European Journal of Drug Metabolism and Pharmacokinetics (IF

Резюмета на трудовете на гл.ас. Магдалена Кондева-Бурдина, дф за
участие в конкурс за заемане на академичната длъжност "ДОЦЕНТ"
по научна специалност „Токсикология”; област на висше
образование 7. „Здравеопазване и спорт“; по професионално
направление 7.3. „Фармация“; за нуждите на преподаването по
„Токсикология”; към катедра „Фармакология, Фармакотерапия и
Токсикология“,
Фармацевтичен
факултет
при
Медицински
университет-София (ДВ, бр. 7/27. 01. 2015 г.)
Mitcheva M, Vitcheva V, Kondeva M, Nikolov S. Possible interaction of cytochrome
P450 (CYP) with biological active substances in plants. PHARMACIA, 2003; Vol. L
(3-4): 31-36.
In plants and animals, cytochrome P450 is a multienzyme essential system,
consisting of an isoenzyme family, coded by different genes. Substrates of
cytochrome P450 included a variety of endogenous substances as well as
xenobiotics, such as drugs. All these substrates could affect its activity. Their coadministration gives an opportunity for interactions on the metabolic level. These
interactions lead very often to unfavorable outcomes. A nomenclature system for
indication of the particular families and sub-families of cytochrome P450 isoenzymes
(CYP) has been accepted. Therefore, arabic numbers and latine characters are used,
e.g. CYP1A2, 2B1, 3A4, 2C19, 2E1, 2D6 etc. A number of herbal biological active
substances, included in drugs, as well as in medicinal herbs and food supplements,
find application for prevention and medication of different diseases. Based on
possible interactions of cytochrome P450 with biological active substances in plants,
their irrational use very often ends in failure.
Kondeva M, Mitcheva M, Nikolov S. Effect of the Diosgenin in fresh isolated rat
hepatocytes, treated with carbon tetrachloride. European Journal of Drug
Metabolism and Pharmacokinetics (IF=0.474), 2003; Vol. 28 (1): P 068
(electronic version).
Isolated hepatocytes are used as a model system to identify metabolic pathways and
to evaluate the hepatoprotective effects of drugs and plant substances. Diosgenin,
isolated from Asparagus officinalis, in concentration 10 µM revealed cytoprotective
and antioxidant activity in model of metabolic bioactivation (induced by carbon
tetrachloride – in concentration 86 µM) in freshly isolated rat hepatocytes. It
statistically significant preserved cell viability and level of reduced glutathione and
decreased the LDH leakage and MDA production, compared to the toxic agent.
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Kondeva M, Mitcheva M, Kitanov G, Ignatova I. Effect of the annulatophenone
(Hd15) on cell viability in fresh isolated rat hepatocytes. European Journal of
Drug Metabolism and Pharmacokinetics (IF=0.474), 2003; Vol. 28 (1): P 067
(electronic version).
Annulatophenone (Hd15), isolated from Hypericum annulatum, showed a good
cytoprotective effect in conditions of carbon tetrachloride-induced toxicity in isolated
rat hepatocytes from adult and young rats.
Age influence the cell viability. The initial viability in young rats is 81 %, while in
adult – is 67 %. The hepatocytes’ viability decreased during age with 23 %. The
hepatocytes were treated with carbon tetrachloride and the cell vibility was
decreased with 43 % - in young rats and 37 % - in adult rats. The viability was lower
with 14 % in adult rats. Hd15 had dose-dependent protective effect in carbon
tetrachloride-induced toxicity. The protection is better in the low concentration in
adult rats (viability rise up with 65 %), which is connected with metabolic
interactions.
Mitcheva M, Vitcheva V, Kondeva M, Simeonova R. Experimental study for liver
toxicity of Kava-Kava extract in rats. PHARMACIA, 2004; Vol. LI (3-4): 25-28.
During the recent years, case reports of severe liver toxicity including hepatitis,
cirrhosis, and liver failure requiring liver transplantation have been reported in
ralation to the use of kava-containing herbal products. The aim of the present study
was to trace the possible hepatotoxic effects of kava-kava extract after a 4-day
administration in rats. Assessments were made for parameters, characterizing regular
hepatic function and connected with kava-kava biotransformation, such as:
transaminase activity (GOT/GPT), MDA quantity, GSH level, changes in the
component of the electron-transport chain – cytochrome b5, P450 and hem. In view
of certain potential metabolic interactions, the effect of kava-kava on hexobarbital
metabolism was examined as well. Considering the results of our study, we could
accept that kava-kava showed hepatotoxicity that is most probably due to its hepatic
metabolism. Its multifold administration, together with other drugs undergoing
hepatic biotransformation, might lead to a potential risk of therapeutic failures.
Mavrova AT, Anichina KK, Vuchev DI, Tsenov JA, Kondeva MS, Mitcheva MK.
Synthesis
and
antitrichinellosis
activity
of
some
2-substituted[1,3]thiazolo[3,2a]benzimidazol-3(2H)-ones. Bioorganic & Medicinal Chemistry
(IF=2.286), 2005; 13: 5550-5559.
Some new thiazolo[3,2-a]benzimidazolone derivatives were synthesized using two
methods. The structures of the synthesized compounds were proved by means of IR,
1H NMR and mass spectral data. Ab initio computations were performed in order to
2
determine the electronic structure and geometry of the investigated molecules and to
compare it to the geometry of albendazole. Biologically, experiments in vitro and in
vivo were accomplished in order to identify the efficacy of the obtained
thiazolobenzimidazolones against Trchinella spiralis. The effectiveness of compounds
4a-c in the intestinal phase of trichinellosis was 100 % and in the muscle phase
were 88 % and 80 % at a concentration of 100 mg/kg mw for the compounds 4a
and 4c. The results of the hepatotoxicity test showed that the compounds 4a and 4b
possess hepatotoxicity comparable to that of albendazole.
Mitcheva M, Kondeva M, Vitcheva V, Nedialkov P, Kitanov G. Effect of
benzophenones from Hypericum annulatum on carbon tetrachloride-induced toxicity
in freshly isolated rat hepatocytes. Redox Report (IF=1.593), 2006; 11(1): 3-8.
Five benzophenones and a xanthone, isolated from Hypericum annulatum Moris,
were investigated for their protective effect against carbon tetrachloride toxicity in
isolated rat hepatocytes. The benzophenones and the xanthone gentisein were
administered alone (100 µM) and in combination with CCl4 (86 µM). CCl4 undergoes
dehalogenation in the liver endoplasmic reticulum. This process leads to
trichlormethyl radical (•CCl3) formation, initiation of lipid peroxidation, and
measurable toxic effects on hepatocytes. The levels of thiobarbituric acid reactive
substances (TBARS) were assayed as an index of lipid peroxidation (LPO). Lactate
dehydrogenase (LDH) leakage, cell viability and reduced glutathione (GSH) depletion
were used as signs of cytotoxicity. CCl4 significantly decreased hepatocytes viability,
GSH level and increased TBARS level and LDH leakage as compared to the control.
Our data indicate that 2,3′,5′,6-tetrahydroxy-4-methoxybenzophenone, 2-O-α-Larabinofuranosyl-3′,5′,6-trihydroxy-4-methoxybenzophenone
and
2-O-α-L-3′acetylarabinofuranosyl-3′,5′,6-trihydroxy-4-methoxybenzophenone showed weaker
toxic effects compared to CCl4 and in combination showed statistically significant
protection against the toxic agent.
