Phase III randomized clinical trial of BV-4051, an Ayurvedic polyherbal formulation in moderate SARS-CoV-2 infections and its impact on inflammatory biomarkers.

SARS-CoV-2 virus and its variants continue to be a challenge inspite of widespread vaccination and preventive measures. We hypothesized an oral, safe polyherbal formulation with antiinflammatory properties may improve the clinical outcome of this disease. BV-4051, a formulation from four Ayurvedic plants namely Ashwagandha, Boswellia, Ginger and Turmeric was used for the treatment of hospitalized moderate COVID-19 patients along with standard of care (SOC). Patients were randomly assigned to receive BV-4051 or placebo tablets for 14 days, at four sites in India during late 2020 to early 2021. Among 208 randomized subjects, 175 completed the study. In BV-4051 group the mean reduction in duration of illness (p = 0.036), alleviation and severity scores of several symptoms like fever, cough, smell, and taste disorders were statistically significant (p ≤ 0.05). A sub-set analysis of subjects treated with or without Remdesivir as SOC showed mean reduction in duration of illness in BV-4051 (p = 0.030), and severity scores (p ≤ 0.05). Mean difference in Interleukin-6 was statistically significant (p = 0.042) on BV-4051 without Remdesivir. BV-4051 may reduce duration of illness, symptoms severity, Interleukin-6, and prevent the incidence of COVID-19 complications. It may have an adjunctive effect with other SOC. Larger extensive clinical testing may give a better understanding of its effect.

Hepatoprotective Activity of BV-7310, a Proprietary Herbal Formulation of Phyllanthus niruri, Tephrosia purpurea, Boerhavia diffusa, and Andrographis paniculata, in Alcohol-Induced HepG2 Cells and Alcohol plus a Haloalkane, CCl4, Induced Liver Damage in Rats.

Excessive alcohol consumption is a worldwide threat with severe morbidity and mortality. Other than abstinence, there is still no FDA-approved drug for alcoholic liver disease (ALD). Liver is the primary site of ethanol metabolism and hence gets the most damage from excessive drinking. It triggers multiple signalling events including inflammation, leading to an array of hepatic lesions like steatosis, hepatitis, fibrosis, and cirrhosis. Similarly, when medications or xenobiotic compounds are ingested orally, the liver gets the highest exposure of those metabolites, which in turn can cause severe liver toxicity. BV-7310 is a standardized mixture of four Ayurvedic plants, namely, Phyllanthus niruri, Tephrosia purpurea, Boerhavia diffusa, and Andrographis paniculata. In different systems of traditional medicine, each of these plants has been known to have use in gastrointestinal disorders. We wanted to assess the combined effect of these plant extracts on alcohol-induced liver damage. First, we investigated the hepatoprotective activity of BV-7310 against alcohol-induced toxicity in human liver HepG2 cells. Ethanol treatment (120 mM for 48 hours) significantly showed toxicity (around 42%) in these cells, and coincubation with BV-7310 prevented ethanol-induced cell death in a dose-dependent manner. Interestingly, the formulation BV-7310 showed synergistic activity than any individual extract tested in this assay. BV-7310 also showed potent antioxidant activity in 2,2-diphenyl-1-picryl-hydrazyl (DPPH) assay. Next, we induced hepatitis in Sprague-Dawley (SD) rats using repeated alcohol (40%) dosing, and carbon tetrachloride (CCl4) 24 hours before termination. Both oral doses of BV-7310 (250 and 500 mg/kg body weight) protected the alcohol-induced body weight loss and significantly improved the elevated levels of liver enzymes compared to the vehicle treated group. Thus, BV-7310 prevents alcohol-induced toxicity in both in-vitro and in-vivo models and could be beneficial for the treatment of ALD or other conditions, which may cause liver toxicity.

Long term effectiveness of RA-1 as a monotherapy and in combination with disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis.

BACKGROUND: Data on long term use of Ayurvedic drugs is sparse. They may prove useful if combined with modern medicine in certain clinical situations (integrative medicine). We present the results of a long term observational study of RA-1 (Ayurvedic drug) used in the treatment of rheumatoid arthritis (RA). OBJECTIVE: The objective was to study safety of long term use of RA-1 for treatment of rheumatoid arthritis (RA). MATERIALS AND METHODS: On completion of a 16 week randomized controlled study, 165 consenting volunteer patients were enrolled into a three year open label phase (OLP) study. Patients were symptomatic with persistent active disease and naïve for disease modifying anti-rheumatic drugs (DMARD). 57 patients were on fixed low dose prednisone. Patients were examined every 10-14 weeks in a routine rheumatology practice using standard care norms. They continued RA-1 (Artrex ™, 2 tablets twice daily) throughout the study period and were generally advised to lead a healthy life style. Based on clinical judgment, rheumatologist added DMARD and/or steroids (modified if already in use) to patients with inadequate response; chloroquine and/or methotrexate commonly used. Treatment response was assessed using American College of Rheumatology (ACR) efficacy measures and ACR 20% improvement index standard update statistical software (SAS and SPSS) were used; significant at p < 0.05. RESULTS: 158, 130 and 122 patients respectively completed evaluations at 1, 2 and 3 year primary end point. The ACR 20 response (range 34-40%) remained stable over three years (p = 0.33). Patients improved optimum for several measures by one year (p < 0.05) and this was sustained. The use of steroids varied from 42 to 49% patients at yearly end points (mean daily dose 5 mg prednisone); correspondingly the use of DMARD varied from 20 to 34% patients. 40% patients on RA-1 did not require DMARD/steroids for control of disease. 77% patients reported adverse events, albeit mild and mostly gut related, and not causing withdrawal. Several study limitations (especially self-selection) were reduced by the high patient retention and consistency in drug use. CONCLUSION: RA-1 is safe and effective in the long term management of symptomatic active chronic RA. DMARDs and/or steroids can be used judiciously along with RA-1 to treat difficult disease/flares. Further studies are required to evaluate RA-1 in early RA. This paves way for research and application of integrative therapeutic approach in clinical medicine.

