Exploring ancient and modern medical learning

Transcription

No
w
re
ad
Vol. L No. 3
Apr–Jun 2011
Quarterly
ISSN 0970-3039
Probe
in
35
co
un
tri
Exploring ancient and modern medical learning
1
Clinical Efficacy and Safety of Septilin Tablets in Respiratory
Tract Infections: A Meta-analysis
8
Efficacy and Safety of JT-2000 (Rumalaya forte)
in Osteoarthritis: A Comparative Clinical Trial
15
Liv.52 in the Prevention of Hepatotoxicity in Patients
receiving Antitubercular Drugs: A Meta-analysis of Eight
Controlled Clinical Trials
22
Septilin in Infective Dermatoses
24
Evaluating the Safety and Efficacy of Rumalaya forte: A
Double-Blind Clinical Trial
es
Prevent chronic and recurrent infections...
Septilin
®
( S Y R U P, T A B L E T )
Builds the body’s own defense mechanism
Improves body’s immune defenses
Increases IgG levels, chemotaxis & phagocytic capacity
Reduces inflammation and allergy – the underlying
pathological features of infections
Decreases pro-inflammatory cytokines & IgE levels
Offers beneficial antimicrobial,
antiviral, and antioxidant actions
• Recurrent RT and ENT infections
(tonsillitis, pharyngitis, bronchitis, sinusitis & otitis media)
• Skin and soft tissue infections
• Wounds and ulcers
• Dental infections
• Ophthalmic infections
Septilin Meta-analysis Study (SMS)
Dosage
Infants: Syrup: ½ to 1 teaspoonful three times daily.
Children: Syrup: 1 to 2 teaspoonfuls three times daily.
Tablet: 1 tablet twice daily.
Septilin – Builds the body’s own defense mechanism
® Regd. Trademark
A meta-analysis of 38 clinical studies conducted over
43 years on 2765 patients confirms the safety and
efficacy of Septilin in upper and lower respiratory tract
infections.
Feedback Form
Dear doctor,
We are always interested in finding out whether the articles included in the magazine are
useful in your practice. Please spend a few moments to fill the following questionnaire and
send it to the address mentioned overleaf.
a) Rate this issue of Probe on the following aspects (on a scale
of 1 to 5; 1 = Poor, 2 = Moderate, 3 = Good, 4 = Very good,
5 = Excellent).
Cut here
Feedback
Form
i) Quality of the selected articles
1
ii) Layout and design
1
iii) Overall content
1
2
2
2
Clinical Insight
Abstracts
Wordsmith
Herbal Notes
Other
Please specify
3
4
5
d) In your opinion, which section of the magazine requires
further improvement?
3
4
5
Herbal Notes
Drug Info Preclinical Evidence
Tech Bytes
Other
Please specify
3
4
5
b) Do the articles included in the magazine provide sufficient evidence to help you prescribe Himalaya’s products?
Yes
c) Which section of the magazine you liked most?
e) A
ny other sections that you would like to be included in the
forthcoming issues
f) Any other comments or suggestions
No
Name:
Phone:
Qualification:
Address:
e-mail:
Medical Crossword 5*
PROBE • Vol. L • No. 3 • Apr–Jun 2011
Across
Cut here
Answer Card
Down
2. 1. 7. 3. 8. 9.
4. 5.
6. *See page 80
Qualification:
Name:
Address:
Phone:
e-mail:
PIL Order Form
I wish to order for FREE reprints of the article published in the “Patient Education” section of this
issue. Kindly send the copies (Patient Information Leaflets) to the below-mentioned address.
Patient
Information
Leaflets
Order Form
Name:
Qualification:
Institution/Clinic/Hospital:
Cut here
Address:
Phone:
e-mail:
PROBE • Vol. L • No. 3 • Apr–Jun 2011• LiSeRfTaSht
Free
Reprints
Medical Crossword 5
Answer
&
win prizes
Probe
No postage
necessary
if posted in
India
Postage
will be
paid by the
addressee
BUSINESS REPLY CARD
Permit No: CNA/BRP - 2/02
Nelamangala P.O., Nelamangala 562 123
To
Scientific Publications Division,
The Himalaya Drug Company,
Makali, Bangalore - 562 123
Probe
Apr–Jun 2011
No. 3
Vol. L
The Editor – PROBE
No postage
necessary
if posted in
India
Postage
will be
paid by the
addressee
BUSINESS REPLY CARD
To
Probe
Apr–Jun 2011
No. 3
Vol. L
No postage
necessary
if posted in
India
Postage
will be
paid by the
addressee
BUSINESS REPLY CARD
To
Apr–Jun 2011
No. 3
Vol. L
Contents
i
E d i t o r i a l ........................................................................................................iii
Clinical Insight
Clinical Efficacy and Safety of Septilin Tablets in Respiratory Tract Infections:
A Meta-analysis........................................................................................................... 1
Evaluation of the Efficacy and Safety of JT-2000 in Osteoarthritis:
A Comparative Clinical Trial........................................................................................ 8
Liv.52 in the Prevention of Hepatotoxicity in Patients receiving
Antitubercular Drugs: A Meta-analysis of Eight Controlled Clinical Trials.....................15
Septilin in Infective Dermatoses................................................................................. 22
Evaluating the Safety and Efficacy of Rumalaya forte:
A Double-Blind Clinical Trial......................................................................................24
Abstracts
Cardiology..................................................................................................................27
Dermatology............................................................................................................. 28
Gastroenterology....................................................................................................... 29
Gynecology............................................................................................................... 30
Hepatology.................................................................................................................31
Infections....................................................................................................................32
Neurology..................................................................................................................33
Ophthalmology......................................................................................................... 34
Orthopedics...............................................................................................................35
Pediatrics................................................................................................................... 36
Psychiatry...................................................................................................................37
Preclinical Evidence
Immunomodulatory Activity of Septilin, a Polyherbal Preparation.............................. 38
Liv.52 Regulates Ethanol Induced PPARγ and TNF-a Expression in HepG2 Cells.........43
Immunopotentiating Activity of Septilin......................................................................47
Clinical Practice Pearls
Prevention of Surgical-site Infections: Best Practices, Better Outcomes........................52
Case Discussion
Acute Hepatitis B and Acute HIV Coinfection in an Adult Patient............................... 54
Drug-induced Granulomatous Interstitial Nephritis in a Patient with Ankylosing
Spondylitis during Therapy with Adalimumab............................................................ 54
Drug Alert
Clinical Course and Outcomes of Drug-induced Liver Injury:
Nimesulide as the First Implicated Medication............................................................55
Severe Lactic Acidosis during Treatment of Chronic Hepatitis B with
Entecavir in Patients with Impaired Liver Function.......................................................55
Herbal Notes
Asparagus racemosus................................................................................................. 56
Valeriana wallichii......................................................................................................57
i
Contents
Saussurea lappa......................................................................................................... 58
Achillea millefolium....................................................................................................59
Drug Info
Septilin® (syrup, tablet)............................................................................................... 60
Rumalaya® forte (tablet)..............................................................................................62
Liv.52® (drops, syrup, DS syrup, tablet, DS tablet)...................................................... 64
Patient Education
Does Your Child Fall Sick Often?............................................................................... 68
Te c h B y t e s
Nucleic Acid Testing to Detect HBV Infection in Blood Donors...................................70
Evaluation of a New, Rapid Test for Detecting HCV Infection,
Suitable for Use with Blood or Oral Fluid....................................................................70
L i v. 52 U p d ate
Safety and Efficacy of Oral HD-03/ES (Liv.52 HB) Given For Six Months in Patients with
Chronic Hepatitis B Virus Infection.............................................................................71
Wordsmith
Musculoskeletal Disorders of the Spines.....................................................................76
Review
Online....................................................................................................................... 78
Hepatitis B Foundation
American Academy of Orthopedic Surgeons
Book......................................................................................................................... 79
Structure and Function of the Musculoskeletal System
Viral Hepatitis in Children: Unique Features and Opportunities
Q u i z C o r n e r ........................................................................................... 80
History of Medicine
Georg Kelling (1866-1945): The Root of Modern Day Minimal Invasive Surgery..........82
John Hunter and the Origins of Modern Orthopedic Research....................................82
From Other Pages
Published and Perished.............................................................................................. 83
Miscellaneous
Laughter, the best medicine....................................................................................... 84
Think Wise................................................................................................................ 84
ii
Editorial
iii
Rheumatoid Arthritis
About 1% of the world’s population is affected by rheumatoid arthritis. According
to recent data, 1.3 million people in the United States are reported to be affected
by rheumatoid arthritis. Although people of any age can be affected by rheumatoid
arthritis, it is observed that women are affected three times more than men and the
onset is most frequent between the age of 40 and 50 years.
Rheumatoid arthritis initiates with the inflammation of the synovial membrane and
accumulation of synovial fluid in the joint space. As the disease progresses, it may
lead to muscle atrophies, flexion contractures, and ankylosis. The management
of rheumatoid arthritis is aimed to reduce pain and inflammation, delay disease
progression, preserve joint movement, and prevent deformities.
Rumalaya® forte (tablet), from The Himalaya Drug Company, has been found to be safe
and effective in the management of all types of arthritis and traumatic inflammatory
conditions of the musculoskeletal system.
The “Clinical Insight” section of this issue highlights articles on the safety and efficacy
of Rumalaya® forte in arthritic conditions. The section also features clinical reports
evaluating the safety and efficacy of Septilin® (tablet, syrup) in various infectious
conditions and Liv.52® (tablet, syrup) in antitubercular therapy-induced hepatitis.
The “Patient Education” section provides information on increasing the child’s
immunity. Please use the patient information leaflet order form, enclosed in the issue,
to avail reprints of this information. Do write to us with your valuable feedback and
suggestions at [email protected].
Happy reading!
Dr Pralhad S Patki, MD
Editor in chief
iii
Editorial
The Infection
Deep within your heart is where the infection lies.
Using your body as a simple disguise.
It gets there from sadness and stays there with hate.
Once you’ve accepted depression, the infection has sealed your fate.
It starts with you and another person and ends when they leave.
The pain that you feel is something that you’ d never believe.
Sitting in a dark room, letting all of the bitterness just sink in.
Trying to escape is pointless, it’s already beneath your skin.
The infection has started, it’s eating away at all the happiness you ever had.
Slowly but surely you start to go mad.
You look in the mirror and you don’ t recognize yourself.
How you got to where you are now would make someone deeply
question himself.
Having the infection is like being lost in your own mind.
Turning corners and looking for something that you’ll probably never find.
With myself having the infection all I can really do is wait.
Until the infection decides my horrible fate.
I hope this helps people in the future as I give my recollection.
On how you will live when you have the infection.
– Anonymous –
Editor in chief: Dr Pralhad S Patki
Managing Editor: Dr Jayashree B Keshav
Editorial Assistants:
Pooja Sinha
Shruthi VB
Riby George
Blessin Dan Varghese
Layout Artist: Dayananda Rao S
Santosh G
Printer:
M/s Sri Sudhindra Offset Process
#97, DT Street, 8th Cross,
Malleshwaram,
Bangalore - 560 003
Published by: Dr Pralhad S Patki
iv
E-mail: [email protected]
Website: www.himalayahealthcare.com
PROBE is published once in 3 months
Subscription rates for four consecutive
issues are
– Inland: Rs. 20/- inclusive of postage
– Abroad: UK£ 5, US$ 12, inclusive of
surface mail postage
All check payments should cover the banker’s
commission
Drafts/checks to be sent in favor of:
“The Himalaya Drug Company,
Makali, Bangalore”
Clinical Insight
1
Clinical Efficacy and Safety of Septilin Tablets in
Respiratory Tract Infections: A Meta-analysis
Kshirsagar M, et al.
Department of Pharmacology, BJ Medical College, and Sassoon General Hospital, Pune, India
Ind J Clin Pract. 2010;20(8):595-600.
Abstract
The aim of this study was to perform meta-analysis on
the efficacy and short- and long-term safety of Septilin
tablet in respiratory tract infections (RTIs), as reported
in 38 published studies conducted between 1958
and 2001 in 2765 patients with RTI. Adults received
one to two tablets, TID for 7 days to three months.
Children were administered one-quarter tablets QID
to one tablet TID for 7 days to three months. Duration
of the treatment varied from 7 days to 3 months.
Improvement in the symptoms, clinical recovery,
and immunoglobulin were taken into consideration.
Results of the study showed statistically significant
improvement in patients with RTI. Of the 1613 patients
with upper respiratory tract infection (URTI), 1211
patients responded to the Septilin therapy and among
the 838 patients with lower respiratory tract infection
(LRTI), 720 patients responded to the therapy. In
comparative control trials conducted with Septilin in
RTIs, 74.42% of patients treated with Septilin improved
as compared to the other treatment (52.86%). But
with Septilin treatment, the improvement was better
with minimal adverse effects. Immunoglobulin (IgG,
IgA, IgM) levels showed significant improvement with
Septilin. Adverse effects included gastrointestinal
disturbances in 11 cases (0.39%), dry mouth in nine
cases (0.32%), and skin rashes in three cases (0.11%).
Adverse effects were mild and no patient withdrew
from the study on their account. Whereas in the
comparative controlled drugs (antibiotics and antiallergics) groups, reported drowsiness and sedation
were reported in 21 cases (18%), dry mouth in seven
cases (7.78%), and dizziness and incoordination of
movements in three cases (3.33%). Therefore, it can be
concluded that Septilin tablets are effective and safe in
treating RTIs.
Key words
Septilin, Respiratory tract infections, meta-analysis
Intro duc tion
The term respiratory tract infection (RTI)
describes acute infections involving the
nose, paranasal sinuses, pharynx, larynx,
trachea, and bronchi. Viruses cause most
upper RTIs (URTIs), with rhinovirus,
parainfluenza virus, coronavirus, adenovirus,
respiratory syncytial virus, coxsackie virus,
and influenza virus accounting for most
cases.1 In the United States, common cold
leads to 75 to 100 million physician visits
annually at a conservative cost estimate of
US $7.7 billion per year. Americans spend
$2.9 billion on over-the-counter drugs and
another US $400 million on prescription
medicines for symptomatic relief.2,3 More
than one-third of patients, who visited a
doctor, received an antibiotic prescription,
which has implications for antibiotic
resistance from overuse of such drugs.3 An
estimated 22 to 189 million school days are
missed annually due to cold. As a result,
parents missed 126 million workdays to
stay home to care for their children. When
added to the 150 million workdays missed
by employees suffering from cold, the total
economic impact of cold-related work
loss exceeds US $20 billion per year.2,3
This accounts for 40% of time lost from
work.4 Most URTIs occur more frequently
during the cold winter months. Adults
develop an average of two to four colds
annually. Antigenic variation of hundreds
of respiratory viruses results in repeated
circulation in the community. Acute
pharyngitis accounts for 1% to 2% of all visits
to outpatient and emergency departments,
resulting in 7 million annual visits by adults
1
Clinical Insight
Septilin in Respiratory Tract Infections
alone.1 Acute bacterial sinusitis develops in 0.5% to 2%
of cases of viral URTIs.5 Approximately 20 million cases
of acute sinusitis occur annually in the United States.
About 12 million individuals are diagnosed with acute
tracheobronchitis annually, accounting for one-third of
patients presenting with acute cough, these infections are
the leading cause of death.6
Transmission of organisms causing URTIs occurs by
aerosol, droplet or direct hand-to-hand contact with
infected secretions, with subsequent passage to the nares
or eyes.7 Thus, transmission occurs more commonly in
crowded conditions. Direct invasion of the respiratory
epithelium results in symptoms corresponding to
the area(s) involved. On examination, patients with
common colds may have low-grade fever, nasal vocal
tone, macerated skin over the nostrils, and inflamed
nasal mucosa.8 There is a need for an effective and safe
formulation to manage respiratory infections. A number
of herbs are claimed to be effective in the management
of these frequent infections. Septilin is a multi-herbal
formulation claimed for its efficacy due to the synergistic
action of the ingredients. It provides immunomodulatory
activity that enhances natural immunity. A number of
clinical studies have been carried out to evaluate the
efficacy and safety of Septilin in various respiratory
ailments. Results of each clinical trial showed that
Septilin, with its immunomodulatory, antioxidant, antiinflammatory, antiallergic, and antimicrobial actions,
was effective in various RTIs, with excellent shortand long-term safety. These studies need to be meta-
analyzed to know the clinical status of Septilin in
respiratory ailments.
Meta-analysis is a two-stage process; first stage is the
extraction of data from each study and calculation
of the result for each. The second stage involves
deciding whether it is appropriate to calculate a pooled
average result across studies. This process gives greater
weightage to the results from the studies that give more
information because these are likely to be closer to the
truth.9 Advantages of meta-analysis include deriving and
statistical testing of overall factors/effect size parameters
in related studies, generalization to the population of
studies, ability to control for between study variation,
including moderators to explain variation. To cumulate the
results of all the studies, a meta-analysis was carried out
to analyze the efficacy and short- and long-term safety of
Septilin in RTI.
Aim of the Study
The aim of the study was to perform a meta-analysis on
the efficacy and short- and long-term safety of Septilin
tablets in RTI.
Material and Metho ds
Study Design
This is a cumulative meta-analysis of 38 published clinical
trials of Septilin tablets in RTIs. Out of the 38 trials, 32
were open, one was placebo-controlled, and five were
comparative controlled trials. The details of clinical studies
evaluated for meta-analysis are mentioned in Table 1.
Table 1. Details of Clinical Studies Included in the Meta-analysis
Sl. No.
2
Investigators names
Year
No. of patients
1986
25
1988
30
1.
Agarwal NK, Agrawal V
2.
Gaunekar L, Pereira P
3.
Gokhale SG, Wakharia PV
1958
44
4.
Koti ST
1992
18
5.
Mishra DN, Singh T
1981
58
6.
Miglani VP
1983
24
7.
Nigam P, et al16
1985
125
8.
Sheth SC, et al17
1959
82
9.
Bhasin RC18
1990
30
10.
Sarkar SK, et al19
1986
50
11.
Luley S, Kalbande V
1984
75
12.
Roy VD
1989
785
13.
Khan A, Mukherjee V
1984
44
10
11
12
13
14
15
20
21
22
Clinical Insight
14.
Mukherjee D23
1984
23
15.
Tawde UJ
1981
30
16.
Garga MK
1980
40
17.
Cooper RAF, Merchant NR
1958
27
18.
Grewal DS, et al
1985
50
19.
Roy S
1992
100
20.
Sharma SC, Singhal KC
1990
100
21.
Singh BPM30
1992
35
22.
Chugh JS31
1984
30
23.
Das MR, Rai D32
1988
50
24.
De Sequeira PA
1979
50
25.
Gadre KC, et al
1964
46
26.
Vishwakarma SK
1979
243
27.
Rastogi PK, et al
1982
64
28.
Bhatia BPR, Tayal VK
1978
24
29.
Banerjee D
1988
20
30.
Dass MR
1988
27
31.
Gadekar HA, et al
1986
50
32.
Motwani VB, Joshi PD
1982
41
24
25
26
27
28
29
33
34
35
36
37
38
39
40
41
33.
Lumba SP, et al
1983
110
34.
Sasikumaran Nair S43
1981
68
35.
Mrityunjay Sarkar44
1983
25
36.
Tawde U, Tawde NU45
1987
60
37.
Lakshmipathi G, Venugopala Rao B
1962
37
38.
Nehru V 2001
25
42
46
47
Inclusion Criteria
All published studies, which evaluated the role of Septilin
in RTIs, were included in the meta-analysis irrespective of
the study design, that is, controlled studies or open clinical
studies. There were no restrictions regarding sex, age, or
duration of the disease. The outcome variables included
measurement data on changes in clinical symptoms and
signs, laboratory results, and incidence of adverse events
during/after the treatment and immunoglobulin levels.
efficacy and short- and long-term safety of Septilin in RTIs.
Duration of the treatment varied from 7 days to 3 months.
Adults received one tablet QID to two tablets TID for 7
days to 3 months. Children recieved one-quarter tablet
QID to 1 tablet TID for 7 days to 3 months. Improvement
in symptoms, clinical recovery, and immunoglobulin
levels were taken into consideration. Incidence of adverse
events during the study period and compliance to the drug
treatment were also evaluated.
Exclusion Criteria
Primary and Secondary Outcome Measure
Phase I studies were excluded from the meta-analysis.
Study Procedures
A meta-analysis of 38 clinical studies conducted between
1958 and 2001 in 2765 patients with RTI (1613 were with
URTI and 838 were with lower RTI) at various reputed
hospitals all over India was performed to evaluate the
Primary predefined outcomes were clinical recovery from
RTIs. Secondary end points were safety and compliance to
Septilin tablets.
Adverse Effects
All adverse events, either reported or observed by
patients, were recorded with information about severity,
3
Clinical Insight
duration, and action taken regarding the study drug.
Relation of adverse events to study medication was
predefined as ‘Unrelated’ (a reaction that does not follow
a reasonable temporal sequence from the administration
of the drug), ‘Possible’ (follows a known response pattern
to the suspected drug, but could have been produced
by the patient’s clinical state or other modes of therapy
administered to the patient), ‘Probable’ (follows a known
response pattern to the suspected drug that could not
be reasonably explained by the known characteristics
of the patient’s clinical state), and ‘Certain’ (the adverse
events must have definitive relationship to the study drug,
which cannot be explained by concurrent disease or any
other agent).
Statistical Analysis
Statistical analysis was done according to the intentionto-treat principles. Changes in various parameters from
baseline values and values at the end of the study were
pooled and analyzed cumulatively using Chi square test
or paired t test. Values are expressed as mean ± SD or
as incidences of patients with or without symptoms. The
minimum level of significance was fixed at 95% confidence
limit and a two-sided P≤.05 was considered significant.
Statistical analysis was performed using GraphPad Prism
Version 4.03 for windows, GraphPad Software, San Diego,
California, United States (www.graphpad.com).
Re sults
The break-ups for upper and lower RTIs are given in
Table 2. Statistically significant improvement was seen in
trials conducted in patients with RTI. Of the 1613 patients
with URTI, 1211 patients responded to the treatment,
with a statistical significance of P<.0001 and percent
protection of 75.08% and among the 838 patients with
lower RTI (LRTI), 720 patients responded to the treatment,
with a statistical significance of P<.0001 and percent
protection of 85.92% (Table 3).
Among patients with URTI, in 565 patients with tonsillitis,
460 patients responded with 81.42% protection; in
599 patients with pharyngitis, 411 responded showing
68.61% protection; in 25 patients with laryngitis 24
showed 96% protection; and in patients with sinusitis and
Table 3. Meta-analysis of Septilin in RTIs (32 open trials +
one placebo-controlled trial + 5 comparative controlled
trial = 38 clinical trials)
No. of
patients
Improvement
Percent
protection
RTIs
2765
2178*
78.77
URTI
1613
1211*
75.08
a. Tonsillitis
565
*
460
81.42
b. Pharyngitis
599
411*
68.61
c. Laryngitis
25
24*
96.00
d. Sinusitis
424
326*
76.89
e. Rhinitis
278
253*
91.01
838
720*
85.92
Indication
Lower RTI
a
Persistent
cough
(COPD)
155
131*
84.52
b
Bronchitis
683
589*
86.24
*P<.0001 compared to the total number of patients with RTI
before treatment.
Table 4. Meta-analysis of Septilin in RTIs in Comparative
Controlled Clinical Trials
No. of patients
Table 2. Break-up of Patients with RTI
Indication
No. of patients
RTIs
2765
1.
URTI
4
Total
no. of
patients
Comparative control
Improvement
Total
no. of
patients
Improvement
565
1
50
47
50
44
b. Pharyngitis
599
2
30
21
30
18
c. Laryngitis
25
3
40
40
10
0
d. Sinusitis
424
4
27
3
25
2
e. Rhinitis
278
5
25
17
25
10
Lower RTI
838
Total
172
128*
140
74
a. Persistent cough (COPD)
155
b. Bronchitis
683
a. Tonsillitis
2.
Study
Septilin
(74.42%)
(52.86%)
*P <.0001 compared to the total number of patients with RTI
before treatment.
Clinical Insight
rhinitis, 76.89% and 91.01% protection was observed,
respectively (Table 3). Similarly in LRTI out of 683
patients with bronchitis, 589 responded with 86.24% and
persistent cough due to varied etiology there was 84.52%
relief (Table 3). In the comparative control trial, 74.42%
of patients treated with Septilin improved as compared
to the control group (52.86%) treated with antiallergics
and antibiotics. The statistical significance was P<.0001
(Table 4) in both Septilin and control groups, but
improvement was found to be better with Septilin
treatment. The comparative drugs were antiallergics
(chlorpheniramine maleate) and antibiotics (cotrimoxazole
and penicillins).
patients (0.11%) treated with septilin. In patients treated
with comparative controlled drugs (antibiotics and
antiallergics), were observed in adverse effects such as
drowsiness and sedation in 21 cases (18%), dry mouth in
seven patients (7.78%), and dizziness and incoordination
of movements in three cases (3.33%). All adverse effects
were mild in nature and did not necessitate withdrawal of
study medication (Table 6). Majority of the adverse effects
were seen in patients treated with comparative controlled
drugs (140) such as antibiotics and antiallergics (28%) as
compared to <1% in Septilin-treated patients.
The
immunoglobulin
levels
showed
significant
improvement, IgG from 1456.00 ± 342.80 mg/dL at
baseline to 1715.00 ± 287.10 mg/dL after the treatment
(P<.009), IgA from 200.80 ± 46.73 mg/dL before
treatment to 241.40 ± 43.26 mg/dL after treatment
(P<.01), and IgM levels from 167.80 ± 68.38 mg/dL
before treatment to 195.70 ± 63.21 mg/dL after treatment
(P<.01), in two open-label clinical trials (Table 5). These
observations support the immunomodulatory effect of
Septilin. Out of the 2765 patients with RTI, gastrointestinal
disturbances were observed in 11 cases (0.39%), dry
mouth in nine cases (0.32%) and skin rashes in three
The number of papers published on meta-analysis in
medical research has increased sharply in the past decade;
however, the merits and perils of the meta-analysis
continue to be debated in the medical community.48,49
A useful definition of meta-analysis was given by Huque
as: A statistical analysis that combines or integrates the
results of several independent clinical trials considered
by the analyst to be combinable.50 A single study often
cannot detect or exclude with certainty clinically relevant
differences in the effects of two treatments. Cumulative
meta-analysis is defined as the repeated performance of
meta-analysis whenever a new trial becomes available
Discussion
Table 5. Meta-analysis of Septilin in Immunoglobulin Levels
(Total = 2 open trials) (n = 49)
Immunoglobulin levels (mean ± SD)
IgG (mg/dL)
IgM (mg/dL)
Before
treatment
After
treatment
1456.00
± 342.80
1715.00
± 287.10*
IgA (mg/dL)
Before treatment
After
treatment
Before treatment
After
treatment
167.80
± 68.38
195.70
± 63.21**
200.80
± 46.73
241.40
± 43.26**
*P<.009 compared to the before treatment values; **P<.001 as compared to the before treatment values.
Table 6. Adverse Events
Treatment
Septilin
(n = 2765)
Comparator Drugs
(n = 140)
No. of patients
Incidences of occurrence
(%)
Gastrointestinal
disturbances
11
0.39
Dry mouth
09
0.32
Skin rashes
03
0.11
Drowsiness and sedation
21
18
Dry mouth
07
7.78
Dizziness and
incoordination
03
3.3
Adverse effects
5
Clinical Insight
for inclusion. Such cumulative meta-analysis can
retrospectively identify the point in time when a treatment
effect first reached conventional levels of significance.51
Meta-analysis thus not only consists of a combination of
data but also includes the epidemiological exploration
and evaluation of results (epidemiology of results).52
Therefore, new hypotheses that were not posed in single
studies can be tested in meta-analyses.53 The number of
patients included in clinical trials is often inadequate, as
in some cases the required sample size may be difficult
to achieve.54 Meta-analysis may, nevertheless, lead to the
identification of the most promising or urgent research
question and may permit a more accurate calculation of
the sample sizes needed in future studies.55 Goals of the
meta-analysis are to enable the overall significance of
an effect to be evaluated, based on the multiple studies
available, to estimate an overall effect size by combining
the individual estimates in multiple studies.56
In the present meta-analysis, clinical trials and their details
were tabulated and analyzed statistically. The outcome of
this analysis showed marked improvement with Septilin in
patients with RTIs.
Septilin has immunomodulatory, antioxidant, antiinflammatory, antiallergic, and antimicrobial actions. It
has an excellent short- and long-term safety. Septilin is a
multiherbal preparation and the effect of the formulation
is due to the synergistic action of the ingredients.
Tinospora cordifolia has potent immunomodulatory
and immunostimulatory actions, which increase the
levels of antibodies and activate macrophages.57,58
Emblica officinalis enhances cell survival and increases
phagocytosis and gamma-interferon production.59
Glycyrrhizin from Glycyrrhiza glabra potentiates
the
reticuloendothelial
system,60
enhances
61
immunostimulation, and acts on macrophage function
in vitro, leading to stimulation of macrophages de novo,62
b-glycyrrhetinic acid from G glabra is a potent inhibitor
of the classical complement pathway.63 Balsamodendron
mukul,64‑66 Rubia cordifolia,67 E officinalis,68 G glabra,69
and Moringa pterygosperma70 have potent antioxidant
actions. B mukul has strong anti-inflammatory potential.71
G glabra72 and M pterygosperma73 have also been
reported for its anti-inflammatory properties.
T cordifolia improves the phagocytic and intracellular
bactericidal capacities of neutrophils.74 Glycyrrhizin from
G glabra has potent antiviral activity.75 E officinalis has
antibacterial properties, especially against Escherichia
coli, Klebsiella pneumoniae, Klebsiella ozaenae, Proteus
6
mirabilis, Pseudomonas aeruginosa, Salmonella typhi,
Salmonella paratyphi A and B, and Serratia marcescens.76
has
antibacterial
properties.77
M pterygosperma possesses antibacterial and antiviral
properties and inhibits the growth of gram-positive
and gram-negative bacteria such as E coli, S typhi,
and S paratyphi.78 T cordifolia79 and E officinalis80
have antipyretic properties. B mukul is beneficial in
RTIs, including chronic tonsillitis, pharyngitis, chronic
bronchitis, nasal catarrh, and laryngitis.81 G glabra is an
expectorant and hence is beneficial in asthma, acute or
chronic bronchitis, and chronic cough.82-84
Conclusion
The outcome of this meta-analysis, which included 38
clinical studies carried out between 1958 and 2001,
in 2765 patients with RTI indicated significant clinical
efficacy and safety of Septilin tablets. The cumulative data
analysis revealed significant clinical improvement with
adequate symptomatic relief in Septilin-treated patients.
Adverse events were negligible (<1%) in Septilin-treated
patients and did not necessitate withdrawal of the drug.
The overall drug compliance was very good. Therefore,
it may be concluded that Septilin tablets are clinically
effective and safe in patients with RTIs. Septilin, a multiingredient formula, has immunomodulatory activity and
enhances natural immunity. It is also a safe and effective
adjuvant to antimicrobials in the management of recurrent
infections. When coprescribed with antibiotics, Septilin
ensures faster recovery and reduces the duration and cost
of therapy, besides preventing reinfections.
Reference s
1. Cooper RJ, et al. Ann Intern Med. 2001;134:509-517.
2. Garibaldi RA. Am J Med. 1985;78(6B):32-37.
3. Fendrick AM, et al. Arch Intern Med. 2003;163(4):487-494.
4. Kirkpatrick GL. Prim Care. 1996;23(4):657-675.
5. Young MT. Infect Dis Clin N Am. 2004;18:919-937.
6. Denny FW (Jr.). Am J Respir Crit Care Med. 1995;152 (Suppl pt 2):S4-S12.
7. Musher DM. NEJM. 2003;348:1256-1266.
8. Monto AS, et al. Clin Infect Dis. 2003;36:253-258.
9. Green S. Singapore Medical J. 2005;46(6):270-273.
10. Agarwal NK, Agrawal V. Med Surg. 1986;26(5):25-27.
11. Gaunekar L, Pereira P. Antiseptic. 1988;85(4):190-191.
12. Gokhale SG, Wakharia PV. Curr Medical Pract. 1958;2(10):616-619.
13. Koti ST. Probe. 1992;31(4):325-328.
14. Mishra DN, Singh T. Med Surg. 1981;21(5):42.
15. Miglani VP. Capsule.1983;2:32.
16. Nigam P, et al. Med Surg. 1985;2:28-30.
Clinical Insight
17. Sheth SC, et al. J Indian Medical Profession. 1959;5:2767.
52. Jenicek M. J Clin Epidemiol. 1989;42:35-44.
18. Bhasin RC. Ind Practit. 1990;43(1):83-86.
53. Gelber RD, Goldhirsch A. Stat Med. 1987;6:371-378.
19. Sarkar SK, et al. Probe. 1986;25(3):273-276.
54. Collins R, et al. BMJ. 1992;304:1689.
20. Luley S, Kalbande V. Ind Practit. 1984:1045-1049.
55. Chalmers I. Stuttgart: Thieme. 1979:260.
21. Roy VD. Probe. 1989;28(3):200.
56. Andrews G, Harvey R. Arch Gen Psychiatry. 1981;38:1203-1208.
22. Khan A, Mukherjee V. Probe. 1984; 23(4):226-227.