Mavrova AT, Anichina KK, Vuchev DI, Tsenov JA, Denkova PS, Kondeva MS,
Mitcheva MK. Antihelminthic activity of some newly synthesized 5(6)-(un)substituted1H-benzimidazol-2-ylthioacetylpiperazine derivatives. European Journal of
Medicinal Chemistry (IF=2.187), 2006; 41: 1412-1420.
Piperazine derivatives of 5(6)-substituted-(1H-benzimidazol-2-ylthio)acetic acids were
synthesized by using two methods and studied for antihelminthic activity. The
antiparasitic screening showed that compounds 18-24 exhibited higher activity
against Trichinella spiralis in vitro in comparison to methyl 5-(propylthio)-1Hbenzimidazol-2-yl-carbamate (albendazole). Most active were compounds 2-({2-[4(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}thio)-1H-benzimidazole 21 and 2-{[2-oxo2-(4-benzhydrylpiperazin-1-yl)ethyl]thio}-5(6)-methyl-1(H)-benzimidazole 19 as well
3
as
2-({2-[4-(4-chlorophenyl)piperazin-1-yl]-2-oxoethyl}thio)-5(6)-methyl-1(H)benzimidazole 23 with efficacy of 96.0 %, 98.4 % and 100 % respectively. The
tested derivatives 15-19 and 20-23 were less active against Syphacia obvelata in
vivo than albendazole and exhibited the same efficacy as piperazine, but in twice
lower
concentration.
Compounds
2-({2-[4-(4-chlorophenyl)piperazin-1-yl]-2oxoethyl}thio)-1H-benzimidazole
21,
1,4-bis[(5(6)-methyl-1(H)-benzimidazol-2ylthio)acethyl]piperazine
17
and
2-({2-[4-(4-chlorophenyl)piperazin-1-yl]-2oxoethyl}thio)-5(6)-methyl-1(H)-benzimidazole 23 had higher efficacies of 73 %, 76
% and 77 %, respectively.
Kondeva-Burdina M, Mitcheva M, Krasteva I, Nikolov S. Effect of Diosgenin on cell
viability in freshly isolated hepatocytes from Phenobarbital-treated rats.
PHARMACIA, 2006; Vol. LIII (4): 21-23.
Diosgenin, isolated from Asparagus officinalis L. (Liliaceae) was investigated on cell
iability in hepatocytes from rats, treated with phenobarbital. Diosgenin was
administered alone in four concentrations: 0.01 µM, 0.1 µM, 10 µM and 100 µM. The
effects were compared to silymarin, which is a known hepatoprotector. For isolation
of the hepatocytes, the two-step collagenase perfusion was used. Cell viability was
assessed by trypan blue vital dye exclusion (0.05 %). The effect was concentration
dependent, most pronounced in the highest concentration – 100 µM. In hepatocytes
from phenobarbital-treated rats, the effect of diosgenin was more extensive in
respect to the controls (hepatocytes from non-treated with phenobarbital rats).
Diosgenin had stronger effect than that of silymarin.
Krasteva A, Mitcheva M, Kondeva-Burdina MS, Descatoire V. In vitro study of
lovastatin interactions with amiodarone and with carbon tetrachloride in isolated rat
hepatocytes. World Journal of Gastroenterology (IF=2.081), 2007; 13(15):
2198-2204.
The aim of this study is to investigate the interactions at a metabolic level between
lovastatin, amiodarone and carbon tetrachloride in isolated rat hepatocytes. For cell
isolation two-step collagenase liver perfusion was performed. Lovastatin was
administered alone in increasing concentrations (1 µmol/L, 3 µmol/L, 5 µmol/L and
10 µmol/L) and in combination with CCl4 (86 µmol/L). The cells were also pre-treated
with 14 µmol/L amiodarone and then the other two compounds were added.
Lovastatin promoted concentration-dependent significant toxicity estimated by
decrease in cell viability and GSH level by 45 % and 84 %, respectively. LDH activity
increased by 114 % and TBARS content by 90 %. CCl4 induced the expected severe
damage on the examined parameters. CCl4-induced toxicity was attenuated after
lovastatin pre-treatment, which was expressed in less increased values of LDH
activity and TBARS levels, as well as in less decreased cell viability and GSH
4
concentrations. However, the pre-treatment of hepatocytes with amiodarone
abolished the protective effect of lovastatin. We suggest that the observed
cytoprotective effect was due to interactions between lovastatin, CCl4 and
amiodarone at a metabolic level.
Mitcheva M, Kondeva-Burdina M, Vitcheva V, Krasteva I, Nikolov S. Effect of
purified saponin mixture from Astragalus corniculatus on toxicity models in isolated
rat hepatocytes. Pharmaceutical Biology (IF=0.488), 2008; 46 (12): 866-870.
A purified saponin mixture (PSM), isolated from Astragalus corniculatus Bieb.
(Fabaceae) was investigated for its protective effect in two models of toxicity, carbon
tetrachloride (CCl4) and tert-butyl hydroperoxide (t-BuOOH), using isolated rat
hepatocytes. CCl4 undergoes dehalogenation in the liver endoplasmic reticulum. This
process leads to trichlormethyl radical (•CCl3) formation, initiation of lipid
peroxidation, and measurable toxic effects on the hepatocytes. Oxidative damage is
widely recognized as being involved in the development of many pathological
conditions. In our experiment, t-BuOOH was used as a model of oxidative stress. The
hepatocytes were incubated with the PSM alone (0.01-100 µM) and along with CCl4
(86 µM) and t-BuOOH (75 µM). As a sign of cytotoxicity, cell viability was used. CCl4
and t-BuOOH significantly decreased hepatocyte viability. Our data indicate that PSM
showed lower toxic effects compared to CCl4 and t-BuOOH and in combination
exerted statistically significant protection of cell viability against the toxic agents.
Kondeva-Burdina M, Deneva S, Mitcheva M. Changes in the activity of some drug
metabolizing enzyme systems and cytochrome P450 quantity after multiple Fluoxeine
administratin in rats. PHARMACIA, 2008; LV(1-4): 34-37.
Fluoxetine is one of the most widely used selective serotonin re-uptake inhibitors
(SSRIs) in psychiatry. It can be used alone and in combination with other drugs.
These combinations can result in adverse drug effects, connected with interactions
on metabolic level. In our study, we investigate the influence of Fluoxetine after
multiple administration on total cytochrome P450 quantity and on drug metabolizing
enzyme systems activity – ethylmorphine N-demethylase (EMND) and aniline
hydroxylase (AH). Microsomes were prepared by two different methods –
ultracentrifugation and low speed centrifugation following sedimentation of the
microsomal membranes in the presence of calcium ions. We found no statistically
significant difference in results of total cytochrome P450 level between microsomes,
prepared by both methods. As a result of the experiment, we found that after
multiple administrations Fluoxeine, like Phenobarbital, increases significantly the level
of total cytochrome P450 and the activity of EMND and AH.
5
Vitcheva V, Kondeva-Burdina M, Mitcheva M. D-Amphetamine toxicity in freshly
isolated rat hepatocytes: a possible role of CYP3A. Arhiv za Higijenu Rada i
Toksikologiju, 2009; 60(2): 139-145.