Acute and chronic toxicity, cytochrome p450 enzyme inhibition, and HERG channel blockade studies with a polyherbal, ayurvedic formulation for inflammation.

Ayurvedic plants are known for thousands of years to have anti-inflammatory and antiarthritic effect. We have recently shown that BV-9238, a proprietary formulation of Withania somnifera, Boswellia serrata, Zingiber officinale, and Curcuma longa, inhibits LPS-induced TNF-alpha and nitric oxide production from mouse macrophage and reduces inflammation in different animal models. To evaluate the safety parameters of BV-9238, we conducted a cytotoxicity study in RAW 264.7 cells (0.005-1 mg/mL) by MTT/formazan method, an acute single dose (2-10 g/kg bodyweight) toxicity study and a 180-day chronic study with 1 g and 2 g/kg bodyweight in Sprague Dawley rats. Some sedation, ptosis, and ataxia were observed for first 15-20 min in very high acute doses and hence not used for further chronic studies. At the end of 180 days, gross and histopathology, blood cell counts, liver and renal functions were all at normal levels. Further, a modest attempt was made to assess the effects of BV-9238 (0.5 µg/mL) on six major human cytochrome P450 enzymes and (3)H radioligand binding assay with human hERG receptors. BV-9238 did not show any significant inhibition of these enzymes at the tested dose. All these suggest that BV-9238 has potential as a safe and well tolerated anti-inflammatory formulation for future use.

Inhibition of LPS-induced TNF-α and NO production in mouse macrophage and inflammatory response in rat animal models by a novel Ayurvedic formulation, BV-9238.

Rheumatoid arthritis is a chronic crippling disease, where protein-based tumor necrosis factor-alpha (TNF-α) inhibitors show significant relief, but with potentially fatal side effects. A need for a safe, oral, cost-effective small molecule or phyto-pharmaceutical is warranted. BV-9238 is an Ayurvedic poly-herbal formulation containing specialized standardized extracts of Withania somnifera, Boswellia serrata, Zingiber officinale and Curcuma longa. The anti-inflammatory and anti-arthritic effects of BV-9238 were evaluated for inhibition of TNF-α and nitric oxide (NO) production, in lipopolysaccharide-stimulated, RAW 264.7, mouse macrophage cell line. BV-9238 reduced TNF-α and NO production, without any cytotoxic effects. Subsequently, the formulation was tested in adjuvant-induced arthritis (AIA) and carrageenan-induced paw edema (CPE) rat animal models. AIA was induced in rats by injecting Freund's complete adjuvant intra-dermally in the paw, and BV-9238 and controls were administered orally for 21 days. Arthritic scores in AIA study and inflamed paw volume in CPE study were significantly reduced upon treatment with BV-9238. These results suggest that the anti-inflammatory and anti-arthritic effects of BV-9238 are due to its inhibition of TNF-α, and NO, and this formulation shows promise as an alternate therapy for inflammatory disorders where TNF-α and NO play important roles.

Immunoprotection by botanical drugs in cancer chemotherapy.

Most of the synthetic chemotherapeutic agents available today are immunosuppressants, cytotoxic, and exert variety of side effects that are particularly evident in cancer chemotherapy. Botanical based immunomodulators are often employed as supportive or adjuvant therapy to overcome the undesired effects of cytotoxic chemotherapeutic agents and to restore normal health. Total extract, polar and non-polar extracts, and their formulations, prepared from medicinal plants mentioned in Ayurveda, namely, Withania somnifera (Linn Dunal) (Solanaceae), Tinospora cordifolia (Miers) (Menispermaceae), and Asparagus racemosus (Willd.) (Liliaceae), exhibited various immunopharmacological activities in cyclophosphamide (CP)-treated mouse ascitic sarcoma. Treatment of ascitic sarcoma-bearing mice with a formulation of total extracts of Withania somnifera and Tinospora cordifolia (80:20) and alkaloid-free polar fraction of Withania somnifera resulted in protection towards CP-induced myelo- and immunoprotection as evident by significant increase in white cell counts and hemagglutinating and hemolytic antibody titers. Treatment with these candidate drugs will be important in development of supportive treatment with cancer chemotherapy.

