In vitro effect of Withania somnifera, AYUSH-64, and remdesivir on the activity of CYP-450 enzymes: Implications for possible herb-drug interactions in the management of COVID-19.

Ayurvedic medicines Withania somnifera Dunal (ashwagandha) and AYUSH-64 have been used for the prevention and management of COVID-19 in India. The present study explores the effect of Ashwagandha and AYUSH-64 on important human CYP enzymes (CYP3A4, CYP2C8, and CYP2D6) to assess their interaction with remdesivir, a drug used for COVID-19 management during the second wave. The study also implies possible herb-drug interactions as ashwagandha and AYUSH-64 are being used for managing various pathological conditions. Aqueous extracts of ashwagandha and AYUSH-64 were characterized using LC-MS/MS. A total of 11 and 24 phytoconstituents were identified putatively from ashwagandha and AYUSH-64 extracts, respectively. In addition, in silico studies revealed good ADME properties of most of the phytoconstituents of these herbal drugs and suggested that some of these might possess CYP-450 inhibitory activity. In vitro CYP-450 studies with human liver microsomes showed moderate inhibition of CYP3A4, 2C8, and 2D6 by remdesivir, while ashwagandha had no inhibitory effect alone or in combination with remdesivir. AYUSH-64 also exhibited a similar trend; however, a moderate inhibitory effect on CYP2C8 was noticed. Thus, ashwagandha seems to be safe to co-administer with the substrates of CYP3A4, CYP2C8, and CYP2D6. However, caution is warranted in prescribing AYUSH-64 along with CYP2C8 substrate drugs. Furthermore, preclinical and clinical PK studies would be helpful for their effective and safer use in the management of various ailments along with other drugs.

Management of Type 2 Diabetes: Current Strategies, Unfocussed Aspects, Challenges, and Alternatives.

Type 2 diabetes mellitus (T2DM) accounts for >90% of the cases of diabetes in adults. Resistance to insulin action is the major cause that leads to chronic hyperglycemia in diabetic patients. T2DM is the consequence of activation of multiple pathways and factors involved in insulin resistance and ß-cell dysfunction. Also, the etiology of T2DM involves the complex interplay between genetics and environmental factors. This interplay can be governed efficiently by lifestyle modifications to achieve better management of diabetes. The present review aims at discussing the major factors involved in the development of T2DM that remain unfocussed during the anti-diabetic therapy. The review also focuses on lifestyle modifications that are warranted for the successful management of T2DM. In addition, it attempts to explain flaws in current strategies to combat diabetes. The employability of phytoconstituents as multitargeting molecules and their potential use as effective therapeutic adjuvants to first line hypoglycemic agents to prevent side effects caused by the synthetic drugs are also discussed.

Understanding the relevance of herb-drug interaction studies with special focus on interplays: a prerequisite for integrative medicine.

Integrative medicine refers to the blending of conventional and evidence-based complementary medicines and therapies with the aim of using the most appropriate of either or both modalities for ultimate patient benefits. One of the major hurdles for the same is the chances of potential herb-drug interactions (HDIs). These HDIs could be beneficial or harmful, or even fatal; therefore, a thorough understanding of the eventualities of HDIs is essential so that a successful integration of the modern and complementary alternative systems of medicine could be achieved. Here, we summarize all the important points related to HDIs, including types, tools/methods for study, and prediction of the HDIs, along with a special focus on interplays between drug metabolizing enzymes and transporters. In addition, this article covers future perspective, with a focus on background endogenous players of interplays and approaches to predict the drug-disease-herb interactions so as to fetch the desired effects of these interactions.

Potential synergistic effects of quercetin with other phytoconstituents of Costus pictus (insulin plant) extract in the control of hyperglycemia and prevention of NSAID-induced gastroenteropathy in diabetic rats.

There is a need of multifactorial management to treat T2DM. Till date, no clinically simulated animal model and therapy for NSAID-induced gastroenteropathic damage (NSAID-iGD) in T2DM patients. T2DM was developed using high-fat diet plus multiple low doses of streptozotocin (30 mg/kg, IP). Rats treated with ethanolic extract of Insulin plant (EIP; 125, 250 and 500 mg/kg, PO; b.i.d.)/Quercetin (QCT; 50 mg/kg)/vehicle for total 10 days. Diclofenac sodium (DCF; 7.5 mg/kg, PO, b.i.d.) administered for final five days of EIP/vehicle administration. Rats fasted after last dose on the 9th day; water was provided ad libitum. 12 h after the last dose on 10th day, GI tracts assessed for haemorrhagic damage, XO activity, LPO, intestinal permeability, luminal pH alterations along with haematological, biochemical and histological parameters. The evidence suggested that DCF administration caused significant gastroenteropathic damage. In presence of T2DM, NSAID-iGD significantly exacerbated. Whereas, QCT/EIP treatment significantly attenuated T2DM dependent exacerbation of NSAID-iGD, and also efficiently managed T2DM in a dose-dependent manner. Low amount of QCT in EIP(190.96 ±â€¯7.5 ng/mg) than its effective dose(50 mg/kg) indicates that EIP's other phytoconstituents (e.g. Kaempferol, Ascorbic acid, Lupeol, Diosgenin, ß-sitosterol, Stigmasterol, ß-amyrin, etc.) giving synergistic actions. Costus pictus/QCT has potential to be promising candidate to treat patient with T2DM and NSAID-gastroenteropathy in T2DM.