The aim of this study was to trace D-amphetamine toxicity in isolated rat
hepatocytes and to elucidate a possible involvement of CYP3A in the mechanisms of
its toxicity. To this end, male Wistar rats were treated with nifedipine (5 mg kg-1 i.p.,
5 days), a substrate and inducer of CYP3A. Hepatocytes isolated from nifedipinetreated and control rats were incubated with D-amphetamine at a concentration 100
µmol L-1, which was determined to be an average toxic concentration (TC50) for the
compound. To evaluate the possible toxic effects of D-amphetamine on freshly
isolated rat hepatocytes, we assessed the following parameters: cell viability, lactate
dehydrogense (LDH) activity, and glutathione (GSH). The results showed that
nifedipine potentiated amphetamine cytotoxicity in vitro, as follows: cell viability
dropped by 65 % (p<0.001), GSH by 80 % (p<0.001), and LDH activity increased by
190 % (p<0.001). To clarify the role of nifedipine in amphetamine cytotoxicity, we
used amiodarone, a substrate and an inhibitor of CYP3A. Pre-incubation of
nifedipine-treated hepatocytes with amiodarone (14 µmol L-1) significantly lowered
amphetamine cytotoxicity. Our results confirmed the toxicity of D-amphetamine in
isolated rat hepatocytes and the involvement of CYP3A in its metabolism and
hepatotoxicity.
Mitcheva M, Kondeva-Burdina M, Krasteva I, Nikolov S. In vitro assessment of
effect of Diosgenin, isolated from Asparagus officinalis, on spontaneously
hypertensive (SHR) and old rats. Archives of the Balkan Medical Union, 2009;
44(2): 137-141.
Diosgenin has anti-hyperholesterolemic and anti-inflammatory activities. Mohsen et
al. Have found that Dioscorea, containing diosgenin, has antioxidative effect in older
patients. Present study aims at investigating of in vitro effect of diosgenin (10 µM),
isolated from Asparagus officinalis L. (Liliaceae) in conditions of oxidative stress.
Experiments are performed in vitro – in cellular (isolated rat hepatocytes) and subcellular (rat microsomes) level. Effect of diosgenin is studied on non-enzymic-induced
lipid peroxidation in isolated microsomes from Normotensive (NTR) and
Spontaneously Hypertensive rats (SHR) and on isolated hepatocytes from young and
old rats. Hypertension as pathological factor and age lead to oxidative stress. Levels
of thiobarbituric acid reactive substances (TBARS) are assayed as an index of lipid
peroxidation (LPO) and reduced glutathione (GSH) depletion – sign of cytotoxicity. In
microsomes protective effects of diosgenin on TBARS are stronger in SHR, comparing
to NTR. These effects are compared to those of promethazine. In isolated
hepatocytes from old rats, diosgenin has more intensive protective effect compared
6
to the young rats. Effects on isolated hepatocytes are compared to the ones of
silymarin.
Mitcheva M, Kondeva-Burdina M, Vitcheva V. Study on hepatotoxicity of cytisine
(TABEX®) compared with nicotine in freshly isolated rat hepatocytes. PHARMACIA,
2009; LVI(1-4): 27-32.
The aim of the study was to investigate the effects of cytisine and nicotine in seven
consequently increasing concentrations (5 nM – 250 µM) in isolated rat hepatocytes.
The level of malondialdehyde (MDA) was assayed as index of lipid peroxidation
(LPO). Lactate dehydrogenase (LDH) leakage, cell viability and reduced glutathione
(GSH) depletion were used as signs of cytotoxicity. Our data indicate that cytisine
has significantly less prominent toxicity on cell viability and GSH level than nicotine.
At the same time, we found higher toxicity of cytisine on MDA level. The higher
cytotoxicity exerted by nicotine on cell viability and GSH level might be due to its
metabolites. The results from this study showed that nicotine did not affect MDA
level in the same extent as cytisine. This might be explained with the ability of
nicotine to inhibit superoxide anion and other reactive oxygen species generation,
involved in the process of lipid peroxidation and oxidative stress.
Mitcheva M, Kondeva-Burdina M, Krasteva I, Nikolov S. Protective effect of
purified saponin mixture from Astragalus corniculatus on toxicity models in vitro.
Medical management of chemical and biological casualties, 2009; Ed. by S.
Tonev, K. Kanev, C. Dishovsky; Publishinf House IRITA: 239-251.
A purified saponin mixture (PSM), isolated from Astragalus corniculatus Bieb.
(Fabaceae) was investigated for its protective effect on different models of toxicity in
vitro on sub-cellular and cellular level. In conditions of non-enzyme and enzyme lipid
peroxidation, PSM showed statistically significant antioxidative effect, similar to the
effect of silymarin. These results correlate with data for antioxidant activity of
saponin cycloestragenol-xylozil-glycoside, isolated from extract of Astragalus
membranaceus in mice liver. In rat brain synaptosomes, prepared by using Percol
reagent, PSM had statistically significant protective effect, similar to those of
silymarin on 6-hydroxy-dopamine-induced oxidative stress. These results correlate
with literature data about protective effects of Astragalus in conditions of stress in
rats. In rat hepatocytes, isolated by two-stepped collagenase perfusion, we
investigate the effect of PSM on two models of liver toxicity: metabolic bioactivation
– carbon tetrachloride (CCl4) and mainly mitochondrial induced oxidative stress –
tert-butyl hydroperoxide (t-BuOOH). In CCl4-induced toxicity, PSM had statistically
significant cytoprotective and antioxidant activity, near to those of silymarin. These
data are supported by literature data about protective effect of saponins, isolated
from Astragalus membranaceus and Astragalus sieversianus on hepatotoxicity,
7
induced by CCl4 and Paracetamol in mice. In model of oxidative stress – induced by
t-BuOOH, PSM had statistically significant cytoprotective and antioxidant activity,
stronger than the effect of silymarin. These effects of PSM may be due to the
influence of the mitochondrial function, which includes the mitochondrial metabolism
of t-BuOOH and correlate with data about antioxidant activity in vitro of water extract
of Astragalus on mitochondria, isolated from rat heart.
Simeonova RL, Vitcheva VB, Kondeva-Burdina MS, Krasteva IN, Nikolov SD,
Mitcheva MK. Effect of purified saponin mixture from Astragalus corniculatus on
enzyme- and non-enzyme-induced lipid peroxidation in liver microsomes from
spontaneously hypertensive rats and normotensive rats. Phytomedicine
(IF=2.662), 2010; 17: 346-349.