57. Kapil A, Sharma S. J Ethnopharmacol. 1997;58(2):89-95.
23. Mukherjee D. Probe. 1984;23(4):211-212.
58. Bishayi B, et al. J Toxicol Sci. 2002;27(3):139-146.
24. Tawde UJ. Probe. 1981;20(3):196-198.
59. Sai Ram M, et al. Phytotherapy Res. 2003;17(4):430-433.
25. Garga MK. Probe. 1980;19(3):201-203.
60. Shimizu N, et al. Chem Pharm Bull. 1991;39(8):2082-2086.
26. Cooper RAF, Merchant NR. Indian J Otolaryngol. 1958;10(3):141-147.
61. Wagner H, Jurcic K. Phytomedicine. 2002;9(5):390-397.
27. Grewal DS, et al. Auris Nasusu Larynx. 1985;12(2):95 -101.
62. Nose M, et al. Biol Pharm Bull. 1998;21(10):1110-1112.
28. Roy S. Probe. 1992;31(2):146-156.
63. Kroes BH, et al. Immunol. 1997;90(1):115-120.
29. Sharma SC, Singhal KC. Indian J Pharmacol. 1990;22(2):103-105.
64. Meselhy MR. Phytochemistry. 2003;62(2):213-218.
30. Singh BPM. Indian Medical J. 1992;86(1):12-13.
65. Wang X, et al. Atherosclerosis. 2004;172(2):239-246.
31. Chugh JS. Probe. 1984;24(1):28-31.
66. Sharma S, et al. J Photochem Photobiol. 2005;78(1):43-51.
32. Das MR, Rai D. Probe. 1988;27(4):254-260.
67. Cai Y, et al. J Agri Food Chem. 2004;52(26):7884-7890.
33. De Sequeira PA. Probe. 1979;19(1):43-44.
68. Ganju L, et al. Biomed Pharmacother. 2003;57(7):296-300.
34. Gadre KC, et al. Probe. 1964;3(3):99-101.
69. Vaya J, et al. Free Radical Biol Med. 1997;23(2):302-313.
35. Vishwakarma SK. Probe. 1979;18(2):85-88.
70. Siddhuraju P, Becker K. J Agri Food Chem. 2003;51(8):2144-2155.
36. Rastogi PK, et al. Probe. 1982;21(3):205-208.
71. Duwiejua M, et al. Planta Medica. 1993;59(1):12-16.
37. Bhatia BPR, Tayal VK. Capsule. 1978;4:79.
72. Herold A, et al. Roum Arch Microbiol Immunol. 2003;62(3-4):217-227.
38. Banerjee D. Capsule. 1988:99.
73. Anwar F, et al. Phytotherapy Res. 2007;21(1):17-25.
39. Dass MR. Curr Medical Pract. 1988;32:1-6.
74. Thatte UM, et al. J Postgrad Med. 1992;38(1):13-15.
40. Gadekar HA, et al. Probe. 1986;25(2):164-165.
75. Badam L. J Commun Dis. 1997;29(2):91-99.
41. Motwani VB, Joshi PD. Probe. 1982;22(1):32-34.
76. Saeed S, Tariq P. Pak J Pharm Sci. 2007;20(1):32-35.
42. Lumba SP, et al. Probe. 1983;22(3):178-180.
77. Qiao YF, et al. Yao Xue Xue Bao. 1990;25(11):834-839.
43. Sasikumaran Nair S. Capsule. 1981;6:128.
78. Eilert U, et al. Planta Medica. 1981;42(5):55-61.
44. Sarkar M. Capsule. 1983;5:104.
79. Ikram M, et al. J Ethnopharmacol. 1987;19(2):185-192.
45. Tawde U, Tawde NU. Med Surg. 1987;2:5-8.
80. Perianayagam JB, et al. J Ethnopharmacol. 2004;95(1):83-85.
46. Lakshmipathi G, Rao VB. J Indian Medical Assoc. 1962;4:174-175.
48. Naylor CD. BMJ. 1997;315:617-619.
81. Asolkar LV, et al. Glossary of Indian Medicinal Plants with Active
Principles. New Delhi: Publications & Information Directorate
(CSIR); 1992:114.
49. Bailar JC 3rd. NEJM. 1997;337:559-561.
82. Haggag EG, et al. J Herb Pharmacotherapy. 2003;3(4):41-54.
50. Huque MF. Proc Biopharm Sect Am Stat Assoc. 1988;2:28-33.
83. Puodziuniene G, et al. Medicina. 2005;41(6):500-505.
51. Lau J, et al. NEJM. 1992;327:248-254.
84. Bielory L. Ann Allergy Asthma Immunol. 2004;93(2 Suppl 1):S45-S54.
47. Nehru V. Ind Practit. 2001;54(7):501-505.
7
Clinical Insight
Rumalaya forte in Osteoarthritis
Evaluation of the Efficacy and Safety of JT-2000* in Osteoarthritis:
A Comparative Clinical Trial
Mathur HH, et al.
Department of Orthopedics, Medical College & S. S. G. Hospital, Vadodara, India
Med Update. 2004;11(9):31-37.
Abstract
Osteoarthritis is a major cause of morbidity and
impaired quality of life among the elderly. The use
of nonsteroidal anti-inflammatory drugs (NSAIDs) is
associated with short-term and long-term adverse
effects. The present study was conducted to evaluate
clinical efficacy (in comparison to Ibuprofen)
and long-term safety of JT-2000 in patients with
osteoarthritis. This study was an open placebo
controlled clinical trial undertaken in 100 patients of
osteoarthritis of either sex, in the age group of 50 to 65
years. Ambulatory patients with primary osteoarthritis
of the knee and clinical symptoms for 6 months,
who had radiological evidence of osteoarthritis,
were included in the study. Patients with established
hypertension or renal, hepatic and cardiac failure, on
steroids and with biochemical and clinical evidence
of rheumatoid arthritis (RA) and gout, were excluded.
Recording signs and symptoms with systemic and joint
examination, biochemical investigations, liver function
test, renal function tests, rheumatoid arthritis factors,
IgA, and IgM levels with radiography of the joints were
done at baseline, 3 months, and 6 months. Subjective
and objective evaluations were carried out every
4 weeks with a final follow-up at the end of 6 months.
The scoring system was used to evaluate subjective
and objective scores. Efficacy was assessed by the
decrease in total signs and symptom score at 6 months;
safety was assessed by incidence of adverse effects
and laboratory evaluation. The minimum level of
significance was fixed at 95% confidence interval and
a 2-sided P value of <.05 was considered significant.
Objective improvement was comparable in both groups
with a significant reduction in symptom scores after
treatment in both groups. No significant alteration was
seen in most of the hematological parameters in both
groups. A significant increase in total proteins, alkaline
*JT-2000 is marketed as Rumalaya forte
8
phosphatase, and blood urea nitrogen was seen in
the Ibuprofen group. There was a significant decrease
in the SGOT and SGPT levels in the JT-2000 group.
Creatinine levels decreased significantly in the JT-2000
group, and increased significantly in the Ibuprofen
group. Radiological examination done at 3 and 6
months did not show any deterioration when compared
to pretherapy images. No untoward side effects were
reported during the trial in all the 50 patients. In the
Ibuprofen group, 40% patients had gastrointestinal,
neurological, and dermatological adverse effects. In
the JT-2000 group, there was a significant decrease of
SGOT and SGPT that was indicative of hepatoprotective
effect of JT-2000, corroborated by significant decrease
in creatinine. Adverse drug reactions were limiting
factors in the long-term safety of Ibuprofen. This study
indicated that JT-2000 was an equally effective, but safe
alternative for long-term use in the management of mild
to moderate osteoarthritis.
Key Words
Osteoarthritis, nonsteroidal anti-inflammatory drugs,
rheumatoid arthritis factors, Rumalaya forte
Intro duc tion
Osteoarthritis (OA) is a slow progressing degenerative
disease of the joints (involving both weight-bearing and
non weight-bearing joints). It is one of the most common
forms of arthritis encountered in clinical practice, which
affects an increasing aging population. Osteoarthritis is a
major cause of morbidity, disability, and impaired quality
of life, especially among the elderly.
The etiology of osteoarthritis is multifactorial, and is
influenced by age, sex, genetic, and biomechanical
factors. The association between repetitive joint trauma
(sports, work-related, or accidental) and osteoarthritis is
well documented.
Clinical Insight
The cardinal feature of osteoarthritis is the osteoarthritic
lesion in the cartilage that disrupts the chondrocytematrix association and alters metabolic responses in the
chondrocytes to contribute to the functional breakdown of
the joint’s cartilage, leading to constant friction between
the bones. Clinically, OA manifests as pain, discomfort,
and swelling and stiffness in the joints. They may be
associated with loss of flexibility of the joint; intraosseous
increase in vascular pressure; periosteal proliferation;
subchondral fracture; and evidence of sclerosis, ligament
laxity, muscle spasm, and synovitis.
Materials and Metho ds
The diagnosis of osteoarthritis is arrived through a detailed
clinical history, physical and radiological examination of
the joint, and if required, aspiration of synovial fluid to
confirm diagnosis. About 60% of patients have suggestive
radiological signs, while only a third of them may have
actual symptoms. Study population
Treatment includes symptomatic therapy for pain,
stiffness, and swelling. The therapy is directed to modify
the joint structure leading to retardation and reversal or
prevention of the disease process. The drug treatment
options available for osteoarthritis include topical and
systemic analgesics, anti-inflammatory agents (mainly
NSAIDs), and intra-articular injections of corticosteroids or
hyaluronic acid.
Cyclo-oxygenase enzyme inhibitors (nonselective,
preferably selective, and specifically selective) are
widely used in the management of OA, but the present
evidence does not suggest their efficacy in preventing
disease progression. Furthermore, the usage of NSAIDs
is linked with numerous short- and long-term adverse
effects and these drugs are associated with an increased
morbidity in older patients. An intra-articular injection of
corticosteroid or hyaluronic acid offers analgesia for 4 to
6 months but is associated with an increased risk of intraarticular infections.
JT-2000 is a polyherbal formulation containing extracts of
Boswellia serrata, Alpinia galanga, Commiphora wightii,
Glycyrrhiza glabra, Tinospora cordifolia, and Tribulus
terrestris, which have clinically been proven to possess
effective anti-inflammatory and analgesic activities.
The present study was conducted to evaluate clinical
efficacy, in comparison with Ibuprofen (a commonly
prescribed NSAID), and long-term safety of JT-2000 in
patients with osteoarthritis in one or both knee joints.
Aim of the study
To evaluate the clinical efficacy and long-term safety of
JT-2000, in comparison with Ibuprofen, in patients with
osteoarthritis of one or both knee joints.
Study design
The study was an open clinical trial approved by the
Institutional Ethics Review Committee. A written informed
consent was obtained from all the patients.
One hundred patients of either sex, in the age group of
50 to 65 years, with osteoarthritis of one or both knee
joints who attended the Department of Orthopedics, SSG
Hospital, Baroda, between April 1, 2002 and August
31, 2002, were enrolled in the study. They were divided
into two groups. The study medication group received 2
capsules of JT-2000, twice daily for a period of 6 months
and the placebo medication group received one tablet
(400mg) thrice daily for a period of 6 months. The two
groups were similar with regard to the demographic data,
baseline parameters, and pain score.
Inclusion criteria
Ambulatory patients of both sexes in the age group of 50
to 65 years, with primary OA of the knee (tibiofemoral
joint) were included in the study. All patients had clinical
symptoms of OA for at least 6 months prior to the study
and were suffering from moderate to severe knee pain
(with or without morning stiffness of <30 minutes
duration). These patients had radiological evidence of
osteophytes with findings like marginal lipping, narrowing
of joint space, and sharpened articular margin or sclerosis
(damaged, thickened, eburnated subchondral bone, or
bone cysts).
Exclusion criteria
Patients with established hypertension, renal, hepatic or
cardiac failure, on long-term steroid treatment, or with
biochemical and clinical evidence of rheumatoid arthritis
or gout were excluded from the study.
Methodology
Selected patients underwent a complete physical
examination before the trial. All signs and symptoms with
regard to severity and duration were recorded before
9
Clinical Insight
commencing treatment. A complete systemic and joint
examination was also performed.
Biochemical investigations and radiography of the joints
were noted at 3 months and after 6 months.
Blood chemistry investigations included complete
hemogram (ESR, WBC, erythrocytes, and platelet count),
liver function tests (including SGOT, SGPT, bilirubin,
serum proteins, alkaline phosphatase, prothrombin
time), renal function tests (including uric acid, urea, and
creatinine), and assessing RA factor and immunoglobulins
(IgA and IgM).
Radiological examination of the affected joints was carried
out for osteophytes, spiking of tibial spine, subchondral
sclerosis, and cysts, loose bodies, and deformities (varus
or valgus). Follow-up and assessment
Subjective and objective evaluation was carried out every
4 weeks for 24 weeks with a final follow-up at the end of
6 months. The scoring system was designed to evaluate
subjective and objective scores, which were compared
before and after treatment.
A complete clinical, biochemical, and radiographical
evaluation was carried out at the end of the three and
six months.
Primary outcome measures
Efficacy was assessed by a decrease in total signs and
symptom score at the end of 6 months. The total symptom
score was based on the number of joints involved, degree
of pain, joint swelling, stiffness, and activity level. The total
sign score was based on joint effusion, and tenderness,
crepitus, range of movements, synovial hypertrophy,
muscle wasting, and joint deformity (Table 1).
Safety was assessed by incidence of adverse effects and
laboratory evaluation of complete hemogram with clinical
biochemistry (including liver and kidney function tests).
Statistical analysis
An analysis was done according to intention-to-treat
principles. Comparison of the two groups for baseline
comparability of different parameters by unpaired t test
was done. Changes in various parameters from baseline
values after the three and six months were evaluated
by paired t test. The reduction in pain and swelling
scores were evaluated to differentiate between the two
treatment groups by unpaired t test. The minimum level
of significance was fixed at 95% confidence limit and a
2-sided P value of <.05 was considered significant.
10 P R O B E • V o l . L • N o . 3 • A p r – J u n 2 0 1 1
Re sults
In JT-2000 group 76% of the patients were in the age
group of 50 to 55 years. The male to female ratio was
equal in the JT-2000 group, while in the Ibuprofen group,
there was a male preponderance (1.77: 1); this difference
was due to randomization (Table 2 and Figure 1).
A majority of patients in both groups had bilateral knee
involvement but only a few (8% in JT‑2000 and 14% in
Ibuprofen group) had unilateral signs and symptoms. A
majority of patients in both groups had a pretherapy total
symptom score of 7 points (72% in JT-2000 and 84% in
the Ibuprofen group).
Before initiation of the therapy, a majority of patients in
both groups had pain during less than routine work,
swelling of joint/s or stiff joints, were comfortable only
with straight walking and found difficulty or inability in
cross-leg sitting, squatting, and stair climbing activities.
In more than 80% of cases in both groups (86% in
JT-2000 and 84% in Ibuprofen), the posttherapy total
symptom score reduced (Table 3 and Figure 2). All these
patients, at the end of the therapy, experienced pain only
during more than routine work, there was a reduction in
swelling and joint stiffness and they were comfortable
with straight walking, cross-leg sitting, squatting, and stair
climbing activities.
The relief in symptoms was comparable in both groups
and the onset of appreciable symptomatic improvement
was marginally faster with Ibuprofen (within 5 days)
as compared to JT-2000 (10-12 days). The objective
improvement was comparable in both groups and there
was statistically significant reduction in the symptom
scores after treatment in both groups. By the end of 6
months, all the patients had significant pain relief, loss of
joint line tenderness, decrease in joint stiffness, increase
in joint mobility, and improved activity level (Table 4
and Figure 3).
No significant alterations were seen in most hematological
parameters in both groups, except a significant decrease
in eosinophils and ESR and a significant increase in
neutrophils in the JT-2000 group (Table 5).
In biochemical parameters, total proteins, ALP, and BUN
showed significant increase in the Ibuprofen group, while
SGOT, SGPT showed significant decrease in JT-2000
group. Creatinine levels were found to be significantly
decreased in the JT-2000 group, and significantly
increased in the Ibuprofen group (Table 6).
Radiological examination done at 3 and 6 months did not
show any deterioration as compared to pretherapy images.
Clinical Insight
Table 1. Symptom and Sign score
Scoring for symptoms
1. No. of joints involved
a. One b. More than 1
2. Pain on
a. More than routine work
b. Routine work c. Less than routine work d. Rest 3. Joint swelling
a. Absent b. Present 4. Joint stiffness
a. Absent b. Present 5. Activity level
a. Straight walking b. Sitting cross-legged c. Squatting d. Stair climbing Scoring for signs
1. Joint effusion
a. Absent : 0
b. Present : 1
2. Joint line tenderness
a. Absent : 0
b. Present :1
3. Crepitus
a. Absent : 0
b. Present : 1
4. Range of movements
a. 0 – 1300 : 1
b. 1000 – 1300 : 2
c. <1000 : 3
5. Synovial hypertrophy
a. Absent : 0
b. Present :1
6. Muscle wasting
a. Absent : 0
b. Present : 1
7. Deformity (varus / valgus)
a. Absent : 0
b. Present : 1
: 0
: 1
: : : : 0
1
2
3
: 0
: 1
: 0
: 1
: Yes / No
: Yes / No
: Yes / No
: Yes / No For each of the above activity level
• If the symptom is present (Yes) : 0
• If the symptom is absent ( No) : 1
Maximum signs score per patient : 9
Maximum symptom score per patient : 10
Table 2. Age-wise Distribution
Age (years)
JT-2000 Group
Ibuprofen Group
Total
Number
%
Number
%
Number
%
50-55
56-60
61-65
38
7
5
76
14
10
26
17
7
52
34
14
64
24
12
64
24
12
Total
50
100
50
100
100
100
Mean ± SD
53.90 ± 4.28
Figure 1. Age-wise distribution of subjects
55.83 ± 4.19
Figure 2. Pre- and posttreatment symptom scores of
JT-2000 group
11
Clinical Insight
Table 3. Symptom Score of Pre- and Posttherapy
Pretherapy
2
-
-
1
1
-
%
4
8
43
1
6
5
10
7
14
12
12
7
36
72
42
84
78
78
-
8
9
7
1
14
2
-
7
1
14
1
2
-
10
1
2
-
1
1
-
Total
50
100
50
100
100
50
100
Total
%
No. of
patients
1
%
Ibuprofen
No. of
patients
-
JT-2000
No. of
patients
%
%
Total
No. of
patients
4
Ibuprofen
No. of
patients
No. of
patients
Score
JT-2000
Posttherapy
%
8
16
12
12
86
42
84
85
85
2
-
1
1
4
100
-
-
-
2
-
-
-
50
100
2
100
100
Table 4. Effect of JT-2000 and Ibuprofen on Symptom Score in Osteoarthritic Patients
Symptom
Score
Parameter
Pain*
Swelling
Joint stiffness
Activity level*
Total score*
JT-2000
Pretreatment
2.040
Posttreatment
0.080
± 0.283
0.160
± 0.274
0.000
± 0.370
0.960
± 0.000
0.000
± 0.198
3.020
± 0.000
0.040
± 0.141
7.140
± 0.283
1.060
Ibuprofen
P value
<.0001; S
<.003; S
<.0001; S
<.0001; S
Pretreatment
1.980
Posttreatment
0.000
± 0.141
0.000
± 0.000
0.000
± 0.000
0.960
± 0.000
0.000
± 0.198
2.980
± 0.000
0.000
± 0.141
6.800
± 0.000
0.840
<.0001; S
± 0.700
± 0.682
± 0.535
*Paired t test, Chi square test; n = 50 in each group; S = Significant; NS = Not significant
Figure 3. Pre- and posttreatment symptom score of patients
with osteoarthritic
± 0.370
P value
<.0001; S
<.0001; S
<.0001; S
<.0001; S
Figure 4. Adverse drug reactions in Ibuprofen group
Clinical Insight
Table 5. Hematological Investigations
Parameter
Hemoglobin
(g%)
JT-2000
Ibuprofen
Pretreatment
Posttreatment
12.95
12.89
± 0.23
± 0.20
Total WBC
Count
(/mm3)
8914.15
8872.00
± 304.21
± 202.31
Polymorphs
(%)
65.90
68.96
± 1.5
± 1.00
30.48
29.44
± 1.02
± 0.97
2.16
1.22
± 0.23
± 0.19
0.28
0.38
± 0.11
± 0.10
32.00
21.04
± 3.47
± 2.34
Lymphocytes
(%)
Eosinophils (%)
Monocytes (%)
ESR (mm/hr)
Platelets
(105/mm3)
Prothrombin
time (sec)
2.49
2.35
± 0.21
± 0.06
14.37
14.42
±0.06
± 0.09
P value
NS
NS
<.012
NS
<.0004
NS
<.001
NS
NS
Pretreatment
Posttreatment
12.73
12.86
± 0.22
± 0.20
8479.59
8600.00
± 315.58
± 266.32
65.24
66.14
± 0.97
± 0.74
32.02
32.67
± 0.92
± 0.67
2.04
0.78
± 0.15
± 0.16
0.59
0.53
± 0.10
± 0.15
23.61
2.73
± 3.37
± 0.23
2.67
2.73
± 0.35
± 0.23
15.59
15.41
± 0.12
± 0.11
P value
NS
NS
NS
NS
<.0001; S
NS
<.038; S
NS
NS
Table 6. Biochemical Investigations
Parameters
Total bilirubin
(mg%)
Total protein (g%)
SGOT (IU/L)
SGPT (IU/L)
ALP (IU/L)
BUN (mg%)
Creatinine (mg%)
IgA (IU/L)
IgM (IU/L)
JT-2000
Pretreatment
Posttreatment
0.78
0.70
± 0.04
± 0.03
6.83
6.73
± 0.07
± 0.06
30.21
26.31
± 2.11
± 1.69
29.63
25.53
± 2.61
± 1.78
152.29
145.36
± 6.25
± 3.83
20.71
21.71
± 0.62
± 0.60
0.88
0.78
± 0.04
± 0.03
1.40
1.51
± 0.11
± 0.12
1.61
1.46
± 0.23
± 0.09
Ibuprofen
P value
<.003
NS
<.0009
<.004
NS
NS
<.003
NS
NS
Pretreatment
Posttreatment
0.75
0.79
± 0.03
± 0.03
6.62
6.78
± 0.06
± 0.05
30.48
28.78
± 2.50
± 1.85
30.98
28.50
± 3.56
± 1.25
142.81
149.25
± 3.68
± 2.93
19.49
22.35
± 0.66
± 0.61
0.85
0.91
± 0.04
± 0.04
1.56
1.60
± 0.18
± 0.16
1.81
1.54
± 0.31
± 0.19
P value
<.029; S
<.0015; S
NS
<.038; S
<.001; S
<.004; S
NS
NS
Note: Statistical analyses were carried out using paired t test; n = 50 patients in each group; S = Significant; NS = Not
significant
13
Clinical Insight
Adverse drug reactions
In the JT-2000 group, one patient complained of headache
for a few days after initiation of treatment, which subsided
on its own in few days, without any treatment. No
untoward side effects were reported during the trial in all
the 50 patients.
In the Ibuprofen group, 20 patients reported adverse drug
reactions (ADRs) and 16 patients had nausea, retrosternal
burning, abdominal discomfort, flatulence, and dyspepsia
at some stage of therapy. These patients were prescribed
H2 receptor antagonist or antacid or both as required
(Figure 4). Three patients developed headache and
dizziness, which eventually subsided on its own and one
patient presented with skin rashes and itching and was
prescribed oral antiallergics for 2 weeks.
Discussion
Osteoarthritis is a chronic, progressive disability
affecting the elderly. The long-term use of NSAIDs in
its management has been shown to be associated with
serious adverse effects.1-5
Herbal formulations have been proven to be effective
and safe alternatives to NSAIDs. The primary constituent
of JT-2000 is B serrata, which has been long used in the
management of osteoarthritic conditions.6 Clinical studies
using herbal formulas with Boswellia have yielded good
results in both osteoarthritis and rheumatoid arthritis.7,8
In B serrata, the active principal compound is boswellic
acid, which has demonstrated antiarthritic effects in
experimental studies and several suggested mechanisms
of action include inhibition of proinflammatory mediators
(5-lipooxygenase including 5-hydroxyeicosa tetranoic acid
and leukotrienes), prevention of decreased glycosaminoglycan synthesis (which is known to accelerate articular
damage), and improved blood supply to joint tissues.9-12
increase in the total proteins, alkaline phosphatase, and
blood urea nitrogen which may not be of any clinical
significance. A significant decrease of SGOT and SGPT
in the JT‑2000 group was indicative for hepatoprotective
effect of JT-2000, which is also corroborated by significant
decrease in creatinine levels in the JT-2000 group, while in
contrast the Ibuprofen group showed a significant increase.
Radiological follow-up also confirmed inflammatory control
by absence of any signs of deterioration as compared to
pretherapy images in both groups.
The major clinically significant difference in both the
groups was noted in ADRs, which was a limiting factor
in the long-term safety of Ibuprofen. In contrast, JT-2000
appeared much safer for long-term usage.
Conclusion
Arthritis and inflammatory disorders are the common
causes of morbidity in the aging population worldwide.
Apart from pain, loss of joint function, and restricted
mobility, there is also considerable compromise in quality
of life.
Current nonsurgical drug therapies (especially NSAIDs)
have their own limitations regarding their host of ADRs
and are therefore of questionable advocacy for long-term
use. Furthermore, the chronic nature of osteoarthritic
process itself demands a long-term drug therapy for
years, especially in cases where patients are not willing to
undergo any surgical intervention.
This study indicated that JT-2000 is an equally effective
and safer alternative for long-term use in management of
mild to moderate osteoarthritis than NSAIDs.
Reference s
1. Schidodt FV, et al. N Engl J Med. 1997;337:12-117.
2. Schlondorf D. Kidney Intl. 1993;44:634-653.
G glabra contains terpinoids (Glycyrrhizin and
glycyrrhetinic acid), which have high affinity and
intrinsic activity toward glucocorticoid receptors,
which are responsible for anti-inflammatory activity.13
Zingiber officinale and T cordifolia in JT-2000 may
have contributed synergistically to its anti-inflammatory
effect.14 A galanga has shown to have a cell membrane
stabilizing effect, which is of primary importance in
cellular metabolic activities leading to subsequent release
of proinflammatory mediators.15
3. Clive DM, Stoff JS. N Engl J Med. 1984;310:563-572.
In this study, there was an excellent relief from pain at the
end of the therapy. An overall improvement in quality of
life was seen in both the groups. No significant changes
were recorded in the hematological investigations of both
groups. In the Ibuprofen group, there was a significant
12. Reddy GK, et al. Biochem Pharm. 1989;38:3527-3534.
4. Woffe MM, et al. N Engl J Med. 1999;340:1888-1899.
5. Simon LS. Curr Opin Rheumatol. 1998;10:153-158.
6. Pizzorno. Textbook of Natural Medicine. 2nd ed.
Churchill Livingstone, Inc; 1999:1449.
7. Kulkarni RR, et al. J Ethnopharmacol. 1991;33:91-95.
8. Ammon HPT, et al. J Ethnopharmacol. 1993;38(2-3):105-112.
9. Singh GB, Atal CK. Agents Action. 1986; 18:407-412.
10. Reddy CK, et al. Biochemical Pharmacol. 1989;20:3527-3534.
11. Omman HP, et al. Planta Medica. 1991;57:203-207.
13. Murray MT, Pizzorno JE. Text Book of Natural Medicine. vol 1,
2nd ed. Churchill, Livingston;1999:767-773.
14. Jana V, et al. Ind J Pharmacology. 1999;31:232-233.
15. Sadique I, et al. Fitoterapia. 1989;10(6):525-532.
Clinical Insight
Liv.52 in the Prevention of Hepatotoxicity in Patients receiving
Antitubercular Drugs: A Meta-analysis of Eight Controlled
Clinical Trials
Dange SV
Prof. of Medicine, D.Y. Patil Medical College, Pune, Maharashtra, India
IJCP. 2010;21(2):81-86.
Abstract
The aim of this study was to conduct a meta-analysis on
the efficacy and short- and long-term safety of Liv.52
as a hepatoprotective in tuberculosis patients receiving
antitubercular drugs, as published in eight controlled
clinical trials. Meta-analysis of eight clinical studies
conducted between 1970 and 1992 in 689 tubercular
patients receiving antitubercular treatment along with
Liv.52 or placebo was taken up for this study. Duration
of the treatment varied from 4 weeks to 1 year.
Children below the age of 2 years received 10 to 20
drops of Liv.52 three to four times daily. Children in the
age group of 2 to 5 years received 20 drops of Liv.52
three times daily. Adults received 1 to 2 teaspoonsful
of Liv.52 syrup three times daily or 1 to 2 tablets of
Liv.52 two to three times daily. Improvement in various
parameters of hepatotoxicity, such as hepatomegaly,
anorexia, weight gain, general well-being, and liver
function test (ALT) and ultrasonographic findings of the
hepatobiliary system were taken into consideration.
Changes in various parameters from baseline values
and values at the end of the study were pooled and
analyzed cumulatively using Fischer’s exact test
or unpaired Students t test. Statistical analysis was
performed using GraphPad Prism software (Version
4.03).
Results of the meta-analysis showed a statistically
significant improvement in the hepatotoxicity in
patients receiving antitubercular drugs and Liv.52.
Significant improvements were observed in associated
symptoms such as anorexia, weight gain, hepatomegaly,
and general well-being. The protective effect of Liv.52
against hepatotoxic reaction caused by antitubercular
treatment (ATT) was further substantiated by a
significant reduction in alanine aminotransferase (ALT)
values and alleviation of gastrointestinal (GI) symptoms
due to hepatitis. No adverse effects were reported or
observed due to Liv.52 during the study period and the
compliance to the drug therapy was good. Therefore,
from the above findings it can be concluded that Liv.52
acts as a hepatoprotective in the hepatotoxicity of
tuberculosis patients receiving antitubercular treatment.
Key Words
Meta-analysis, Liv.52, hepatotoxicity, antitubercular drugs
Intro duc tion
Tuberculosis is a common problem worldwide, especially
after the recent increase in the incidence of acquired
immunodeficiency syndrome (AIDS) and multiple
drug resistant tuberculosis (MDR-TB) due to inefficient
management.1 Every year, an estimated eight million new
cases and two million deaths occur due to TB worldwide.2
At present, most commonly used anti-TB drugs are more or
less hepatotoxic, especially when several anti-TB drugs are
used in combination. Liver dysfunction caused by anti-TB
drugs often results in interruption of anti-TB therapy and
acute hepatic failure, which is life threatening.3,4 Druginduced hepatotoxicity is a potentially serious adverse
effect of antituberculosis treatment regimens containing
isoniazid, rifampicin, and pyrazinamide.5
The underlying mechanism of antitubercular treatment
(ATT)-induced hepatotoxicity and the factors predisposing
to its development are not clearly understood. Age and
sex of the patients, chronic alcoholism and chronic liver
disease, hepatitis B virus carrier status, and acetylator and
nutritional status have all been incriminated as possible
predisposing factors in earlier studies. As enzymes for
drug metabolism in hepatocyte microsomes may have
congenital defect, malformation, and low activity or may
be inhibited by drugs, drugs or drug metabolites are very
toxic to hepatocytes. The other reason is hypersensitivity
to drugs. The drugs as a hapten cause allergic reaction
by immune mechanism, leading to an increase in alanine
aminotransferase (ALT) alone in clinical situation.6
15
Clinical Insight
Commonly used antitubercular drugs, such as isoniazid,
rifampicin, and pyrazinamide, are hepatotoxic.6
Isoniazid causes hepatic damage by either toxicity
or hypersensitivity induced by its metabolite—
acetylhydrazine. Rifampicin may accelerate the
metabolism of isoniazid as a strong enzyme inducer,
resulting in an increase in acetylhydrazine. This combines
with biomacromolecules in liver, leading to hepatocellular
damage (usually seen in aged patients with excessive
drinking), malnutrition, or liver ailment. Pyrazinamide
hepatotoxicity is dose dependent and the general dose
rarely causes hepatic damage. Isoniazid and rifampicin
are the first-line anti-TB medicines because of their strong
bactericidal effects.7,8
The clinical presentation of ATT-associated hepatitis is
similar to that of acute viral hepatitis. ATT can cause varied
degree of hepatotoxicity from a transitory asymptomatic
rise in transaminases to acute liver failure. The frequency
of hepatotoxicity in different countries varies widely
from 2% to 39%.9 The occurrence of drug-induced
hepatotoxicity is unpredictable, but it is observed that
certain patients are at a relatively higher risk as compared
to others.
Liv.52, a polyherbal formulation, is used extensively in
the management of various hepatic disorders over the
past 55 years. The principal herbs used in the preparation
of Liv.52 include Capparis spinosa, Cichorium intybus,
Solanum nigrum, Terminalia arjuna, Cassia occidentalis,
Achillea millefolium, and Tamarix gallica.
Liv.52 was evaluated for its efficacy in the prevention of
hepatotoxicity induced by antitubercular drugs in 689
tuberculosis patients receiving ATT, as reported in eight
controlled clinical trials conducted between 1970 and
1992. Results of each clinical trial with Liv.52 showed
significant hepatoprotective effect, both clinically and as
determined through liver function test (ALT). The study
also showed good short- and long-term safety. These
studies need to be meta-analyzed to further substantiate
the clinical efficacy of Liv.52 as a hepatoprotective in
tuberculosis patients receiving antitubercular drugs.
A meta-analysis is a two-stage process; the first stage is the
extraction of data from each study and the calculation of
result for each study. The second stage involves deciding
whether it is appropriate to calculate a pooled average
result across studies. This process gives greater weightage
to the results from the studies that give more information.10
Advantages of meta-analysis include deriving and
generalization of the population studies, ability to control
Liv.52 in ATT-induced toxicity
between study variation, and statistical testing of overall
factors/effect size parameters in related studies.
To cumulate the result of all the studies, a meta-analysis
was done to analyze the efficacy and short- and long-term
safety of Liv.52 as a hepatoprotective in tuberculosis
patients receiving antitubercular drugs.
Aim of the study
The aim of the study was to conduct a meta-analysis on
the efficacy and short- and long-term safety of Liv.52 in
patients receiving antitubercular drugs, as reported in
eight controlled clinical trials.
Study design
This is a cumulative meta-analysis of eight published
controlled clinical trials of Liv.52 in the prevention of
hepatotoxicity in patients receiving antitubercular drugs.
Of these eight controlled trials, one was a double-blind
placebo-controlled study and the remaining seven were
controlled studies.
Inclusion criteria
All published studies, which evaluated the efficacy and
safety of Liv.52 in hepatotoxicity due to antitubercular
treatment, were included in the meta-analysis irrespective
of the study design. The meta-analysis included eight
controlled clinical trials and there were no restrictions
regarding sex, age, or duration of the disease. The
outcome variables included measurement of data on
changes in clinical symptoms and signs of hepatotoxicity,
laboratory results, and incidence of adverse events during/
after the treatment.
Exclusion criteria
Phase I studies conducted with Liv.52 and uncontrolled
studies were excluded from the analysis.
Study procedures
Eight controlled clinical studies conducted between 1970
and 1992 in 689 tubercular patients receiving ATT and
presenting with hepatotoxicity were subjected to metaanalysis. Duration of the treatment varied from 4 weeks
to 1 year. Children below the age of 2 years received 10 to
20 drops of Liv.52 three to four times daily. Children in the
age group of 2 to 5 years received 20 drops of Liv.52 three
times daily. Adults received 1 to 2 teaspoonsful of Liv.52
syrup three times daily or 1 to 2 tablets of Liv.52 two to
Clinical Insight
three times daily. Improvement in the various parameters
of hepatotoxicity, such as hepatomegaly, anorexia, weight
gain, and general well-being and ultrasonographic findings
of the hepatobiliary system were taken into consideration.
Changes in various parameters from baseline and at the
end of the study were pooled and analyzed.
The incidence and type of adverse events reported
by various studies were also tabulated separately. All
adverse events, either reported or observed by patients
or investigators, were recorded with information about
severity, duration, and action taken regarding the study
drug. Relation of adverse events to study medication was
predefined as “Unrelated” (a reaction that does not follow
a reasonable temporal sequence from the administration
of the drug), “Possible” (follows a known response pattern
to the suspected drug, but could have been produced
by the patient’s clinical state or other modes of therapy
administered to the patient), “Probable” (follows a known
response pattern to the suspected drug that could not
be reasonably explained by the known characteristics
