Clinical Pharmacokinetic Drug Interaction Potential of MenoAct851 in Adult, Female Healthy Volunteers.

BACKGROUND: MenoAct851 (Varanasi BioResearch Pvt. Ltd., Varanasi, India) is a patented polyherbal formulation developed to manage menopause symptoms that can be taken along with other allopathic medicines. OBJECTIVE: The present study aims to evaluate the drug interaction potential of MenoAct851 to inhibit cytochrome (CY) P450 in vitro in rats, and to measure its effects on simvastatin pharmacokinetic parameters in healthy human volunteers. METHODS: CYP450-carbon monoxide assay of MenoAct851 was performed in rat liver microsomes to calculate the percentage inhibition. Fluorometric assays of CYP3A4 and CYP2D6 determined half maximal inhibitory concentration value. A double-blind, randomized, placebo-controlled drug interaction study of MenoAct851 was conducted in 24 healthy adult female volunteers aged 25 to 50 years. The selected volunteers were randomized to receive placebo or MenoAct851 500 mg BID PO for 14 days. On the 15th day, each group received 40 mg single-dose simvastatin. Blood samples were drawn at different intervals to measure simvastatin pharmacokinetic parameters. RESULTS: The mean (SD) CYP450 concentration of the diluted microsome sample was calculated and found to be 0.405 (0.12) nmol/mg. The inhibitory potential of MenoAct851 (41.16% [1.24%]) was found to be less than ketoconazole. Half maximal inhibitory concentration values of MenoAct851 on CYP3A4 and CYP2D6 were 11.96 (1.04) µg/mL and 15.24 (0.58) µg/mL, respectively, but they were higher than respective positive controls. There was no statistically significant difference between MenoAct851 and placebo groups concerning the pharmacokinetic parameters such as Cmax, Tmax, t½, and mean residence time of simvastatin; however, AUC showed a significant difference (P < 0.05) between the groups. CONCLUSIONS: MenoAct851 produced weaker interaction potential with CYP3A4 and CYP2D6 substrates based on in vitro assays, but the findings of clinical pharmacokinetic analysis indicate that MenoAct851 increased the AUC of simvastatin and simvastatin hydroxy acid. Therefore, coadministration of MenoAct851 might lead to drug-herb interaction, thereby affecting the therapeutic effect of CYP3A4 substrates. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Comparative pharmacokinetic study of mangiferin after oral administration of pure mangiferin and US patented polyherbal formulation to rats.

The US patented polyherbal formulation for the prevention and management of type II diabetes and its vascular complications was used for the present study. The xanthone glycoside mangiferin is one of the major effector constituents in the Salacia species with potential anti-diabetic activity. The pharmacokinetic differences of mangiferin following oral administration of pure mangiferin and polyherbal formulation containing Salacia species were studied with approximately the same dose 30 mg/kg mangiferin and its distribution among the major tissue in Wistar rats. Plasma samples were collected at different time points (15, 30, 60, 120, 180, 240, 360, 480, 600, 1,440, 2,160, and 2880 min) and subsequently analyzed using a validated simple and rapid LC-MS method. Plasma concentration versus time profiles were explored by non-compartmental analysis. Mangiferin plasma exposure was significantly increased when administered from formulation compared to the standard mangiferin. Mangiferin resided significantly longer in the body (last mean residence time (MRTlast)) when given in the form of the formulation (3.65 h). Cmax values of formulation (44.16 µg/mL) administration were elevated when compared to equivalent dose of the pure mangiferin (15.23 µg/mL). Tissue distribution study of mangiferin from polyherbal formulation was also studied. In conclusion, the exposure of mangiferin is enhanced after formulation and administration and could result in superior efficacy of polyherbal formulation when compared to an equivalent dose of mangiferin. The results indicate that the reason which delays the elimination of mangiferin and enhances its bioavailability might the interactions of the some other constituents present in the polyherbal formulation. Distribution study results indicate that mangiferin was extensively bound to the various tissues like the small intestine, heart, kidney, spleen, and liver except brain tissue.