The aim of the following study was to evaluate the effect of a purified saponin
mixture (PSM), isolated from Astragalus corniculatus Bieb. (Fabaceae), on enzymeinduced and non-enzyme-induced lipid peroxidation (LPO), in liver microsomes from
spontaneously hypertensive rats (SHRs) – strain Okamoto Aoki, as compared to
normotensive Wistar rats (NTRs). The enzyme-induced lipid peroxidation was
performed by incubating rat liver microsomes with carbon tetrachloride (CCl4) in the
presence of NADPH. In non-enzyme-induced LPO, the microsomes were incubated
with a solution of iron sulphate and ascorbinic acid (Fe2+/AA). The effect of PSM
(196.5 µg/ml) was assessed at 20 minutes’ incubation time. MDA, a product of LPO,
was measured spectrophotometrically. The results of our study showed that initial
MDA quantity in SHRs was significantly higher, than in NTRs. The incubation of the
microsomes from both strains with PSM (196.5 µg/ml), resulted in significant
reduction of MDA level, by 25 % in SHRs. In NTRs, the formation of MDA was
unchanged. In enzyme-induced LPO model, PSM significantly decreased the
formation of MDA, by 55 % in NTRs and by 35 % in SHRs, compared to the
respective control groups. In the model of non-enzyme induced LPO, PSM
significantly decreased the formation of MDA by 95 % in NTRs and practically
restored it to the control level. The MDA quantity in SHR’s microsomes was reduced
by 25 %. According to the results of this experiment we could conclude that PSM,
isolated from Astragalus corniculatus, shows antioxidant activity both in SHRs and
NTRs and the effect in NTRs is more pronounced.
Kondeva-Burdina M, Astroug H, Bechar E, Vitcheva V, Valkova I, Mitcheva M.
Comparative studies of two new valproic acid derivatives on rat hepatocytes.
PHARMACIA, 2010; LVII(1-4): 51-55.
The cytotoxicity of two new valproic acid derivatives: N-(4-acetylphenyl-2-propylpentanamide) (E-31) and 4-((2-propylpentanoyl)-aminobenzoic acid) (E-21), with
proven anti-epileptic activity, are compared to valproic acid (VPA), using freshly
8
isolated rat hepatocytes, a well-controlled biological model system in vitro with high
metabolizing capacity. In rats, as in humans, VPA is metabolized in the liver by
cytochrome P450. As derivatives of VPA, we hypothesize that changes in their
structure will result in differences in their metabolism and toxicity. Hepatocytes are
treated for two hours with each compound at three concentrations: 0.1 mM, 0.3 mM
and 1 mM. Effects of E-31 and E-21 on the cells are assessed by measuring cell
viability, lactate dehydrogense (LDH) activity and reduced glutathione (GSH) level. E31 and E-21 are less cytotoxic than VPA in isolated rat hepatocytes most pronounced
at the highest concentration (1 mM). This is probably related to the different
metabolism of the newly synthesized compounds, compared to VPA.
Mitcheva M, Vitcheva V, Kondeva-Burdina M, Simeonova-Vitanska R. Adverse drug
reactions: experimental studies on metabolic-mediated toxicity. Autonomic &
Autacoid Pharmacology, 2010; 30(2): 117-120.
Our scientific studies included a group of medicines and prospective bioactive
substances (BAS), from natural and synthetic origin, with a certain pharmacological
activity and proved or supposed hepatic biotransformation. The compounds have
been investigated for cytotoxicity and in some cases for antioxidant and protective
effects. These studies were performed in cellular and sub-cellular models of toxicity,
both in vitro and in vivo. The effects of the examined compounds have been
compared to the effects of referent compounds. Elucidating of these effects might
contribute to enrichment of their characteristics, linked to their metabolism and to
prevent possible metabolic interactions. These experiments are part of the preclinical studies of novel compounds. In many cases they could explain some of the
future serious clinical problems, as well as to elucidate the main causes for the
failure of certain molecules, as candidate-drug.
Simeonova R, Krasteva I, Kondeva-Burdina M, Benbassat N. Effects of extract
from Astragalus glycyphylloides on carbon tetrachloride-induced hepatotoxicity in
Wistar rats. International Journal of Pharma and Bio Sciences (IF=0.470),
2013; 4(3): 179-186.
The antioxidant effect of aqueous-ethanolic extract from Astragalus glycyphylloides
(Fabaceae), and its protection against carbon tetrachloride-induced hepatotoxicity
were investigated in male Wistar rats. For seven consequent days the animals were
treated orally with A. glycyphylloides extract (EAG) (100 mg/kg). Two hours after the
last administration the animals were charged with carbon tetrachloride (10 %, 1.25
ml/kg p.o.). The rats were sacrificed 18 hours later by decapitation. Carbon
tetrachloride, administered alone, induced significant hepatotoxicity, manifested with
reduced glutathione (GSH) depletion, increased level of malondialdehyde (MDA) and
reduced antioxidant defense. EAG pre-tretment, however, completely reversed the
9
effect of carbon tetrachloride on GSH and MDA concentrations and antioxidant
enzyme activities as catalase (CAT), superoxide dismutase (SOD), glutathione
peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST).
The results of this study showed an antioxidant activity of extract from Astragalus
glycyphylloides and its protective effect against cerbon tetrachoride-induced
oxidative stress and hepatotoxicity.
Kondeva-Burdina M, Simeonova R, Krasteva I, Benbassat N. Protective effects of
extract from Astragalus glycyphylloides on carbon tetrachloride-induced toxicity in
isolated rat hepatocytes. Biotechnology & Biotechnological Equipment
(IF=0.379), 2013; 27(3): 3866-3869.
Ethanol extract from Astragalus glycyphylloides was investigated for possible
protective effect on carbon tetrachloride (CCl4)-induced cytotoxicity (model of
metabolic bioactivation) (86 µmol/L) in isolated rat hepatocytes, a well-controlled
biological model system in vitro with high metabolizing capacity. Hepatocytes isolated
by two-step collagenase perfusion were treated with 10 µg/ml and 100 µg/ml of the
extract and with silymarin – 7 µg/ml and 70 µg/ml. In this model, the extract had
statistically significant cytoprotective and antioxidant activity, near to those of
silymarin. These data are supported by reports about the protective efects of saponin
isolated from Astragalus membranaceuse and Astragalus sieversianus on
hepatotoxicity induced by CCl4 and Paracetamol in mice.
Simeonova R, Vitcheva V, Kondeva-Burdina M, Krasteva I, Manov V, Mitcheva M.
Hepatoprotective and antioxidant effects of saponarin, isolated from Gypsophila
trichotoma Wend. on paracetamol-induced liver damage in rats. BioMed Research
International (IF=2.880), 2013; article ID 757126: 1-10.
The hepatoprotective potential of saponarin, isolated from Gypsophila trichotoma,
was evaluated in vitro/in vivo using a hepatotoxicity model of paracetamol-induced
liver injury. In freshly isolated rat hepatocytes, paracetamol (100 µmol/L) led to a
significant decrease in cell viability, increased LDH leakage, decreased level of
cellular GSH, and elevated MDA quantity. Saponarin (60-0.006 µg/ml) preincubation,
however, significantly ameliorated paracetamol-induced hepatotoxicity in a
concentration-dependent manner. The beneficial effect of saponarin was also
observed in vivo. Rats were challenged with paracetamol alone (600 mg/kg i.p.) and
after 7-day pre-treatment with saponarin (80 mg/kg, oral gavage). Paracetamol
toxicity was evidenced by increased in MDA quantity and decrease in cell GSH levels
and antioxidant defence system. No changes in phase I enzyme activities of AH and
EMND and cytochrome P450 quantity were detected. Saponarin pre-treatment
resulted in significant increase in cell antioxidant defence system and GSH levels and
decrease in lipid peroxidation. The biochemical changes are in good correlation with
10
the histopathological data. Protective activity of saponarin was similar to the activity
of postive control silymarin. On the basis of these results, it can be concluded that
saponarin exerts antioxidant and hepatoprotective activity against paracetamol liver
injury in vitro/in vivo.
