Still in search of a herbal medicine: Culprit is poor methodological quality of research

1. Thatte U. Still in search of a herbal medicine. Indian J Pharmacol 2009;41:1-3. 2. Pandora P. Where is the evidence that animal research beneÞ ts humans? BMJ 2004;328:514-17. 3. Knight A. Systematic reviews of animal experiments demonstrate poor human clinical and toxicological utility. ALTEX 2007;14:125-30. 4. Bebarta V, Luyten D, Heard K. Emergency medicine animal research: Does use of randomization and blinding affect the results? Acad Emerg Med 2003;10:684-7. 5. Hackam DG. Translating animal research into clinical beneÞ t. BMJ 2007;334: 163-4. Still in search of a herbal medicine: Culprit is poor methodological quality of research


Still in search of a herbal medicine: Culprit is poor methodological quality of research
Sir, I read the editorial "Still in search of a herbal medicine…" by Thatte. [1]She mentioned that "in spite of increasing research in herbal medicines… there is still no product, no drug, that has made a difference to therapeutics".She mentioned various problems inherently associated with herbal research such as identification of plants, standardization, toxicological data etc.I believe something else we should not overlook is "methodological problems associated with the animal studies".Studies show that animal studies are poor predictors of effects in humans. [2]Among 20 reviews examining clinical utility, animal models demonstrated the potential to contribute significantly toward the development of human clinical interventions in only two cases. [3]There are various types of methodological problems associated with these studies.Some of these are as follows: [2] • Disparate animal species and strains.• Different models for inducing illness or injury with varying similarity to the human condition.• Variations in drug dosing schedules and regimen that are of uncertain relevance to the human condition.• Variability in the way animals are selected for study.
• Methods of randomization.
• Choice of comparison therapy (none, placebo, vehicle).• Reporting of loss to follow-up.• Small experimental groups with inadequate power.
• Simplistic statistical analysis that does not account for potential confounding.• Failure to follow intention to treat principles.
• Nuances in laboratory technique that may influence results may be neither recognized nor reported-e.g.methods for blinding investigators and selection of a variety of outcome measures, which may be disease surrogates or precursors and which are of uncertain relevance to the human clinical condition, etc.I observed that in 2007 and 2008 among the articles published in IJP 84% were animal studies and many of the studies incorporated one of the problems mentioned above, such as randomization and blinding which can easily be done in animal experiments.Unfortunately either randomization or blinding are not done or are not declared in the many articles published in the journals. [2,3]In clinical research where the drug is administered to the human, both randomization and blinding are very important. [4,5]It has been shown that human clinical trials that lack randomization or blinding often overestimate the magnitude of treatment effects. [5]Animal studies that do not

Letters to the Editor
Can we prevent ondansetron induced fatal ventricular tachycardia?
Sir, We have read with interest the article 'Ondansetron induced fatal ventricular tachycardia' by Chandrakala et al., published in the Indian Journal of Pharmacology, August 2008.We would like you to give us the opportunity to discuss some of our observations on the same.
Ondansetron is a racemic compound having one chiral centre.Racemic Ondansetron is a 50:50 mixture of two enantiomers, R-Ondansetron and S-Ondansetron.In one animal study (in dogs), effects of R-Ondansetron, S-Ondansetron and racemic Ondansetron on cardiac arrhythmias (cardiotoxicity) were evaluated.QTc interval was most prolonged among animals receiving S-Ondansetron and racemic Ondansetron and was shortest among animals receiving R-Ondansetron.Based on these results it was reported that R-Ondansetron has less cardiotoxicity than S-Ondansetron or racemic Ondansetron. [1]odhankar et al. in 2006 studied the effect of racemic Ondansetron, R-Ondansetron and S-Ondansetron on QTc interval in electrocardiograms of rats.The Ondansetron and its enantiomers were administered IV in a dose of 3 mg/Kg and changes in QT and RR interval and heart rate were calculated.The results of this study showed that racemic Ondansetron and S-Ondansetron significantly prolonged QTc interval, while R-Ondansetron did not prolong QTc interval as compared to the vehicle treated group.They concluded that R-Ondansetron is safer on the heart.Authors reported that S-Ondansetron might have higher inhibitory effects on Bezold-Jarisch reflex and this might be the reason for QTc prolongation with S-Ondansetron and racemic Ondansetron. [2] multicentric, randomized, double-blind, parallel group, comparative study on efficacy and safety of R-Ondansetron 4 mg versus racemic Ondansetron 8 mg in 240 Indian patients with nausea and vomiting concluded that R-Ondansetron 4 mg BID was equally effective compared to racemic Ondansetron 8 mg BID with a slightly better safety profile compared to racemic Ondansetron. [3]This suggests that the S-Ondansetron component can be omitted without loss of efficacy.Efficacy and safety of R-Ondansetron solution was also studied in 410 pediatric patients confirming R-Ondansetron solution is safe and effective in pediatric patients with nausea and vomiting. [4]rom the above discussion it is clear that R-Ondansetron 4 mg alone is sufficient for its anti-emetic potential and is preferable without its counterpart -the S-isomer which can prolong the QTc.So switching from racemic Ondansetron to R-Ondansetron is a rational therapeutic approach.R-Ondansetron has been approved by the DCGI on 15 th April 2005 and is available as tablets (2 mg/4 mg), solution (1 mg/ 5 ml) and injection (1 mg/ml).