A 32-week randomized, placebo-controlled clinical evaluation of RA-11, an Ayurvedic drug, on osteoarthritis of the knees.

BACKGROUND: The ancient Indian (Asian) Ayurvedic medicinal system uses herbomineral drugs to treat arthritis. Despite centuries of use, very few have been tested by drug trials. RA-11 (ARTREX, MENDAR), a standardized multiplant Ayurvedic drug (Withania somnifera, Boswellia serrata, Zingiber officinale, and Curcuma longa) is currently used to treat arthritis. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of RA-11 in patients with symptomatic osteoarthritis (OA) of the knees. METHODS: A total of 358 patients with chronic knee pain were screened free-of-cost in "arthritis camps" in an Indian metropolis. Ninety patients with primary OA of the knees (ACR classification; Arthritis Rheum 1986;29:1039-1049) were found eligible (postanalgesic washout pain visual analog score [VAS] > or =40 mm in either or both knees on body weight-bearing activities) to enroll into a randomized, double-blind, placebo-controlled, parallel efficacy, single-center, 32-week drug trial (80% power to detect 25% difference, P = 0.05, 2-sided). Concurrent analgesics/nonsteroidal antiinflammatory drugs and steroids in any form were not allowed. Lifestyle and/or dietary restrictions, as per routine Ayurveda practices, were not imposed. Pain VAS (maximum pain in each knee recorded by the patient during the preceding 48 hours) and modified WOMAC (Western Ontario McMaster University OA Index, Likert scale, version 3.0) were the primary efficacy variables. The WOMAC section on "physical function difficulty" was modified for Indian use and validated before the trial. Routine laboratory testing was primarily done to monitor drug safety. At baseline, the groups (active = 45, placebo = 45) were well matched for several measures (mean pain VAS: active = 6.17; placebo = 6.5). RESULTS: 1) EFFICACY: Compared with placebo, the mean reduction in pain VAS at week 16 (active = 2.7, placebo = 1.3) and week 32 (active = 2.8, placebo = 1.8) in the active group was significantly (P <0.05, analysis of variance [ANOVA]) better. Similarly, the improvement in the WOMAC scores at week 16 and week 32 were also significantly superior (P <0.01, ANOVA) in the active group. 2) SAFETY: Both the groups reported mild adverse events (AE) without any significant difference. 3) Withdrawals: Twenty-eight patients were discontinued. None reported drug-related toxicity. The majority failed follow up/compliance. No differences were observed between the groups. CONCLUSION: This controlled drug trial demonstrates the potential efficacy and safety of RA- 11 in the symptomatic treatment of OA knees over 32 weeks of therapy.

Clinical validation of efficacy and safety of herbal cough formula: study of herbal cough syrup.

OBJECTIVE OF THE STUDY: To clinically validate the efficacy and safety of herbal cough formula CORSHE-E of ayurvedic origin. PROCEDURE: An open label, uncontrolled clinical study was done on thirty patients with history of cough. The patients were given the cough syrup after they were enrolled in the study and were followed up for a period of seven days. The cough severity, frequency (as recorded on Visual Analogue Scale from 0 to 10 cm), chest discomfort, quantity and type of sputum were recorded at screening, on the fourth day and on the seventh day of treatment. The patient recorded the severity and frequency of cough on a Visual Analogue Scale which was divided into ten equal parts of 1 cm each. The patient marked the extent of symptoms on this scale at screening and after four days of consumption of the cough syrup. The scores were marked on these days and reduction in score was examined for efficacy evaluation of the cough syrup. The clinical and hematological safety parameters and parameters for acceptability of cough syrup (palatability, color, odor and consistency) were also studied. Global assessment by the patient and the physician was also carried out on the fourth day. RESULTS: Twenty-six of the thirty patients studied showed a significant decrease in the frequency and severity of cough (on Visual Analogue Scale). The sputum quantity and consistency also showed steady decrease and liquefaction respectively. Four patients who had longer duration of did not respond adequately to treatment. These patients had history of sub-acute to chronic cough with mean duration of cough being forty days (40 +/- 34 days), sore-throat and fever, highly suggestive of bacterial upper respiratory tract infection and a long duration of cough before initiation of therapy. Most of the patients found the cough syrup to be acceptable in terms of these criteria. Nineteen patients rated the cough syrup as excellent in palatability, two in color, four in odor and five in consistency. Six patients rated the syrup as good to taste, twenty-eight patients rated the natural color as good and twenty five and twenty patients rated the odor and consistency as good, respectively. Five patients described the taste as bad, none described the color as bad, one patient found the odor bad and five described the consistency as bad. All patients described a soothing effect of the study drug and appreciated the natural color and flavor of the same. Global assessment was based on improvement in symptoms, acceptability and overall efficacy and safety as reported by the physician and the patient. Thirteen of the thirty patients rated the trial medicine as excellent, thirteen rated it as good and four considered it poor. The investigator in charge of the patients rated the trial medicine as excellent in eighteen cases, good in eight cases, fair in two cases and poor in two cases. CONCLUSION: The test drug CORSHE-E is an effective and safe cough syrup that is highly acceptable for patients with cough of short duration.