Kondeva-Burdina M, Zheleva-Dimitrova D, Nedialkov P, Girreser, Mitcheva M.
Cytoprotective and antioxidant effects of phenolic compoundds from Haberlea
rhodopensis Friv. (Gesneriaceae). Pharmacognosy Magazine (IF=1.525), 2013;
9(36): 294-301.
Heberlea rhodopensis Friv. (Gesneriaceae) is a rare poikilohydric endemic and
preglacial relict growing in Balkan Peninsula. Previous investigations demonstrated
strong antioxidant, antimicrobial and antimutagenic potential of alcoholic extract
from the plant. The isolation of known caffeoyl phenylethanoid glucoside –
myconoside
and
flavone-C-glycosides
hispidulin
8-C-(2-O-syringoyl-βglucopyranoside), hispidulin 8-C-(6-O-acetyl-2-O-syringoyl-β-glucopyranoside), and
hispidulin 8-C-(6-O-acetyl-β-glucopyranoside) from the leaves of H. Rhodopensis was
carried out. The aim of this study was to investigate cytoprotective and antioxidant
effects of isolated compounds. Antioxidant activity of isolated substances was
examined using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) radicals; ferric
reducing antioxidant power (FRAP) assay and inhibition of lipid peroxidation (LPO) in
linoleic acid system by ferric thyocianate method. The compounds were in vestigated
for their possible protective and antioxidant effects against tert-butyl hydroperoxideinduced oxidative stress in isolated rat hepatocytes. The levels of thiobarbituric acid
reactive substances were assayed as an index of LPO. Lactate dehydrogenase
leakage, cell viability and reduced glutathione depletion were used as signs of
cytotoxicity. Myconoside demonstrated the highest DPPH radical scavenging, ABTS,
FRAP and antioxidant activity in linoleic acid system as well as the highest and
statistically most significant protection and antioxidant activity against the toxic
agent. Phenolic scavenging potential and inhibit lipid peroxidation, moreover,
myconoside was found to be a new powerful natural antioxidant.
Kondeva-Burdina M, Krasteva I, Nikolov S, Mitcheva M. In vivo effects of
diosgenin on the activity of some drug-metabolizing enzyme systems. PHARMACIA,
2013; 60(4): 21-25.
This study investigated the in vivo effect of diosgenin, isolated from Asparagus
officinalis, on the total quantity of cytochrome P450, the activity of some enzymes –
ethylmorphine N-demethylase (marker for CYP3A) and aniline hydoxylase (marker for
CYP2E1), the quantity of malondialdehyde and reduced glutathione, compared to
phenobarbital in rats. Diosgenin and phenobarbital, administered alone, increased
11
statistically significant, compared to control, the total amount of cytochrome P450 –
with 36 % and with 85 %; the activity of EMND with 58 % and with 184 %.
Diosgenin didn’t influenced the AH activity, compared to phenobarbital. Both
diosgenin and phenobarbital had no statistically significant effect on GSH level. On
the quantity of MDA, diosgenin had no effect, while phenobarbital increased it with
27 %. Our results showed that diosgenin exhibited inducible effect similar to the
effect of phenobarbital on the activity of some drug-metabolizing enzyme systems.
Кондева-Бурдина М. Бактериална резистентност. Здравен навигатор, 2013;
3: 6-7.
Основен проблем свързан с терапията на инфекциозните заболявания е бързата
поява на резистентност от страна на микроорганизмите към съответния
химиотерапевтик. Статията дава информация за възможните механизми на
бактериална резистентност, както и за факторите, допринасящи за развитието
на резистентност. Бактериалната резистентност налага необходимостта от
разработването на нови антимикробни средства, което е дълъг и скъпоструващ
процес за фармацевтичната индустрия. Познавайки механизмите на
бактериална резистентност и факторите, които допринасят за развитието ѝ, е
възможно да се осигури контрол на антибиотичната терапия, което ще намали
риска от повишаване процента на резистентни щамове микроорганизми и
компрометиране на терапията.
Simeonova R, Kondeva-Burdina M, Vitcheva V, Mitcheva M. Some in vitro/in vivo
chemically-induced experimental models of liver oxidative stress in rats. BioMed
Research International (IF=2.880), 2014; article ID 706302: 1-6.
Oxidative stress is critically involved in a variety of diseases. Reactive oxygen species
(ROS) are highly toxic molecules that are generated during the body’s metabolic
reactions and can react with and damage some cellular molecules such as lipids,
proteins, or DNA. Liver is an important target of the oxidative stress because of its
exposure to various pro-oxidant toxic compounds as well as of its metabolic function
and ability to transform some xenobiotics to reactive toxic metabolites (as ROS). To
investigate the processes of liver injuries and especially liver oxidative damages,
there are many experimental models.
Kondeva-Burdina M, Simeonova R, Vitcheva V, Kratseva I, Mitcheva M.
Cytoprotective effects of saponarin from Gypsophila trichotoma on tert-butyl
hydroperoxide and cocaine-induced toxicity in isolated rat hepatocytes.
TOXICOLOGICAL PROBLEMS, 2014; Ed. by C. Dishovsky & J. Radenkova-Saeva,
Military Publishing House: 313-318.
12
Saponarin, isolated from Gypsophila trichotoma Wend., was investigated for its
protective effects on two models of oxidative stres – tert-butyl hydroperoxide (tBuOOH) (75 µM) and cocaine (50 µM) in rat hepatocytes, isolated by two-stepped
collagenase perfusion. The effects of saponarin were compared with those of
silymarin. Cell incubation with t-BuOOH and cocaine led to a significant decrease in
cell viability, increased LDH leakage, decrease levels of cellular GSH and elevation in
MDA quantity. Cells’ pre-incubation with saponarin (60 µg/ml; 6 µg/ml; 0.06 µg/ml;
0.006 µg/ml) significantly ameliorated, in a concentration-dependent manner, the
toxicants-induced hepatocytes damage. The effects are similar to those of silymarin
(50 µg/ml; 5 µg/ml; 0.05 µg/ml; 0.005 µg/ml). Our results suggest that saponarin,
isolated from Gypsophila trichotoma Wend., showed cytoprotective and antioxidant
activity against two models of oxidative stress, possibly by affecting the metabolism
of tert-butyl hydroperoxide and cocaine.
Mitcheva M, Danchev N, Astroug H, Tzankova V, Simeonova R, Kondeva-Burdina
M, Vitcheva V. Toxicology – Faculty of Pharmacy, Medical University, Sofia – in the
years. TOXICOLOGICAL PROBLEMS, 2014; Ed. by C. Dishovsky & J. RadenkovaSaeva, Military Publishing House: 233-240.
Some forty five years ago the toxicology lectures have entered the curriculum of the
Faculty of Pharmacy with the Medical Academy in Sofia with the idea that the
pharmacy students need a broader knowledge in the medical-biological sciences. The
pioneers of these days understood that the alumni in Pharmacy should be familiar
not only with the activity, but with the mechanisms of toxic drug effects and with the
risks in their use, also improving their capacity to support the optimising and
individualising the proper drug therapy. The present achievement in implementation
of these demanding, but noble tasks is a result of the pioneers’ pledging efforts, of
their enthusiasm, dedication and responsibility. Since then the toxicology as a
discipline in the Faculty had developed and today it is an essential element of the
pharmaceutical education. It really interacts with Pharmacology, Pharmacotherapy
and other disciplinesand structures with the Faculty. The Department of
Pharmacology, Pharmacotherapy and Toxicology since the begining created a
favourable, friendly and cosy environment for creating of considerable scientific and
academic resources in Toxicology. One can distinguish the Toxicology teaching with
vanguard tendencies in the education and the formation of students, master-thesis’
students, specialists and PhD students. The toxicologists in the department have a
reach palette of scientific studies and publications in the fields of characterizing of
new molecules, of toxicokinetics, of drug metabolism and drug toxicity, of factors
affecting it, of bioactivation and deactivation, of drug abuse, of nanotoxicology etc.