Effects of methanolic extract of Cuminum cyminum on total serum cholesterol in ovariectomized rats
Sir, Estrogens have a protective role in lipid metabolism [1] and postmenopausal women are at high risk for developing cardiovascular disorders due to estrogen deficiency.As suggested by many epidemiological studies, hormone replacement therapy (HRT) in postmenopausal women appears to be associated with reduction in the risks of coronary heart disease. [2]Protection against cardiovascular disorders is an attractive side of HRT in postmenopausal women, but at the same time it is associated with serious side effects like breast and endometrial cancers and is also associated with patient incompatibility which presents many limitations in long-term use.
Phytoestrogens, polyphenolic non-steroidal plant compounds with estrogen-like biological activity are currently offering an effective and safe alternative to hormone replacement therapy.Owing to the estrogen-like property they are effective in a variety of aliments such as menopausal symptoms and postmenopausal disorders, such as osteoporosis and cardiovascular disorders. [3]mple evidence from epidemiological studies and clinical trials suggests the plausibility of a causal, inverse relationship between phytoestrogens and cardiovascular disease.The well established low rates of cardiovascular disease and high intake of dietary phytoestrogens in Asian populations are consistent with a potential cardioprotective effect of phytoestrogens. [2]ruits of Cuminum cyminum (Apiaceae), commonly known as jeera are consumed as condiment across the globe.Fruits of Cuminum cyminum (CC) are rich in estrogenic isoflavonoids luteolin and apigenin. [4]CC extract is included as one of the major components in some polyherbal formulations because of its estrogenic nature.The estrogenic activity of acetone extract of CC has been reported earlier in immature ovariectomized rats. [5]It has been reported to reduce plasma cholesterol levels in diabetic rats. [6]he present study was undertaken to evaluate hypocholesterolemic effect of methanolic extract of Cuminum cyminum (MCC) as a part of anti-osteoporotic evaluation of MCC in ovariectomized (OVX) rats.Methanol was the solvent of choice owing to its excellent penetration and extraction ability.
Forty adult Sprague Dawley female rats of 3 months age, weighing 200-250 gm were divided into four groups with N = 10 per group.Three groups were bilaterally ovariectomized while one was sham operated (SH control).MCC 1000 mg/kg and estradiol benzoate equivalent to 0.15 mg/kg of estradiol were administered to OVX rats per orally for 10 weeks.MCC was administered in two divided doses with 2 ml/kg dose volume.SH control and OVX control groups were administered with vehicle 0.5% sodium carboxy methyl cellulose.The treatment was started the day after ovariectomy.
At the termination of study, blood was collected from overnight fasted animals; serum was harvested and preserved at 4°C until the analysis.Total serum cholesterol was determined colorimetrically using standard cholesterol estimation kit (Erba).Results were analyzed by one-way ANOVA at P < 0.05.
OVX rats showed significantly elevated levels of serum total cholesterol at the end of 10 weeks as compared to SH control.Treatment with estradiol and MCC both significantly decreased total cholesterol levels in serum.The decrease in total serum cholesterol caused by MCC was significantly greater than that caused by standard drug estradiol.It was observed that total cholesterol levels in MCC treated rats were lower but not significantly than SH control rats.The results indicated that estradiol as well as MCC protected OVX rats against increased cholesterol levels due to ovariectomy while MCC was better than estradiol [Table 1].
It is likely that the hypocholesterolemic effect of MCC may Letter to the EditorIndian J Pharmacol | Apr 2009 | Vol 41 | Issue 2 | 91-93