Overcoming the exacerbating effects of ranitidine on NSAID-induced small intestinal toxicity with quercetin: Providing a complete GI solution.

There is a need to find/discover novel leads to treat complex and/or multi-factorial-pathogenic disease(s) like Nonsteroidal anti-inflammatory drugs (NSAID)-induced gastroenteropathy or gastrointestinal (GI) toxicity as it has emerged as an important medical and socioeconomic problem. There is no approved therapeutic strategy to prevent NSAID-induced enteropathic damage and highly effective gastro-protective drugs such as ranitidine hydrochloride (RAN) exacerbate it. In this purview, the multi target drug discovery approach (MTDD), combination approach and hit to lead strategies based on the foundation of ethnopharmacology and/or reverse pharmacology holds strong potential. Hence, the primary objectives of the current study were to explore the mechanism behind the preventative/curative effects of quercetin (QCT) on RAN exacerbated diclofenac sodium (DIC)-induced enteropathic damage and to assess the effects of co-administration of QCT and RAN on DIC-induced gastropathic damage in rats. Rats were treated twice daily with QCT (35, 50 and 100 mg kg-1 PO) and/or RAN (15 mg kg-1 PO) or vehicle for a total of 10 days. In some experiments, DIC (9 mg kg-1) was administered orally twice daily for the final 5 days of RAN/QCT + RAN/vehicle administration. Rats in all the groups were fasted after the last dose on 9th day (free access to water). 12 h after the last dose on 10th day, rats were euthanized and their GI tracts were assessed for haemorrhagic damage, alteration in xanthine oxidase (XO) activity, lipid peroxidation, intestinal permeability and GI luminal pH alterations along with haematological and biochemical estimations. The macroscopic, haematological, biochemical and histological evidences suggested that, though, RAN prevented the DIC-induced gastric injury, it exacerbated enteropathic damage. However, QCT not only significantly attenuated the RAN-induced exacerbation of enteropathic damage caused by DIC at the doses of 50 and 100 mg kg-1, but, this combination provided complete GI safety against the toxic effects of DIC too. The mechanisms behind the gastro-enteroprotective ability of QCT may be related to its ability to inhibit XO activity thus, preventing enhanced oxidative stress on GI tissues, prevent lipid peroxidation, IP alteration and alteration in GI luminal pH. The preventative effects of QCT on NSAID-induced gastroenteropathy were ably supported by the QCT induced prevention of GI blood loss and serum protein loss. These pharmaco-mechanistic results of QCT are aligning to combination based MTDD approach and hence we propose it as a promising lead to treat NSAID-gastroenteropahty and related complications.

Effects of Ayurvedic Rasayana botanicals on CYP3A4 isoenzyme system.

OBJECTIVE: Consuming botanical dietary supplements or herbal drugs along with prescription drugs may lead to potential pharmacokinetic-pharmacodynamic (PK-PD) herb-drug interactions (HDI). The present study focuses on the importance of and novel approach for assessing HDI in integrative medicine with case examples of two frequently-used Ayurvedic Rasayana botanicals. METHODS: The aqueous extracts of Asparagus racemosus (ARE) and Gymnema sylvester (GSE) were prepared as per Ayurvedic Pharmacopoeia of India. Chemoprofiling of these extracts was done using high-performance liquid chromatography (HPLC). Additionally, ARE was characterized for the presence of shatavarins IV and I using HPLC & mass spectroscopy respectively. Effects of ARE and GSE were investigated on rat liver microsome using testosterone probe drug assay. The changes in formation of metabolite (6-ß hydroxy testosterone) were monitored on incubation of testosterone alone, testosterone with ketoconazole, ARE and GSE using HPLC. Half inhibitory concentration (IC50) was used to predict plausible HDI. RESULTS: ARE and GSE showed no inhibition with IC50 values >1 000 µg/mL while the standard inhibitor ketoconazole completely abolished CYP3A4-dependent activity at 0.531 µg/mL and IC50 was found to be 0.036 µg/mL. CONCLUSION: ARE and GSE prepared as per Ayurvedic Pharmacopoeia of India were found to be safe for CYP3A4-mediated inhibitory HDI in rats. Our in vitro study suggests the need of further in vivo investigation for HDI in order to provide clinical relevance.