The in vivo and the in vitro studies refer the latest trends in the different fields of
Toxicology and Pharmacy in collaboration with the leading Bularian and European
13
study centres. The activities in the field of toxicology contribute to the highest
accreditation rating of the Faculty of Pharmacy.
Mitcheva M, Kondeva-Burdina M. The processes of bioactivation, toxicity and
detoxication – experimental models for evaluation of the toxicity. TOXICOLOGICAL
PROBLEMS, 2014; Ed. by C. Dishovsky & J. Radenkova-Saeva, Military Publishing
House: 292-300.
Liver is the organ, where the main processes of biotransformation – deactivation,
bioactivation and detoxication of enobiotics – take place. The main experimental
models for evaluation of these processes are: carbon tetrachloride (CCl4)-induced
cytotoxicity (model of metabolic bioactivation) and tert-butyl hydroperoxide (tBuOOH)-induced oxidative stress. Our studies are connected with evaluation of in
vitro/in vivo harm effects of reactive metabolites, formed at metabolic level. We have
investigated the possibilities and the conditions of detoxication and protection by
different drugs and new perspective compounds from synthetic and natural origin.
The results show that the used experimental models are suitable for evaluation of
the bioactivation and detoxication processes.
Simeonova R, Kondeva-Burdina M, Vitcheva V, Mitcheva M. Effects of Damphetamine on brain and hepatocytes, isolated from male and female
spontaneously hypertensive rats (SHR). TOXICOLOGICAL PROBLEMS, 2014; Ed.
by C. Dishovsky & J. Radenkova-Saeva, Military Publishing House: 254-262.
D-Amphetamine is widely used drug of abuse, known to cause enhancement in blood
pressure, neurotoxicity and hepatotoxicity, both in humans and rats. Spontaneously
hypertensive rats (SHR) are generally used for studies in cardiovascular research. It
is well known that SHR are more sensitive to liver injury, provoked by some toxic
compounds than their normotensive controls. Regarding this information, the aim of
the following study was to investigate D-amphetamine brain toxicity and
hepatotoxicity in isolated hepatocytes from SHR, compared to normotensive WistarKyoto rats (WKY). In the first series of our experiments male and female SHRs and
WKY rats were treated with D-amphetamine (5 mg/kg bw/day, 5 days) and brain
toxicity of the compound was assessed by measuring nNOS activity, MDA quantity
and GSH levels. Neuronal NOS activity was statistically significant increase in the
brains taken from WKY rats but not in SHRs. MDA quantity increased and GSH levels
depleted in a similar way in both strains. Liver toxicity of D-amphetamine was
investigated in vitro in isolated rat hepatocytes, incubated with 100 µM of the
compound. D-amphetamine hepatotoxicity judged by decrease in cell viability and
GSH depletion was more pronounced in SHRs. However, MDA production was less
increased when compared to WKY rats. On the basis of this study we might suggest
that the observed differences are probably due to pathophysiology of SHR and it was
14
speculated that this strain possess
hepatoprotection and neuroprotection.
some
compensatory
mechanisms
to
Kondeva-Burdina M, Gorneva G, Mitcheva M. Effect of myosmine, administered
alone and on tert-butyl hydroperoxide-induced toxicity in isolated rat hepatocytes.
TOXICOLOGICAL PROBLEMS, 2014; Ed. by C. Dishovsky & J. Radenkova-Saeva,
Military Publishing House: 307-312.
The alkaloid myosmine [3-(1-pyrrolin-2-yl)-pyridine] is presented not only in tobacco
product but also in various foods. The cytotoxicity of myosmine was compared to
nicotine, using isolated rat hepatocytes. It was investigated also for possible
protective effect on tert-butyl hydroperoxide-induced toxicity. The effects of
myosmine were evaluated on rat hepaocytes, a well-controlled biological model
system in vitro, with high metabolizing capacity, isolated by two-stepped collagenase
perfusion. Hepatocytes were treated with equi toxic concentrations of myosmine (50
µM – 2 mM) and nicotine (5 nM – 250 µM). In tert-butyl hydroperoxide (75 µM)
model of toxicity, myosmine was in concentrations 100 µM and 250 µM. Administered
alone, myosmine revealed statistically significant, cytotoxic effects, which were
concentration-dependent and less toxic to those of nicotine. In tert-butyl
hydroperoxide model of toxicity, myosmine had statistically significant cytoprotective
effects. According to these results, we can suggest that such cytoprotective effect of
myosmine might be due to an influence on tert-butyl hydroperoxide metabolism in
rat hepatocytes.
Vitcheva V, Kondeva-Burdina M, Simeonova R, Mitcheva M. Cocaine toxicity in
freshly isolated rat hepatocytes – role of CYP2B and CYP3A. FARMACIA
(IF=1.251), 2014; 62(2): 264-272.
Cocaine is a psychoactive compound that undergoes extensive hepatic
biotransformation leading to formation of toxic metabolites responsible for its
hepatotoxicity. The objectives of this study were to investigate the influence of
induction and inhibition on cocaine hepatotoxicity examined in freshly isolated rat
hepatocytes. For investigating the role of induction male Wistar rats have been
treated in vivo with phenobarbital (75 mg kg-1, 4 days) and then isolated hepatocytes
were exposed of cocaine (50 µmol L-1 for one hour). Compared to control (nontreated hepatocytes), phenobarbital induction resulted in greater cocaine
hepatotoxicity, witnessed by decrease in cell viability by 52 %, increase in lactate
dehydrogenase (LDH) leakage into the medium by 120 %, depletion of reduced
glutathione (GSH) levels by 84 % and increase in malondialdehyde (MDA) quantity
by 74 %. Experimental data in the literature reported two major cytochrome P450
isoforms CYP3A and CYP2B to be involved in cocaine biotransformation and toxicity.
In order to trace the relative contribution of these isoforms to cocaine hepatotoxcity
15
in rats, isolated hepatocytes were pre-incubated for 15 min with amiodarone (15
µmol L-1) and with chloramphenicol (100 µmol L-1) inhibitors of CYP3A and CYP2B,
respectively. Pre-incubation with either of the inhibitors ameliorated cocaine
hepatotoxicity. Our results prove the role of both isoforms CYP3A and CYP2B in
cocaine biotransformation in rats.
Bratkov V, Kondeva-Burdina M, Simeonova R, Tzankova V, Kratseva I.
Phytochemical evaluation and effect of saponins’ mixture, isolated from Astragalus
monspessulanus on HepG2 cell line. European Journal of Medicinal Plants,
2014; 4(5): 522-527.