of the patient’s clinical state), and “Certain” (the adverse
events must have definitive relationship to the study drug,
which cannot be explained by concurrent disease or any
other agent).
302 served as controls. The age varied from 2 months to
60 years and the duration of the treatment varied from 4
weeks to 1 year (Table 1). Details of the eight controlled
clinical trials are enumerated in Table 2.
Among the 220 patients presenting with anorexia, who
received Liv.52 in addition to antitubercular treatment,
only 16 patients were presenting with anorexia at the
end of the treatment, showing a significant improvement
(P<.0001). Whereas in 163 patients (controls) received
antitubercular treatment, anorexia was persistent in 160
patients (Table 3).
Among the 186 patients presenting with weight loss, who
received Liv.52 in addition to antitubercular treatment,
Table 1. Demographic Details
No. of controlled
trials
7
No. of placebocontrolled trial
(double blind)
1
No. of patients
Total: 689 (Liv.52: 367; control: 302;
placebo: 20)
Age range
2 months to 60 years
Children aged <2 years: Liv.52 drops
10 to 20 drops three to four times daily
Children in the age group of 2 to 5
years: Liv.52 drops 20 drops three
times daily
Primary and secondary outcome measures
Primary predefined outcomes were clinical recovery from
hepatotoxicity due to antitubercular drugs. Secondary
outcomes were safety and compliance to Liv.52.
Dose
Adults
Liv.52 syrup: 1 to 2 teaspoonsful three
times daily
Liv.52 tablet: 1 to 2 tablets three to four
times daily
Values are expressed as incidences of patients with or
without symptoms or Mean ± SD. Changes in various
parameters from baseline values and values at the end
of the study were pooled and analyzed cumulatively
using Fischer’s exact test or unpaired Students t test.
The minimum level of significance was fixed at 95%
confidence limit and a two-sided P value of <.05 was
considered significant. Statistical analysis was performed
using GraphPad Prism Version 4.03 for windows,
GraphPad Software, San Diego, California, United States.
Re sults
The demographic details of the clinical trials are provided
in Table 1. Among the eight controlled studies, one was
a double-blind placebo controlled study. A total of 689
tuberculosis patients receiving antitubercular treatment
presenting with hepatotoxicity were included in the study;
of which 367 received Liv.52, 20 received placebo, and
Duration
4 weeks to 1 year
Table 2. Details of the Eight Studies Included for the
Meta-analysis of Liv.52 in Patients Receiving ATT
Sl.
No
Name
Year
Trial
design
Duration
No. of
patients
1976
DBPCT
4 weeks
95
1.
Dabral et al11
2.
Indirabai et al
1970
CT
4 weeks
50
3.
Saxena13
1971
CT
30 days
100
4.
Khare A14
1992
CT
6-8
weeks
70
5.
Kishore B et al15
1978
CT
4 weeks
81
6.
Kumar, Ram S16
1975
CT
1 year
50
7.
Galitsky et al17
1997
CT
8 weeks
143
8.
Purohit et al18
1988
CT
1 month
100
-
-
-
689
12
Total
DBPCT: Double-blind placebo-controlled trial; CT: controlled trial
17
Clinical Insight
Table 3. Effect of Liv.52 on Anorexia with ATT Treatment
Treatment
No. of
patients
Patients showing symptoms at
the end of treatment
ATT
163
160
ATT + Liv.52
220
16*
Statistical analysis: Fischer’s exact test; *P<.0001 as
compared to ATT alone
only 23 patients did not gain weight at the end of the
treatment, showing a significant improvement (P<.0001).
In the control group, of the 190 cases 178 cases did not
show any gain in the weight (Table 4).
Hepatomegaly
was
evaluated
through
clinical
examination, symptom evaluation, and ultrasonographic
Table 4. Effect of Liv.52 on Weight Gain in Patients
Receiving ATT
Treatment
No. of
patients
Table 6. Effect of Liv.52 on General Well-being in Patients
Receiving ATT
Treatment
No. of
patients
No. of patients showing
improvement after treatment
ATT
25
0
ATT + Liv.52
25
21*
offered by Liv.52 in preventing the increased levels of
ALT in patients received ATT was significant at P<.0003
(Table 7).
Table 7. Protective Effect of Liv.52 on ALT Levels in Patients
Receiving ATT
Treatment
No. of
patients
Patients showing no weight
gain after treatment
No. of patients with
increase in ALT levels after
treatment
ATT
82
15
82
1*
ATT
190
178
ATT + Liv.52
ATT + Liv.52
186
23*
Initial values of ALT <40 U
examination. In patients treated with Liv.52, it was
seen that out of 25 patients 24 patients improved with
regression of liver size as well as with the symptomatic
improvement in the pain in the right hypochondriac
region, showing a statistical significance of P<.0001,
whereas in control group there was no improvement in
any patient (Table 5).
Evaluation of general well-being in patients receiving
antitubercular treatment showed that of the 25 cases
Table 5. Protective Effect of Liv.52 on Hepatomegaly in
Patients Receiving ATT
Treatment
No. of patients
Regression of liver
size after treatment
ATT
25
0
ATT + Liv.52
25
24*
treated with Liv.52, 21 showed significant improvement
(P<.0001) whereas in control group, none of the cases
showed any improvement (Table 6).
Among the 82 patients who received antitubercular
treatment along with Liv.52, only one patient showed an
increase in the ALT levels as compared to 15 cases out
of 82 presented with increased ALT levels in following
treatment with antitubercular drugs alone. The protection
Among the 82 patients presenting with GI symptoms and
symptoms related to hepatitis, addition of Liv.52 showed
a significant improvement (P<.0001) in patients receiving
antitubercular treatment. Whereas among the 82 patients
receiving antitubercular treatment as controls, 44 patients
still presented with symptoms (Table 8).
Table 8. Protective Effect of Liv.52 on Protection of GI
Symptoms and Symptoms Related to Hepatitis
Treatment
No. of patients
Patients showing
symptoms
ATT
82
44
ATT + Liv.52
82
3*
In one clinical trial, the drug–drug interactions of
rifampicin with Liv.52 was studied, which compared the
initial and subsequent serum rifampicin levels in both
control (ATT alone) and treated (liv.52 + ATT) groups.18
The serum rifampicin levels in group 1 (control) and
group 2 (Liv.52), on days 1, 15, and 30 were comparable
and not significant, though there was a falling trend in the
levels as compared to the initial and subsequent readings.
It appears that the process of enzymatic induction
witnessed with rifampicin metabolism is not influenced by
the addition of Liv.52 (Table 9).
Clinical Insight
There were no adverse effects observed or reported
during the clinical trials in patients who received Liv.52
Table 9. Initial and Subsequent Serum Rifampicin Levels in
Both the Groups After 2 Hours of Rifampicin Ingestion
(in μg/mL)
Day of estimation
Group 1 (control)
Group 2 (Liv.52)
1st day
8.5 ± 4.2
9.01 ± 5.3
15th day
7.6 ± 4.9
7.4 ± 4.7
30th day
7.1 ± 5.1
7.9 ± 4.5
Statistical analysis: Unpaired Students’ “t” test
along with antituberculosis treatment and compliance to
the use of formulation was good. There were no drop outs
or withdrawal from the study.
Discussion
A useful definition of meta-analysis was given by Huque
as “A statistical analysis that combines or integrates the
results of several independent clinical trials considered by
the analyst to be combinable.”19
A single study often cannot detect or exclude with
certainty clinically relevant differences in the effects of
two treatments. Cumulative meta-analysis is defined as the
repeated performance of meta-analysis whenever a new
trial becomes available for inclusion. Such cumulative
meta-analysis can retrospectively identify the point in time
when a treatment effect first reaches conventional levels
of significance.20
Meta-analysis thus not only consists of the combination
of data but also includes the epidemiological exploration
and evaluation of results (epidemiology of results).21
Therefore, new hypotheses that were not posed in single
studies can be tested in meta-analyses.22 The number of
patients included in clinical trials is often inadequate, as
in some cases the required sample size may be difficult
to achieve.23 Meta-analysis may, nevertheless, lead to the
identification of the most promising or urgent research
question and can permit a more accurate calculation of
the sample sizes needed in future studies.24 Goals of metaanalysis are to enable the overall significance of an effect
to be evaluated, based on the multiple studies available,
and to estimate an overall effect size by combining the
individual estimates in multiple studies.25
In the present meta-analysis, clinical trials and their
details were tabulated and analyzed statistically. The
clinical trial included in the meta-analysis consisted of
patients suffering from various types of tuberculosis
such as pulmonary, abdominal, childhood tuberculosis,
tuberculous meningitis, military tuberculosis, and
tubercular cervical lymphadenitis. The outcome of this
analysis showed marked improvement with Liv.52 as a
hepatoprotective in patients treated with antitubercular
drugs, as indicated by relief in clinical symptoms,
maintenance of ALT levels, and regression of liver size (as
observed clinically and ultrasonographically). The efficacy
of Liv.52 is attributed to the potent hepatoprotective herbs
present in the formulation, which is described below in
detail.
C spinosa was found to possess potent hepatoprotective
activity against CCl4 -, paracetamol (in vivo)-,
thioacetamide-, and galactosamine (in vitro)‑induced
hepatotoxicity.26 Strong anti-inflammatory activity of C
spinosa was demonstrated, which was comparable to
oxyphenbutazone.27 C spinosa was found to possess
significant antioxidant, antimicrobial, and antifungal
activities.28-30
C intybus revealed hepatoprotective effect against
CCl4 -induced hepatotoxicity as indicated by significant
prevention of the elevation of malondialdehyde formation
(plasma and hepatic) and enzyme levels (aspartate
aminotransferase [AST] and ALT) along with restoration
of the histoarchitecture.31,32 C intybus showed significant
increase in the number of circulating leukocytes, the
weights of concerned organs (liver, spleen, and thymus),
number of splenic plaque-forming cells, hemagglutination
titers, and the secondary IgG antibody response against
ethanol-induced toxicity. There were also significant
increases in delayed-type hypersensitivity reaction,
phagocytic activity, natural killer cell activity, cell
proliferation, and interferon gamma-secretion.33 Reports
suggest that the observed hepatoprotective effect of
C intybus might be due to its ability to suppress the
oxidative degradation of DNA in the tissue debris34 and
potent antioxidant activity (radical scavenging effects,
inhibition of hydrogen peroxide, and iron chelation).35
It also showed marked cytoprotective activity, which
was established against ethanol-induced liver damage.
The cytoprotective activity was further supported by
restoration of histoarchitecture of the liver.36
S nigrum investigated against CCl4 -induced hepatic
damage showed remarkable hepatoprotective activity
as confirmed by evaluated biochemical parameters
including AST, ALT, ALP, and total bilirubin levels.37 It
also demonstrated to protect DNA against oxidative
19
Clinical Insight
damage and suppress the oxidative degradation of DNA
in the tissue debris.34 S nigrum was found to possess a
potent antioxidant activity, which was demonstrated by
scavenging of hydroxyl radicals and DPPH radicals.38,39
The potent antioxidant activity of T arjuna might be
due to its effects on lipid peroxidation.40 T arjuna was
found to inhibit nitric oxide (NO) production41 and
decrease inducible nitric oxide synthase (iNOS) levels in
lipopolysaccharide-stimulated peritoneal macrophages.42
Potent antiviral (by virtue of inhibition of viral attachment
and penetration) and antibacterial activities of T arjuna
were reported.43,44
Therefore, it can be concluded from the meta-analysis
that Liv.52 treatment prevented hepatotoxic reactions
in patients received antitubercular treatment. These
findings clearly suggest the beneficial role of Liv.52 in the
management of drug-induced (ATT) hepatotoxicity.
Reference s
1. Global tuberculosis control. World health organization report, 2001.
Geneva, Switzerland: who/cds/tb; 2001:287.
2. Nehaul LK. In: Walker R, Edwards C, eds. Clinical Pharmacy
and Therapeutics. 3rd edn. Edinburgh: Churchill Livingston;
2003:583-595.
3. Chen L, et al. Di 4 Jun Yi Da Xue Xue Bao. 2000;21:872-874.
Significant hepatoprotective effects of C occidentalis
in chemically induced liver damage were noted.45
C occidentalis modulates hepatic enzymes and provides
hepatoprotection against cyclophosphamide-induced
immunosuppression.46 Antimicrobial properties of
C occidentalis were comparable with standard reference
antibiotics.47 Strong antibacterial activity of C occidentalis
against Salmonella typhi was demonstrated.48
4. Wong WM, et al. Hepatology. 2000;31:201-206.
Clinically beneficial effects of A millefolium in the
treatment of chronic hepatitis was demonstrated.49 Similar
clinical improvements in chronic hepatocholecystitis
and angiocholitis with A millefolium were established.50
Antioxidant and antimicrobial activities of A millefolium
was also reported.51
12. Indira Bai K, et al. Antiseptic. 1970;6(7):615-617.
Therefore, as discussed above, these synergistic actions
(hepatoprotective, antimicrobial, antioxidant, and antiinflammatory) exhibited by the ingredients of Liv.52 might
provide the protective action against hepatotoxic reaction
in patients receiving antitubercular treatment.
18. Purohit SD, et al. Probe. 1988;XXVII(4):261-265.
Conclusion
23. Collins R, et al. BMJ. 1992;304:1689.
This meta-analysis of eight controlled clinical trials
revealed a highly significant hepatoprotective activity of
Liv.52 in tuberculosis patients receiving antitubercular
treatment, as evidenced from improvement in clinical
parameters and liver function test (ALT). These remarkable
results might be due to the synergistic activities of the
potent hepatoprotective individual herbs of Liv.52. It
was also observed that Liv.52 offered hepatoprotective
activity without interfering the pharmacokinetics of
antitubercular drugs such as rifampicin, which is the most
common first-line drug in ATT. There were no clinically
significant adverse reactions due to Liv.52 in any of these
studies. In all these eight studies, overall compliance to
Liv.52 treatment among patients who received ATT was
good, and no treatment discontinuations were reported.
5. Mahashur AA, Prabhudesai PP. J Assoc Physicians India. 1991;39:595-596.
6. Yew WW, et al. Drugs Exp Clin Res. 1995;21:79-83.
7. Yew WW, et al. Int J Clin Pharmacol Res. 1992;12:173‑178.
8. Schaberg T, et al. Eur Respir J. 1996;9:2026-2030.
9. Anand AC, et al. Med J Armed Forces India. 2006;62(1):98.
10. Green S. Singapore Med J. 2005;46(6):270.
11. Dabral PK, et al. Probe. 1976;XV(3):199-201.
13. Saxena S. Curr Med Pract. 1971;15:580‑583.
14. Ashish Khare. Probe. 1992;XXXI(3):260-261.
15. Kishore B, et al. Probe. 1978;XVII(2):125-131.
16. Kumar P, Ram S. Ind Practit. 1975;535-537.
17. Galitsky LA, et al. Probl Tuberculosis. 1997;4:35.
19. Huque MF. Proc Biopharmaceutical Sect Am Stat Assoc. 1988;2:28-33.
20. Lau J, et al. N Engl J Med. 1992;327:248-254.
21. Jenicek M. J Clin Epidemiol. 1989;42:35-44.
22. Gelber RD, Goldhirsch A. Stat Med. 1987;6:371-378.
24. Chalmers I. In: Thalhammer O, Baumgarten K, Pollak A, eds.
Perinatal Medicine. Stuttgart: Thieme; 1979:260.
25. Smith, et al. Arch Gen Psych. 1981;36:1203-1208.
26. Gadgoli C, Mishra SH. J Ethnopharmacol. 1999;66(2):187-192.
27. Al-Said MS, et al. Pharmazie. 1988;43(9):640-641.
28. Bonina F, et al. J Cosmet Sci. 2002;53(6):321-335.
29. Germano MP, et al. J Agric Food Chem. 2002;50(5):1168-1171.
30. Mahasneh AM. Phytother Res. 2002;16(8):751-753.
31. Aktay G, et al. J Ethnopharmacol. 2000;73(1-2):121-129.
32. Ahmed B, et al. J Ethnopharmacol. 2003;87(2-3):237-240.
33. Mun JH, et al. Int Immunopharmacol. 2002;2(6):733-744.
34. Sultana S, et al. J Ethnopharmacol. 1995;45(3):189-192.
35. El SN, Karakaya S. Int J Food Sci Nutr. 2004;55(1):67-74.
36. Gurbuz I, et al. J Ethnopharmacol. 2002;83(3):241-244.
37. Raju K, et al. Biol Pharm Bull. 2003;26(11):1618-1619.
Clinical Insight
38. Moundipa PF, Domngang FM. Br J Nutr. 1991;65(1):81-91.
45.Jafri MA, et al. J Ethnopharmacol. 1999;66(3):355-361.
39. Son YO, et al. Food Chem Toxicol. 2003;41(10):1421-1428.
46. Bin-Hafeez B, et al. J Ethnopharmacol. 2001;75(1):13-18.
40. Munasinghe TC, et al. Phytother Res. 2001;15(6):519-523.
47. Samy RP, Ignacimuthu S. J Ethnopharmacol. 2000;69(1):63-71.
41. Ali A, et al. Pharmazie. 2003;58(12):932-934.
48. Perez C, Anesini C. J Ethnopharmacol. 1994;44(1):41-46.
42. Ali A, et al. J Asian Nat Prod Res. 2003;5(2):137-142.
49. Harnyk TP. Lik Sprava. 1999;7-8:168-170.
43. Cheng HY, et al. Antiviral Res. 2002;55(3):447-455.
50. Krivenko VV, et al. Vrach Delo. 1989;3:76-78.
44. Perumal Samy R, et al. J Ethnopharmacol. 1998;62(2):173-182.
51. Candan F, et al. J Ethnopharmacol. 2003;87(2-3):215-220.
21
Clinical Insight
Septilin in infective dermatoses
Septilin in Infective Dermatoses
Sharma SK, et al.
Dr. Ram Manohar Lohia Hospital, New Delhi.
Curr Med Pract. 1984;28(8):603-606.
Intro duc tion
Abstract
The aim of this study was to evaluate the role of Septilin
in infective dermatoses. A total of 50 patients with
dermatological conditions such as acne vulgaris, acne
pustulosa, impetigo, infective eczema, folliculitis, and
carbuncles were selected for this study. These patients
were randomly selected, irrespective of age, sex, and
duration of disease. Septilin was administered at a
dosage of 2 tablets twice a day to 2 tablets thrice a day,
depending on the age and severity of infection. The
patients were followed up every week up to 4 weeks
and the number of lesions, site, and type of lesions
were recorded in detail. The findings of the study
showed a definite improvement in cases of chronic
infective dermatoses although no encouraging results
were seen in acute infective dermatoses.
Key Words
Septilin, infective
dermatoses
dermatoses,
chronic
infective
Septilin is an Ayurvedic preparation which contains
antibacterial and anti-inflammatory principles.1 Septilin has
been reported to stimulate phagocytosis.2 Cahu and Hirsh3
demonstrated the presence of an antibacterial protein
(phagocytin) in the cytoplasmic granules of polymorphs.
This protein of polymorphs has an antibacterial effect on
both gram-positive and gram-negative organisms. Given
orally, Septilin has been shown to inhibit the growth of
staphylococci, streptococci, pneumococci, Micrococcus
catarrhalis, Neisseria catarrhalis, Hemophilus influenzae,
diphtheroids, and Klebsiella sps.4,5
Septilin was tried in acute and chronic infective
dermatoses because it is economical and can be given
for a long time without any untoward side-effects, in
comparison to antibiotics which are expensive and may
have side-effects.
Therapeutic Ac tion of Ingre dients
Balsamodendron mukul (Guggulu) has been regarded as
a sovereign remedy in ancient medicine. As described
in standard Ayurvedic texts, Guggulu is reputed to be an
ancient “broad spectrum” drug with a wide therapeutic
range. Its therapeutic action is similar to that of ACTH
as it raises the general defense mechanism of the body
and thus helps overcome infective and inflammatory
processes.
Maharasnadi quath: It is a compound containing over
20 ingredients and is useful in rheumatism, lumbago,
and sciatica.
Phyllanthus emblica: It is the richest natural source of
ascorbic acid. The effects of vitamin C on the adrenal
cortex and in building resistance to infections are
well known.
Tinospora cordifolia:
tonic properties.
This
plant
has
diuretic
and
Rubia cordifolia: This plant is well known for its
antipyogenic properties and is widely used externally for
healing ulcers and burn wounds.
Clinical Insight
Septilin in infective dermatoses
Moringa pterygosperma: The root bark of young trees
contains a physiologically active, basic principle
“spirochin” and an antibiotic substance “pterygospermin.”
Spirochin is effective in combating gram-positive
infections, specially staphylococcal and streptococcal.
Pterygospermin exhibits pronounced antibacterial activity
against gram-negative and gram-positive organisms.
Fifty cases of various dermatological conditions like acne
vulgaris, acne pustulosa, impetigo, infective eczema,
folliculitis, and carbuncles were selected. All the cases
were selected at random, irrespective of age, sex, and
duration of disease.
Dosage of Septilin was 2 tablets twice a day to 2 tablets
thrice a day, depending on the age and severity of
infection. No other local medication or oral antibiotic was
given. The patients were followed up every week up to 4
weeks. In few cases, clinical photographs were also taken.
The patients who failed to come for a follow-up were
excluded from the study and they were substituted with
an equal number of new patients. The number of lesions,
site, and type of lesions were recorded in detail.
The results were recorded as good when there was 50%
improvement in inflammation and itching.
O bser vations and Re sults
Study findings showed good results in 46% of cases, status
quo in 44%, and deterioration in 10% (Table 1).
Good results were seen in chronic infective dermatoses
like acne vulgaris and chronic folliculitis. But no
encouraging results were seen in acute infective
dermatoses like impetigo, infective eczema, carbuncles,
and furunculosis. In all the above conditions no dramatic
results were seen.
In the case of acne vulgaris, half the number of total cases
showed improvement, there was reduction in existing
pustules and cysts, as well as reduction in the number of
new papules, pustules, and cystic lesion. The other half
maintained status quo. These patients were followed up
for 4 to 6 weeks.
In cases of infective eczema, only three cases showed
improvement in erythema and oozing. In 7 cases, there
was no improvement at all. In 4 cases there was a increase
in erythema, oozing, and crusting. In these cases, patients
had to be put on other medicines after 7 to 10 days of
follow-up.
In case of carbuncles and furunculosis, there were not very
encouraging results except in one case of sycosis barbae.
Case of chronic folliculitis showed good results, with the
reduction of existing lesions and also reduction in the
appearance of new lesions.
Summar y
Fifty cases of infective dermatoses were treated with
Septilin for 1 to 4 weeks, irrespective of age, sex, and
duration of the inflammatory process. Septilin was given
in doses of 2 tablets twice a day to 2 tablets thrice a
day. No other medication was given. There was definite
improvement in cases of chronic infective dermatoses.
but no encouraging results were seen in acute infective
dermatoses.
Reference s
Table 1. Response to Septilin Treatment
Good
Status
quo
Worse
Acne vulgaris
5
5
-
3. Cahu ZA, Hirsh JG. J Exp Med. 1960:112, 983, 1105.
Acne pustulosa
2
1
1
4. Gadre KC. Probe. 1964;3:99.
Infective eczema
3
7
4
5. Vishwakarma SK. Probe. 1979;2:85.
Furunculosis
2
4
-
Carbuncles
1
3
1
Impetigo contagiosa
2
1
-
Chronic folliculitis
8
1
-
Total
23
22
5
Disease
1. Mascarenhans, et al. Probe. 1980;2:124.
2. Bhel PN, Pradhan BK. Probe. 1978;3:245.
23
Clinical Insight
Evaluation of the Safety and Efficacy of Rumalaya forte:
A Double-Blind Clinical Trial
Rastogi S, et al.
Department of Orthopedics, All Indian Institute of Medical Sciences, New Delhi, India
Orthopaedics Today. 2003;V(1):63-65.
Abstract
A double-blind clinical study was conducted to evaluate
the efficacy and safety of Rumalaya forte, a polyherbal
formulation in the management of osteoarthritis. Fifty
patients of either sex in the age group of 50 to 65 years
with clinical and radiological evidence of osteoarthritis
were selected for the trial. The patients were randomly
divided into two groups. Group A patients received
Rumalaya forte at a dosage of 1 tablet twice daily,
and Group B received a placebo at the same dosage.
All symptoms along with severity and duration were
recorded prior to the drug treatment. Routine blood
chemistry and radiography were done before and at the
end of the treatment period. Patients were followed up
every 4 weeks for 6 months. At the end of 6 months,
symptomatic assessment was carried out to determine
the clinical efficacy of the trial drug. Results revealed
that the average score for the number of joints involved
before the treatment was 3.44 in Group A and 2.72
in Group B. The score was reduced from 3.44 to 1.16
in Group A and from 2.72 to 1.47 in Group B. Thus,
there was 66.28% reduction in the number of joint
involvements in the Rumalaya forte-treated group
and 51.94% in the placebo group. In subjective
symptomatic evaluation, Group A had an average
score of 18.56, which reduced to 8.02 indicating
45.96% relief in various symptoms. The subjective
symptomatic score in Group B reduced from 19.63 to
13.92, indicating 29.09% relief in various symptoms.
Twenty of the 25 patients in Group A were satisfied
with the drug and showed significant improvement
in the symptoms and mobility. In Group B, only few
patients expressed their satisfaction to relief in pain.
Therefore, patients belonging to Group A therefore had
significant alleviation of symptoms in terms of relief
of pain and free mobility of the joints. No side effects
were reported by any of the patients.
Key Words
Rumalaya forte, osteoarthritis, joints
Intro duc tion
Osteoarthritis is the most common arthritic condition
affecting an increasing aging population. It is a slowly
progressing joint disease with multiple etiologies involving
biomechanical and genetic factors, which may contribute
to the osteoarthritic lesion in the cartilage by disrupting
the chondrocyte-matrix association and altering metabolic
responses in the chondrocytes. Osteoarthritis is a major
cause of morbidity and disability, limiting activity, and
impaired quality of life, especially among the elderly.
The primary complaints of patients with osteoarthritis
are pain and difficulty in joint mobility. The etiology
of pain is multifactorial, including inflammatory and
noninflammatory causes. These multiple causes include
intraosseous increase in vascular pressure, periosteal
proliferation, subchondral fracture and sclerosis, ligament
laxity, muscle spasm, and synovitis. The treatment includes
symptomatic therapy for pain, stiffness and swelling,
and therapy directed at joint structure modification
leading to retardation and reversal or prevention of the
disease process.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely
used to alleviate the symptoms. However, these drugs are
associated with an increased morbidity in older patients.
This study was conducted to evaluate the efficacy and
safety of Rumalaya forte, a polyherbal formulation
containing extracts of important herbs like Boswellia
serrata, Alpinia galanga, Commiphora wightii, Glycyrrhiza
glabra, Tinospora cordifolia, and Tribulus terrestris, in
patients with osteoarthritis.
Fifty patients of either sex in the age group of 50 to 65
years who attended the orthopedic outpatient department
of All India Institute of Medical Sciences, New Delhi, with
clinical and radiological evidence of osteoarthritis were
selected for the trial. Patients on concurrent or recent
steroids were included. The Institutional Ethics Committee
Clinical Insight
approved the study protocol. All the patients as per the
selection criteria underwent physical examination. This
was a double-blind placebo-controlled trial, and the
patients received the drug through random selection.
Group A patients received Rumalaya forte at a dosage of
1 tablet, twice daily, and Group B received a placebo at
the same dosage. All the participants provided written
informed consent. All symptoms along with severity
and duration were recorded prior to the drug treatment.
Routine blood chemistry and radiography were done
before and at the end of the treatment period.
Patients were followed up every 4 weeks for 6 months. At
the end of 6 months subjective (symptomatic) assessment
was carried out using the scores below to determine the
clinical efficacy of the trial drug.
A symptomatic evaluation was done using the scoring
system involving symptom scores and signs. The total
score taken into consideration for evaluation was
as follows:
Number of joints involved : One
:
1
Multiple :
2
Swelling
:
2
:
1
: Joints
Muscle
Pain
: Worse on loading:
2
Night pain:
2
Joint malfunction
2
: Limitation of mobility:
average score for the number of joints involved before
the treatment was 3.44 in Group A and 2.72 in Group B.
The score was reduced from 3.44 to 1.16 in Group A and
from 2.72 to 1.47 in Group B. Thus, there was 66.28%
reduction in the number of joint involvements in the
Rumalaya forte-treated group and 51.94% in the placebo
group. The reduction of joint involvement was more with
Rumalaya forte treatment (Table 1).
Table 1. Average Number of Joints Involved
Group A
Before
treatment
3.44
1.16
2.72
1.47
0.14
0.14
0.15
0.11
Percent
of
inhibition
Group A
2
Secondary muscle weakness
:
2
Mean
2
SEM
Walking distance:
2
Stiffness of joints:
2
Percentage
of
inhibition
Postural deformity:
2
There were 11 males and 14 females in group A and 14
males and 11 females in Group B. Almost all patients had
bilateral knee joint involvement with a few of them having
additional joint involvement.
All the patients were examined clinically at every
follow-up, and analysis was carried out at 6 months. The
51.94%
Table 2. Symptomatic Evaluation
:
Re sults
66.28%
In subjective symptomatic evaluation, Group A had an
average score of 18.56, which reduced to 8.02 indicating
45.96% relief in various symptoms. The subjective
symptomatic score in Group B reduced from 19.63 to
13.92, indicating 29.09% relief in various symptoms
(Table 2).
Stiffness
The symptom score was compared before and after
treatment. Objective improvement was assessed using
radiological examination of the joint. Relief in pain and
other subjective symptoms were considered as the criteria
for efficacy.
After
treatment
SEM
2
: Climbing stairs:
Before
treatment
Mean
Instability :
Difficulty with steps
Group B
After
treatment
Before
treatment
Group B
After
treatment
Before
treatment
After
treatment
18.56
8.02
19.63
13.92
0.29
0.40
0.23
0.40
45.96%
29.09%
Twenty of the 25 patients in Group A were satisfied with
the drug and showed significant improvement in the
symptoms and mobility. In Group B, only few patients
expressed their satisfaction with regard to relief in pain.
None of the patients reported any adverse reaction to
either Rumalaya forte or the placebo.
In this double-blind placebo-controlled study, most of the
patients belonging to Group A had a satisfactory outcome,
in terms of relief of pain and free mobility of the joints. No
side effects were reported by any of the patients.
Since, the sample size in this clinical trial was very small, a
larger number of patients need to be evaluated in further
trials with cross-over design.
25
Clinical Insight
Discussion
Rumalaya forte reduced the symptoms of osteoarthritic
knee joint. Although there was subjective improvement in
the placebo group, this was much less compared to the
Rumalaya forte-treated group. Moreover, this study had a
very small population size. This could be the limiting factor
to obtain greater clinical significance when compared to
the placebo group. This may be further confirmed in a
larger number of patients with cross-over design.
The important constituents of Rumalaya forte that reduce
inflammation and pain are B serrata and C wightii,
both resinous compounds. B serrata has been used
in folk medicine to treat inflammatory conditions like
arthritis and bursitis. The significant inhibition of joint
swelling and control of progressive joint involvement
could be attributable to B serrata. In vitro experiments
have demonstrated the inhibition of synthesis of proinflammatory 5-lipo-oxygenase viz., 5-hydroxyeicosa
tetranoic acid and leukotriene with boswellic acid.1
Our clinical trial confirms the same with early inhibition
of joint swelling and pain with Rumalaya forte.2
Moreover, B serrata significantly reduces the degradation
of glycosaminoglycan and checks the progressive
degeneration of joints.3 Moreover, boswellic acids are
specific, in terms of non-redox inhibition of leukotriene
synthesis either by interacting directly with 5-lipooxygenase or blocking its translocation. C wightii also acts
synergistically with B serrata to reduce inflammation and
pain. T cordifolia plays a vital role of immunomodulation.
Long-term use of Rumalaya forte helps in the functional
aspects of joints in osteoarthritic patients, thereby
improving the quality of life.
Reference s
1. Ammon HPT, et al. J Ethnopharmacol. 1993;38(2-3):105-112.
2. Omman HP, et al. Planta Medica. 1991;57:203-207.
3. Reddy GK, et al. Biochem Pharm. 1989;38:3527-3534.
CARDIOLOGY
Altered Cardiac Rhythm in Infants with
Bronchiolitis and Respiratory Syncytial
Virus Infection
Vascular Disease Associated
with Facet Joint Osteoarthritis
Esposito S, et al.
Osteoarthritis Cartilage. 2010;18(9):1127-1132.
BMC Infect Dis. 2010;10:305.
This study was conducted to examine
whether vascular disease was associated with
lumbar spine facet joint osteoarthritis (FJ OA)
in a community-based population.
Although
the
most
frequent
extra-pulmonary
manifestations of respiratory syncytial virus (RSV) infection
involve the cardiovascular system, no data regarding heart
function in infants with bronchiolitis associated with RSV
infection have yet been systematically collected. The
aim of this study was to verify the real frequency of heart
involvement in patients with bronchiolitis associated with
RSV infection, and whether infants with mild or moderate
disease also risk heart malfunction.
A total of 69 otherwise healthy infants aged 1 to 12
months with bronchiolitis hospitalized in standard
wards were enrolled. Pernasal flocked swabs were
performed to collect specimens for the detection of RSV
by real-time polymerase chain reaction, and a blood
sample was drawn to assess troponin I concentrations. On
the day of admission, all the infants underwent 24-hour
Holter ECG monitoring and a complete heart evaluation
with echocardiography. Patients were re-evaluated
by investigators blinded to the etiological and cardiac
findings four weeks after enrollment.
Regardless of their clinical presentation, sinoatrial blocks
were identified in 26 out of 34 (76.5%) RSV-positive
patients and 1 out of 35 (2.9%) RSV-negative patients
(P<.0001). The blocks recurred more than three times
over 24 hours in 25 out of 26 (96.2%) RSV-positive
patients and none of the RSV-negative infants. Mean
and maximum heart rates were significantly higher in the
RSV-positive infants (P<.05), as was low-frequency power
and the low- and high-frequency power ratio (P<.05). The
blocks were significantly more frequent in children with
an RSV load of ≥100,000 copies/mL than in those with a
lower viral load (P<.0001). Holter ECG after 28 ± 3 days
showed complete regression of the heart abnormalities.
RSV seemed to be associated with sinoatrial blocks
and transient rhythm alterations even when the related
respiratory problems were mild or moderate. Further
studies are needed to clarify the mechanisms of these
rhythm problems and whether they remain asymptomatic
and transient even in presence of severe respiratory
involvement or chronic underlying disease.
Abstracts
27
Suri P, et al.
This ancillary study included 441 participants
from the Framingham Heart Study multidetector computed tomography (MDCT).
The authors used a quantitative summary
