Evaluation of subacute toxicity and herb-drug interaction potential of an herbal Arishta formulation.

Background Arishta technology is an age-old heritage and uses herbal decoctions to prepare self-generated alcoholic medicines. In Ayurveda, Arishta preparations are widely used as a remedy for metabolic disorders. However, their safety and influence on herb metabolism pathways were not yet explored. Aim: To study the subacute toxicity of a polyherbal Arishta formulation (coded as DB-07) in rats and to evaluate its potential for inhibition of the drug-metabolizing enzyme (Cytochrome P450 3A4). Methodology Experimentally naive rats were treated with graded oral doses of DB-07 (10 and 20 mL/kg/day) for 28 days. During the course of the experiment, all the animals were closely observed for apparent behavioural abnormalities and mortalities. Tissue histology was performed to assess any sign of toxicity. In addition, in vitro CYP3A4 inhibition assay was performed to study the effect on drug metabolism pathways. Results Animals did not show any change in body weight, organ toxicity and food consumption throughout the dosing period of 28 days. Pathophysiological, behavioural status and locomotor activity were not altered. DB-07 did not inhibit CYP3A4 enzyme and drug metabolism pathway in-vitro. Gallic acid and quercetin were identified as phytomarker from the formulation that may be responsible for its activity related safety issue. Conclusion These results indicate that use of DB-07 may be safe with no sign of toxicity for up to 28 days in rats. Further, CYP3A4 inhibition assay indicated that DB-07 is less likely to have herb-drug interactions when concomitantly administered with CYP3A4 inhibitors or inducer.

Clinical efficacy of water extract of stem bark of Terminalia arjuna (Roxb. ex DC.) Wight & Arn. in patients of chronic heart failure: a double-blind, randomized controlled trial.

BACKGROUND: The stem bark of Terminalia arjuna (Roxb. ex DC.) Wight and Arn. (Arjuna) is used in Indian system of medicine (Ayurveda) for treatment of various cardiac diseases, including heart failure. However, well designed clinical trials exploring its efficacy and safety in chronic heart failure (CHF) are lacking. PURPOSE: To ascertain the add-on efficacy and safety of a standardized water extract of stem bark of Arjuna (Arjuna extract) in CHF patients on standard pharmacotherapy. STUDY DESIGN: Double-blind, parallel, randomized, placebo-controlled add-on clinical trial. METHODS: After approval of institutional ethics committee, 100 patients of CHF of New York Heart Association (NYHA) functional class II on standard pharmacotherapy having an echocardiographic left ventricular ejection fraction (LVEF) ≤ 40% were consecutively recruited with informed consent and randomized 1:1 to Arjuna extract 750 mg or matching placebo twice daily. The primary outcome measure was change in LVEF at 12 weeks. Secondary outcome measures included changes in (i) NYHA functional class, (ii) distance covered in 6 min walk test (6MWT), (iii) quality of life (QoL), as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ), (iv) plasma brain natriuretic peptide, (v) plasma cytokines (interleukin-6, high sensitivity C-reactive protein and tumour necrosis factor-α) and (vi) oxidative stress markers [serum thiobarbituric acid reactive substances (TBARS), red blood cell (RBC) superoxide dismutase (SOD), RBC catalase and RBC glutathione (GSH)] at 6 and 12 weeks. Safety assessment was done by adverse event monitoring and laboratory investigations. Results were expressed as mean ± SD or median (interquartile range) and analysed with intention-to- treat principle using appropriate two-sided statistical tests. A p-value < 0.05 was considered significant. RESULTS: Arjuna extract was well-tolerated, but did not change LVEF (24.3 ± 7.1 versus 25.5 ± 7.7%; p = 0.4) or secondary outcome measures except preservation of RBC catalase activity [1275(104, 10350) versus 1243.5(104, 10350) U/g haemoglobin; p = 0.01] compared to placebo. Significantly greater percentage increases occurred in distance covered in 6 MWT, RBC-SOD, RBC catalase, RBC GSH and in symptom severity and stability domains of KCCQ in patients on Arjuna extract versus those on placebo, on a post-hoc analysis, between subgroups of patients who improved in these outcomes. CONCLUSION: Arjuna extract did not improve LVEF in CHF patients over 12 weeks, although there was improvement in functional capacity, antioxidant reserves and symptom-related QoL domains in some patients.

Cissampelos pareira Linn: Natural Source of Potent Antiviral Activity against All Four Dengue Virus Serotypes.

BACKGROUND: Dengue, a mosquito-borne viral disease, poses a significant global public health risk. In tropical countries such as India where periodic dengue outbreaks can be correlated to the high prevalence of the mosquito vector, circulation of all four dengue viruses (DENVs) and the high population density, a drug for dengue is being increasingly recognized as an unmet public health need. METHODOLOGY/PRINCIPAL FINDINGS: Using the knowledge of traditional Indian medicine, Ayurveda, we developed a systematic bioassay-guided screening approach to explore the indigenous herbal bio-resource to identify plants with pan-DENV inhibitory activity. Our results show that the alcoholic extract of Cissampelos pariera Linn (Cipa extract) was a potent inhibitor of all four DENVs in cell-based assays, assessed in terms of viral NS1 antigen secretion using ELISA, as well as viral replication, based on plaque assays. Virus yield reduction assays showed that Cipa extract could decrease viral titers by an order of magnitude. The extract conferred statistically significant protection against DENV infection using the AG129 mouse model. A preliminary evaluation of the clinical relevance of Cipa extract showed that it had no adverse effects on platelet counts and RBC viability. In addition to inherent antipyretic activity in Wistar rats, it possessed the ability to down-regulate the production of TNF-α, a cytokine implicated in severe dengue disease. Importantly, it showed no evidence of toxicity in Wistar rats, when administered at doses as high as 2g/Kg body weight for up to 1 week. CONCLUSIONS/SIGNIFICANCE: Our findings above, taken in the context of the human safety of Cipa, based on its use in Indian traditional medicine, warrant further work to explore Cipa as a source for the development of an inexpensive herbal formulation for dengue therapy. This may be of practical relevance to a dengue-endemic resource-poor country such as India.