Purified saponin fraction was obtained from butanol extract of the aerial parts of
Astragalus monspessulanus. The fraction was analyzed by HPLC and six saponines
were determined. The saponin mixture was investigated for possible cytotoxicity on
HepG2 cell line. The saponin mixture was studied on HepG2 cell line in 3 different
concentrations – 1, 2, 4 mg/ml for 24, 48 and 72 hours. The release of lactate
dehydrogenase (LDH) in the medium was measured spectrophotometrically. It was
found that the saponins have statistically significant cytotoxicity only in the highest
concentration 4 mg/ml on 48 and 72 hours. At this concentration the sample
increased the level of LDH with 37 % on 48 h and with 52 % on 72 h. Purified
saponin fraction, isolated from Astragalus monspessulanus was found to be cytotoxic
at the highest concentration 4 mg/ml on 48 and 72 hours in HepG2 cell line.
Georgieva D, Kostova B, Ivanova S, Rachev D, Tzankova V, Kondeva-Burdina M,
Christova D. pH-Sensitive cationic copolymers of different macromolecular
architecture as potential dexamethasone sodium phosphate delivery systems.
Journal of Pharmaceutical sciences (IF=3.007), 2014; 103: 2406-2413.
This paper describes the synthesis and characterization of cationic copolymers with
different macromolecular architecture and drug delivery properties of the
corresponding dexamethasone sodium phosphate (DSP)-loaded systems.
Copolyelectrolytes comprising poly[2-(acryloyloxy)ethyl]-trimethylammonium chloride
(PAETMAC) and poly(ethylene glycol) blocks as well as a tri-arm star-shaped
PAETMAC were synthesized using cerium (IV)-ion-mediated polymerization method.
The obtained copolyelectrolytes and corresponding ionic associates with DSP have
been characterized by 1H NMR, Fourier Transform Infrared spectroscopy, and
differential scanning calorimetry. The average diameter, size distribution, and ξpotential of the copolymers and DSP-copolymer ionic associates were determined by
dynamic light scattering, and particles were visualized by scanning electron
microscopy and transmission electron microscopy. The biocompatibility and
cytotoxicity of obtained copolymers were determined. In vitro drug release
16
experiments were carried out to estimate the ability of the obtained nanoparticles for
sustained release of DSP for a period of 24 h.
Simeonova R, Kondeva-Burdina M, Vitcheva V, Krasteva I, Manov V, Mitcheva M.
Protective effects of the apigenin-O/C-diglucoside saponarin from Gypsophila
trichotoma on carbon tetrachloride-induced hepatotoxicity in vitro/in vivo in rats.
Phytomedicine (IF=2.877), 2014; 21: 148-154.
This study investigated the hepatoprotective activity of saponarin, isolated from
Gypsophila trichotoma Wend., using in vitro/in vivo hepatotoxicity model based on
carbon tetrachloride (CCl4)-induced liver damage in male Wistar rats. The effect of
saponarin was compared with those of silymarin. In vitro experiments were carried
out in primary isolated rat hepatocytes. Cell incubation with CCl4 (86 µmol L-1) led to
a significant decrease in cell viability, increase LDH leakage, decreased levels of
cellular GSH and elevation in MDA quantity. Cell pre-incubation with saponarin (600.006 µg/ml) significantly ameliorated CCl4-induced hepatic damage in a
concentration-dependent manner. These results were supported by the following in
vivo study. Along with decreased MDA quantity and increased level of cell prtector
GSH, seven day pre-treatment of rats with saponarin (80 mg/kg bw, p.o.) also
prevented CCl4 (10 %, p.o.)-caused oxidative damage by increasing antioxidant
enzyme activities (CAT, SOD, GST, GPx, GR). Biotransformation phase I enzymes
were also assessed. Administered alone, saponarin decreased EMND and AH
activities but not at the same extent as CCl4 did. However, pre-treatment with
saponarin significantly increased enzyme activities in comparison to CCl4 only group.
The observed biochemical changes were consistent with histopathological
observations where the hepatoprotective effect of saponarin was comparative to the
effects of the known hepatoprotector silymarin. Our results suggest that saponarin,
isolated from Gypsophila trichotoma Wend., showed in vitro and in vivo
hepatoprotective and antioxidant activity against CCl4-induced liver damage.
Kokanova-Nedialkova Z, Kondeva-Burdina M, Zheleva-Dimitrova D, Bücherl D,
Nikolov S, Heilmann J, Nedialkov P. A new acylated flavonol glycoside from
Chenopodium foliosum. Records of Natural Products (IF=1.019), 2014; 8(4):
401-406.
A new acylated flavonol glycoside, namely gomphrenol-3-O-(5′′′-O-E-feruloyl)-β-Dapiofuranosyl-(1→2)[β-D-glucopyranosyl-(1→6)]-β-D-glucopyranoside
(1)
was
isolated from the aerial parts of Chenopodium foliosum Asch. The structure of 1 was
determined by means of spectroscopic methods (1D and 2D NMR, UV, IR and
HRESIMS). Radical scavenging and antioxidant activities of 1 were established using
DPPH and ABTS radicals, FRAP assay and inhibition of lipid peroxidation (LP) in
linoleic acid system by the ferric thiocyanate method. Compound 1 showed low
17
activity (DPPH and ABTS) or lack of activity (FRAP and LP). In combination with CCl4,
1 reduced the damage caused by the hepatotoxic agent and preseved cell viability
and GSH level, decreased LDH leakage and reduced lipid damage. Effects were
concentration dependent, most visible at the highest concentration (100 µg/ml) and
similar to those of silymarin.
Kondeva-Burdina M, Krasteva I, Mitcheva M. Effects of rhamnocitrin 4-β-Dgalactopyranoside, isolated from Astragalus hamosus on toxicity models in vitro.
Pharmacognosy Magazine (IF=1.525), 2014; 10(39): 487-493.
Astragalus hamosus L. (Fabaceae) is used in herbal medicine as emollient,
demulcent, aphrodisiac, diuretic, laxative, and good for inflammation, ulcers, and
leukoderma. It is useful in treating irritation of the mucous membranes, nervous
affections, and catarrh. Rhamnocitrin 4-β-D-galactopyranoside (RGP), isolated from
A. hamosus, was investigated for its possible protective effect on different models of
toxicity in vitro on sub-cellular and cellular level. The effects of RGP were evaluated
on isolated rat brain synaptosomes, prepared by Percoll reagent and on rat
hepatocytes, isolated by two stepped collagenase perfusion. In synaptosomes, RGP
had statistically significant protective effect, similar to those of silymarin, on 6hydroxy-dopamine (6-OHDA)-induced oxidative stress. These results correlate with
literature data about protecive effects of kempferol and rhamnocitrin on oxidative
damage in rat pheochromocytoma PC12 cells. In rat hepatocytes, we investigate the
effect of RGP on two models of liver toxicity: bendamustine and cyclophosphamide.
In these models, the compound had statistcally significant cytoprotective and
antioxidant activity, similar to those of sylimarin. According to these results, we can
suggest that such cytoprotective effect of RGP might be due to an influence on
bendamustine and cyclophosphamide metabolism in rat hepatocytes. In isolated rat
hepatocytes, in combination with bendamustine and cyclophosphamide and in 6-OHdopamine-induced oxidative stress in isolated rat synaptosomes, RGP, isolated from
A. hamosus, was effective protector and antioxidant. The effects were close to those
of flavonoid silymarin – the classical hepatoprotector and antioxidant.