measure of abdominal aortic calcification
(AAC) from the parent study as a marker for
vascular disease. FJ OA was evaluated on
computerized tomography (CT) scans using a
four-grade scale. For analytic purposes, FJ OA
was dichotomized as moderate FJ OA of at
least one joint from L2-S1 versus no moderate
FJ OA. The association of AAC and FJ OA was
examined using logistic regression before and
after adjusting for age, sex, and body mass
index (BMI). Furthermore, the independent
effect of AAC on FJ OA was examined
after including the known cardiovascular
risk
factors;
diabetes,
hypertension,
hypercholesterolemia, and smoking.
Low AAC (OR 3.84 [2.33–6.34]; P≤.0001)
and high AAC (OR 9.84 [5.29–18.3];
P≤.0001) were strongly associated with FJ
OA, compared with the reference group.
After adjusting for age, sex, and BMI, the
association with FJ OA was attenuated
for both low AAC (OR 1.81 [1.01–3.27];
P = .05) and high AAC (OR 2.63 [0.99–5.23];
P = .05). BMI and age were independently
and significantly associated with FJ OA. The
addition of cardiovascular risk factors to the
model did not substantially change parameter
estimates for either AAC tertile.
AACs were associated with FJ OA in this
community-based population, when adjusted
for epidemiologic factors associated with
spinal degeneration and cardiovascular risk
factors. Potentially modifiable risk factors for
facet degeneration unrelated to conventional
biomechanical paradigms may exist.
27
Abstracts
DERMATOLOGY
Prevalence, Characteristics, and Severity
of Nonalcoholic Fatty Liver Disease in
Patients with Chronic Plaque Psoriasis
Importance of Colonization Site in the
Current Epidemic of Staphylococcal Skin
Abscesses
Miele L, et al.
Faden H, et al.
J Hepatol. 2009;51(4):778-786.
Pediatrics. 2010;125(3):e618-e624.
Objective
Objective
The aim of this two-phase study was to study the clinical
features of nonalcoholic fatty liver disease (NAFLD) in
patients with psoriasis.
The aim of this study was to compare rectal and nasal
Staphylococcus aureus colonization rates and S aureus
pulsed-field types (PFTs) for children with S aureus skin
and soft-tissue abscesses and normal control subjects.
Methods
Phase 1: Investigation of prevalence and characteristics
of NAFLD in an unselected cohort of 142 adult Italian
outpatients with psoriasis vulgaris. Phase 2: Comparison
of psoriasis cohort subgroup with NAFLD and an age- and
body mass index-matched retrospective cohort of 125
nonpsoriasis patients with biopsy proven NAFLD.
Results
Based on histories, laboratory tests, and ultrasound
studies, 84 (59.2%) patients showed clinical diagnosis of
NAFLD; 30 patients had factors potentially associated
with liver disease other than NAFLD (eg, viral hepatitis
and significant ethanol and methotrexate usage); and 28
(19.7%) had normal livers. Comparison of the normal
liver and NAFLD subgroups revealed that NAFLD in
psoriasis patients (Ps-NAFLD) was significantly correlated
with metabolic syndrome (P<.05), obesity (P = .043),
hypercholesterolemia (P = .029), hypertriglyceridemia
(P<.001), AST/ALT ratio >1 (P = .019), and psoriatic
arthritis (PsA) (P = .036). The association with PsA
remained significant after logistic regression analysis (OR
= 3.94 [CI, 1.07–14.46]). Compared with the retrospective
nonpsoriatic NAFLD cohort (controls), patients with
Ps-NAFLD were likely to have severe NAFLD reflected by
noninvasive NAFLD Fibrosis Scores and AST/ALT >1.
Conclusions
NAFLD is highly prevalent among patients with psoriasis,
where it is closely associated with obesity (overall and
abdominal), metabolic syndrome, and PsA and more
likely to cause severe liver fibrosis (compared with nonPsNAFLD). Routine work-up for NAFLD may be warranted
in patients with psoriasis, especially when potentially
hepatotoxic drug therapy is being considered.
Methods
Sixty consecutive children with S aureus skin and softtissue abscesses that required surgical drainage and 90
control subjects were enrolled to the study. Cultures of
nares and rectum were taken in both groups. S aureus
isolates from all sites were characterized through
multiple-locus variable-number tandem-repeat analysis,
pulsed-field gel electrophoresis, staphylococcal cassette
chromosome mec typing for methicillin-resistant S aureus
isolates, and determination of the presence of PantonValentine leukocidin genes.
Results
S aureus was detected significantly more often in the
rectum of children with abscesses (47%) compared with
those in the control group (1%; P = .0001). Rates of nasal
colonization with S aureus were equivalent for children
with abscesses (27%) and control subjects (20%; P = .33).
S aureus recovered from the rectum was identical to
S aureus in the abscess in 88% of cases, compared with
75% of nasal isolates. PFT USA300, staphylococcal
cassette chromosome mec type IV, and Panton-Valentine
leukocidin genes were significantly increased in the
S aureus isolates from children with abscesses compared
to that from control subjects.
Conclusions
Skin and soft-tissue abscesses in the current epidemic of
community-associated staphylococcal disease are strongly
associated with rectal colonization by PFT USA300. Nasal
colonization in children does not seem to be a risk factor.
Abstracts
GASTROENTEROLOGY
Higher Prevalence of Gastrointestinal
Symptoms among Patients with
Rheumatic Disorders
Acid-suppressive Drugs and Communityacquired Pneumonia
Chong VH, Wang CL.
Epidemiology. 2009;20(6):800-806.
Singapore Med J. 2008;49(5):419-424.
Rodríguez LA, et al.
Background
Chronic disorders, such as rheumatic disorders, are
associated with increased gastrointestinal (GI) complaints.
Medications may be a contributory factor. This study
assessed the prevalence of GI symptoms among patients
followed-up in a rheumatology clinic.
Acid suppression may increase the risk of communityacquired pneumonia. The authors investigated this
association in the United Kingdom primary care system
taking account of the potential for confounding by
indication.
Patients were enquired about GI, psychological,
and psychosomatic symptoms (headache, insomnia,
anxiety, backache, and depression). Non-related visitors
served as the control group. The underlying disorders
were rheumatoid arthritis (RA; 37%), systemic lupus
erythematosus (SLE; 23%) and others (40%).
Methods
The symptom prevalence of the following complaints
was reduced: appetite (10.2%), nausea (20.2%), vomiting
(10.7%), dysphagia (7.3%), odynophagia (5.1%), early
satiety (27.5%), heartburn (15.2%), dyspepsia (44.6%),
abdominal bloating (20.8%) and irregular bowel habit
(6.7%). There were no differences between the various
rheumatic disorders (RA/SLE and RA/others) except for
more heartburn in SLE compared to others (P<.05). There
was no significant difference between nonsteroidal antiinflammatory drug (NSAID) users and nonusers. Patients
on medications with GI (disease modifying/steroid/
NSAIDs) adverse effects, experienced a higher rate of
early satiety (odds ratio [OR] 3.5, 95% confidence interval
[CI] 1.4–8.9) and dyspepsia (OR 2.1, 95% CI 1.2-4.3).
Compared to the control group, patients had more GI
symptoms (P<.05) except for irregular bowel habits.
Patients also experienced more anxiety (OR 2.1, 95% CI
1.1-2.4) and backache (OR 2.6, 95% CI 1.6–4.2), and had
significantly higher symptom clustering (>2 symptoms)
compared to the controls (P<.001).
GI symptoms are common among patients with rheumatic
disorders. Medications alone do not account for the high
prevalence, suggesting that the underlying conditions
predispose to GI symptoms.
The authors identified patients aged 20 to 79 years in
The Health Improvement Network database with a
new diagnosis of pneumonia between 2000 and 2005
(n = 7297). Cases were validated by manual review and
compared with age- and sex-matched controls (n = 9993).
Using unconditional logistic regression, the relative risk
(RR) of pneumonia associated with current use of acidsuppressive drugs as compared to nonuse was estimated.
Results
Newly diagnosed community-acquired pneumonia was
increased with current use of proton pump inhibitors (RR
= 1.16, 95% confidence interval [CI] 1.03–1.31) but not
H2-receptor antagonists (RR = 0.98, 95% CI 0.80–1.20).
An increased risk of pneumonia was evident only in the
first 12 months of treatment with proton pump inhibitors.
There was some evidence of a dose response. Among
patients taking proton pump inhibitors for <1 year, the
risk of community-acquired pneumonia was stronger
when current use was for dyspepsia or peptic ulcer (RR =
1.73, 95% CI 1.29–2.34) than for gastroesophageal reflux
disease or prevention of upper gastrointestinal injury
associated with aspirin or nonsteroidal anti-inflammatory
drugs (RR = 1.22, 95% CI 0.97–1.52).
Conclusions
A small increase in the risk of community-acquired
pneumonia associated with current proton pump inhibitor
use was observed, especially during the first 12 months of
treatment and at higher doses. This may be due in part to
the underlying indication.
29
Abstracts
GYNECOLOGY
Rheumatic Diseases and Pregnancy
Märker-Hermann E, et al.
Curr Opin Obstet Gynecol. 2010;22(6):458–465.
Aim
This review was conducted to discuss the effect of
inflammatory rheumatic diseases (rheumatoid arthritis,
ankylosing spondylitis, and systemic lupus erythematosus
[SLE]) of the mother on the course of pregnancy and the
development of fetus. Antirheumatic drug therapy of
the mother and strategies to prevent fetal complications
namely in SLE must be considered with care.
Recent Findings
The current literature is presented discussing hypotheses
about the immunologic mechanisms leading to
amelioration or exacerbation of the rheumatic symptoms
in rheumatoid arthritis and ankylosing spondylitis
during pregnancy. In SLE, several recent studies have
been published concerning fetal complications in the
antiphospholipid syndrome and in Ro/SSA-positive and
La/SSB-positive mothers and how to diagnose, treat, or
prevent these.
Summary
Today, women with inflammatory rheumatic diseases
are normally fertile and can be encouraged to become
pregnant, when there is a stable and quiescent phase of
the disease. This is in particular important for patients with
SLE, although pregnancy outcome in SLE has improved
over the last decades. Pregnancy in SLE is still a high risk
period during the disease course with the highest risk in
women with active lupus nephritis. In contrast, women
with rheumatoid arthritis develop amelioration of the
rheumatic symptoms during the course of pregnancy in
most cases. Female ankylosing spondylitis patients are
likely to show unaltered or aggravated symptoms of back
pain and impaired function.
Neonatal Outcome in Obstetric
Cholestasis Patients
Sultana R, et al.
J Ayub Med Coll Abbottabad. 2009;21(4):76–78.
Background and Aim
Obstetric cholestasis is a liver disease specific to
pregnancy characterized by pruritus affecting the whole
body, especially the palms and soles, and abnormal liver
function tests. Objective of this cross-sectional study was
to evaluate obstetric cholestasis as a potential risk factor
for adverse neonatal outcome. The study was conducted
at Department of Obstetrics and Gynecology, Unit ‘B’,
Ayub Teaching Hospital, Abbottabad between April 1,
2007 and March 31, 2008.
Methods
All patients presenting with obstetric cholestasis
irrespective of their age and parity were included in the
study. Patients presenting with other causes of pruritus
during pregnancy such as Hepatitis (A, B, and C), eczema,
pruritus gravidarum, and herpes gestationis were excluded
from the study. Patients with liver involvement due to
pre-eclampsia were also excluded. Baseline investigations,
liver chemistries, viral screening, liver autoimmune
screen, and liver and obstetrical ultrasound were done
before the diagnosis was confirmed. Patients were treated
symptomatically. Neonatal outcome was calculated in
terms of increased incidence of passage of meconium,
preterm delivery, and fetal distress requiring delivery by
cesarean section.
Results
The study included 30 patients. Babies of 10 patients did
well after delivery, 8 required NICU care within first 24
hours of birth, and rest were delivered with low Apgar
score. Two babies were delivered stillborn.
Conclusion
Pruritus is quite common during pregnancy with obstetric
cholestasis being one of them and earlier detection of the
disease allows better identification of fetuses at risk.
Abstracts
HEPATOLOGY
What Factors Determine the Severity of
Hepatitis A-related Acute Liver Failure?
Ajmera V, et al.
Prevalence of Rheumatologic
Manifestations of Chronic Hepatitis C
Virus Infection among Egyptians
J Viral Hepat. 2010.
Mohammed RH, et al.
The reason(s) that hepatitis A virus (HAV) infection may
progress infrequently to acute liver failure are poorly
understood. The host and viral factors were examined in
29 consecutive adult patients with HAV-associated acute
liver failure enrolled at 10 sites participating in the US ALF
Study Group.
Clin Rheumatol. 2010;29(12):1373–1380.
Eighteen out of twenty-four acute liver failure sera were
PCR positive while six had no detectable virus. HAV
genotype was determined using phylogenetic analysis and
the full-length genome sequences of the HAV from acute
liver failure sera were compared to those from self-limited
acute HAV cases selected from the CDC database.
It was observed that rates of nucleotide substitution
did not vary significantly between the liver failure and
non-liver failure cases and there was no significant
variation in amino acid sequences between the two
groups. Four out of 18 HAV isolates were sub-genotype
IB, acquired from the same study site over a period of
3.5 years. Sub-genotype IB was found more frequently
among acute liver failure cases compared to the non-liver
failure cases (χ2 test, P<.01). At another center, a mother
and her son presented with HAV and liver failure within
one month of each other. Predictors of spontaneous
survival included detectable serum HAV RNA, while
age, gender, HAV genotype, and nucleotide substitutions
were not associated with outcome. The more frequent
appearance of rapid viral clearance and its association
with poor outcomes in acute liver failure as well as the
finding of familial cases implied a possible host genetic
predisposition that contributes to a fulminant course.
Recurrent cases of the rare sub-genotype IB over several
years at a single center implied a community reservoir of
infection and possible increased pathogenicity of certain
infrequent viral genotypes.
Chronic hepatitis C virus (HCV) viremia has been
known to provoke a plethora of autoimmune syndromes
referred to as extrahepatic manifestations of chronic
HCV infection. Aim of the current study was to assess
the prevalence of rheumatologic manifestations among
Egyptians with hepatitis C infection and its association
with cryoglobulin profile. The current study represents a
cross-sectional study where patients with chronic HCV
infection attending the outpatient clinic of the National
Hepatology and Tropical Medicine Research Institute
over a period of 1 year were interviewed. Patients with
decompensated liver disease, on interferon therapy,
having end-stage renal disease or coexisting viral infection
such as patients with hepatitis B surface antibody positive
were excluded from the study. Laboratory investigations
as well as serological assay including cryoglobulin
profile, rheumatoid factor, antinuclear antibody, and
HCV-PCR were performed. Three hundred and six
patients with chronic HCV infection were interviewed
during this research. The overall estimated prevalence
of rheumatologic manifestations in the current research
was 16.39%, chronic fatigue syndrome 9.5%, sicca
symptoms 8.8%, arthralgia 6.5%, fibromyalgia 1.9%,
myalgia 1.3%, arthritis 0.7%, cryoglobulinemic vasculitis
0.7%, autoimmune hemolytic anemia 0.7%, and
thrombocytopenia 0.7%. Xerophthalmia was significantly
present in male population (P = 0.04), whereas
fibromyalgia, cryoglobulinemic vasculitis, arthritis, and
autoimmune hemolytic anemia were significantly present
in female population in the study (P<.05). In chronic HCV
genotype 4 infection, the prevalence of rheumatologic
manifestations was 16.3% with chronic fatigue syndrome
and sicca symptoms being the most common with no
significant correlation to the degree of elevation of liver
disease or viral load.
31
Abstracts
INFECTIONS
Administrative Codes Combined
with Medical Records Based Criteria
Accurately Identified Bacterial Infections
a mong Rheumatoid Arthritis Patients
Community-associated Methicillinresistant Staphylococcus aureus
(CA-MRSA) Skin Infections
Patkar NM, et al.
Curr Opin Pediatr. 2010;22(3):273-277.
J Clin Epidemiol. 2009;62(3):321–327.e7.
Objective
This study was conducted to evaluate diagnostic
properties of International Classification of Diseases,
Version 9 (ICD-9) diagnosis codes and infection criteria
to identify bacterial infections among patients with
rheumatoid arthritis (RA).
Study Design and Setting
A cross-sectional study of RA patients with and without
ICD-9 codes for bacterial infections was conducted.
Sixteen bacterial infection criteria were developed.
Diagnostic properties of comprehensive and restrictive
sets of ICD-9 codes and the infection criteria were tested
against an adjudicated review of medical records.
Results
Records of 162 RA patients with and 50 without purported
bacterial infections were reviewed. Positive and negative
predictive values of ICD-9 codes ranged from 54% to
85% and 84% to 100%, respectively. Positive predictive
values of the medical records based criteria were 84% and
89% for “definite” and “definite or empirically treated”
infections, respectively. Positive predictive value of
infection criteria increased by 50% as disease prevalence
increased using ICD-9 codes to enhance infection
likelihood.
Conclusion
ICD-9 codes alone may misclassify bacterial infections
in hospitalized patients with RA. Misclassification varies
with the specificity of the codes used and strength of
evidence required to confirm infections. Combining
ICD-9 codes with infection criteria identified infections
with greatest accuracy. Novel infection criteria may limit
the requirement to review medical records.
Odell CA.
Background and Aim
Community-associated methicillin-resistant Staphylococcus
aureus (CA-MRSA) has become increasingly important
as a cause of skin and soft tissue infections (SSTIs),
particularly abscesses, in patients attending the emergency
department setting. The antibiotic sensitivity profile of
S aureus isolates from SSTIs has changed over time in many
geographic locations. Whether antibiotics are needed
in the management of skin abscesses, and, if so, when,
is controversial.
Recent Findings
A number of studies have looked at antibiotic therapy
in conjunction with incision and drainage in managing
abscesses. Factors evaluated were resolution of infection,
need for change in antibiotic therapy, hospitalization after
initial outpatient management, need for an additional
drainage procedure, and recurrence of infection within
30 days after the initial incision and drainage procedure.
For abscesses, clinical failure was associated with lack
of adequate incision and drainage and not antibiotic
use, regardless of the size of the abscess or the choice
of antibiotic therapy. For other soft tissue infections,
when antibiotic susceptibility data were available for the
infection (impetigo or cellulitis with purulent drainage but
no abscess), there was no difference in clinical resolution
of MRSA infection even if the infecting organism was
resistant to the antibiotic chosen for therapy.
Summary
CA-MRSA has become an important cause of SSTIs.
Current data suggest that most abscesses can be treated
successfully with incision and drainage alone. Antibiotic
choice is more crucial for management of cellulitis and
should be guided by the prevalence of CA-MRSA in the
community and its antibiotic susceptibility profile.
Abstracts
NEUROLOGY
Neurological Complications
of Ankylosing Spondylitis:
Neurophysiological Assessment
Prevalence and Characteristics of
Peripheral Neuropathy in Hepatitis C
Virus Population
Khedr EM, et al.
Santoro L, et al.
Rheumatol Int. 2009;29(9):1031–1040.
J Neurol Neurosurg Psychiatry. 2006;77(5):626-629.
Studies examining the neurological involvement of
ankylosing spondylitis (AS) are limited. This study aimed
to assess the frequency of myelopathy, radiculopathy,
and myopathy in AS correlating them to the clinical,
radiological, and laboratory parameters. The study
included 24 patients with AS. Axial status was assessed
using bath ankylosing spondylitis metrology index
(BASMI). Patients underwent standard cervical and lumbar
spine and sacroiliac joint radiography, somatosensory
(SSEP) and magnetic motor (MEP) evoked potentials of
upper and lower limbs, and electromyography (EMG)
of trapezius and supraspinatus muscles. Patients’ mean
age and duration of illness were 36 and 5.99 years,
respectively. BASMI mean score was 4.6. Neurological
manifestations were observed in 25% (n = 6) of patients,
myelopathy in 8.3%, and radiculopathy was observed
in 16.7% of patients. Ossification of the posterior
(OPLL) and anterior (OALL) longitudinal ligaments
were found in 8.3% (n = 2) and 4.2% (n = 1) of the
patients, respectively. About 70.8% (n = 17) had ≥1
neurophysiological test abnormalities. SSEP abnormalities
were observed in 12 patients (50%) and prolonged
central conduction time (CCT) of median and/or ulnar
nerves was observed in 7 patients, suggesting cervical
myelopathy. Delayed peripheral or root latencies at Erb's
or interpeak latency (Erb's-C5) were noted in 6 patients,
suggesting radiculopathy. Motor evoked potentials was
abnormal in 54% (n = 13). Abnormal MEP of upper
and lower limbs were noted in 12 (50%) and 5 (20.8%)
patients, respectively. About 50% (n = 12) of patients
had myopathic features of trapezius and supraspinatus
muscles. Only 8.3% (n = 2) had neuropathic features. It
was concluded that subclinical neurological complications
are frequent in AS as compared to clinically manifest
complications. Somatosensory evoked potential and
MEP are useful to identify AS patients prone to develop
neurological complications.
Objective
To assess the prevalence of peripheral neuropathy (PN)
and its correlation with cryoglobulinemia (CG) in an
unselected, untreated referral hepatitis C virus (HCV)
population.
Patients and Methods
The study included 234 patients (120 women and 114
men) with untreated HCV infection were consecutively
enrolled by seven Italian centers. Clinical neuropathy
was diagnosed when symptoms and signs of peripheral
sensory or motor involvement were present. Median,
ulnar, peroneal, and sural nerves were explored in
all patients and distal symmetric polyneuropathy was
diagnosed when all explored nerves or both lower
limb nerves were affected. Mononeuropathy and
mononeuropathy multiplex were diagnosed when one
nerve or two noncontiguous nerves with asymmetrical
distribution were affected. Screening for CG was done in
191 unselected patients.
Results
Clinical signs of PN were observed in 25 out of 234
patients (10.6%). Electrophysiological PN was found in 36
(15.3%). CG was present in 56 out of 191 patients (29.3%).
The prevalence of CG increased significantly with age
(P<.001) and disease duration (P<.05). PN was present in
12 out of 56 (21%) patients with CG and 18 out of 135
(13%) without CG (P = NS). PN increased significantly
with age (P<.001) and logistic regression analysis
confirmed age as the only independent predictor of PN
(OR 1.10 for each year; 95% CI 1.04–1.15; P<.001).
Conclusions
Electrophysiological examination detected subclinical
neuropathy in 11 patients (4.7%). Statistical analysis
showed that CG was not a risk factor for PN whereas PN
prevalence increased significantly with age.
33
Abstracts
OPHTHALMOLOGY
Paranasal Sinus Inflammation and Nonspecific Orbital Inflammatory Syndrome:
An Uncommon Association
Evaluation of Ocular Surface Damage and
Dry Eye Status in Chronic Hepatitis C at
Different Stages of Hepatic Fibrosis
Leibovitch I, et al.
Gumus K, et al.
Graefes Arch Clin Exp Ophthalmol. 2006;244(11):1391–
1397.
Cornea. 2009;28(9):997-1002.
Objectives
The aim of this study was to present a series of patients
with orbital inflammatory symptoms associated with
significant paranasal sinus inflammation, and to discuss
the diagnostic and management modalities.
Methods
A retrospective, noncomparative, interventional case
series of all patients diagnosed with orbital inflammatory
syndrome and significant sinus inflammation, seen at two
Orbital Units between January 1999 and October 2005.
The clinical records of all patients were reviewed.
Results
Of 91 cases diagnosed with nonspecific orbital
inflammatory syndrome, 6 (6.6%; 4 males, 2 females;
mean age = 51±17 years) had significant sinus
inflammation. Symptoms and signs were periorbital
swelling and erythema, proptosis, globe displacement,
and ocular motility restrictions with diplopia. On
imaging, there was extraocular muscle enlargement
and/or orbital fat haziness, as well as almost complete
ipsilateral maxillary sinus opacification with varying
degrees of opacification of adjacent sinuses. Sinus
biopsy in four cases showed a nonspecific inflammatory
reaction. Treatment with steroids alone (four cases) or a
combination of oral antibiotics and systemic steroids (two
cases) resulted in resolution of signs and symptoms within
24 to 72 hours. One case of recurrence was noted during
a mean follow-up period of 9 months (range = 3–24
months), and this responded well to oral steroids.
Conclusion
Although uncommon, paranasal sinusitis can be associated
with a nonspecific orbital inflammatory syndrome. When
an infectious etiology is excluded, systemic steroids may
play a major role in the management of these patients and
result in prompt resolution of orbital signs and symptoms.
Aim
The aim of this study was to explore changes in ocular
surface and tear function parameters in chronic hepatitis C
at different stages of hepatic fibrosis.
Methods
Fifty-four patients with biopsy-proven chronic hepatitis C
and 54 age- and sex-matched healthy control subjects
without systemic hepatitis C infection were examined with
the Ocular Surface Disease Index questionnaire, Schirmer
with and without anesthesia, tear film breakup time, and
scoring of ocular surface Lissamine green staining using
modified Oxford and van Bijsterveld scoring systems and
corneal fluorescein staining.
Results
Patients with chronic hepatitis C scored significantly worse
than the control subjects on all parameters: modified
Oxford scores of Lissamine green staining (5.5/3.0;
P<.001), Oxford and van Bijsterveld scores (4.0/2.0;
P<.001), and corneal fluorescein staining (1.5/0.0;
P = .001). The chronic hepatitis C group also had higher
Ocular Surface Disease Index scores than the control
subjects (22.3/13.7; P = .001). Schirmer with and without
anesthesia and tear film breakup time scores were found
to be lower in patients with chronic hepatitis C (P<.001).
Moreover, patients with advanced stages of hepatic
fibrosis (stages 4–6) had significantly lower values of tear
film breakup time and worse Ocular Surface Disease
Index scores and ocular surface vital dye staining than
those with initial stages of hepatic fibrosis (stages 0–3).
Conclusion
Patients with chronic hepatitis C, especially those with
advanced stages of hepatic fibrosis, were more likely to
exhibit severe ocular surface damage and signs of dry eye.
Abstracts
ORTHOPEDICS
Comprehensive Rehabilitation of Patients
with Rheumatic Diseases in Warm
Climate: A Literature Review
Prevalence of Reactivation of Hepatitis B
Virus Replication in Rheumatoid Arthritis
Patients
Forseth KO, et al.
Urata Y, et al.
J Rehabil Med. 2010;42(10):897–902.
Mod Rheumatol. 2011;21(1):16–23.
Objective
Reactivation of hepatitis B involves the reappearance
of active necroinflammatory liver disease after an
inactive hepatitis B surface antigen (HBsAg) carrier
state or resolved hepatitis B, occurring during or after
immunosuppression therapy or chemotherapy. The
authors prospectively investigated the reactivation rate
for hepatitis B virus (HBV) DNA replication in cases of
rheumatoid arthritis (RA) with resolved hepatitis B. HBV
markers were evaluated in 428 patients with RA. Patients
with positive findings of HBsAg or HBV DNA at enrolment
were excluded. The study population comprised 422
patients with RA, with resolved hepatitis B diagnosed in
135 patients based on HBsAg-negative and antihepatitis
B core antibody/antihepatitis B surface antibody-positive
results. HBV DNA was measured every 3 months in this
group, and if HBV DNA became positive after enrolment,
measurement was repeated every month. HBV DNA
became positive (≥3.64 log copies/mL) in 7 out of
135 patients for 12 months. Use of biologic agents was
significantly more frequent in patients who developed
reactivation of HBV DNA replication (85.7%) than in
patients who did not (36.0%, P = .008). Hazard ratios
for use of biologic agents and etanercept were 10.9 (P =
.008) and 6.9 (P = .001), respectively. Patients with RA,
with resolved hepatitis B, need careful monitoring while
receiving biologic agents, regardless of HBV DNA levels.
Objective of the study was to present the evidence for the
efficacy of comprehensive rehabilitation in a warm climate
of patients with a wide variety of rheumatic diseases.
Methods
A systematic review of the literature was undertaken,
searching in PubMed, CINAHL, PEDro, SweMed, and
Embase from 1970 to 2010, and using the GRADE
(Grading of Recommendations, Assessment, Development
and Evaluation system) criteria.
Results
Six studies met the inclusion criteria. For patients with
rheumatoid arthritis, moderate evidence was observed
for reduction of disease activity, pain, fatigue, and global
disease impact. Also, there was moderate evidence
suggesting that comprehensive rehabilitation in warm
climate did not improve fitness or reduce activity limitation
beyond levels reached by rehabilitation in Scandinavia.
Among patients with ankylosing spondylitis, evidence
was low for reduction of disease activity, pain, joint range
of motion, activity limitation, and global disease impact.
In groups with mixed rheumatic diagnoses, evidence
was low for reduction of pain, activity limitation, global
disease impact, and improved health-related quality
of life. No studies on psoriatic arthritis, osteoarthritis,
fibromyalgia, or osteoporosis were found.
Conclusion
Well-designed studies to validate and improve the low-tomoderate evidence for the efficacy of comprehensive
rehabilitation in warm climate among patients with
inflammatory rheumatic disease are greatly needed.
Hepatitis B
35
Abstracts
PEDIATRICS
Skin and Soft Tissue Complications in
Pediatric Leukemia Patients with and
without Central Venous Catheters
Lipid Profile in Children with Acute Viral
Hepatitis A
Demircioğlu F, et al.
Pediatr Int. 2007;49(2):215–219.
J Pediatr Hematol Oncol. 2008;30(1):32–35.
This study was conducted to retrospectively evaluate the
skin and soft tissue complications secondary to procedures
in acute leukemia patients with and without catheters.
Eighty-seven patients with acute leukemia (acute
lymphoblastic leukemia = 75 and acute myeloid leukemia
= 12) were included. There were 30 patients with 37
catheter use (6 port and 31 Hickman catheter) and 57
patients without catheter.
In patients with catheters, skin and soft tissue
complications were seen in 20 (66%) children. The most
frequent complication was cellulitis (55%). In patients
without catheter, skin and soft tissue complications
were seen in 37 (65%) patients. Cellulitis (37.8%) and
extravasation (37.8%) were the most frequent causes.
When the frequency of skin and soft tissue complications
in patients with and without catheters were compared
with each other, there was statistically no significant
difference (P = .792). The duration of chemotherapy was
significantly longer in patients who developed skin and
soft tissue complications with or without catheters when
compared with the duration of the therapy in patients
without any skin and soft tissue complications (259.2 ±
36.3 and 218.3 ± 58.3 day, respectively; P<.0001).
In pediatric leukemia patients, with or without catheters,
skin and soft tissue complications are common and these
complications may prolong the duration of chemotherapy.
Hickman catheter
Selimoglu MA, et al.
Most of the knowledge about lipid parameters in acute
hepatitis is originated from adult studies. In this study, the
authors investigated lipid profile of children with acute
hepatitis A (AVH) at diagnosis and recovery in order to
observe the behavior of lipid parameters in such children.
A total of 28 children (mean age = 8.2 ± 2.7 years) with
AVH and 20 gender- and age-matched healthy children
were included. In addition to the routine tests, triglyceride,
cholesterol, low-density lipoprotein (LDL), high-density
lipoprotein (HDL), plasma apo A-I and apoB were studied
at diagnosis and recovery.
The levels of serum triglyceride and apoB were higher
(P<.01 and P<.05, respectively) and apo A-I was lower
(P<.01) in patients compared to healthy children. On
admission, three children had fulminant hepatic failure
(FHF). Serum lipid parameters were evaluated with
respect to the presence of icterus and FHF, and found that
apo A-I level was lower in icteric children and LDL and
apo A-I were lower in FHF compared to others (P<.05,
P<.01, and P<.05, respectively). At recovery, levels of
triglyceride, cholesterol, LDL, and apoB decreased (P<.01)
and HDL and apo A-I increased (P<.01). Serum apo A-I
level was inversely correlated with serum ammonia level
but was positively correlated with serum albumin (P<.05).
It was shown that serum triglyceride and apoB level
increased, but apo A-I level decreased in patients with
AVH. While cholestasis lowers apo A-I level, severe
hepatic damage lowers both apo A-I and LDL. These
parameters return to normal levels within 30 days. An
interesting relationship between ammonia and apo A-I
deserves further investigations, speculatively focused on
hepatocyte nuclear factor 4 alpha.
Abstracts
PSYCHIATRY
Prevalence of Anxiety and Depression in
Osteoarthritis
Axford J, et al.
Predictors of Relapse to Significant
Alcohol Drinking after Liver
Transplantation
Clin Rheumatol. 2010;29(11):1277–1283.
Karim Z, et al.
The aims of this study are to ascertain the prevalence
of anxiety and depressive disorders in an outpatient
population with osteoarthritis (OA), examine the
interrelationships between severity of OA, pain, disability,
and depression, and evaluate the Hospital Anxiety and
Depression Scale (HADS) as a screening tool for this
population. Patients with lower limb OA were evaluated
with the Short Form McGill Pain and Present Pain Index
Questionnaires, and a visual analogue scale, WOMAC
Osteoarthritis Index-section C, and HADS. Participants
underwent a structured clinical interview by a liaison
psychiatrist (AB). X-rays of affected joints were rated for
disease severity. Fifty-four patients (42 females; mean age
63.3 years) were investigated. The prevalence of clinically
significant anxiety and/or depression was 40.7% (95%
confidence interval [CI], 27.6–55.0). HADS was a good
predictor of anxiety and depression with a sensitivity and
specificity of 88% (95% CI, 64–99) and 81% (95% CI,
65–92), respectively. Pain correlated with HADS anxiety
and depression scores (eg, Rank correlation coefficients
[Kendall’s tau-b] between total HADS scores and Pain
VAS scores 0.29; P = .003). Disability was greater in
patients with depression and/or anxiety (eg, total HADS
