533
Van Duijnhoven E.M. 382
Van Meenen E. 732
Van Ree J.M. 581
Vanjari H. 378
Varon J. 397
Vavrinková H. 447
Verma J. 715
Vetter M. 557
Vicuña-Fernández N. 578
Villegas I. 597
Vittorio F. 601
Vlasuk G.P. 545
Vlietinck A. 732
Volonteri L.S. 486
Wadsworth R.M. 512
Wainwright C.L. 512
Wakonigg G. 489
Walters C.L. 467
Wan C. 498
Wang B.-C. 467
Wang D. 630
Wang G.-J. 520
Wang H. 733
Wang Q.G. 402
Wang Z. 377, 498
Wardas J. 462
Waring M.J. 423
Watkins W.J. 673
Weaver E.A. 663
Weaver M. 624
Weetman A.P. 537
Weiss H.R. 509
Westbrook L. 656
Wexler I.D. 560
Wheeler R. 712
Wiedmann T.S. 387
Wigler I. 589
Wilkinson J.M. 448
Wilson A.D.H. 572
Winter J.C. 460
Wise A. 439
Wisniecki A. 469
Wojta J. 548
Wójtowicz H. 683
Wolfarth S. 462
Wong N. 600
AUTHOR INDEX
Wood N.J. 618
Wu D.-Z. 440
Wu Q.-M. 653
Xaplanteri M.A. 688
Xue Z.-H. 623
Yabuta T. 538
Yagi M. 734
Yamamoto K. 503, 620
Yamamoto T. 588
Yan J. 735
Yang G. 569
Yao G. 717
Yaraee R. 718
Yaron M. 589
Yasuda T. 417
Yasui-Furukori N. 412
Yeh R.W. 549
Yeung W.S.B. 402
Yim D.-S. 679
Yokogawa K. 386
Yoneda T. 611
Yoo H. 684
Yoon Y.D. 736
Yoshida M. 525
Yu B.-P. 603
Yu J.-P. 653
Yuan Z.-R. 571
Yun B.Y. 646
Zabielski R. 536
Zacchigna M. 384
Zagorska A. 476
Zamora P. 615
Zanetti S. 685
Zaslavskaya R.M. 499
Zawalich K.C. 568
Zawalich W.S. 568
Zernig G. 489
Zhang H.-W. 648
Zhang J. 411
Zhang W.-J. 548
Zhang X. 681
Zhang Z. 377
Zhao Q. 595
Zhao W.-C. 570
Zhou B. 498
Zhou Y. 508
Zhu J.-X. 570
Zippel H. 450
Zittermann A. 449
Ziyyat A. 740
Zong H. 735
Županović Z. 714
Zurenko G.E. 664

contents - Médecins d`Afrique

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