Kondeva-Burdina M, Krasteva I, Nikolov S, Mitcheva M. Effects of diosgenin,
isolated from Asparagus officinalis, on isolated hepatocytes from rats, treated with
phenobarbital. PHARMACIA, 2014; 61(4):11-17.
Diosgenin, isolated from Asparagus officinalis, was investigated for its possible
protective effects on carbon tetrachloride (86 µM)-induced toxicity in hepatocytes,
isolated from rats, treated with phenobarbital. Hepatocytes were isolated by twostepped collagenase perfusion. The effects were compared with those of silymarin.
Cell incubation with carbon tetrachloride (CCl4) led to a significant decrease in cell
viability, increased LDH leakage, decrease levels of cellular glutathione and
18
evaluation in MDA quantity. Following the induction with phenobarbital, carbon
tetrachloride, administered alone, increased its toxic effects. Pre-incubation with
diosgenin (0.01 µM, 0.1 µM, 10 µM and 100 µM) significantly ameliorated the exam
parameters in the model of CCl4-induced hepatotoxicity damage. The effects of
diosgenin were concentration-dependent and were similar to those of silymarin (0.01
µM, 0.1 µM, 10 µM and 100 µM). Our results suggest that diosgenin, isolated from
Asparagus officinalis, showed cytoprotective and antioxidant activity against this
model of hepatotoxicity, possibly by affecting the metabolism of carbon tetrachloride.
Момеков Г, Кондева-Бурдина М. PIRACETAM – quo vadis? MEDINFO, 2014; 7:
20-24.
Piracetam е прототипът на т. нар. „ноотропни” лекарства с основна
характеристика повлияване на когнитивните функции (в резултат на мозъчно
стареене, процеси на хипоксия, намалено количество глюкоза в мозъка,
мозъчна увреда, както дори невродегенерация) без седиране и възбуда. Всички
тези патологични процеси са свързани с т. нар. “порочен кръг“ между
индуциран оксидативен стрес – повишена продукция на свободни радикали –
митохондриална увреда – намалена продукция на енергия за клетката –
повишена продукция на свободни радикали.
Кондева-Бурдина М, Фердинандов Д, Момеков Г. Фармакологични свойства и
профил на безопасност на инхибиторите на протонната помпа. TopPharma,
2014; 2: 2-6.
Инхибиторите на протонната помпа (ИПП) са най-ефективните антисекреторни
лекарствени средства и респективно са най-често използваните средства при
киселинно-обусловени гастроинтестинални нарушения поради тяхната доказана
ефикасност и безопастност. Настоящата статия дава подробна информация за
фармакологичните свойства и профила на безопастност на ИПП.
Кондева-Бурдина М, Цанкова В. Пробиотици – роля и значение в
антибиотичната терапия. Здравен навигатор, 2014; 7: 6-8.
Потискането и елиминирането на патогенните микроорганизми от
антибиотиците е доказан подход в терапията. Независимо от безспорните ползи
от тази терапия обаче, се наблюдава един основен проблем – дисбактериозата.
Основните средства за терапия на дисбактериозата са пробиотиците. В
настоящата статия се разглеждат основните функции на пробиотиците, тяхното
терапевтично действие, клиничните им приложения, тяхната безопасност и
възможната им бъдеща употреба за: възможна профилактика на ревматоиден
артрит; инхибиране прогресията на рак на дебелото черво и пикочния мехур;
19
инхибиране абсорбцията на афлатоксин, участващ в прогресията на
чернодробния рак; понижаване нивата на гликиран хемоглобин и подобряване
глюкозния толеранс при диабет.
Gevrenova R, Kondeva-Burdina M, Denkov N, Zheleva-Dimitrova D. Flavonoid
profiles of three Bupleurum species and in vitro hepatoprotective activity of
Bupleurum flavum Forsk. Pharmacognosy Magazine (IF=1.525), 2015; 11(41):
14-23.
Bupleurum L. (Aspiaceae) species are used as herbal remedy in Chinese traditional
medicine. The aim was to investigate the flavonoids in three annual European
Bupleurum species, including B. baldense, B. affine and B. flavum, and to test their
antioxidant and possible hepatoprotective effects. Flavonoids from the methanolaqueous extracts were quantified by solid-phase extraction-high-performance liquid
chromatography. Bupleurum extracts (1-220 mg/ml) were tested for their antioxidant
activity in DPPH and ABTS assays, as well as on isolated liver rat microsomes. In
vitro hepatoprotective activity of B. flavum flavonoid (BFF) mixture and rutin, and
narcissin, isolated from the same mixture, were evaluated on carbon tetrachloride
(CCl4) and tert-butyl hydroperoxide (t-BuOOH) toxicity models in isolated rat
hepatocytes. Narcissin was the dominant flavonol glycoside in B. flavum being
present at 24.21 ± 0.19 mg/g, whilst the highest content of rutin (28.63 ± 1.57
mg/g) was found in B. baldense. B. flavum possessed the strongest DPPH (IC50
22.12 µg/ml) and ABTS (IC50 118.15 µg/ml) activity. At a concentration 1 mg/ml of
BFF (rutin 197.58 mg/g, narcissin 75.74 mg/g), a stronger antioxidant effect in
microsomes was evidenced in comparison with silymarin, rutin and narcissin. The
hepatoprotective effect of BFF significantly reduced the elevated levels of lactate
dehydrogenase and malondialdehyde, and ameliorated glutathione, being most
active in t-BuOOH-induced injury model when compared with CCl4 toxicity (P <
0.001). In BFF, synergism of rutin and narcissin could be responsible for stronger
protection against mitochondrial induced oxidative stress.
Shkondrov A, Simeonova R, Kondeva-Burdina M, Vitcheva V, Krasteva I. Study to
evaluate the antioxidant activity of Astragalus glycyphyllos extract in carbon
tetrachloride-induced oxidative stress in rats. European Journal of Medicinal
Plants, 2015; 7(2): 59-66.
This study investigates the possible antioxidant and hepatoprotective effects of
purified extract obtained from aerial parts of Astragalus glycyphyllos (EAG) using in
vivo model of CCl4-induced liver damage in male Wistar rats. A total of 36 animals
were randomly allocated in six experimental groups, each consisted of six animals:
control rats (group 1), rats challenged orally with CCl4 (10 % solution in olive oil)
(group 2), rats treated for 7 days with silymarin (100 mg.kg-1, 0,5 ml/100 g) alone
20
(group 3) and challenged with CCl4 after 7-day pre-treatment with silymarin (group
4); animals in group 5 and 6 were either treated with EAG (100 mg.kg-1, 0,5 ml/100
g) alone or challenged with CCl4 after 7-day pre-treatment with the extract. One day
eight of the experiment, the animals in all groups, were sacrificed and livers were
removed and the following biochemical markers of oxidative stress: MDA quantity,
GSH levels, GPX, GR and GST were measured spectrophotometrically. It was found
that EAG has statistically significant effect on hepatic antioxidant defense system in
in vivo model of carbon tetrachloride liver damage in rats. A hepatoprotective effect
comparable to silymarin can be supposed. The results indicate that EAG has similar
significant protective effect against CCl4-induced hepatotoxicity in rats as silymarin.
This may be explained with the antioxidant and hepatoprotective properties of its
bioactive compounds.
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