score; Kendall’s rank correlation coefficient tau-b = 0.26,
P = .007) OA severity as determined by radiological
score was not a good predictor for anxiety nor depression
and only weakly associated with disability. Anxiety and
depression are very common in OA patients. HADS
anxiety was a better predictor of diagnosed anxiety
than HADS depression was of diagnosed depression.
HADS is a valid and reliable screening instrument for
detecting mood disorder, but not a diagnostic tool or
a substitute for asking about symptoms of depression.
The interrelationship between mental health, pain, and
disability is strong. Therefore, a multidisciplinary approach
should be adopted for the management of OA.
Can J Gastroenterol. 2010;24(4):245–250.
End-stage alcoholic liver disease is common, with many
of these patients referred for liver transplantation (LT).
Alcohol relapse after LT can have detrimental outcomes
such as graft loss and can contribute to a negative
public perception of LT. Aim of this study was to identify
factors that predict the recurrence of harmful alcohol
consumption after LT.
A total of 80 patients who underwent LT for alcoholic
cirrhosis or had significant alcohol consumption in
association with another primary liver disease, from
July 1992 to June 2006 in British Columbia, were
retrospectively evaluated by chart review. Several
demographic-, psychosocial-, and addiction-related
variables were studied. Univariate and multivariate logistic
regression analyses were used to test possible associations
among the variables studied and a return to harmful
drinking after LT.
The relapse rate of harmful alcohol consumption postliver transplant was 10%, with two patient deaths
occurring directly as a result of alcohol relapse.
Univariate analysis revealed relapse was significantly
associated with pretransplant abstinence of less than six
months (P = .003), presence of psychiatric comorbidities
(P = .016), female sex (P = .019) and increased personal
stressors (P = .044), while age at transplant <50 years
approached significance (P = .054). Multivariate logistic
regression analysis revealed the following independent
factors for relapse: pretransplant abstinence of less than
six months (OR 77.07; standard error 1.743; P = .013) and
female sex (OR 18.80; standard error 1.451; P = .043).
The findings of the present study strongly support a
required minimum of six months of abstinence before
LT because duration of abstinence was found to be the
strongest predictor of recidivism. Female sex, younger
age at transplant, and psychiatric comorbidities were also
associated with relapse to harmful drinking.
37
38
Immunomodulatory Activity of Septilin, a Polyherbal
Preparation
Daswani BR, Yegnanarayan R
Department of Pharmacology, B.J. Medical College and Sassoon General Hospitals, Pune, India.
Phytother Res. 2002;(16):162-165.
Abstract
Intro duc tion
The present experimental study was
undertaken to evaluate the effect of
Septilin on different arms of the immune
system. The experimental animals (male
albino rats and mice) were divided into
three groups. Group I received distilled
water; group II received Septilin at a dose
of 1 g/kg (rats) or 1.5 g/kg (mice); group
III received Septilin 2 g/kg (rats) or 3 g/
kg (mice) orally for 28 days. They were
evaluated for immunological function on
day 29 by studying weight gain, resistance
against Escherichia coli sepsis, hemogram,
phagocytic activity of polymorphonuclear
(PMN) cells and reticuloendothelial
system, delayed hypersensitivity to
oxazolone, and the plaque-forming cell
response of splenic lymphocytes to sheep
erythrocytes.
Septilin (The Himalaya Drug Company, Bangalore,
India) is a herbal preparation containing powders
of Balsamodendron mukul and Shankha bhasma;
Maharasnadi quath; and extracts of Tinospora
cordifolia, Rubia cordifolia, Emblica officinalis, Moringa
pterygosperma, and Glycyrrhiza glabra. It has been
reported to possess antibacterial,1 anti-inflammatory,2
and wound-healing properties.3 It is said to be helpful
in treating gram-positive as well as gram-negative
infections.4,5 There are reports that Septilin is effective in
chronic stubborn URTI,6 tonsillitis,4 tropical eosinophilia,7
infective dermatoses,5 and dental infections.
Neither of the doses of Septilin altered
weight gain, absolute lymphocyte counts,
or host resistance against E coli sepsis.
The higher dose of Septilin reduced
phagocytic activity of the PMN cells/
reticuloendothelial system, but both doses
increased the percentage and absolute
number of circulating neutrophils,
stimulated humoral immunity, and
suppressed cellular immunity. Thus,
Septilin has dual effects on the immune
system, with lower doses showing greater
stimulant and higher doses showing
predominantly suppressant effects.
Key Words
Septilin, upper respiratory tract infection,
tonsillitis, cutaneous infection, dental
infection, immune function
Septilin is claimed to build up resistance to infection6,7
and is widely used as a health supplement. In view of
the various claims about the efficacy of Septilin in the
treatment of infections at different sites, the present
experimental study was designed to evaluate the effect of
Septilin on different arms of the immune system.
The experiments were performed on male albino mice
weighing 20 to 30 g, except for the carbon clearance
test where male albino rats weighing 150 to 200 g were
used. The experimental protocol was approved by the
Institutional Ethical Committee. The experimental animals
were acclimatized in the laboratory animal house for
at least 1 week. The animals were provided standard
animal feed (Chakan Oil Mills) and tap water ad libitum.
They were randomly divided into three groups. Group I
received pretreatment with distilled water and acted as
the control group. In group II, mice received 1.5 g/kg and
rats received 1 g/kg of Septilin, while in group III, mice
received 3 g/kg and rats received 2 g/kg of Septilin in
the form of an aqueous suspension orally, daily for 28
days. At the end of the pretreatment phase, the animals
were subjected to immunological screening using the
following experimental models: resistance to E coliinduced abdominal sepsis; hemogram; carbon clearance;
Septilin in infections
polymorphonuclear function; delayed hypersensitivity
to oxazolone (cellular immunity); plaque-forming cell
response of splenic lymphocytes to sheep erythrocytes
(humoral immunity). A fresh set of animals was used for
each test.
Experimental Mo dels
Determination of host resistance against E coliinduced abdominal sepsis8
This test was performed on male albino mice that had
completed the drug pretreatment. On day 29 of the
test, abdominal sepsis was induced in the test mice
by challenging them, intraperitoneally, with 3x108
E coli (hospital strain), suspended in phosphate buffered
saline. The test mice were observed for 24 hours and the
percent mortality at 24 hours after induction of sepsis was
estimated. The survivors were observed further for 7 days.
Determination of hematological parameters
At the end of the drug therapy, blood was collected by
cardiac puncture and the total and differential WBC
counts were done.
Determination of phagocytic function: carbon
clearance9
To evaluate the phagocytic activity of the
reticuloendothelial system in vivo, a carbon clearance test
was performed after completion of the drug pretreatment.
On day 29, the treated rats received an intravenous
injection of carbon suspension (1:50 dilution of Indian
ink, Camel) at a dose of 0.5 mL/100 g body weight. Blood
was withdrawn from the retro-orbital venous plexus
before injection, immediately after injection, and at 5
minute intervals up to 20 minutes after injection of the
carbon suspension. 0.05 mL of blood was lysed with 4
mL of 0.1% Na2CO3 and the optical density was measured
spectrophotometrically at 650 nm wavelength. The results
were expressed as the granulopectic index, calculated by
the formula
Log(OD0) – log (ODt)
-------------------------
t
where, OD0 is the OD at 0 min and ODt is the OD at
t min.
In vitro phagocytic activity of
polymorphonuclear cells10
At the end of the drug treatment phase, two drops of blood
were collected on a clean, dry glass slide and placed in
a moist chamber to permit adherence of PMN cells, after
which the clot was gently removed without disturbing
the adherent PMN cells. This layer of PMNs was covered
with a suspension of Candida albicans (yeast cells) (106
Candida/mL) and incubated for 1 hour. The slide was
then stained with Giemsa stain and the effect of Septilin
on phagocytic activity was expressed as the percentage
of cells showing phagocytosis and the average number of
Candida per PMN.
Determination of T-lymphocyte function11-13
To determine the effect of the drugs on cell mediated
immunity, the delayed hypersensitivity to oxazolone was
assessed.
On day 20 of drug therapy, the mice were shaved from
the mid-abdominal region. 0.1 mL of a 3% solution of
oxazolone sensitizing agent in ethanol was applied to
this region 24 h later. Drug therapy was continued and 7
days later (ie, on day 28 of drug therapy), 0.01 mL of 3%
oxazolone sensitizing agent was applied to the inner and
outer aspect of the left ear after measuring the initial ear
thickness with a micrometer screw gauge. After 24 hours
of the challenge, thickness of the left ear was measured
again. The increase in the ear thickness was taken as a
measure of delayed hypersensitivity to oxazolone.
Determination of B-lymphocyte function14,15
To determine the effect of the drugs on humoral
immunity, the plaque-forming cell response of splenic
lymphocytes to sheep erythrocytes was assessed. On
day 23 of pretreatment, the mice were challenged with
1 mL of a suspension of sheep RBCs (107 RBC/mL) in
saline, intraperitoneally. Drug therapy was continued
until day 28. At the end of the pretreatment phase, the
mice were killed and the spleen was removed and gently
homogenized. The splenic lymphocytes were suspended
in 10 mL of cold Hank’s gelatin solution. The number of
lymphocytes per spleen was counted and 0.05 mL of this
suspension of splenic lymphocytes was incubated with
0.05 mL of 8% SRBC suspension in 0.5 mL of agarose
on an immunodiffusion plate at 37°C for 2 hours. Later,
1 mL of 20% fresh guinea-pig serum was surfaced on the
immunodiffusion plate and incubation continued at 37°C
for another 1 hour. At the end of incubation, the number
39
Similarly,
the
granulopectic
index
of
the
reticuloendothelial system was reduced by the high dose
of Septilin (P<.01) while the lower dose of Septilin did not
affect it (Table 4).
of plaques (clear zones) per spleen were calculated and
taken as a measure of humoral immunity.
The results obtained in each of the treatment groups were
compared with those of the control group using unpaired
t test for all tests except for the host resistance against
E coli-induced abdominal sepsis where the Chi square test
was applied.
The number of lymphocytes per spleen was not altered
by either dose of Septilin. However, the number of plaque
forming cells per spleen, which is a measure of humoral
immunity was increased by both the doses of Septilin (low
dose P<.001; high dose P<.05) (Table 5).
Re sults
Delayed hypersensitivity to oxazolone (cellular immunity)
was reduced by both doses of Septilin (low dose P<.05;
high dose P<.01) (Table 6).
Measurement of body weights before and after drug
treatment showed that the change in weight was not
significantly different from the control group (Table 1).
Similarly, neither of the doses of Septilin improved the
host resistance against E coli-induced abdominal sepsis
(mortality at 24 h: control 100%; low dose Septilin 83.3%;
high dose Septilin 100%) (Table 2).
Table 1. Effect of Septilin Treatment on Weight Gain (n=6
per group)
Group
Weight gain (g)
Group I (Control)
Both the doses of Septilin increased the percentage of
neutrophils (P<.001) as well as the absolute number
of circulating neutrophils (low dose P<.001; high
dose P<.01). Both the doses showed a trend toward
leucocytosis, but it was not statistically significant
(Table 3).
2.2 ± 0.33
Group II (low dose)
1.1 ± 0.37
Group III (high dose)
2.5 ± 0.72
All values are mean ± SE.
Table 2. Effect of Septilin on Host Resistance against E coliinduced Abdominal Sepsis (n=12 per group)
The high dose of Septilin reduced the phagocytic activity
of PMN cells as evidenced by a decrease in the average
number of Candida per PMN cell (P<.001) and reduction
in the percentage of PMN cells showing phagocytosis
(P<.01) while the lower dose of Septilin did not affect the
PMN function (Table 4).
Group
Mortality at 24 h
Group I (Control)
12/12
Group II (low dose)
10/12
12/12
The differences were not significant
Table 3. Effect of Septilin Treatment on Hemogram (n=6 per group)
Lymphocyte counts
Neutrophil counts
Total WBC
(cells/mm3)
%
Absolute
%
Absolute
Group I (Control)
10267 ± 1032
76.7 ± 2.8
8302 ± 899
17.5 ± 2.6
2022 ± 482
Group II (low dose)
14533 ± 1585
52.2 ± 1.5b
7665 ± 1010
41.2 ± 1.5b
5903 ± 530b
14866 ± 2231
55.3 ± 2.2
8109 ± 999
39.0 ± 2.2
5945 ± 1246a
Group
b
b
All values are mean ± SE. a0.001<P<.01; bP<.001.
Table 4. Effect of Septilin on the Phagocytic Activity of Blood Polymorphonuclear Cells and Carbon Clearance
(Granulopectic Index) (n=6 per group)
Phagocytic activity of PMN cells
Group
Average number of Candida/
PMN
PMN showing
phagocytosis (%)
Carbon clearance Granulopectic index
(per min)
Group I (Control)
3.87 ± 0.26
87.2 ±2.3
Group II (low dose)
3.88 ± 0.13
90.0 ± 1.2
0.035 ± 0.0046
2.96 ± 0.084
79.7 ± 1.3
0.023 ± 0.0036a
b
0.043 ± 0.0048
a
Table 5. Effect of Septilin on Humoral Immunity (Plaque
Forming Cell Response of Splenic Lymphocytes to Sheep
Erythrocytes) (n=6 per group)
Lymphocytes/
spleen (x 107)
Plaques/106
splenic
lymphocytes
Plaques/
spleen
(x 102)
Group I
(Control)
9.40 ± 0.94
221.3 ±
19.51
198.7 ±
12.49
Group II
(low dose)
9.76 ± 0.63
313.3 ±
28.38a
299.7 ±
18.11b
Group III
(high dose)
9.49 ± 0.97
267.2 ±
20.89
245.0 ±
9.79a
Group
Table 6. Effect of Septilin on Cellular Immunity (Delayed
Hypersensitivity to Oxazolone) (n=6 per group)
Group
Ear thickness
Group I (Control)
5.25 ± 0.44
Group II (low dose)
3.42 ± 0.60a
2.75 ± 0.38b
and inflammation. Studies by Kumar et al and Udapa
et al have already reported the anti-inflammatory effect
of Septilin.2,3 To what extent this anti-inflammatory
effect could have contributed to the lesser increase in
the ear thickness in response to oxazolone cannot be
commented upon at this stage. In fact, there is a report
where rohitukine, a compound isolated from the plant
D binectariferum, showed anti-inflammatory effects in
models of acute inflammation but actually enhanced
delayed hypersensitivity to oxazolone.11 Thus, it appears
that the anti-inflammatory effect of Septilin may have
contributed only negligibly to the reduction in delayed
hypersensitivity to oxazolone and that the reduction in
delayed hypersensitivity must be a result of the inhibitory
effect of Septilin on cell mediated immunity.
Conclusion
The humoral immunity was enhanced by Septilin. The
increase in humoral immunity is in accordance with
the studies by Bhasin et al6 where Septilin treatment
increased serum IgG levels, and Sharma and Ray et al17
where Septilin increased the primary as well as secondary
immune response to sheep RBCs.
Septilin has dual effects on the immune system as it
stimulates some of the immune functions but suppresses
others. Also, it is observed that the immunostimulant
effects are more prominent with the lower dose, while
the immunosuppressant activity was better documented
with the higher dose of Septilin. The immunomodulatory
activity of drugs is known to vary with the dose level and
most of the immunosuppressants show immunostimulation
at low dilutions.19,20 A study by Abrams et al21 observed
that administration of low doses of cyclophosphamide,
an immunosuppressant, to volunteers with advanced
malignancies enhanced the lymphokine activated killer
cell activity induced by co-administration of interleukin-2.
Similar immunostimulating properties have been found
to be associated with other immunosuppressants such
as glucocorticoids and 6-thioguanine.20 This suggests
that immunostimulation may be a general feature of
immunosuppressive drugs and a similar phenomenon
may be responsible for the dual effects of Septilin,
observed in the present study. Another consideration is
the presence of extracts of several plants in the Polyherbal
preparation Septilin, some of which may contribute to the
immunostimulant and others to the immunosuppressant
effects of Septilin on the immune system. Therefore, it is
likely that different doses of Septilin could have different
indications and this should be borne in mind while
prescribing it.
The cellular immunity was suppressed by Septilin. Skin
test response to an antigen is complex and involves
many aspects of the immune response.18 The delayed
hypersensitivity that was measured here has a few
major components—sensitization, release of cytokines,
Finally, it was proposed that still lower doses
Septilin should be studied to assess its effect
the immune system and individual components
the polyherbal preparation should be screened
immunomodulator activity.
All values are mean ± SE.
a
0.01<P<.05; b0.001<P<.01.
Discussion
In the present study six different animal models were used
to monitor the influence of Septilin on different arms of
the immune system. The results show that neither of the
doses studied altered weight gain, lymphocyte counts, or
host resistance against acute abdominal sepsis.
Both the doses of Septilin increased the percentage of
neutrophils as well as the absolute number of circulating
neutrophils but the higher dose reduced the phagocytic
activity of the circulating polymorphonuclear cells as well
as the reticuloendothelial system. This is contradictory
to effects of Septilin on phagocytic function,16 which is
probably because the doses used in our study are higher
than the previously reported studies.
of
on
of
for
41
Reference s
1. Ross DG, et al. Probe. 1984;23:84-87.
2. Kumar PV, et al. Probe. 1993;33:1-5.
3. Udapa AL, et al. Indian J Physiol Pharmacol. 1989;33:39-42.
4. Gadekar HA, et al. Probe. 1986;25:164-165.
13. Florentin I, et al. In: Werner GH, et al, eds. Pharmacology of
Immunoregulation – A Round Table Conference held in Paris (NovDec 1977). London: Academic Press; 1978:335-351.
14. Jerne N, et al. In: Amos B, et al, eds. Cell Bound Antibody.
Philadelphia: Wistar Institute Press; 1963:109.
5. Sharma SK, et al. Probe. 1986;25:156-161.
15. Dresser DW. In: Weir DM, ed. Handbook of Experimental
Immunology. vol II, 4th edn. Blackwell Scientific: Oxford; 1986:64.1.
6. Bhasin RC. Indina Practit. 1990;43:83‑87.
16. Rao CS, et al. Indian J Exp Biol.1994;32:553-558.
7. Prusty PK, et al. Indian Med J. 1985;79:161-165.
17. Sharma SB, et al. Indian J Physiol Pharmacol. 1997;41:293-296.
8. Thatte U, et al. Indian Drugs. 1987;25:95-97.
18. Urbaniak SJ, et al. In: Weir DM, ed. Handbook of Experimental
Immunology. vol IV, 4th edn. Blackwell Scientific: Oxford;
1986:126.10.
9. Biozzi G, et al. Br J Exp Pathol. 1953;34:426-457.
10. Sood P. In: Hazra A, et al, eds. Techniques in Pharmacology,
Pharmatech–96 Manual. Mumbai: G.S. Medical College;
1996:91‑94.
11. Lakadawala A, et al. Asia Pacific J Pharmacol. 1988;3:91-98.
12. Borell J, et al. Immunology. 1977;32:1017-1025.
19. Patwardhan B, et al. Indian Drugs. 1990;28:56-63.
20. Van Dijk H, Voermans. In: Werner GH, Floch F, eds. Pharmacology
of Immunoregulation–A Round Table, Conference held in Paris
(Nov-Dec 1977). London: Academic Press; 1978:301-304.
21. Abrams JS, et al. J Immunother. 1993;14:56-64.
Liv.52 Regulates Ethanol Induced PPARγ and TNF-a Expression in
HepG2 Cells
Mitra SK, et al.
The Himalaya Drug Company, Bangalore.
Mol Cell Biochem. 2008;315:9-15.
Abstract
Liver is a prime target of alcohol-induced damage
by inducing inflammatory cytokines especially
tumor necrosis factor alpha (TNF-α). Activator of
peroxisome proliferator activator receptor gamma
(PPARγ) is protective against alcohol-induced liver
injury in animals. Liv.52, one of the major herbal
hepatoprotective drugs, is shown to protect the liver
from toxicity and is considered to be an effective
hepatoprotective agent. However, the signal pathway
involved in the Liv.52-induced hepatoprotection is not
well-understood, especially in the case of cultured
liver cells treated with ethanol. Hence, this study was
aimed at determining whether ethanol and Liv.52
could modulate PPARγ and TNF-a induction in human
hepatoma cells, HepG2. The present study with
RT-PCR and confocal microscopy experiments showed
that ethanol (100mM) induced suppression of PPARγ
expression in HepG2 cells. The ethanol-induced PPARγ
suppression was abrogated by Liv.52. Moreover, Liv.52
also induced upregulation of PPARγ mRNA in liver cells
as compared to the untreated cells. Further, 100 mM
ethanol has also induced TNF-α gene expression in
HepG2 cells and interestingly Liv.52 abolished ethanolinduced TNF-α. The study also showed that Liv.52 is
capable of attenuating ethanol-induced expression of
TNF-α and abrogating ethanol-induced suppression
of PPARg in liver cells. These results indicate that
Liv.52-induced PPARg expression and concomitant
suppression of ethanol-induced elevation of TNF-α
in HepG2 cells suggest the immunomodulatory and
hepatoprotective nature of Liv.52.
Key Words
Liv.52, TNF-α, PPARg, alcoholic liver diseases, HepG2
Intro duc tion
Alcohol is one of the major hepatotoxicants. Acute or
chronic alcohol consumption favors liver injuries caused
by other toxins.1 Ethanol-enhanced liver injury is known
to be evoked by pro-inflammatory mediators.2 Studies
involving patients with alcoholic liver disease have shown
increased level of TNF-α and other pro-inflammatory
cytokines.3-5 Research findings from animal studies have
also suggested the role of alcohol-induced TNF-α and
other pro-inflammatory cytokines in causing liver injury.6
Ethanol-induced hepatotoxicity in HepG2 cells by TNF-α
has been demonstrated by various studies.7,8 Peroxisome
proliferator-activated receptor gamma (PPARγ) is a
member of the nuclear hormone receptor superfamily and
is an important transcription factor in glucose homeostasis
in relation to type II diabetes.9 Although PPARγ is a wellstudied drug target for type II diabetes,10 the role of PPARγ
in manifestation of inflammation is gaining momentum.11
Expression of PPARγ in hepatoma cell line indicates its
potential role in liver function.12 Animal experiments
have also shown the effect of ethanol in regulating PPARγ
expression in liver and PPARγ agonist is found to prevent
alcohol-induced liver injury.13-15
Availability of synthetic and herbal drugs is useful in
protecting liver from toxicity induced by alcohol and
other toxicants. Among herbal preparation, Liv.52 is one
of the major herbal drug preparations for protecting liver
against damage caused by various toxicants.16 Various
animal experiments using different chemical toxicants
have demonstrated the hepatoprotective effect of
Liv.52.17-19 Liv.52-mediated liver protection from ethanolevoked toxicity was also reported from animal and
human studies.19-21 However, the molecular mechanism
underlying the hepatoprotective effect of Liv.52 is not
explored well using suitable in vitro models, especially in
the case of alcohol-induced liver toxicity. Therefore, the
above information gave us impetus to determine whether
Liv.52 could in any way modulate TNF-α and PPARγ
expression, if any, induced by ethanol in human hepatoma
cells, HepG2.
43
Materials
Culture media and fetal bovine serum (FBS), MTT, TRI
reagent, and custom prepared oligonucleotides were
obtained from Sigma Chemical Co. (USA). Penicillin
and streptomycin were from Hi-media, India. Liquid
preparation of Liv.52 was received from the Distribution
unit of Himalaya Drug Company, Bangalore, India, and
the details of the drug have been described previously.19
MMLV reverse transcriptase, dNTP, and Taq DNA
polymerase were MBI Fermentas (USA).
Cell culture conditions
HepG2 were obtained from National Center for Cell
Science (NCCS), Pune. These cells were maintained in
Dulbecco’s Modified Essential Media (DMEM) containing
10% FBS at 37°C with 5% CO2, and 95% humidity.
HepG2 cells were treated with ethanol as described
previously.22,23 Unless specified, cells treated or untreated
with ethanol were gently sealed with parafilm to avoid
evaporation of ethanol. The cells were incubated for 24
hours at 37°C with 5% CO2. Cells sealed with and without
parafilm did not show any change in the cell viability.
Cytotoxicity assay
Colorimetric
MTT
(3-(4,
5-dimethylthiazol-2-yl)-2,
5-diphenyl tetrazolium bromide) assay was done to
determine whether any of the test concentration of Liv.52
and ethanol has toxicity in HepG2 cells. For this, cells
were seeded in 96-well flat bottom culture plates and
incubated overnight. The cells were exposed to different
concentration of Liv.52 and ethanol diluted in medium
containing 2% FBS and incubated for 24 hours. About
10 μL MTT (5 mg/mL) was added to each well and
incubated for 4 hours. The formazan dye formed was
extracted with dimethyl sulfoxide and absorbance
recorded as described previously.24
RNA isolation and RT-PCR
HepG2 cells were seeded in 40 mm culture dishes (1x105
cells/mL) and incubated overnight. Cells were treated
with ethanol (100 or 200 mM), 1% or 2% Liv.52 or
together prepared in medium with 2% FBS. Treated and
untreated cells were incubated for 24 hours. Cells were
homogenized in TRI reagent and RNA was extracted
(as per manufacturer’s instructions) and stored at -70°C.
RNAs were further treated with DNase I to remove traces
Liv.52 in alcohol-induced liver damage
of contaminating DNA. Quantity and integrity of RNAs
were examined with spectrophotometer and agarose
gel electrophoresis, respectively. First strand cDNA
was synthesized from 1 μg total RNA with oligo dT
primers. Oligonucleotides used in reverse transcription
polymerase chain reaction (RT-PCR) analysis and PCR
amplification is from previous reports for PPARγ, For5’-GCAGGAGCAGAGCAAAGAGGTG-3’,
Rev-5’AAATATTGCCAAGTCGCTGTCATC-3’,
for
TNF-a,
For-5’–ATGAGCACTGAAAGCATGATC-3’,
Rev-5’TCACAGGGCAATGATCCCAAAGTAGACCTGCCC-3’,
and
for
GAPDH,
For-5’–
GACCACAGTCCATGCCATCAC-3’,
Rev-5’TCCACCACCCTGTTGCTGTAG-3’.25,26
First strand cDNA was generated from total RNA using
oligo dT/random hexamer primers and was amplified by
PCR following the addition of specific primer pairs and
Taq DNA polymerase. Human GAPDH primer set was
used as a control for each RNA sample. The PCR reaction
for PPARγ and GAPDH was carried out with an initial
denaturation of 2 minutes at 95°C followed by 30 cycles
of denaturation at 95°C for 20 seconds, annealing at 60°C
for 30 seconds, and elongation at 72°C for 40 seconds.
The final extension was carried out at 72°C for 10 minute.
For TNF-α , the PCR conditions consisted of an initial
denaturation at 94°C for 30 seconds, annealing at 60°C
for 30 seconds, and elongation at 72°C for 10 minutes.
Amplification products were analyzed by 1.5% agarose
gel electrophoresis and visualized by ethidium bromide
staining. The molecular weight of the amplified cDNA
was determined by comparison with a standard molecular
weight marker (1Kb ladder) and densitometry analysis was
carried out for determining relative levels of PPARγ and
TNF-α mRNA in comparison with GAPDH RNA.
Confocal laser scanning microscope
Immunfluorescence was done essentially as carried out
previously.27 HepG2 cells were grown overnight on cover
slips. The cells were exposed to 1% Liv.52, 100 mM
ethanol, or ethanol and Liv.52 together. Untreated cells
remained as controls. Treated and untreated cells were
incubated for 24 hours and cells were fixed with chilled
ethanol. Cells were incubated with rabbit polyclonal
anti-PPARγ antibody. Secondary antibody consists of
CY3 labeled anti-rabbit IgG antibody. The cover slips
with cells were mounted on mounting medium and then
visualized by confocal microscope (Carl Zeiss) at 63x and
photomicrographs were documented.
Data analysis
Statistical analysis of data was carried out using GraphPad
Prism4. Unpaired Student’s t test was used to analyze the
data. Data were represented as mean ± SEM and P<.05
was considered significant.
Re sults and Discussion
Aim of the present study was to determine whether Liv.52
modulates any signaling pathway in HepG2 cells, which
are exposed to ethanol without affecting cell viability.
Hence, the model system was HepG2 cells treated with
nontoxic concentration of ethanol without any detectable
cytotoxicity to the cells studied for 24 hours using MTT
assay. MTT assay demonstrated that both Liv.52 and
ethanol were not toxic to the HepG2 cells at the tested
concentration. Although we have taken wider range of
concentration for ethanol and Liv.52 for cytotoxicity
determination, lower concentration of ethanol (200 mM)
and Liv.52 (2% and 1%) were taken for the subsequent
experiments. HepG2 cells were exposed to ethanol at a
concentration of 100 mM for 24 hours and looked for the
mRNA expression of PPARγ. Ethanol exhibited about 0.8fold reduction in the PPARγ mRNA level in HepG2 cells
as compared to the control cells and the decrease was
marginally significant. Previous studies have suggested
that ethanol-mediated liver injury could be regulated by
PPARγ activators.13-15
These studies using animals suggest that the PPARγ agonist
was found to prevent various signal pathways induced
by ethanol and thereby protecting the liver from ethanol
toxicity. Hence, these findings support the view that acute
ethanol treatments even at a concentration 100 mM can
downregulate PPARγ in the liver cells. However, when
cells were exposed to ethanol and 1% or 2% Liv.52,
there was 1.5- and 1.7-fold increase, respectively, in the
mRNA level of PPARγ as compared to cells treated with
ethanol alone (P<.05, P<.01). Interestingly, Liv.52 alone
at both concentrations induced enhanced PPARγ protein
expression by confocal immunofluorescence microscopy
using anti-PPARγ antibody. Confocal analysis revealed
increased staining of PPARγ in cells treated with Liv.52.
The PPARγ expression was localized and concentrated
on the perinuclear region, mainly in the cytoplasm.
About 100 mM ethanol reduced the expression pattern of
the PPARγ as compared to the untreated cell. But when
cells were treated with ethanol and Liv.52, the PPARγ
expression was increased to a greater extent as compared
to the controls and cells treated with ethanol alone. It
appears there was a slight diffused translocation of PPARγ
to the nucleus from the perinuclear region in cells treated
with Liv.52 and ethanol. In vivo animal studies elucidated
the hepatoprotective nature of Liv.52.16 Activation of
PPARγ can lead to battery of cellular events especially the
translocation or redistribution of PPARγ.28,29 Such cellular
events seem to be specific to the cell types and nature
of cell signaling initiated by agonist or antagonist.28,29 It
remains to be studied whether Liv.52 could evoke any
such cell-signaling event, which in turn can regulate
the intracellular distribution of PPARγ in HepG2. The
protective effects of Liv.52 in alcoholic patients have also
been documented.21 This is the first report to suggest
that Liv.52 could upregulate PPARγ expression in HepG2
cells. The anti-inflammatory effect of PPARγ has been
demonstrated in various models.11 Some studies show
that PPARγ activation is associated with anti-inflammatory
properties30 whereas other studies show no relationship.31
Activators of PPARγ is known to protect liver and gastric
mucosa from alcohol-induced injury by modulating the
inflammatory mediators thus suggesting the importance
of hepatic PPARγ in controlling alcohol-mediated cellular
events.14,32 Hence, from the present study, it could be
well argued that upregulation of PPARγ in liver cells by
Liv.52 and its capacity to abrogate the ethanol-mediated
suppression of PPARγ may be suggesting the protective
effect of this herbal drug, Liv.52.
Alcohol is known to affect the functions of hepatocytes.33
In vitro studies have shown that alcohol could induce
many pro-inflammatory cytokines and mediators favoring
the toxic effect of alcohol. Many laboratory studies suggest
that TNF-α is a major mediator in the alcohol-mediated
liver diseases.8,14,34 It was also reported that PPARγ
activators could protect alcohol-induced liver injury by
inhibiting TNF-α.13,14 The results obtained from this study
showing the induction of PPARγ by Liv.52 gave further
impetus to look into the status of TNF-α gene expression
in HepG2 cells with and without ethanol exposure. It
was observed that ethanol at 100 and 200 mM induced
TNF-a gene expression. About 1.8-fold increase in TNF-a
gene expression was observed at 100 and 200 mM
ethanol (P<.01). Previous studies have demonstrated the
induction of TNF-α in HepG2 cells by even 50 to 80 mM
ethanol.35,36 It was further analyzed whether Liv.52 could
modify ethanol-induced expression of TNF-α in HepG2
cells. The results showed that there was about 1.5-fold
decrease in the TNF-α gene expression when cells were
treated with Liv.52 and ethanol as compared to the TNF-α
induced by the ethanol (P<.05). Interestingly, it was also
45
observed that Liv.52 itself could slightly downregulate the
TNF-α gene expression in HepG2 cells as compared to
untreated cells. Therefore, PPARγ activation by Liv.52 and
inhibition of ethanol-mediated TNF-α induction in HepG2
cells by Liv.52 is suggesting the hepatoprotective activity
of this herbal drug. In vivo studies have documented the
protective nature of Liv.52 against liver damage induced
by various types of chemicals and toxicants.16 Data are
scanty to suggest the protective effect of Liv.52 in ethanolinduced liver damage in relation to pro-inflammatory
mediators such as TNF-α. However, an earlier report
showed that Liv.52 could decrease serum TNF-α levels
in experimental hepatitis induced by carbon tetrachloride
in rats.37 The induction of TNF-α in HepG2 cells by
ethanol and its perturbation by Liv.52 as observed in the
present study is novel information. In their experiments,
authors could not detect ethanol-induced cell death in
HepG2 cells observed for 24 hours. Previous studies have
also shown that ethanol did not exert much toxicity to
HepG2 cells incubated even for more than 24 hours.22,23
However, the induction of TNF-α by ethanol as noticed
in our study and induction of many other mediators in
tissues by ethanol 4,7 could be denoting the early sign of
ethanol-induced deleterious effect. Hence, findings from
our present in vitro studies also provide information to
explore further the role of Liv.52 in ethanol-induced liver
damage in relation to PPARγ and TNF-α using suitable
in vivo model. Others have reported the importance
of cytochrome P4502E1 (CYP4502E1) in the ethanolmediated cell death,22, 23 and hence, it would also be
rational to study further the efficacy of Liv.52 in ethanolmediated toxicity in HepG2 cells expressing CY4501E1.
Hence, taken together, the upregulation of PPARγ and
concomitant downregulation of ethanol-mediated TNF-α
expression in HepG2 cells by Liv.52 may be denoting the
hepatoprotective as well as anti-inflammatory activity of
Liv.52 in the liver.
Conclusion
26. Matsuda T, et al. J Gen Virol. 2005;86:1055–1065.
The findings from the present study suggest that Liv.52
could attenuate the TNF-α production induced by
alcohol in these cells. In addition to this, interestingly this
study further suggests that Liv.52 itself could suppress
TNF-α production in HepG2 cells. The suppression of
ethanol-induced TNF-α expression in HepG2 cells by
Liv.52 as observed in the present study suggests the
immunomodulatory property of Liv.52. It is interesting
to observe that Liv.52 is capable of upregulating PPARγ
in HepG2 cells while downregulating the TNF-α
expression in the presence or absence of ethanol.
Reference s
1. Thiele GM, et al. Semin Liver Dis. 2004;24:273–287.
2. Day CP, James OF. Gastroenterol. 1998;114:842–845.
3. MaClain CJ, Cohen DA. Hepatology. 1989;3:349–351.
4. McClain CJ, et al. Alcohol Health Res World. 1997;21:317–320.
5. Neuman MG. Alcohol Res Health. 2003;27:307–316.
6. Yin M, et al. Gastroenterol. 1999;117:942–952.
7. Gutie´rrez-Ruiz MC, et al. Toxicology. 1999;134:197–207.
8. Rodriguez DA, et al. Alcohol. 2004;33:9–15.
9. Evans RM, et al. Nat Med. 2004;10:355–361.
10. Saltiel AR, Olefsky JM. Diabetics.1996;45:1661–1669.
11. Szeles L, et al. Biochim Biophys Acta. 2007;1771:1014–1030.
12. Koga H, et al. Hepatology. 2001;33:1087–1097.
13. Enomoto N, et al. J Pharmacol Exp Ther. 2003;306:846–854.
14. Ohata M, et al. Alcohol Clin Exp Res. 2004;28:139S–144S.
15. Tomita K, et al. Gastroenterology. 2004;126:873–885.
16. Mitra SK. Hepatology. 2000;31:546–547.
17. Huseini HF, et al. Phytomedicine. 2005;12:619–624.
18. Mandal SC, et al. Phytother Res. 2000;14:457–459.
19. Sandhir R, Gill KD. Indian J Exp Biol. 1999;37:762–766.
20. Gopumadhavan S, et al. Alcohol Clin Exp Res. 1993;17:1089–1092.
21. Chauhan BL, Kulkarni RD. Eur J Clin Pharmacol. 1991;40:189–191
22. Wu D, Cederbaum AI. J Biol Chem. 1996;271:23914–23919.
23. Jime´nez-Lo´pez JM. Biochem Pharmacol. 2002;63:1485–1490.
24. Chakravortty D, Nandakumar KS. Biochem Biophys Res Commun.
1997;240:458–463.
25. Klopotek A, et al. Exp Biol Med. 2006;23:1365–1372.
27. Chakravortty D, Nanda Kumar KS. Biochim Biophys Acta.
2000;1500:125–136.
28. Rousseaux C, et al. J Exp Med. 2005;201:1205–1215.
29. Varley CL, et al. J Cell Sci. 2004;117:2029–2036.
30. Jiang C, et al. Nature. 1998;391: 82–86.
31. Thieringer R, et al. J Immunol. 2000;164:1046–1054.
32. Brzozowski T, et al. Inflammopharmacology. 2005;13:317–330.
33. Castaneda F, et al. Int J Med Sci. 2006;4:28–35.
34. Pastorino JG, Hoek JB. Hepatology. 2000;3:1141–1152.
35. Neuman MG, et al. Gastroenterology. 1998;115:157–166.
36. Gutierrez-Ruiz MC, et al. Isr Med Assoc J. 2001;3:131–136.
37. Roy A, et al. Indian J Exp Biol. 1994;32:694–697.
Immunopotentiating Activity of Septilin
Praveenkumar V, et al.
Amala Cancer Research Centre, Amala Nagar, Thrissur, India
Indian J Exp Biol. 1997;(35):1319-1323.
Abstract
Intro duc tion
Oral administration of Septilin (100 mg/animal/
dose; five doses) was found to enhance natural killer
cell-mediated cytotoxicity and antibody-dependent
cellular cytotoxicity in normal mice as well as tumorbearing mice. Septilin treatment also activated the
peritoneal macrophages, which produced cytotoxicity
to L929 cells. Septilin increased proliferation of bonemarrow cells and there was an increase in the number
of a-naphthyl acetate esterase staining cells in the
bone marrow. In addition to the activation of cellular
immunity, Septilin was found to increase the number of
antibody producing cells in the spleen and activation of
antibody-dependent complement-mediated cell lysis.
These studies justify the use of this herbal preparation
in improving immunocompetence in disease states.
Septilin is a proprietary Ayurvedic product of The
Himalaya Drug Company, Bombay, containing various
herbs and minerals.1 It is extensively used in the
treatment of several acute/chronic infections.2,3 It has
been demonstrated that Septilin stimulated phagocytosis
and thereby helped in controlling infections.4 Recently
we have shown that Septilin could increase the total
count of leukocytes and the percentage of polymorphs
in the peripheral blood.5 It could also protect mice from
cyclophosphamide-induced
myelosuppression
and
subsequent leukopenia.6 In the present study, the effect
of Septilin on the cell-mediated and humoral immune
responses in mice has been investigated.
Keywords
Drug
Septilin, cytotoxicity, immunocompetence, infections,
immune response
Pure Septilin powder was supplied by The Himalaya Drug
Co., Bombay. Its main ingredients are Balsamodendron
mukul, Shankha bhasma, Maharasnadi quath, Tinospora
cordifolia, Rubia cordifolia, Emblica officinalis, Moringa
pterygosperma, and Glycyrrhiza glabra.
Drug extraction
Septilin powder (6 g) was boiled in 600 mL of distilled
water for 30 minutes. It was centrifuged and filtrate
evaporated to dryness on a water bath and made up
to 45 mL. This extract (0.75 mL) was used for oral
administration and it contained the extract from 100 mg
of Septilin.5 For all the experiments a total of 5 doses of
this extract was given orally on alternate days unless
mentioned. This concentration was found to be nontoxic.5
The control animals received an equal volume of saline.
Reagents and chemicals
Eagles minimum essential medium (MEM), Rosewell Park
Memorial Institute medium (RPMI)-1640, and Dulbeco’s
minimum essential medium (DMEM) were purchased
from Hi-media Laboratories, Bombay. Concanavalin-A
(CON-A) was purchased from Sigma Chemicals, St. Louis,
47
MO, USA, and phytohemagglutinin (PHA) from Difco
Laboratories, USA. 3H-thymidine (sp. activity 10,00025,000 mCi/mmol) and sodium chromate (Na252CrO4) (sp.
activity 5mCi/mg) were brought from Board of Radiation
and Isotope Technology, BARC, Bombay. Alpha-naphthyl
acetate and pararosaniline were obtained from Loba
chemie, Bombay, agarose from SRL Bombay. All other
reagents and chemicals were of Analytical grade.
Cell lines
L-929 (mouse lung fibroblast) cells and YAC-1 (mouse
lymphoma) cells were obtained from National Facility
for Animal Tissue and Cell Culture, Pune. Ehrich ascites
tumor (EAT) cells (spontaneous tumor of mammary gland
of mice) were initially obtained from Cancer Institute,
Bombay and were maintained as ascites tumor in Swiss
albino mice. Sheep red blood cells (SRBC) were freshly
collected in Alsever’s solution.
Animals
Female Balb/C mice 20 to 22 g (6–8 weeks old)
were purchased from National Institute of Nutrition,
Hyderabad. They were housed in ventilated cages in air
controlled rooms.
Balb/C mice were divided into four groups (20 animals/
group). Group I - normal controls; Group II - Septilintreated animals; Group III - tumor-bearing controls; and
group IV - tumor-bearing animals treated with Septilin.
Five doses of 0.75 mL of Septilin (equal to 100 mg
powder) were given orally daily to groups II and IV. Group
I received only saline. Along with the last dose, EAC (106)
were injected to groups III and IV. The animals were
sacrificed on various days and the spleens were processed
into single cell suspension in RPMI-1640 containing 10%
FCS and used as effector cells. Blood was collected from
these animals by heart-puncture, sera separated and heat
inactivated at 56°C for 30 minutes. Sera was used as
anti-EAC antibody for ACC estimation.
YAC-1 cells (106 cells) or SRBC (107 cells) were incubated
along with Na2 51CrO4 (100 μCi) at 37°C for 1 hour. They
were washed, suspended at a concentration of 105 cells/
mL and used as targets for NK cells (YAC-1) and ADCC
(SRBC) assay as given below:
The labeled target YAC-1 cells (1x104 cells/tube) were
incubated with spleen cells at an effector target ratios of
100:1, 50:1, and 25:1 at 37°C for 4 hours. After incubation,
100 μL of the supernatant was counted for radioactivity
released after cell death using a gamma ray spectrometer.
Immunopotentiating activity of Septilin
The percent lysis due to NK-cell activity was calculated by
the formula:
ER – SR
% Lysis = –——— x 100
TR-SR
where, ER is the experimental release, SR is the
spontaneous release, and TR is the total release. SR and
TR were determined by incubating the target cells alone or
with HCl (IN, 100 μL), respectively.
Determination of antibody-dependent cellular
cytotoxic activity
ADCC activity was determined using a chromium release
assay described by Kim et al.8 Labeled SRBC (1x104 cells)
were incubated with effector cells at different effector:
target ratios of 100:1, 50:1, and 25:1 along with 0.1 mL
of anti-SRBC antibody. An aliquot of the supernatant was
counted for released radioactivity as above.
Determination of antibody-dependent
complement-mediated lysis
Ehrlich ascites tumor cells (1x104 cells) were incubated
with serially diluted sera sample (100 μL), and 50 μL of
1:10 diluted fresh rabbit serum as a source of complement
at 37°C for 3 hours. The cytotoxicity was assessed by
trypan blue exclusion method.9
Lymphocyte blastogenesis assay
Lymphocyte blastogenesis assay was done as described
previously10. 24 hours after the drug treatment the
animals were sacrificed and spleen cells were used for
lymphocytes. Controls received only saline. Spleen cells
(106 cells/mL) were incubated with various concentrations
of mitogens (CON A – 10 and 5 μg/mL or PHA – 6
and 3 μg/mL) at 37°C for 48 hours in 3 mL or RPMI1640 supplemented with 10% FCS after incubation
3H-thymidine (2 μCi/vial) was added to each vial and
incubated for 18 hours. DNA was precipitated with
10% PCA and the amount of radioactive thymidine
incorporated into DNA were counted using liquid
scintillation counter (Rack Beta).
Bone marrow cell proliferation assay
The assay was done as described for lymphocyte
proliferation assay. Instead of spleen cells, bone marrow
cells (106 cells/mL) from treated and untreated animals
were incubated in the presence and absence of mitogens.
The amount of radioactive thymidine incorporated into
the cells were used as a measure of cell proliferation.
Determination of macrophage-mediated
cytotoxicity
heat inactivated at 56°C for 30 minutes. The titer was
determined by hemagglutination method.13
Peritoneal macrophages were induced by injecting (IP)
0.2 mL of sodium caseinate (5%) on the last day of drug
treatment. After 5 days, the macrophages were collected
in Hank’s Balanced Salt Solution (HBSS). It was washed
and suspended in DMEM containing 10% FCS at a
concentration of 2.5x105 cells. Target L929 cells (5x103
cells/well) were incubated with macrophages (100 μL)
from treated and untreated animals for 48 hours in a final
volume of 200 μL at 37°C in a humidified atmosphere
having 5% CO2. After incubation, cells were fixed and
stained with crystal violet and cellular cytotoxicity was
assessed morphologically.11
Re sults
Determination of antibody-producing cells
Effect of Septilin on antibody-dependent
cellular cytotoxicity activity
All animals of both treated and untreated groups (10/
group) received SRBC (2.5x108 cells) along with the last
dose of Septilin. The animals from each group were
sacrificed on various days and the spleen cells were used
to perform Jerne’s plaque assay.12
Quantitation of circulating antibody titer
Along with the last dose of Septilin treatment, all
animals (6/group) received 0.1mL of 20% SRBC. Blood
was collected from the tail vein prior to SRBC injection
and on every third day thereafter. Sera separated and
Effect of Septilin on natural killer cell activity
The NK-cell activity was found to increase progressively
from 48 hours after drug treatment in both Septilin
treated normal and tumor-bearing mice (Figure 1 [A]). The
maximum NK-cell activity was observed on day 7 with a
percentage cell lysis of 55 and 58, respectively. In the case
of control tumor-bearing animals the maximum NK-cell
activity was observed on day 9 of tumor inoculation with
a target cell lysis of 48%.
ADCC was found to be enhanced in normal and tumorbearing animals after Septilin treatment (Figure 1 [B])
Maximum ADCC activity was observed on day 5 in both
groups with percent target lysis of 63 and 69. In tumorbearing controls the maximum ADCC was observed on
day 7 after tumor inoculation with a target, cell lysis of
47%.
Effect of Septilin on antibody-dependent
complement-mediated lysis activity in mice
Administration of Septilin produced only a marginal
increase in ACC activity in tumor-bearing animals (data
not shown). The maximum cytotoxicity (24%) was found
on day 15 in Septilin-treated animals and on day 21 in
control animals (19%).
Effect of Septilin on Macrophage Activation
Administration of Septilin was found to activate the
macrophages and was cytotoxic towards L929 cells
(Figure 2) as seen from the loss of tumor cell morphology.
Figure 1. Effect of Septilin on NK-cell activity (A) and ADCC
activity (B)
Figure 2. Effect of Septilin on macrophage activation. (A)
Normal L929 cell grown in monolayer. (B) L929 cells treated
with peritoneal macrophages from Septilin-treated mice.
49
Macrophages isolated from untreated animals did not
show any cytotoxic effect.
Effect of Septilin on bone marrow and spleen
cell proliferation
Septilin treatment significantly enhanced the proliferation
of bone-marrow cells in culture (Table 1). Degree of
enhancement of proliferation was nearly 10 times in
animals treated with Septilin, as seen from the increased
incorporation of 3H-thymidine when compared to
controls. Addition of mitogens did not alter the rate of
proliferation of bone-marrow cells in the treated animals.
The proliferation of spleen cells in presence or absence
of mitogens were not affected by the treatment of Septilin
(data not shown).
Table 1. Effect of Septilin on Bone Marrow Cell
Proliferation in Mice
Thymidine incorporation (CPM)
Treatment
No
mitogens
PHA
6 μg/mL
CONA
10 μg/mL
Control
909 ± 154
934 ± 114
869 ± 48
Septilin
10951 ±
1546*
10281 ±
891
10177 ±
704*
Five doses of Septilin equivalent to 100 mg of extract was
given orally, and 24 hours after the drug treatment bone
marrow cells were cultured to assess the proliferation. The
values are mean ± SD of triplicates of two experiments.
*
P<.001.
In a similar experiment, α-naphthyl acetate esterasepositive bone marrow cells were found to be enhanced
by Septilin treatment (804 cells/4000 bone marrow cells)
compared to controls (648/4000 bone-marrow cells).
Effect of Septilin on antibody-producing cells
and circulating antibody titer
The effect of Septilin on number of antibody producing
cells which is represented as plaque forming cells (PFC)
Table 2. Effect of Septilin on the Number of Antibodyproducing Cells in Mice Spleen (Values are mean ± SD of 6
animals/group done in triplicates)
Antibody producing cells (PFCs)/106 spleen cells
Days after treatment
Control
(SRBC
alone)
Septilin
+ SRBC
3
4
5
6
7
150
±5
205
±8
273
±6
253 ±
31
245
±7
110
±8
193
±7
680
± 21*
303
±4
253
±6
P<.001
*
per million spleen cells is shown in (Table 2). Septilin
treatment enhanced the number of PFC in the spleen. The
number of PFCs gradually increased from day 3 up to day
5 (680 PFC/106 spleen cells), which was twice the number
of PFCs formed in the controls (273 PFC/106 spleen cells).
There was no increase in the circulating antibody titer in
Septilin-treated animals compared to controls.
Discussion
The data presented here demonstrate the effect of Septilin
on both cellular and humoral immune response. Null cells
such as NK and killer cells are lymphoid cells lacking both
T- and B-cell markers. They have a great role to play in
reducing the development of cancer and its metastasis.14
Oral administration of Septilin significantly enhanced
NK-cell activity, ADCC, and ACC in both normal as well
as tumor-bearing animals. Moreover, Septilin-activated
peritoneal macrophages were highly cytotoxic to L929
cells. It has been reported that L929 cells are highly
sensitive to cytotoxicity mediated by tumor necrosis
factor (TNF).15 Thus the mechanism of tumor cell kill by
the macrophages isolated from Septilin-treated animals
may be mediated by TNF. It has already been shown that
Septilin could increase the life span of tumor-bearing
animals.5 Septilin was not directly cytotoxic to tumor cells.
Hence, the tumor reducing activity of Septilin may be by
the activation of macrophages.
Septilin administration significantly enhanced proliferation
of bone marrow cells from the treated animals in culture.
There was also an increase in the number of cells positive
for esterase (data not shown). In a previous study,6 Septilin
was found to protect mice from cyclophosphamide
induced myelosuppression. This may be due to the
stimulation of bone marrow stem cells either directly or
indirectly through augmented secretion of growth factors.
In addition to the augmentation of cellular immune
responses, Septilin was found to activate humoral
responses. Septilin treatment enhanced the number
of plaque forming cells in the spleen and marginally
activated the secretion of antibodies into the circulation
and ACC in mice.
Septilin contains several herbomineral principles and at
present we do not know the active material involved in
the stimulation of the immune system. Septilin was shown
to contain polysaccharides which activate properdin
system, and increase chemotaxis of polymorphs at the
site of infection, phagocytosis and subsequent destruction
of microorganisms.17 At present we do not know the
component in Septilin responsible for this action.
Reference s
1. Shakani S, et al. Probe.1993;3:7.
2. Ross DR. Probe. 1984;23:84.
3. Udupa AL, et al. Indian J Physiol Pharmacol. 1989;1:39.
4. Ross DR. Probe. 1983;22:100.
5. Praveenkumar V, et al. Probe. 1993;33:1.
6. Praveenkumar V, et al. Indian J Phrm Sci. 1995;57:215.
10. Mustafa AS. In: Talwar GP, ed. A handbook of practical immunology.
New Delhi: Vikas Publishing House; 1983:318.
11. Kuttan G, Kuttan R. Cancer Letters. 1992;66:123.
12. Mehrotra NN. In: Talwar GP, ed. A handbook of practical
immunology. New Delhi: Vikas Publishing House; 1983:122.
13. Singh AK. In: Talwar GP, ed. A handbook of practical immunology.
New Delhi: Vikas Publishing House; 1983:122.
7. Weynad C, et al. J Gen Virol. 1981;55:25.
14. Reller R. In Herberman RB, ed. NK cells and other natural effector
cells. New York: Academic Press; 1982:1353.
8. Kim YB, et al. J Immunol . 1980;125:735.
15. Cui S, et al. Cancer Res. 1994;54:2462.
9. Gupta SK, Bhattacharya A. In: Talwar GP, ed. A handbook of practical
immunology. New Delhi: Vikas Publishing House; 1983:328.
16. Bashin RC. Indian Practit. 1990;43:83.
17. Saraswat PK, Gangil R. Indian Med Gaz. 1984:152.
51
52
Prevention of Surgical-site Infections: Best Practices, Better
Outcomes
Dellinger EP, et al.
Airway, breathing, and circulation—ABC—
are important in the management of a
critically ill patient. This can be done in the
operating room by managing temperature,
oxygen, and fluids. If these are done well and
have optimal physiology, one “D” for drugs
(mainly antibiotics) can be added—ABCD—
for a further reduction in the risk of surgical
site infections (SSIs). In addition, optimal
glucose control, hair removal, antisepsis,
teamwork, and surgical techniques help in
reducing the risk of SSI.
Box 1. Preventing SSI
• ABC for critically ill patients =
airway, breathing, and circulation
• ABC for surgical patient =
temperature, oxygen, and fluids
(intravascular volume)
• ABCD = temperature, oxygen,
fluids, and drugs (ie, antibiotic)
• ABCD plus = add glucose control
and optimal processes and
techniques:
»» Hair removal
»» Antisepsis
»» Teamwork
»» Surgical procedure
Oxygen
It is well established that the risk for SSI is
closely related to the amount of oxygen
available to the tissues in the wound. Patients
with high levels of tissue oxygen tension
have lower infection rates than expected,
while those with low oxygen tensions have
higher infection rates than expected.
A number of studies have randomly assigned
surgical patients to high and low inspired
oxygen concentration (FiO2). Several
randomized controlled trials have assessed
the benefit of perioperative supplemental oxygen therapy.
Although the overall results have been inconsistent, it
has been observed that the use of supplemental oxygen
reduces the risk of SSIs.
Temperature
The patient’s body temperature influences local blood
flow and thus the delivery of oxygen to the wound. In a
multicenter study in Germany and Austria, colorectal
surgery patients were randomly assigned to be kept warm
or to be allowed to get cold. A 3-fold difference was
observed in the SSI rate, favoring patients who were kept
warm throughout the operation and therefore maintained
good blood flow and oxygen tension.
Blood Transfusion
Blood transfusion affects the risk of infection. The
increased surgical risk increases the risk of transfusion
leading to an increased risk of infection. Factors such as
large tumors, difficult procedures, longer operations,
lower preoperative hematocrit, and greater loss of blood
that leads to hemodynamic changes and hypothermia
may contribute to increased risk of infections. Hence,
surgeries such as colorectal and gastric cancer surgeries,
liver transplantation, coronary artery bypass surgery, hip
replacement, and spinal surgery increase the risk of SSI.
Blood Glucose Level
Blood glucose level increases the risk of SSI. In a study,
it was observed that high glucose levels were associated
with an increased rate of infection, whether or not the
patient was diabetic; almost half of the patients with high
blood sugar levels were not diabetic. Results of another
study showed that the use of insulin to control blood sugar
levels in patients undergoing surgery significantly reduced
the rate of SSI in patients with diabetes and it was lower
than that in nondiabetic patients.
The optimal level of glucose control in the perioperative
period is unknown. High blood glucose levels increase
the risk for SSI and other perioperative infections, and
hypoglycemia increases the risk for morbidity and
mortality.
Box 2. Optimal Perioperative Blood Glucose Level
• Increased glucose level
• Hypoglycemia Increased risk for SSI and other perioperative infections
Increased risk for morbidity and mortality
Surgical Techniques
Teamwork
Another factor that affects the risk of SSI is surgical
technique. In recent years, it has been observed that the
practice of double-gloving helps in preventing SSI from
glove perforation as surgical glove perforation increases
the risk for SSI.
Teamwork also plays a major role in reducing the risk of
SSI. There has to be accountability among all of the team
members. Safety culture training such as set the behavior
expectations, education of the team, and reinforcement
and accountability is important.
As the period of maximum influence on SSI begins and
ends in the operating room, these can be prevented through
appropriate use of antibiotics, antisepsis, good oxygenation,
temperature control, moderate control of glucose levels,
method of hair removal, and teamwork.
The risk of SSI can be reduced by implementing a program
to reduce the risk of either all infections through meticulous
technique, avoiding shaving, and timing of antibiotic
prophylaxis (horizontal program) or an infection caused by
a single pathogen such as Streptococcus aureus (vertical
program). A change in the surgical scrub can reduce
the rate of SSI by approximately 40%, regardless of the
organism, and also prevents half of the S aureus infections.
S aureus infections comprise approximately 25% of SSI, so
this change would reduce that rate to 12.5%.
Box 3. SSI Prevention (Vertical and
Horizontal Program)
• High-risk patients
• Patients with implanted prosthetic devices
•
•
•
•
Horizontal
Vertical
Pathogen-specific program—S aureus screening and
eradication in
Meticulous surgical technique
Best practice for surgical skin prep (antisepsis)
Clippers, not razors
Right antibiotic, given at right time, stopped at
right time
• Glycemic control
• Normothermia
• Appropriate transfusion practices
Box 4. Safety Culture Training
• Step 1: Set expectation
»» Define safety behaviors and error-prevention
tools proven to reduce human error
• Step 2: Educate
»» Educate all staff about safety behaviors and
error-prevention tools
• Step 3: Reinforce and build accountability
»» Practice safety behaviors and make them
personal work habits
In the operating room, a preprocedure huddle or sign-in
before the surgery begins is found to be effective. The
huddle is an interactive discussion, in which the surgeon
briefs the entire operating room team on any special
concerns or challenges related to the patient’s planned
operation. The patient is included if required. After a
time-out to review the surgical checklist, anesthesia is
induced. All team members must be empowered to
advocate for the patient to ensure patient safety.
Box 5. Safe Surgery: Preprocedure Huddle
Checklist
• Prior to induction of anesthesia
• Team discussion to assure correct patient, side,
site, procedure, documentation, images, and labs
• Discussion of critical plans and needs for
the case
• Patient included in discussion if required
Excerpted from:
MedscapeCME Infectious Diseases.
Available at: http://www.medscape.org
53
Case Discussion
54
Acute Hepatitis B and Acute
HIV Coinfection in an Adult
Patient
Bansal R, et al.
Case Report Med. 2010;2010:820506.
Abstract
Acute HIV and acute hepatitis B coinfection
is extremely rare. A 23-year-old homosexual
man was admitted to the hospital with
5-day history of fever, malaise, and back
pain with initial laboratory values showing
severe transaminitis. The clinical picture was
initially suggestive of acute viral hepatitis,
which on further testing revealed acute
hepatitis B and acute HIV coinfection.
Although the patient was asymptomatic,
a decision was made to start antiretroviral
therapy. At 2-month follow up, liver function
tests were normal with undetectable viral
loads. The early treatment of acute HIV/HBV
coinfections likely contributed to eventual
seroconversion with immunity to HBV in a
severely immunocompromised host. This
is probably the first case report of acute
Hepatitis B and acute HIV coinfection and its
management. In conclusion, early treatment
of acute hepatitis B in immunocompromised
patients may be beneficial.
Drug-induced Granulomatous Interstitial
Nephritis in a Patient with Ankylosing
Spondylitis during Therapy with
Adalimumab
Korsten P, et al.
Am J Kidney Dis. 2010;56(6):e17-21.
Abstract
Tumor necrosis factor (TNF-α) inhibitors are used in the
treatment of rheumatoid arthritis, psoriasis, psoriatic
arthritis, Crohn disease, ankylosing spondylitis, and
juvenile idiopathic arthritis. Use of TNF inhibitors is
associated with the induction of autoimmunity (systemic
lupus erythematosus, vasculitis, psoriasis, and sarcoidosis/
sarcoid-like granulomas). This study reports a case of
interstitial granulomatous nephritis in a patient with
ankylosing spondylitis after 18 months of treatment with
adalimumab. Previously reported cases of sarcoid-like
reactions secondary to the use of TNF-α inhibitors involved
the liver, lung, lymph nodes, central nervous system, and
skin. Granulomatous nephritis after adalimumab treatment
has not been described. Close observation of patients
undergoing treatment with TNF inhibitors for evolving
signs and symptoms of autoimmunity is required. Organ
involvement is unpredictable, which makes correct
diagnosis and management extremely challenging.
Spine with
ankylosing spondylitis
Normal spine
Vertebra
Disk
Nerve
Syndesmophytes
(fusion of vertebrae)
HIV
Ankylosing spondylitis
Clinical Course and Outcomes of Druginduced Liver Injury: Nimesulide as the
First Implicated Medication
Licata A, et al.
Dig Liver Dis. 2010;42(2):143-148.
Severe Lactic Acidosis during
Treatment of Chronic Hepatitis
B with Entecavir in Patients
with Impaired Liver Function
Lange CM, et al.
Drug Alert
55
Hepatology. 2009;50(6):2001-2006.
Background and Aim
Drug-induced liver injury (DILI) is the most common
cause of death from acute liver failure. The clinical
presentation of DILI covers a wide spectrum, from
asymptomatic liver test abnormalities to symptomatic
acute liver disease, prolonged jaundice and disability, or
overt acute or subacute liver failure. The aim of this study
was to evaluate the number of DILI cases admitted from
1996 to 2006 and to identify the drugs responsible.
Patients and Methods
A database was constructed, reporting demographic,
clinical features at onset, laboratory results, suspected
drugs, and follow-up. Liver damage was defined as
hepatocellular, cholestatic or mixed, according to clinical
and laboratory data.
Results
Forty-six patients were admitted with a diagnosis of DILI.
Presentation was jaundice in 22 patients and hepatic
failure in 3 (all attributed to nimesulide). Liver damage was
of a cytolytic pattern in 19 cases (41%), cholestatic in 15
(33%) and mixed in 12 cases (26%). Jaundice was found to
be higher in nimesulide-induced liver damage compared
to other drugs (P = .007). Three out of 14 patients with
nimesulide-induced DILI developed encephalopathy and/
or ascites. Time of recovery in the nimesulide group was
significantly lower than DILI from other drugs (P<.001).
Conclusion
Nonsteroidal anti-inflammatory drugs, psychotropic
drugs and antimicrobials are the most common causes of
DILI. Nimesulide-induced DILI is usually reversible upon
discontinuation of the drug, but occasionally progresses to
liver failure.
NHSO2CH3
O
Abstract
Entecavir is a potent nucleoside inhibitor of
the hepatitis B virus (HBV) polymerase with
a high antiviral efficacy and a high genetic
barrier to viral resistance. After approval in
2006, knowledge on the side effect profile
in patients with advanced liver disease
and impaired liver function is still limited.
The study reports 16 patients with liver
cirrhosis and chronic hepatitis B who were
treated with entecavir. Five of these patients
developed lactic acidosis during entecavir
treatment. All patients who developed lactic
acidosis had highly impaired liver function
(model for end-stage liver disease [MELD]
score ≥20). Lactic acidosis (lactate 26-200
mg/dL, pH 7.02-7.40, base excess -5 mmol/L
to -18 mmol/L) occurred between 4 and 240
days after treatment initiation with entecavir.
Lactic acidosis was lethal in one patient but
resolved in the other cases after termination/
interruption of entecavir treatment. No
increased lactate serum concentrations were
observed during treatment with entecavir in
the other 11 patients with chronic hepatitis B
and liver cirrhosis who all had MELD scores
below 18. The MELD score correlated
with the development of lactic acidosis
(P<.005) as well as its single parameters
bilirubin, international normalized ratio, and
creatinine. In contrast, Child-Pugh Score did
not correlate with the development of lactic
acidosis. These data indicate that entecavir
should be applied cautiously in patients with
impaired liver function.
NO2
Nimesulide
55
Herbal Notes
56
Asparagus racemosus
Sanskrit name/Indian name: Shatavari; English name: Asparagus
Effect of Asparagus racemosus Rhizome (Shatavari) on Mammary Gland
and Genital Organs of Pregnant Rat
Pandey SK, et al.
Phytother Res. 2005;19(8):721-724.
Asparagus racemosus (AR) Willd (family
Liliaceae) is commonly known as Shatavari.
The alcoholic extract of its rhizome was
administered orally to adult pregnant
female albino rats at a dose of 30 mg/100 g
body weight, daily for 15 days (days 1-15
of gestation). The macroscopic findings
revealed a prominence of the mammary
glands, a dilated vaginal opening and a
transversely situated uterine horn in the
treated group of animals. The weight of the
uterine horns of the treated group was found
to be significantly higher (P<.001) but the
length was shorter (P>.01). Microscopic
examination of the treated group showed
proliferation in the lumen of the duct of
mammary gland. It was obliterated due to
hypertrophy of ductal and glandular cells.
Hyperplasia of the glandular and muscular
tissue and hypertrophy of the glandular
cells were observed in the genital organs.
The parenchyma of the genital organs
showed abundant glycogen granules with
dilated blood vessels and thickening of the
epithelial lining. The oviduct in the treated
group showed hypertrophied muscular wall,
whereas the ovary revealed no effect of the
drug. The results suggest an estrogenic effect
of Shatavari on the female mammary gland
and genital organs.
Asparagus racemosus
Herbal Notes
Valeriana wallichii
Sanskrit name/Indian name: Tagara; English name: Indian Valerian
Effectiveness of Valerian on Insomnia: A Meta-analysis of Randomized Placebocontrolled Trials
Fernández-San-Martín MI, et al.
Sleep Med. 2010;11(6):505–511.
Background
Insomnia is an often seen primary health care problem.
Valerian might be an alternative treatment with fewer
secondary effects. The aim of this study was to evaluate
its effectiveness on insomnia through a meta-analysis of
published literature.
been demonstrated with quantitative or objective
measurements. The authors recommend future
investigations oriented toward improving insomnia with
other more promising treatments.
Methods
Search for randomized clinical trials (RCTs) of Valerian
preparations compared with a placebo on Medline,
Cochrane Library, Embase, and Biosis. Outcomes:
sleep-quality improvement (SQ, yes/no), sleep-quality
improvement quantified through visual analogical scales
(SQS) and the latency time (LT) in minutes until getting to
sleep. Three meta-analyses were carried out using inversevariance weighted random effects models. Heterogeneity
was determined with the Q-statistic and was explored
through a sub-groups analysis. Publication bias was
evaluated using the funnel plot.
Valeriana wallichii
Results
The meta-analysis included 18 RCTs—eight had a score of
5 on Jadad’s scale. The mean differences in LT between
the Valerian and placebo treatment groups was 0.70 min
(95% CI, -3.44 to 4.83); the standardized mean differences
between the groups measured with SQS was -0.02 (95%
CI, -0.35 to 0.31); treatment with Valerian showed a
relative risk of SQ of 1.37 (95% CI, 1.05-1.78) compared
with the placebo group. There was heterogeneity in
three meta-analyses, but it diminished in the sub groups
analysis. No publication bias was detected.
Conclusion
The qualitative dichotomous results suggested that
valerian would be effective for a subjective improvement
of insomnia, although its effectiveness has not
57
Herbal Notes
Saussurea lappa
Sanskrit name/Indian name: Kushtha; English name: Costus
Inhibitory Effects of Sesquiterpenes from Saussurea lappa on the Overproduction of
Nitric Oxide and TNF-alpha Release in LPS-Activated Macrophages
Zhao F, et al.
J Asian Nat Prod Res. 2008;10(11-12):1045-1053.
Nitric oxide (NO), derived from L-arginine, is produced
by two types (constitutive and inducible) of nitric oxide
synthase (NOS: cNOS and iNOS). The NO produced in
large amounts by the iNOS is known to be responsible
for inflammation, vasodilation, and hypotension observed
in septic shock and cancer metastasis. Inhibitors of the
overproduction of NO, thus, may be useful candidates for
the treatment of inflammatory diseases. The authors have
found that the petroleum ether extract of Saussurea lappa
Decne, which is a wild species wildly distributed in India,
can strongly inhibit the overproduction of NO in mouse
macrophage RAW 264.7 cells. Through bioassay-guided
fractionation, 13 sesquiterpenes were isolated from the
active petroleum ether extract. Furthermore, another five
sesquiterpenes were synthesized by chemical methods.
In the present study, their effects on LPS-induced
NO production and TNF-alpha release are reported.
Compounds 1, 3, 9, 17, and 18 showed significant
inhibitory activities on the production of NO and release
of TNF-alpha with IC50 values lower than 1 micromol/L.
SAR studies suggest that the exocyclic double bond
(Delta(11(13))) is necessary for the inhibitory activities of
sesquiterpenes on the NO production.
Saussurea lappa
Herbal Notes
Achillea millefolium
Sanskrit name/Indian name: Biranjasipha; English name: Yarrow
Antiulcerogenic Activity of Hydroalcoholic Extract of Achillea millefolium L.:
Involvement of the Antioxidant System
Potrich FB, et al.
J Ethnopharmacol. 2010;130(1):85-92.
Background and Aim
Achillea millefolium L. is a member of the Asteraceae
family that is commonly referred to as “yarrow”
and has been used in folk medicine against several
disturbances including skin inflammations, spasmodic
and gastrointestinal disorders, as well as hepato-biliary
complaints. In the present study, the hydroalcoholic
extract of A millefolium (HE) was evaluated for
gastroprotective properties and additional mechanism(s)
involved in this activity.
Materials and Methods
Rats were treated with HE and subsequently exposed
to both acute gastric lesions induced by ethanol PA
and chronic gastric ulcers induced by 80% acetic acid.
Following treatment, glutathione (GSH) levels and
superoxide dismutase (SOD) activity were measured. The
activity of myeloperoxidase (MPO) and histological and
immunohistochemical analysis were performed in animals
with acetic acid-induced gastric ulcers.
Achillea millefolium
Results
Oral administration of HE (30, 100, and 300mg/kg)
inhibited ethanol-induced gastric lesions by 35%, 56%,
and 81%, respectively. Oral treatment with HE (1 and
10mg/kg) reduced the chronic gastric ulcers induced by
acetic acid by 43% and 65%, respectively, and promoted
significant regeneration of the gastric mucosa after ulcer
induction denoting increased cell proliferation, which was
confirmed by PCNA immunohistochemistry. HE treatment
prevented the reduction of GSH levels and SOD activity
after acetic acid-induced gastric lesions. In addition, HE
(10mg/kg) inhibited the MPO activity in acetic acidinduced gastric ulcers.
Conclusions
Results of the present study indicate that the antioxidant
properties of HE may contribute to the gastroprotective
activity of this extract.
59
Drug Info
60
Septilin
®
(syrup, tablet)
Builds the body’s own defense mechanism
Intro duc tion
Exts.
Septilin, a phytopharmaceutical formulation,
is recommended for the treatment and
management of various infections, and
to prevent their recurrence. Septilin’s
immunomodulatory action potentiates the
immune responses of the body. Septilin
also reduces inflammation and allergy,
and corrects the underlying pathological
features associated with recurrent infections.
Septilin is a valuable adjuvant in infection
management as it builds the body’s own
defense mechanism. When co-prescribed
with antibiotics, Septilin ensures faster
recovery and prevents recurrence. Septilin
provides excellent short- and long-term
safety.
Maharasnadi quath Composition
Each 5 mL of Septilin syrup contains:
Pdr.
Guggulu (Balsamodendron mukul)
(Purified) 80 mg
Exts.
Maharasnadi quath
30 mg
Manjishtha (Rubia cordifolia) 15 mg
Guduchi (Tinospora cordifolia) 14 mg
Trikatu
13 mg
Kushtha (Saussurea lappa) 13 mg
Amalaki (Emblica officinalis) 8 mg
Yashtimadhu (Glycyrrhiza glabra) 6 mg
Each Septilin tablet contains:
Pdrs.
Guggulu (B mukul) (Purified) Shankha bhasma
0.324 g
64 mg
130 mg
Guduchi (T cordifolia) 98 mg
Manjishtha (R cordifolia) 64 mg
Amalaki (E officinalis) 32 mg
Shigru (Moringa pterygosperma) 32 mg
Yashtimadhu (G glabra) 12 mg
Clinical Pharmacolog y
Septilin has immunomodulatory, antioxidant,
inflammatory, and antimicrobial actions.
anti-
Septilin possesses immunomodulatory and antiinflammatory
properties,
which
potentiate
the
nonspecific immune responses of the body. Septilin
decreases eosinophil and IgE levels, and thus alleviates
allergy. Septilin stimulates phagocytosis by macrophage
activation, increases the polymorphonuclear cells, and
helps overcome infection. Septilin builds up resistance to
infection and helps prevent reinfection. Septilin augments
granulocyte-macrophage differentiation, natural killer cell
activity, and antibody-dependent cytotoxicity. Septilin’s
stimulatory effect on the humoral immunity increases the
antibody-forming cells, thereby enhancing the secretion
of antibodies into circulation. Septilin also augments the
synthesis of erythropoietic and granulopoietic precursor
cells, stab cells, and primary myelocytes.
Indications
• As an immunomodulator in the management of:
-- Upper respiratory tract infections
-- Lower respiratory tract infections
-- Allergic disorders of the upper respiratory tract
-- Skin and soft tissue infections
-- Dental and periodontal infections
-- Ocular infections
-- Bone and joint infections
-- Urinary tract infections
• For early recovery in postoperative conditions
• To reduce recurrence in infection-prone individuals
Drug Info
• As an adjuvant to anti-infective therapy
• Resistance to antibiotic therapy
ß-glycyrrhetinic acid from G glabra is a potent inhibitor of
the classical complement pathway.
2. Antioxidant action
Dos age
Infants:
Syrup: 1/2 to 1 teaspoonful three times daily
Children:
Syrup: 1 to 2 teaspoonfuls three times daily
B mukul (Purified), R cordifolia, S lappa, E officinalis,
G glabra, and M pterygosperma have potent
antioxidant actions.
Tablet: 1 tablet twice daily
3. Anti-inflammatory action
Adults:
Syrup: 2 teaspoonfuls three times daily
Tablet: 2 tablets twice daily till the symptoms are relieved, followed by 1 tablet twice daily as maintenance therapy
B mukul (Purified) and S lappa have strong antiinflammatory potential.
Adverse Ef fe c ts
No adverse effects have been reported.
The anti-inflammatory activity of S lappa is due to the
stabilization of lysosomal membranes, antiproliferative
effects, and inhibition of inducible nitric oxide synthase
(iNOS).
Contraindications
G glabra and M pterygosperma have anti-inflammatory
properties.
Not recommended in early pregnancy.
4. Antimicrobial action
Drug Interac tions
T cordifolia improves the phagocytic and intracellular
bactericidal capacities of neutrophils.
No clinically significant drug interactions have been
reported.
Pre sentation
Syrup: Pilfer-proof bottles of 200 mL
Tablet: Sealed packs of 60 tablets
Pharmacological Ac tions of
Principal Ingre dients
1. Immunomodulatory action
T cordifolia has potent immunomodulatory and
immunostimulatory actions, which increase the levels of
antibodies and activate macrophages.
E officinalis enhances cell survival, increases phagocytosis
and interferon-gamma (IFN-γ) production.
Glycyrrhizan
from
G
glabra
potentiates
the
reticuloendothelial system, enhances immunostimulation,
acts on macrophage function in vitro, leading to
stimulation of macrophages de novo.
Glycyrrhizin
from
antiviral activity.
G
glabra
exhibits
potent
E officinalis has antibacterial properties, especially against
Escherichia coli, Klebsiella pneumoniae, K ozaenae,
Proteus mirabilis, Pseudomonas aeruginosa, Salmonella
typhi, S paratyphi A & B, and Serratia marcescens.
R cordifolia has antibacterial properties.
M pterygosperma possesses antibacterial and antiviral
properties, and inhibits the growth of gram-positive and
gram-negative bacteria like E coli, S typhi, and S paratyphi.
5. Other beneficial activities
T cordifolia and E officinalis possess antipyretic properties.
B mukul (Purified) is beneficial in respiratory tract
infections including chronic tonsillitis, pharyngitis, chronic
bronchitis, nasal catarrh, and laryngitis.
G glabra is an expectorant, beneficial in asthma, acute or
chronic bronchitis, and chronic cough.
61
Drug Info
Rumalaya forte
®
(tablet)
Dual advantage arthritis control
Intro duc tion
Indications
Rumalaya forte is a phytopharmaceutical formulation,
recommended for the management of all types of arthritis
and traumatic inflammatory conditions of musculoskeletal
system, such as osteoarthritis, spondylitis, rheumatoid
arthritis, arthralgia, frozen shoulder, fibrositis, bursitis,
synovitis, capsulitis, tenosynovitis, myositis, and sciatica.
Rumalaya forte offers dual advantage in arthritis control—
symptomatic relief and long-term safety. Rumalaya
forte provides relief from joint pain, swelling, early
morning stiffness, and joint immobility and improves the
quality of life. Rumalaya forte reduces degeneration of
glycosaminoglycans (GAGs), inhibits master cytokines,
and prevents cartilage damage. Rumalaya forte offers
long-term safety.
• All types of arthritis:
-- Rheumatoid arthritis
-- Osteoarthritis
-- Cervical and lumbar spondylitis
-- Gout
• Traumatic inflammatory conditions like fibrositis,
bursitis, synovitis, capsulitis, tenosynovitis, myositis,
and sciatica
• Arthralgia
• Frozen shoulder
Dos age
1 tablet twice daily. Treatment may be continued till the
symptoms are relieved.
Adverse Ef fe c ts
Composition
Each Rumalaya forte tablet contains:
Contraindications
Pdrs.
Shallaki (Boswellia serrata) 240 mg
Guggulu (Commiphora wightii) (Purified) 200 mg
Rasna (Alpinia galanga) 70 mg
Yashtimadhu (Glycyrrhiza glabra) 70 mg
Not recommended in the first trimester of pregnancy.
S pe cial Pre cautions
Pregnancy and lactation.
Drug Interac tions
reported.
Exts.
Gokshura (Tribulus terrestris) 60 mg
Guduchi (Tinospora cordifolia)
60 mg
Processed in Nirgundi (Vitex negundo) and Sunthi
(Zingiber officinale).
Rumalaya forte has potent anti-inflammatory and
analgesic, antioxidant, glycosaminoglycan-building and
cartilage-protective, and immunomodulatory actions.
The cartilage-protective action of Rumalaya forte helps in
decreasing disease progress in osteoarthritis.
Pre sentation
Box of 2 blister-pack strips of 30 tablets each.
1. Anti-inflammatory and analgesic actions
B serrata is a proven potent anti-inflammatory agent as it
inhibits leukotriene (LT) biosynthesis. 11-keto-boswellic
acids from B serrata potently prevented TNF-induced
expression and activity of matrix metalloproteinases
Drug Info
(MMP-3, MMP-10, and MMP-12), showing potent antiinflammatory properties both in vitro and in vivo.
A galanga suppresses prostaglandin synthesis through
inhibition of COX-1 and COX-2, and thus provides antiinflammatory action.
T terrestris inhibits prostaglandin E2 and COX-2 activity,
thus proving to be a potent anti-inflammatory agent.
T cordifolia protects against lipid peroxidation by its
high reactivity towards DPPH, superoxide, and hydroxyl
radicals. It decreases plasma thiobarbituric acid-reactive
substances and ceruloplasmin, along with an increase in
glutathione and ascorbic acid.
V negundo also has antioxidant action.
T cordifolia reduces IL-1 production and inhibits TNF, and
hence, is a potent anti-inflammatory agent.
Z officinale has antioxidant effect comparable to ascorbic
acid. It lowers lipid peroxidation while maintaining the
activities of other antioxidant enzymes (superoxide
dismutase, catalase, and glutathione peroxidase).
V negundo is
analgesic agent.
and
3. Glycosaminoglycan-building and cartilage-protective
actions
Z officinale is a potent inhibitor of prostaglandinbiosynthesizing enzyme (PG synthetase) and arachidonate
5-lipoxygenase (an enzyme of LT biosynthesis), and
inhibits biotransformation of arachidonic acid (AA)
comparable to indomethacin. Z officinale attenuates
COX-1/TX synthase (thromboxane synthase) enzymatic
activity, and has inhibitory effect on COX-2 enzymes.
COX-1 and 2 (regulated by the eukaryotic transcription
factor NF-kappa B) are recognized as molecular targets
for actions of Z officinale. Gingerol in Z officinale acts
by interfering with intracellular signaling cascades, those
involving NF-kappa B and mitogen-activated protein
kinases. Z officinale significantly inhibits prostaglandin
E2 production.
Boswellic acids in B serrata lessen the degree of
degradation of glycosaminoglycans (GAGs), and play an
essential role in cartilage-protective action.
The activation of macrophages by T cordifolia leads to an
increase in granulocyte–macrophage colony-stimulating
factor (GM-CSF), which leads to leukocytosis and
improved neutrophil function.
a
strong
anti-inflammatory
C wightii (Purified) causes inhibition of nitric oxide (NO)
formation, and has a scavenging effect on 2,2-diphenyl-1picryl-hydrazyl (DPPH) radicals.
A galanga inhibits lipid peroxidation.
Glabridin from G glabra has potent antioxidant activity.
4. Immunomodulatory action
B serrata has a strong immunomodulatory activity.
A galanga stimulates the reticuloendothelial system.
G glabra stimulates macrophages de novo, and inhibits the
classical complement pathway.
T cordifolia reduces chemotactic activity of macrophages
and protects against myelosuppression, with an increase
in white blood cells (WBCs) and antibody titers.
T
cordifolia
immunosuppression.
reverses
chemically-induced
Z officinale has immunomodulatory actions—it raises the
thymus and spleen indices, phagocytosis, rate of alphanaphthyl acetate esterase, and titer of IgM.
63
Drug Info
Liv.52
®
(drops, syrup, DS syrup, tablet, DS tablet)
Unparalleled in liver care
Intro duc tion
Each 5 mL of Liv.52 syrup contains:
Liv.52 is a hepatospecific formulation, designed for the
treatment and management of liver disorders.
Exts.
Himsra (C spinosa)
34 mg
Liv.52 has a wide spectrum of therapeutic applications.
Liv.52 restores the metabolic efficiency of the liver,
minimizes damage to the hepatic parenchyma, and
accelerates the rate of recovery in various liver disorders
like infective hepatitis, drug-induced (ATT-and statininduced) hepatitis, and alcohol-induced hepatic
damage. Liv.52 is a valuable adjuvant during prolonged
illness. In anorexia, Liv.52 improves appetite, digestion,
and assimilation.
Kasani (C intybus)
34 mg
Kakamachi (S nigrum)
16 mg
Arjuna (T arjuna)
16 mg
Liv.52 is one of the world’s most enduring phytomedicines,
accredited with more than 250 studies, and is available in
a wide range of dosage forms to suit patient requirements
from infancy to old age.
Kasamarda (C occidentalis)
8 mg
Biranjasipha (A millefolium)
8 mg
Jhavuka (T gallica)
8 mg
Processed in Bhringaraja (E alba), Bhumyaamalaki
(P amarus), Punarnava (B diffusa), Guduchi (T cordifolia),
Daruharidra (B aristata), Mulaka (R sativus), Amalaki
(E officinalis), Chitraka (P zeylanica), Vidanga (E ribes),
Haritaki (T chebula), and Parpata (F officinalis).
Each Liv.52 tablet contains:
Liv.52 is safe even for long-term use.
Pdrs.
Composition
Himsra (C spinosa)
65 mg
Each mL of Liv.52 drops contains:
Kasani (C intybus)
65 mg
Exts.
Mandura bhasma
33 mg
32 mg
Arjuna (T arjuna)
32 mg
16 mg
16 mg
Jhavuka (T gallica)
16 mg
Himsra (Capparis spinosa)
17 mg
Kasani (Cichorium intybus)
17 mg
Kakamachi (Solanum nigrum)
8 mg
Arjuna (Terminalia arjuna)
8 mg
Kasamarda (Cassia occidentalis)
4 mg
Biranjasipha (Achillea millefolium)
4 mg
Jhavuka (Tamarix gallica)
4 mg
Processed in Bhringaraja (Eclipta alba), Bhumyaamalaki
(Phyllanthus amarus), Punarnava (Boerhaavia diffusa),
Guduchi (Tinospora cordifolia), Daruharidra (Berberis
aristata), Mulaka (Raphanus sativus), Amalaki (Emblica
officinalis), Chitraka (Plumbago zeylanica), Vidanga
(Embelia ribes), Haritaki (Terminalia chebula), and Parpata
(Fumaria officinalis).
Each 5 mL of Liv.52 DS syrup contains:
Exts.
Himsra (C spinosa)
68 mg
Kasani (C intybus)
68 mg
Drug Info
32 mg
Arjuna (T arjuna)
32 mg
16 mg
16 mg
Jhavuka (T gallica)
16 mg
Liv.52 diminishes the lipotropic activity in chronic
alcoholism, and prevents fatty infiltration of the liver.
In precirrhotic conditions, Liv.52 arrests the progress of
the disease and prevents further liver damage.
In anorexia and suboptimal growth, Liv.52 normalizes
the basic appetite–satiety rhythm. Liv.52 helps overcome
anorexia during pregnancy. As a daily health supplement,
Liv.52 improves appetite, digestion and assimilation
processes, and promotes weight gain.
Indications
• For the prevention and treatment of:
-- Viral hepatitis
-- Alcoholic liver disease
-- Precirrhotic conditions and early cirrhosis
-- Anorexia/Loss of appetite
-- Liver damage due to radiation therapy
• Liver disorders including fatty liver associated with
protein–energy malnutrition
• Jaundice and anorexia during pregnancy
• A valuable adjuvant during prolonged illness and
convalescence
• As a supportive treatment during hemodialysis
• As an adjuvant to hepatotoxic drugs like
antitubercular drugs, statins, chemotherapeutic
agents, and antiretrovirals
Each Liv.52 DS tablet contains:
Pdrs.
Himsra (C spinosa)
130 mg
Kasani (C intybus)
130 mg
Mandura bhasma
66 mg
64 mg
Arjuna (T arjuna)
64 mg
32 mg
32 mg
Jhavuka (T gallica)
32 mg
(Phyllanthus amarus), Punarnava (B diffusa), Guduchi (T
cordifolia), Daruharidra (B aristata), Mulaka (R sativus),
Amalaki (E officinalis), Chitraka (P zeylanica), Vidanga
(E ribes), Haritaki (T chebula), and Parpata (F officinalis).
Liv.52 has hepatoprotective, antioxidant, antimicrobial,
antiviral, and anti-inflammatory actions.
Liv.52 restores the metabolic efficiency of the liver
by protecting the hepatic parenchyma and promoting
hepatocellular regeneration.
The antiperoxidative activity of Liv.52 prevents the loss
of functional integrity of cell membranes, maintains
cytochrome P450 enzyme system, shortens the disease
recovery period, and ensures early restoration of hepatic
functions in infective hepatitis.
Liv.52 offers protection against alcohol-induced hepatic
damage by facilitating a rapid elimination of acetaldehyde,
the toxic intermediate metabolite of alcohol metabolism.
Dos age
Acute viral hepatitis:
Drops
Syrup
Tablet
Infants: 5 to 10 TID
–
–
Children: 10 to 20 TID
5 mL TID
1 TID
–
10 mL TID
2 TID
Adults: Alcohol-induced liver damage:
Syrup: 10 to 15 mL TID
Tablet: Two to three tablets TID
Anorexia and suboptimal growth:
Drops
Syrup
Tablet
Infants: 5 to 10 TID
–
–
Children: 10 to 20 TID
5 mL BID/TID
1 TID
–
10 mL BID/TID
2 TID
Adults: PROBE • Vol. L • No. 3 • Apr–Jun 2011
65
Drug Info
Drug-induced hepatitis:
DS syrup/DS tablet: One to two teaspoonfuls/tablets
BID with anti-TB/ statin/ chemotherapy/ antiretroviral
treatment.
Jaundice and anorexia during pregnancy:
DS syrup/DS tablet: One teaspoonful/tablet BID for eight
weeks.
Chronic active hepatitis:
DS syrup/DS tablet: Two teaspoonfuls/tablets BID for
six months.
Early cirrhotic conditions:
DS syrup/DS tablet: One teaspoonful/tablet TID for 6 to
12 months.
As a supportive treatment during hemodialysis:
DS syrup/DS tablet: One teaspoonful/tablet BID for three
to four months.
As an adjuvant to anticancer drugs:
hepatotoxicity, and prevents elevation of malondialdehyde
levels (plasma and hepatic) and enzyme levels (AST
and ALT). C spinosa is a hepatic stimulant that improves
the functional efficiency of the liver and spleen, with
protective action on the histological architecture of
the liver, and a salutary effect on liver glycogen and
serum proteins.
C intybus protects the liver against alcohol toxicity. It
increases circulating leukocytes, splenic plaque-forming
cells, hemagglutination titers, secondary IgG antibody
response, phagocytic activity, natural killer cell activity,
cell proliferation, and interferon-gamma secretion. The
hepatoprotective activity of C intybus suppresses the
oxidative degradation of DNA in tissue debris.
S nigrum has hepatoprotective activity against chemicallyinduced hepatic damage. It decreases the elevated LFT
biochemical parameters (AST, ALT, ALP, and TB), and
increases the activities of aminopyrine N-demethylase,
uridine diphosphate, glucuronyl transferase, and
glutathione S-transferase.
DS syrup/DS tablet: One teaspoonful/tablet BID for
four months.
C occidentalis has significant hepatoprotective effects in
chemically-induced liver damage. It modulates hepatic
enzymes and provides hepatoprotection.
Adverse Ef fe c ts
A millefolium is beneficial in chronic hepatitis,
chronic hepatocholecystitis, and angiocholitis, and has
antihepatoma activity.
Contraindications
No absolute contraindications.
Drug Interac tions
reported with Liv.52.
Pre sentation
Drops: Pilfer-proof bottles of 60 mL and 120 mL.
Syrup: Pilfer-proof bottles of 100 mL and 200 mL.
Tablet: Sealed packs of 100 tablets.
DS syrup: Pilfer-proof bottles of 100 mL.
DS tablet: Sealed packs of 60 tablets.
1. Hepatoprotective action
P-methoxy benzoic acid from C spinosa has potent
hepatoprotective activity against chemically-induced
Mandura bhasma has hepatoprotective property, and
is beneficial in chemically-induced hepatotoxicity as it
prevents changes in liver enzyme activities.
T arjuna reduces cholesterol levels, and is also useful in
liver disorders.
T gallica is a hepatic stimulant, digestive, and
hepatoprotective, and has a salutary effect on liver
glycogen and serum proteins.
Apigenin, luteolin, 4-hydroxybenzoic acid, and
protocateuic acid are constituents from E alba, which
exhibit maximum hepatoprotective activity.
P amarus is antiviral against hepatitis B and C viruses, and
has hepatoprotective and immunomodulating activities.
B diffusa has hepatoprotective activity, and produces
an increase in normal bile flow, suggesting strong
choleretic activity.
T cordifolia has well-known hepatoprotective and
immunostimulatory functions, and improves appetite.
B aristata has antihepatotoxic action through its inhibitory
effect on microsomal drug metabolizing enzymes and
Drug Info
cytochrome P450s. It maintains serum levels of alkaline
phosphatase ALP and aminotransaminases (AST and ALT)
at normalcy, which is suggestive of hepatoprotection, and
helpful in various forms of jaundice.
3. Antimicrobial action
T chebula has hepatoprotective activity against
antitubercular drug-induced toxicity due to its
antioxidative and membrane-stabilizing activities.
T arjuna has potent antibacterial activity.
F officinalis pacifies colicky pain affecting the gallbladder,
biliary system, and the GI tract.
Flavonoids of C spinosa have significant antioxidant
activity, as demonstrated by lipid peroxidation, bleaching
of free radicals, and autoxidation of iron ions.
C intybus has potent antioxidant action, as evident by its
free radical scavenging effects, and inhibition of hydrogen
peroxide and iron chelation.
The hepatoprotective activity of C intybus suppresses the
oxidative degradation of DNA in tissue debris.
C
intybus
and
A
antimicrobial activity.
millefolium
have
potent
C occidentalis has antimicrobial properties comparable to
those of standard reference antibiotics.
C spinosa has potent antibacterial action against grampositive and gram-negative bacteria.
4. Antiviral action
T arjuna has strong antiviral activity, inhibiting viral
attachment and penetration.
5. Anti-inflammatory action
C spinosa has anti-inflammatory activity comparable to
that of oxyphenbutazone.
E alba has anti-inflammatory action.
S nigrum protects DNA against oxidative damage, and
also acts as a potent scavenger of hydroxyl and diphenyl
picrylhydrazyl radicals. The cytoprotective effect of
S nigrum against gentamicin-induced toxicity showed a
significant inhibition of cytotoxicity, and hydroxyl radical
scavenging potential.
The anti-inflammatory properties of B diffusa are useful
in jaundice and ascites that usually happen due to early
cirrhosis of liver and chronic peritonitis.
T arjuna has potent antioxidant activity, which is due to
its effect on lipid peroxidation. Arjunaphthanoloside
from T arjuna inhibits nitric oxide (NO) production, and
terminoside A decreases inducible NO synthase levels in
lipopolysaccharide-stimulated peritoneal macrophages.
T cordifolia is an immunomodulator.
A millefolium has antioxidant activities.
6. Other beneficial action
Mandura bhasma is a powerful hematinic and tonic.
R sativus is a laxative, tonic and carminative, and helpful
in jaundice.
T chebula is a tonic and carminative, useful in jaundice,
constipation, and rejuvenation.
67
Patient Education
68
Does Your Child Fall
Sick Often?
Increase your child’s immunity
Why do infants or children fall
sick often?
Some infants who are
born with defective
immunity
(breast
feeding
builds
immunity in children)
and young children
who are constantly exposed to infections
through interaction with other children in
school may fall sick often.
Normally, infections by bacteria and viruses
in the body are kept under control by the
immune system. Antibodies present in the
body are capable of fighting all of them
successfully. But when immune resistance
is low, these organisms multiply rapidly and
cause illness like common cold, fever, etc.
What kind of diet can boost a child’s
immunity?
The optimum diet for the best immune
function can be defined in three words—
balance, variety, and
moderation.
Balance - foods should
be included from all food
groups including fruit,
vegetable, cereal, grain,
dairy product, and meat.
Variety - within each food group, a variety
should be consumed (eg, different kinds of
fruits and vegetables).
Moderation - neither too little nor too much
is good for the immune system.
What factors affect a child’s immune
system?
Some common factors • Stress (physical
or emotional)
- especially
in the school
environment,
children are stressed by class discipline, exams,
homework, peer pressure and sports performance
• Stress at home and inadequate sleep can take a toll
on your child’s immune system, leaving them more
vulnerable to colds.
• Lack of physical exercise (children who hardly play
outside).
• Irregular meals or improper diet.
Do’s and Don’ts for boosting a child’s immunity
Do’s
Good nutrition is an important factor in staying healthy.
• Provide food rich in vitamin C (oranges, grapes,
pineapple, etc.), vitamin A (eggs,
milk, cereals, etc.) and vitamin
E (apple, apricots, pumpkin,
chicken, vegetable oils, etc.).
These vitamins are particularly
beneficial for the immune system.
• Your child must drink plenty of
water/fluids daily and more in
summer.
• Have your children wash their
hands several times a day - teach
your children to wash their hands
thoroughly and have them do so
often throughout the day, especially
before eating and after using the
bathroom. Hand sanitizers (PureHands) are very
effective, as they prevent handtransmitted infections.
• Ensure children get enough sleep
• Make sure your child gets plenty
of fresh air and exercise through
outdoor games.
Patient Education
Does the child need antibiotics to treat
common cold that occurs often?
Don’ts
•
Avoid letting your children share
cups - germs can hang around on
drinking glasses
•
Don’t let them share food or
utensils with other kids
Children fall ill due to low immunity. Boost your child’s
immunity through natural methods. Antibiotics are
powerful medications. They are to be used only when
prescribed by a doctor.
•
When your child is ill, avoid all
sugary foods and drinks - sugar is
the worst culprit for suppressing
the immune system
Your doctor will know best for your child’s treatment. Do
not self-medicate your child. Antibiotics may kill many
bacteria, but not viruses (which cause many respiratory
tract infections).
•
Limit TV viewing. Encourage them
to play outdoors instead.
If your child has a viral infection, antibiotics will not
cure it.
Order for
FREE
reprints of
this article
Dear Doctor,
We hope you found this article useful for your patients. You can order for FREE
reprints of this article (25, 50, 75, or 100 nos.), by using the tear-out card enclosed in
this issue, and use them as patient information leaflets in your clinic.
– Editor
69
TechBytes
70
Nucleic Acid Testing to Detect
HBV Infection in Blood Donors
Stramer SL, et al.
N Engl J Med. 2011;364(3):236-247.
The authors performed nucleic acid testing
on 3.7 million blood donations and further
evaluated those that were HBV DNA-positive
but negative for HBsAg and anti-HBc. They
determined the serologic, biochemical,
and molecular features of samples that
were found to contain only HBV DNA and
performed similar analyses of follow-up
samples and samples from sexual partners
of infected donors. Seronegative HIV and
HCV-positive donors were also studied.
The authors identified 9 donors who
were positive for HBV DNA (1 in 410,540
donations), including 6 samples from donors
who had received the HBV vaccine, in
whom subclinical infection had developed
and resolved. Of the HBV DNA-positive
donors, 4 probably acquired HBV infection
from a chronically infected sexual partner.
Clinically significant liver injury developed in 2
unvaccinated donors. In 5 of the 6 vaccinated
donors, a non-A genotype was identified as
the dominant strain, whereas subgenotype
A2 (represented in the HBV vaccine) was the
dominant strain in unvaccinated donors. Of 75
reactive nucleic acid test results identified in
seronegative blood donations, 26 (9 HBV, 15
HCV, and 2 HIV) were confirmed as positive.
Triplex nucleic acid testing detected
potentially infectious HBV, along with HIV
and HCV, during the window period before
seroconversion. HBV vaccination appeared
to be protective, with a breakthrough
subclinical infection occurring with non-A2
HBV subgenotypes and causing clinically
inconsequential outcomes.
Evaluation of a New, Rapid Test for
Detecting HCV Infection, Suitable for
Use With Blood or Oral Fluid
Lee SR, et al.
J Virol Methods. 2010.
The availability of a highly accurate, rapid, pointof-care test for hepatitis C virus (HCV) may be useful in
addressing the problem of under-diagnosis of HCV, by
increasing opportunities for testing outside of traditional
clinical settings. A new HCV rapid test device (OraQuick®
HCV Rapid Antibody Test), approved recently in Europe
for use with venous blood, fingerstick blood, serum,
plasma, or oral fluid was evaluated in a multicenter study
and performance compared to established laboratorybased tests for detection of HCV. The HCV rapid test
was evaluated in prospective testing of subjects with
signs and/or symptoms of hepatitis, or who were at risk
for hepatitis C using all 5 specimen types. Performance
was assessed relative to HCV serostatus established
by laboratory methods (enzyme immune assay [EIA]),
recombinant immunoblot assay, and polymerase chain
reaction) approved in Europe for diagnosis of hepatitis C
infection. Sensitivity to antibody in early infection was
also compared to EIA in 27 seroconversion panels. In
addition, the reliability of the oral fluid sample for accurate
detection of anti-HCV was assessed by studying the
impact of various potentially interfering conditions of oral
health, use of oral care products, and consumption of food
and drink. In this large study of at-risk and symptomatic
persons, the overall specificities of the OraQuick® were
equivalent (99.6%-99.9%) for all 5 specimen types and
the 95% CIs substantially overlapped. Overall sensitivities
were virtually identical for venous blood, fingerstick
blood, serum, and plasma (99.7%–99.9%). Observed
sensitivity was slightly lower for oral fluid at 98.1%
though the upper CI (99.0%) was equal to the lower CI
for venous blood and fingerstick blood. Most of the HCV
positive subjects which gave nonreactive results in oral
fluid had serological and virological results consistent
with resolved infection. Sensitivity for anti-HCV in early
seroconversion was virtually identical between the HCV
rapid test and EIA. Detection of anti-HCV in oral fluid
appeared generally robust to conditions of oral health,
consumption of food and drink and use of oral care
products. The OraQuick® HCV Rapid Antibody Test
demonstrated clinical performance that was equivalent to
current laboratory-based EIA.
Safety and Efficacy of Oral HD-03/ES* Given For
Six Months in Patients with Chronic Hepatitis B
Virus Infection
Rajkumar JS, et al.
Lifeline Rigid Hospitals, Chennai, Tamilnadu, India
World J Gastroenterol. 2007;13(30):4103-4107.
ABSTRACT
Aim
To investigate the safety and efficacy of the formulation
HD-03/ES capsules in the management of patients with
chronic hepatitis B infection.
Methods
A total of 25 patients were recruited to the study and
were given HD-03/ES, two capsules twice daily for six
months. Clinical assessment of symptoms and signs
were done using the “clinical observation table” once
a month before and after the treatment. Biochemical
investigations of total bilirubin, alanine transaminase
(ALT), aspartate aminotransferase (AST), and serum
protein for liver function tests were done every month
after initiating treatment. Serum was analyzed for HBV
markers for HBsAg, HbeAg, and HBV DNA at baseline
and 4 and 6 months after therapy using enzyme linked
immunosorbent assay (ELISA) kits from Roche.
Results
After 6 months of therapy with HD-03/ES, a significant
reduction in ALT values from 66.5 ± 11.1 to 39.1 ± 5.2
(P<.01) and a significant HBsAg loss (52%, P<.001),
HBeAg loss (60%, P<.05) and HBV DNA loss (60%,
P<.05) was observed. Adverse effects were mild and
never warranted withdrawal of the drug.
Conclusion
The results of this pilot study indicate that HD-03/
ES might be a safe and effective treatment for chronic
hepatitis B infection and a long-term multicentric
comparator trial is warranted and under way.
Key Words
HD-03/ES, chronic hepatitis B, liver function tests,
hepatitis B virus markers, clinical trial, HBsAg, HBeAg
Intro duc tion
Liv.52 Update
71
Hepatitis B virus (HBV) is a hepadnavirus
that is noncytopathic and causes significant
morbidity and mortality worldwide.1 Chronic
hepatitis B (CHB) affects an estimated 400
million people worldwide with over 50,000
fatalities each year.2 About 82% of the
world’s 530,000 cases of liver cancer per
year are caused by viral hepatitis infection,
with 316,000 cases associated with
hepatitis B infection.3 According to a WHO
report, India has intermediate endemicity of
hepatitis B, with hepatitis B surface antigen
(HBsAg) prevalence between 2% and 7%
among populations studied. The prevalence
does not vary significantly by region in the
country. The number of HBsAg carriers
in India has been estimated to be over 40
million (4 crore). It has been estimated that,
in India, of the 25 million infants born every
year, over one million run the lifetime risk
of developing chronic HBV infection. Every
year more than 100,000 people in India die
due to illnesses related to HBV infection.
Ayurveda, an indigenous system of medicine
in India, has a long tradition of treating liver
disorders with plant drugs.4 On the basis
of leads available from folklore usage and
recent experimental studies, HD-03/ES (a
capsule formulation consisting of 125 mg
each of hydroalcoholic extracts of the herbs
Cyperus rotundus and Cyperus scariosus) was
evolved to elicit hepatoprotective activity.
Surface antigen suppression and HBV
elimination activities of herbal extract
containing C rotundus and C scariosus were
examined using two HBsAg expressing
human hepatocellular carcinoma cell
*HD-03/ES is marketed as Liv.52 HB
71
Liv.52 Update
lines, PLC/PRF/5 and HepG2.2.215 polymerase chain
reaction (PCR) for the study of amplification of DNA
specific to HBV, reverse transcriptase inhibition assay,
immunomodulatory effects and hepatoprotective ability
against oxidative damage to hepatocytes were some of
the other studies performed to evaluate the efficacy of the
plant extract. The efficacy of the plant extract to eliminate
the duck hepatitis B virus was assessed in experimentally
infected Pekin ducks in a duck model study. Investigations
indicated that the extracts could reversibly inhibit cell
growth and suppress HBsAg expression in both of the
human hepatocellular carcinoma cell line models. Acute
and sub-acute toxicity studies conducted in rats indicated
that HD-03/ES is devoid of significant toxicity following
acute and repeated administration in rats.
A preliminary case study report indicated that there was
significant reduction of HBsAg along with disappearance
of viral DNA in a patient treated with HD-03/ES at a
dosage of two capsules twice daily for a period of six
months.5 At the moment, there is no data to show whether
HD-03/ES treatment is adequate for the treatment of HBV
infection. Therefore, this clinical study was conducted to
evaluate the safety and efficacy of HD-03/ES in patients
with chronic hepatitis B infection.
Patients
An open prospective controlled clinical trial was carried
out in the Department of Gastroenterology, Lifeline Rigid
Hospitals, Chennai, Tamilnadu, India, between March
2005 and June 2006 to evaluate the safety and efficacy
of HD-03/ES capsules alone in the management of
chronic hepatitis B infection. Informed written consent
was obtained from all study participants and the protocol
of the study was approved by the ethical committee
of the institute. The study in general was conducted
in accordance with Declaration of Helsinki and GCP
Guidelines issued by the Ministry of Health, Government
of India.
Liv.52 HB in chronic hepatitis B
Criteria for enrollment
Patients, aged 18 to 60 years, with their serum alanine
aminotransferase (ALT) level being 41 to 200 IU/L and
who had positive serum HBsAg, were enrolled.
Criteria for exclusion
Patients who were more than 60 years or less than 18
years of age, pregnant or lactating women, patients
who had hepatitis C or other hepatic viral infection,
autoimmune hepatitis and drug-induced hepatitis or
alcoholic hepatitis; patients with severe complications
of cardiovascular, renal or hematopoietic system; and
patients with mental disorders were excluded. Patients
were excluded if they had decompensated liver disease
(defined by serum albumin ≤360 g/L, bilirubin ≥150
g/L, prothrombin time ≥2 s prolonged, or a history of
ascites, variceal hemorrhage or hepatic encephalopathy),
pancytopenia (defined as hemoglobin <110 g/L, white
cell count <4000/mm3 or platelets <105/mm3). Patients
with a history of using interferon or antiviral agents
or corticosteroids or immunosuppressive drugs were
also excluded.
Treatment
Each patient was asked to take two capsules of HD-03/
ES (The Himalaya Drug Company, Bangalore, India) twice
daily, two capsules in the morning and two capsules at
bedtime after food for a period of six months.
Recording and observation of symptoms
and signs
The symptoms and signs of patients were recorded in
detail using the “Clinical Observation Table” once a
month before and during the treatment.
Etiological markers of hepatitis B
Serum samples collected from patients were stored at
-20oC until analysis. Serum was assayed for HBsAg,
hepatitis B e-antigen (HBeAg), and HBV DNA at baseline,
four and six months after therapy using commercially
available enzyme-linked immunosorbent assay kits from
Roche.
Diagnostic criteria
Liver function
Patients with a history of hepatitis B or HBsAg carriers for
at least 6 months, who still had symptoms and signs of
hepatitis as well as abnormal liver function and positive
HBsAg, were diagnosed as having CHB infection in the
present study.
The patients had liver function examinations every month
during the treatment, including contents of serum proteins,
total bilirubin (TB), and activities of ALT and aspartate
aminotransferase (AST).
Liv.52 Update
Safety analysis
Safety analysis included data for all treated patients during
dosing. The primary safety end point was discontinuation
of study medication because of adverse events. Other
safety evaluations included incidence of adverse effects.
End points
The primary end point was HBsAg clearance. Secondary
end points included HBV DNA levels and ALT
normalization to 40 IU/L at the end of treatment.
Table 1. Demographic Data
Characteristic
Mean (SD)
Median (range)
Sex
Male
Female
Body weight (kg)
Mean (SD)
HD-03/ES
33.7 (6.6)
36 (20-45)
22
3
56 (10)
Age (years)
Table 2. Effect of Six Months Treatment with HD-03/ES on
Liver Function Tests
Parameter
Day 0
(Mean ±
SD)
Four
months
(Mean
± SD)
Six
months
(Mean ±
SD)
66.5 ±
11.1
41.6 ±
05.1
39.1 ±
05.2
47.5 ±
9.5
42.4 ±
10.7
40.2 ±
10.1
3.5 ±
0.8
2.9 ±
0.3
6.2 ±
0.7
1.3 ±
0.6
3.5 ±
0.7
3.1 ±
0.2
6.5 ±
0.7
1.2 ±
0.5
3.6 ±
0.7
3.2 ±
0.2
6.5 ±
0.7
155.5 ±
9.8
140.2 ±
9.0
The intention-to-treat analysis included all randomized
patients who were HBsAg-positive at baseline and
received at least one dose of the study medication.
Data were expressed as mean ± SD. One-way ANOVA
with Bonferroni’s multiple comparison test or Dunnett’s
multiple comparison test was performed wherever
appropriate using GraphPad Prism version 4.00 for
Windows, GraphPad Software, San Diego California USA.
A P value of <0.05 was taken as statistically significant.
Alanine
aminotransferase
(ALT) (IU/L)
Aspartate
aminotransferase
(AST) (IU/L)
Serum albumin
(g%)
Serum globulin
(g%)
Re sults
Total protein (g%)
Twenty five patients (22 males and 3 females) aged
between 20 and 45 years with a mean age of 33.7
years participated in this open study. Their baseline
characteristics are shown in Table 1.
Serum bilirubin
(mg%)
Alkaline
phosphatase
(IU/L)
Clinical response
Table 3. Biochemical and Serological Response to 6 Months
of HD-03/ES Therapy
Six months of therapy with HD-03/ES capsules was
markedly effective in majority of the patients as it resulted
in disappearance or alleviation of chief clinical symptoms
such as abdominal pain and poor appetite. The effect of
six months of treatment with HD-03/ES on liver function
tests are shown in Table 2. As shown in the table, there
was a trend toward normalization of liver function tests in
all patients treated with HD-03/ES.
ALT normalization
Levels of ALT before and after six months of treatment
with HD-03/ES are shown in Table 3. After six months of
treatment, the levels of ALT were decreased from initial
value of 66.5 ± 11.1 to 39.1 ± 5.2, and this reached levels
of statistical significance (P<.01). In 14 of the 25 patients
(56%), ALT levels were normalized. Although ALT levels
were not normalized in the remaining 11 patients, there
was a trend toward reduction and in none of the patients
there was a rise in ALT levels (Figure 1).
127.0 ±
7.5
Four months
HD-03/ES
(No. of patients)
32
Six months
56
Variable
ALT
normalization
(%)
1.1 ± 0.5
d0
HBsAg
Four months
Six months
D0
HBeAg
Four months
Six months
D0
HBV DNA
Four months
Six months
a
P<.05; vs D 0; bP<.001 vs D 0
Positive
25
19
12
16
11
10
16
11
10
Negative
0
6
13b
9
14
15a
9
14
15a
73
Liv.52 Update
Figure 1. Improvement in ALT normalization after treatment
with HD-03/ES.
Figure 3. Improvement in HBeAg loss after treatment with
HD-03/ES.
Figure 2. Improvement in HBsAg loss after treatment with
HD-03/ES.
Figure 4. Improvement in HBV DNA loss after treatment with
HD-03/ES.
Virological response
Table 4. List of Adverse Effects
The effect of 6 months of treatment with HD-03/ES on
virological response is shown in Table 3. Thirteen of
the 25 patients (52%) at the end of treatment, who were
treated with HD‑03/ES, had undetectable HBsAg. This
difference was statistically significant (P<.001) (Figure
2). HBeAg loss (60%, P<.001) and HBV DNA loss (60%,
P<.05) also occurred during treatment with HD-03/ES in
those 6 patients who were positive for both HBeAg and
HBV DNA initially, but were negative for the same at the
end of therapy (Figures 3 and 4).
Adverse effect
Abdominal discomfort
Fatigue
Headache
Insomnia
Adverse events
HD-03/ES was well tolerated in this study. No patient
was withdrawn from therapy either for adverse effects or
for other reasons. The adverse events observed during
therapy are shown in Table 4. Most of the observed sideeffects were mild (fatigue, headache, and insomnia) in
nature. The most common adverse event was abdominal
discomfort. No serious biochemical abnormalities were
experienced by any patient.
HD-03/ES
3
2
1
1
Discussion
High morbidity and mortality have been found in Asia
among HBsAg-positive patients, even in the absence
of overt liver disease.6,7 The goals of treatment in CHB
infection are sustained viral suppression, normalization
of ALT levels, and improvement in liver histology
leading to long-term reduction in the risk of cirrhosis
and hepatocellular carcinoma.8 Loss of HBsAg, HbeAg,
and normalization of ALT levels and improvement in
liver histology are the usual short-term end points of
therapy.9 The results of this preliminary study indicated
that short-term therapy with HD-03/ES is effective in
the management of CHB. Although the initial results of
this study are promising, it remains to be seen whether
virological response will be sustained during chronic
Liv.52 Update
dosing and whether relapse rates after cessation of therapy
would be low unlike conventional therapies whose relapse
rates are high after treatment cessation.10
Although the initial results of this study are promising, it
The ultimate endpoint of antiviral therapy for CHB
infection is loss of HBsAg, which is accompanied by
disease remission in terms of ALT normalization.11 In
this study, HBsAg loss was observed in 52% of the
patients after 6 months of therapy with HD-03/ES. This
is in contrast to several clinical trials of lamivudine or
adefovir where HBsAg loss was not reported12,13 or tends
to occur later than 24 weeks as with interferon therapy.14
Although six months of therapy is limited and not capable
of inducing pronounced viral suppression, five patients
lost their HBV DNA after six months of therapy, which is
highly encouraging.
rates after cessation of therapy would be low unlike
Loss of HBeAg either spontaneously or following therapy
significantly improves the clinical outcome and survival
in chronic HBV patients. Therefore, HBeAg loss has
remained as a major end point of antiviral therapy in
chronic HBV infection. Monotherapy with alpha interferon
for 16 to 26 weeks is associated with loss of serum HBeAg
in 20% to 40% of the patients.15 These results (55%) are
slightly better.
The possible mechanisms of action as studied using
HBsAg expressing human hepatocellular carcinoma
cell lines PLC/PRF/5 and HepG2.2.2.15 indicate to
HBsAg suppression by binding to the antigen, and
HBV elimination by reverse transcriptase inhibition.
Immunomodulatory effects occur by causing the release
of nitric oxide (NO) by macrophages and cytokines such
as TNF-a. It was found to have an hepatoprotective effect
by reversing the oxidative damage caused by hepatocytes.
A strong correlation was found between HBV DNA levels
and histology activity index scores in HBeAg negative
patients.16 As ALT levels are consistent with histological
activity index scores, the findings in the present study of
ALT normalization, HBsAg loss together with loss of DNA
during short-term treatment with HD-03/ES indicated that
patients treated with HD-03/ES may lose their infectivity
faster and relapse rates would be low.
remains to be seen whether virological response will be
sustained during chronic dosing and whether relapse
conventional therapies whose relapse rates are high after
treatment cessation.17 This study has several obvious
limitations including the small sample size.
In summary, this trial demonstrated that 24 weeks of
HD-03/ES treatment resulted in clinically significant
virological and biochemical benefits in patients with
CHB infection. Hence to conclude the potential benefit of
HD-03/ES in the management of CHB, HD-03/ES should
be studied in long-term comparative trials with standard
drugs with extended duration of follow-up.
Reference s
1. Asmuth DM, et al. Clin Infect Dis. 2004;39:1353-1362.
2. Lim SG, et al. Arch Intern Med. 2006;166:49-56.
3. Lai CL, et al. Lancet. 2003;362:2089-2094.
4. De S, et al. Ind Drugs. 1993;30:355-363.
5. Kulkarni KS, et al. Med Update. 2002;7:61-63.
6. Beasley RP. Cancer. 1988;61:1942-1956.
7. Sakuma K, et al. Gastroenterol. 1982;83:114-117.
8. Jacobson IM. Am J Gastroenterol. 2006;101(Suppl 1):S13-S18.
9. Yuen MF, Lai CL. J Antimicrob Chemother. 2003;51:481-485.
10. Marcellin P, et al. N Engl J Med. 2004;351:1206-1217.
11. Flink HJ, et al. Am J Gastroenterol. 2006;101:297-303.
12. Hadziyannis SJ, et al. Hepatology. 2000;32:847-851.
13. Santantonio T, et al. J Hepatol. 2000;32:300-306.
14. Brunetto MR, et al. J Hepatol. 2002;36:263-270.
15. van Nunen AB, et al. Gut. 2003;52:420-424.
16. Peng J, et al. Chin Med J (Engl). 2003;116:1312-1317.
17. Marcellin P, et al. N Engl J Med. 2003;348:808-816.
75
Wordsmith
76
Musculoskeletal Disorders of Spine
Ankylosing spondylitis, a type of arthritis
of the spine, is a systemic disorder
characterized by inflammation of the
axial skeleton, large peripheral joints, and
digits; nocturnal back pain; back stiffness;
accentuated
kyphosis;
constitutional
symptoms; aortitis; cardiac conduction
abnormalities; and anterior uveitis. The
most common symptom is back pain, but
the disease can begin in peripheral joints,
especially in children and women, and rarely
with acute iridocyclitis (iritis or anterior
uveitis). Other early signs and symptoms
are diminished chest expansion from diffuse
costovertebral involvement, low-grade fever,
fatigue, anorexia, weight loss, and anemia.
Over time, ankylosing spondylitis can fuse
the vertebrae together, limiting movement.
Normal anatomy
Normal
S-curve
of spine
Loss of
normal
curvature
Pott disease
Pott
disease,
also
known as tuberculous
spondylitis,
is
a
presentation
of
extrapulmonary
tuberculosis that affects
the spine, a kind of
tuberculous arthritis of
the intervertebral joints.
The most commonly
affected
areas
are
the
lower
thoracic
and upper lumbar vertebrae of the spine.
Tuberculous involvement of the spine may
cause serious morbidity such as permanent neurologic
deficits and severe deformities. Pott disease results from
hematogenous spread of tuberculosis from other sites,
often pulmonary. The basic lesion involved in Pott disease
is a combination of osteomyelitis and arthritis involving
more than one vertebra. Progressive bone destruction
may lead to vertebral collapse and kyphosis. The kyphotic
deformity is caused by collapse in the anterior spine.
Spondylosis
Spondylosis, a common degenerative joint disease that can
be very painful in some cases, refers to the degenerative
osteoarthritis of the joints between the centra of the spinal
vertebrae and/or neural foraminae. Aging is the primary
cause of this degeneration. Discs lose their cushioning
effect between the spinal bones, ligaments become
weaker, and the bones may develop bony growths or
spurs. In this condition the interfacetal joints are not
involved. If severe, it may cause pressure on nerve roots
with subsequent sensory and/or motor disturbances, such
as pain, paresthesia, or muscle weakness in the limbs.
Narrowing of the space between two adjacent vertebrae
that compresses a nerve root emerging from the spinal
cord may result in radiculopathy (sensory and motor
disturbances, such as severe pain in the neck, shoulder,
arm, back, and/or leg, accompanied by muscle weakness).
Occasionally, direct pressure on the spinal cord (typically
the cervical spine)
Cervical spondylosis in
may result in myelopathy
(characterized by global
weakness, gait dysfunction,
loss of balance, and loss
of bowel and/or bladder
control).
Spondylosis
is known as cervical
spondylosis when vertebrae of the neck are involved and
lumbar spondylosis when lower back is involved.
Spondylolysis
Spondylolysis, a common clinical condition that may result
in low back pain, is a specific defect in the connection
between vertebrae. Patients with spondylolysis have
a defect in the pars interarticularis of the neural arch
that connects the superior and inferior articular facets.
The most commonly affected part is the lowest lumbar
vertebra (L5); however, other lumbar and thoracic
Wordsmith
vertebrae may also be affected. The defect can lead to
small stress fractures in the vertebrae that can weaken
the bones so much that one slips out of place, leading to
spondylolisthesis.
it. This displacement can be of a single vertebra or the
Generally,
spondylolysis
is
However
when
Spondylolysis asymptomatic.
symptoms occur, low back pain is
the most common. The pain usually
spreads across the lower back, and
might feel like a muscle strain.
The pain is generally worse
with vigorous exercise or activity.
Symptoms often appear during the teenage growth spurt.
Although exact cause of spondylolysis is not known,
it can be either hereditary or caused due to
repeated microtrauma that weakens the pars
interarticularis.
anterolisthesis—the upper portion of the vertebral body
Spondylolisthesis
Spondylolisthesis
Spondylolisthesis is a condition, often
associated with pain, in which a vertebra
in the lower part of the spine slips out of
the proper position onto the bone below
whole vertebral column leading to a gradual deformity
of the lower spine and narrowing of the vertebral canal.
Spondylolisthesis can be categorized into two types:
moves forward as compared to the rest of the lower
vertebral body—and retrolisthesis—the vertebral body is
displaced backwards in respect to the adjoining structure.
Spondylolisthesis may be associated with symptoms such
as lumbago, tight hamstring muscle, stiffness, pain in the
thighs and buttocks, tenderness in the area of slipped disc,
and nerve damage as a result of pressure on nerve roots
causing pain radiating down the legs.
Traumatic spondylopathy
Traumatic spondylopathy, a form of dorsopathy, is a
group of symptoms associated with spinal injury involving
compression fracture of the vertebrae. The common
symptoms of traumatic spondylopathy are spinal pain,
changes in the shape of the spine, and weakness in the legs.
77
Review
78
Online
Hepatitis B Foundation
http://www.hepb.org
Hepatitis B Foundation (HBF) is the only
national nonprofit organization solely
dedicated to the global problem of
hepatitis B. HBF is dedicated to finding a
cure and improving the quality of life for
those affected by hepatitis B worldwide.
HBF is committed to funding focused
research, promoting disease awareness,
supporting immunization and treatment
initiatives, and serving as the primary source
of information for patients and their families,
the medical and scientific community, and
the general public.
HBF has grown into a professional
organization with a global reach. The goal of
HBF is to improve the lives of those affected
by hepatitis B through a comprehensive
program of research, education, and
patient advocacy.
American Academy of Orthopedic Surgeons
http://www.aaos.org
The American Academy of Orthopedic
Surgeons (AAOS) is a preeminent provider
of education on musculoskeletal system
and its related disorders to orthopedic
surgeons and allied health professionals
across the globe. AAOS, founded in
1933 at Northwestern University, is the
world’s largest medical association of
musculoskeletal specialists and serves more
than 36,000 members worldwide.
The Academy offers continuing medical
education (CME) services by organizing
world-renowned annual meetings and
multiple CME courses and developing
various medical and scientific publications
and electronic media materials. AAOS also
serves as an advocate for improved patient
care and updates the public about the
science of orthopedics.
Review
Books
Structure and Function of the Musculoskeletal
System (Edition 2, illustrated)
Viral Hepatitis in Children: Unique Features and
Opportunities
James Watkins
Maureen M Jonas (Editor)
Publisher:
Human Kinetics, 2009
Publisher:
Springer, 2010
ISBN-10:
0736078908
ISBN 10:
1607613727
Price:
$82.00
Price:
$139.00
Paperback:
399 pages
Paperback:
174 pages
Written by James Watkins,
Structure and Function
of the Musculoskeletal
System, Second Edition,
integrates
anatomy
and
biomechanics
to
describe
the
intimate
relationship between the
structure and function of
musculoskeletal
system.
This unique reference
thoroughly
explores
the
biomechanical
characteristics
of
musculoskeletal
components
and
the
response and adaptation of these components to the
physical stress imposed by everyday activities. Following
a systematic approach, the book describes the basic
composition and function of the musculoskeletal system;
mechanical concepts and principles that underlie human
movement; functional anatomy of the skeletal, connective
tissue, articular, and neuromuscular systems; mechanical
characteristics of musculoskeletal components; structural
adaptation of musculoskeletal components; and etiology
of musculoskeletal disorders and injuries. Also available
as an e-book, this unique resource will assist both
future and current professionals in the diagnosis and
treatment of musculoskeletal disorders by enhancing their
understanding of the relationship between the structure
and function of the musculoskeletal system.
Viral Hepatitis in Children:
Unique Features and
Opportunities is a unique
volume that has been
created to address the
special
considerations
regarding viral hepatitis
in children. It includes
the latest information
and
recommendations
specifically directed at the
pediatric population and
highlights the knowledge
gaps which will need to
be filled to improve our
understanding of these
infections and treatment
of this special group.
Experienced practitioners from around the world have
contributed these reviews, incorporating the latest studies,
the current recommendations, and the distinctive pediatric
issues that shape clinical care. This material will determine
the research agenda for this field going forward. Viral
Hepatitis in Children: Unique Features and Opportunities
is a valuable resource for pediatricians, pediatric
gastroenterologists, hepatologists, and infectious disease
specialists who care for children with viral hepatitis.
79
Quiz Corner
80
Dear doctor,
Welcome to the Quiz Corner! This issue features the 5th Medical Crossword. You can win exciting prizes by sending in correct
answers using the Answer card enclosed in this issue. Please let us know your feedbacks and suggestions on the same.
Wish you the very best!
Medical Crossword 5
1
2
3
4
5
6
7
8
9
Across
Down
2. Airway inflammation is the characteristic feature
of_______ (6)
7. A yellowish pigmentation of the skin, tissues, and
certain body fluids caused by the deposition of bile
pigments (7)
8. A thin lamella of yellow elastic cartilage that
ordinarily projects upward behind the tongue and
just in front of the glottis (10)
9. Pain in joints (10)
Answers to Medical Crossword 3
1. Inflammation of the larynx, usually associated with
hoarseness or loss of voice (10)
3. Inflammation of the middle ear (6,5)
4. Prolonged loss of appetite (8)
5. Inflammation of the lung caused by infection (9)
6. A metabolic disease marked by a painful
inflammation of the joints and deposits of urates in
and around the joints (4)
(Vol. L • No. 1 • Oct–Dec 2010)
Across: 3) Ligament 5) Bursitis 7) Tendon 8) Skeletal 9) Sprain
Down: 1) Gout 2) Joints 4) Osteoarthritis 5) Bone 6) Spondylosis
81
E. Secondary hypertrophic osteoarthropathy
Hypertrophic osteoarthropathy is a syndrome of clubbing, periostitis, and synovitis. It is characterized by new subperiosteal
bone formation at the distal ends of long bones. More than 95% of cases are secondary (ie, they are associated with an
underlying systemic disease, most often a neoplasm or infection). Primary hypertrophic osteoarthropathy describes a case
in which the cause is familial or idiopathic.
Secondary hypertrophic osteoarthropathy can present with acute onset of redness, swelling, pain, and limited range of
motion of the affected joints and bones. It is typically symmetric and associated with clubbing.
The results of laboratory tests such as rheumatoid factor and antinuclear antibodies are normal. Periosteal new bone
formation causes an elevated serum alkaline phosphatase level. If a joint effusion is present, the joint aspirate shows a
noninflammatory fluid (cell count of <500 cells/μL) with a lymphocytic and monocytic predominance.
Because hypertrophic osteoarthropathy is more often secondary than primary, an underlying cause must be sought.
Furthermore, the only definitive therapy for secondary hypertrophic osteoarthropathy is treatment of the underlying
condition.
Rheumatoid arthritis is a chronic, progressive disorder that symmetrically involves the synovial and articular surfaces of
multiple joints. In rheumatoid arthritis, clubbing is absent and radiography shows periosteal sparing.
Primary hypertrophic osteoarthropathy, also known as pachydermoperiostosis or Touraine-Solente-Golé syndrome, is a
rare autosomal dominant disorder occurring mainly in young males, characterized by hypertrophic osteoarthropathy with
thickening and furrowing of facial skin (ie, leonine faces).
Carpal tunnel syndrome is associated with insidious onset of hand paresthesias without any visible clinical swelling,
erythema, or wrist deformity. Nerve conduction studies often help confirm the diagnosis.
Acute osteomyelitis is more common in children and immunosuppressed adults. Constitutional symptoms such as fever
and malaise are usually present. Skin over the affected bone may be erythematous. Positive blood cultures with an
elevated erythrocyte sedimentation rate aid in the diagnosis. Radiographic images can be normal early in the disease
course, in which case a nuclear bone scan or magnetic resonance imaging can assist in the diagnosis.
Answer (Picture Quiz 22)
Based on the patient’s history and physical examination,
which one of the following is the most likely diagnosis?
A. Acute osteomyelitis
B. Carpal tunnel syndrome
C. Primary hypertrophic osteoarthropathy
D. Rheumatoid arthritis
E. Secondary hypertrophic osteoarthropathy
Question
Picture Quiz 22
A 67-year-old man presented with pain and swelling
of both wrists that began a few weeks earlier. He also
reported a poor appetite and a 12 lb (5.4 kg) weight loss,
as well as a productive cough and shortness of breath.
He denied experiencing any morning joint stiffness,
paresthesias, or other constitutional symptoms. On
examination, the patient appeared ill and dyspneic. His
lung examination revealed decreased breath sounds in his
right upper lung field. There was broadening of the wrists
with tenderness, warmth, and mild erythema along both
distal forearms and wrists. Bilateral nail clubbing was also
noted (see the accompanying figure).
Quiz Corner
History of Medicine
82
Georg Kelling (1866-1945): The
Root of Modern Day Minimal
Invasive Surgery
John Hunter and the Origins of Modern
Orthopedic Research
Schollmeyer T, et al.
J Orthop Res. 2007;25(4):556-560.
Arch Gynecol Obstet. 2007;276(5):505-509.
On September 23, 1901, at the 73rd meeting
of the Society of German Natural Scientists
and Physicians in
Hamburg, following
his lecture “On the
inspection of the gullet
and the stomach with
flexible instruments”,
the surgeon and
gastroenterologist
Georg Kelling from
Dresden performed
a laparoscopy on a
dog. He called this procedure coelioscopy.
Kelling’s ingenious idea to connect his
oral insufflation device with the Fiedler
trocar and the Nitze cystocope, led to the
coelioscopy in 1901 and marked the hour
of birth of laparoscopy. Until today, Georg
Kelling has not experienced the appreciation
he is entitled to. He is the forgotten pioneer
of a method that today plays an important
role in diagnostics and therapeutics.
The present standard of endoscopy has
confirmed the anticipations of Georg Kelling
that he had hundred years ago. His name
therefore deserves a fixed place in the
history of medicine and especially in the
history of endoscopy. Georg Kelling and his
wife were killed during the heavy air raids
on Dresden on February 13 and 14, 1945,
but his vague footprints are still in the sands
of medical history.
Evans CH.
Orthopedic research is a multidisciplinary, eclectic pursuit
conducted in a scientific
manner. John Hunter (17281793), the Founder of Scientific
Surgery, was the first to engage
systematically in this enterprise.
Born in Scotland, Hunter
moved to London to help
his brother, William, run an
anatomy school. This involved both the procurement and
dissection of cadavers, for which activities John showed
great aptitude. Further training and a spell as an army
surgeon equipped him for his life’s work as a practitioner,
researcher, and teacher. Hunter amassed an enormous
collection of specimens displayed in a specially designed
house he constructed in Leicester Square, and maintained
an extensive menagerie and additional laboratories in
Earl’s Court. Many of his specimens are now housed in the
Hunterian Museum of the Royal College of Surgeons in
London. Among Hunter’s contributions to orthopedics are
his discovery of bone remodeling, and his studies on the
repair and regeneration of bone, cartilage, and tendon.
He developed numerous new surgical procedures, and
provided detailed anatomical descriptions that often
corrected existing theories. Many of his pupils became
famous in their own right and two of them founded
the USA’s first medical school. John Hunter died of a
heart attack.
Published and Perished
Taff ML
JAMA. 1996;275(24):1862.
While walking to a lecture at Columbia University in New
York City on an unusually warm and sunny afternoon last
February, I passed by an open-air display in front of The
Last Word bookstore on 118th Street and Amsterdam
Avenue. To my amazement, my eyes came upon Dr Arthur
C. Allen’s textbook: The Skin: A Clinicopathologic Treatise.
I had last seen my late mentor’s “bible” of skin pathology
about 20 years ago, when it was considered to be the most
authoritative book on the subject. There it was—lined up
with other dust-covered, out-of-print, used medical and
science books. I wondered how many people had walked
by the display of “All Books Outside—$1” and never
blinked an eye at this oversized atlas of skin diseases. One
dollar! I could not believe it.
I opened the book to check its condition and was struck
by the simple dedication—”To S.S.”—printed in the middle
of the frontispiece surrounded by a sea of blank paper.
I knew the initials stood for Sophie Spitz, Dr Allen’s wife,
also a pathologist, who had died of cancer shortly before
the completion of the book. I had never met Dr Spitz, but
I had heard about her untimely and tragic death that left
Dr Allen a young widower. I had learned from talking to
others at my hospital that Dr Allen had adored his beautiful
and gifted wife and was never quite the same after she died.
He shied away from social events and kept to himself. Most
likely, I surmised, he mourned his wife and, after her death,
channeled his creative energies into finishing his textbook
and reliving their time together. Both had been credited
for recognizing the morphological difference between
the benign juvenile melanoma and the true melanoma.
Between 1948 and 1954, they published several papers,
concluding that the so-called juvenile melanoma is really
a benign form of a compound nevus (mole) found in
childhood and not requiring aggressive therapy.
I knew Dr Allen—a great diagnostician whose labor of
love, published in 1954, contributed to the saving of
thousands of lives. It saddened me to think how one man’s
life’s work was now tossed upon a heap of old books in
Upper Manhattan. I thought fondly of our days together
at Brooklyn Jewish Hospital in Bedford Stuyvesant in the
mid 1970s, but I was glad that he was no longer alive to
see how his work was treated with such little regard. I
realized that my career as a forensic pathologist has so far
been successful—thanks to Dr Allen, who steered me into
pathology and a reputable training program.
When I was a medical student, Dr Allen was
only too glad to be my mentor and share with
me his knowledge of a subject he so loved. If
no one else remembers him, at least I do.
I learned of his death after seeing his obituary
listed in the June 28, 1995, issue of JAMA:
“ALLEN, Arthur Charles, 82, Brooklyn, NY;
University of California, San Francisco, School
of Medicine, 1936; certified by the American
Board of Pathology; died October 1, 1993.”
I read that obituary over and over again
until it hit home that Dr Allen had actually
died. Obituaries never seem to do justice
to an individual’s life and work, unless the
person is a celebrity who is honored with
an accompanying full biography. Obits are
always too short—always leaving something
more to be said about a person one cared for.
From Other Pages
83
Regrettably, I had lost contact with Dr Allen
over the years and I had never known he was
ill. It was a shock to learn that he had passed
away and I had missed his funeral. I knew
that by purchasing his book, I was paying
my last respects to him. Now, when I see
his cleaned-up atlas on the bookshelf in my
library, I realize I have a memento of a man
who helped me along the way.
I never thought that browsing old books could
evoke such emotion in me. This humbling
experience reminded me of other quirks of
our profession and our throwaway society. In
order to climb the academic ladder, members
of the medical profession are expected to do
research and publish their findings. In turn,
such academic endeavors should bring lasting
recognition to those who strive to advance
the sciences. Unfortunately, many medical
writers never consider the possibility that,
one day, their efforts might also end up in
obscurity. The passing of Dr Allen reminds us
that “fame” is not forever.
83
Miscellaneous
84
Laughter, the Best Medicine
The boss was complaining in our staff meeting the other day that he wasn’t getting any respect. The
next day, he brought a small sign that read:
“I’m the Boss!”
He then taped it to his office door.
Later that day when he returned from lunch, he found that someone had taped a note
to the sign that said, “Your wife called, she wants her sign back!”
•••
Three New Zealanders and three Aussies were travelling by train to a cricket match at the
World Cup in England.
At the station, the three Aussies each buy a ticket and watch as the three New Zealanders buy just
one ticket between them.
“How are the three of you going to travel on only one ticket?” asks one of the Aussies. “Watch and
learn,” answers one of the New Zealanders.
They all board the train. The Aussies take their respective seats but all three New Zealanders cram
into a toilet and close the door behind them.
Shortly after the train has departed, the conductor comes around collecting tickets. He knocks on
the toilet door and says, “Ticket please.”
The door opens just a crack and a single arm emerges with a ticket in hand. The conductor takes it
and moves on.
The Aussies see this and agree it was quite a clever idea. So after the game, they decide to copy the
New Zealanders on their return trip.
When they get to the station, they buy a single ticket for the return trip. To their astonishment, the
New Zealanders don’t buy a ticket at all!!
“How are you going to travel without a ticket?” says one perplexed Aussie.
“Watch and learn,” answers a New Zealander. When they board the train, the three Aussies cram
into a toilet soon after which the three New Zealanders cram into another nearby. The train departs.
Shortly afterwards, one of the New Zealanders leaves the toilet and walks over to the toilet where
the Aussies are hiding.
He knocks on the door and says, “Ticket please.”
•••
Think Wise
Imagination is more important than knowledge.
Knowledge is limited. Imagination encircles the world.
— Albert Einstein
Write to Us
We would like to hear from you. Write to us at [email protected]
The DUAL advantage arthritis control
The DUAL advantage arthritis control
A publication of The Himalaya Drug Company
Registered with the Registrar of Newspaper for India under R.N. 6227/61
Only for reference by a registered medical practitioner, hospital or laboratory

Exploring ancient and modern medical learning

Transcription

Similar documents

Probe Year in Review

the liver beyond surgery in colorectal metastatic disease

CRYOGEN-FREE Models

Mixed connective tissue disease associated autoimmune hepatitis

Commonly Asked Questions About Chronic Hepatitis C

ALF Great Lakes 2015 Year in Review

Saf-T-Log ® Thermomètre enregistreur HACCP

Jean Louisa Kelly

Cirrhosis - American Liver Foundation

w w w .tajfun