In Silico and In Vitro Screening of Natural Compounds as Broad-Spectrum ß-Lactamase Inhibitors against Acinetobacter baumannii New Delhi Metallo-ß-lactamase-1 (NDM-1).

Antibiotic resistance is one of the significant problems globally; there is an increase in resistance with introducing every new class of antibiotics. Further, this has become one of the reasons for arising of new resistance mechanisms in Acinetobacter baumannii. In this study, we have screened natural compounds as a possible inhibitor against the NDM-1 ß-lactamase enzyme from A. baumannii using a combination of in silico methods and in vitro evaluation. The database of natural compounds was screened against NDM-1 protein, using Glide docking, followed by QM-polarised ligand docking (QPLD). When the screened hits were validated in vitro, withaferin A and mangiferin had good IC50 values in reducing the activity of NDM-1 enzymes, and their fractional inhibitory concentration index (FICI) was ascertained in combination with imipenem. The withaferin A and mangiferin-NDM-1 docking complexes were analyzed for structural stability by molecular dynamic simulation analysis using GROMACS for 100 ns. The molecular properties of the natural compounds were then calculated using density functional theory (DFT). Withaferin A and mangiferin showed promising inhibitory activity and can be a natural compound candidate inhibitor synergistically used along with carbapenems against NDM-1 producing A. baumannii.

Impact of Pseudomonas putida RRF3 on the root transcriptome of rice plants: Insights into defense response, secondary metabolism and root exudation.

Pseudomonas putida is widely used as a biocontrol agent, however, mechanisms by which it initiates the plants' defense response remains obscure. To gain an insight into the molecular changes that occur in plants upon plant growth-promoting rhizobacteria colonization, root transcriptome analysis by using a microarray was performed in rice using P. putida RRF3 (a rice rhizosphere isolate). Data analysis revealed a differential regulation of 61 transcripts (48 h post-treatment), of which, majority corresponded to defense response, cell wall modification and secondary metabolism. Seven genes encoding salicylic acid (SA) responsive pathogenesis-related proteins were up-regulated significantly (fold change ranges from 1 to 4), which suggests that RRF3 has a profound impact on a SA-mediated defense signaling mechanism in rice. Investigations performed at later stages of RRF3 colonization by real-time polymerase chain reaction and high-performance liquid chromatography (HPLC) analysis confirmed the above results, demonstrating RRF3 as a potent biocontrol agent. Further, the impact of RRF3 colonization on root exudation, in particular, exudation of SA was investigated by HPLC. However, analysis revealed RRF3 to have a negative impact on root exudation of SA. Overall, this study shows that P. putida RRF3 immunizes the rice plants by re-organizing the root transcriptome to stimulate plant defense responses ('priming'), and simultaneously protects itself from the primed plants by altering the rhizosphere chemical constituents.

Comparative pharmacokinetic interactions of Quercetin and Rutin in rats after oral administration of European patented formulation containing Hipphophae rhamnoides and Co-administration of Quercetin and Rutin.

Quercetin and Rutin are most common flavone constituents of some herb extracts such as Hippophae rhamnoides L. Inter and intra herb pharmacokinetics interactions of Quercetin and Rutin were investigated in the present study. Pharmacokinetic study was investigated in the two groups of rats (n = 6) for pharmacokinetic interactions between the Quercetin and Rutin (2.5 mg/kg) mixture treated alone with European patented polyherbal formulation containing equivalent weight of the above. The total plasma concentrations of Quercetin and Rutin were determined by liquid chromatography mass spectrometry (LC-MS). A method was developed and validated according to the ICH guidelines. The results of the present study shows that there are great differences in the pharmacokinetics of Quercetin and Rutin when they are administered together and from the polyherbal formulation which will be interacted by many other constituents. The bioavailability of Quercetin was lowered from the polyherbal formulation when compared with the co-administration, whereas the Rutin bioavailability has increased from the polyherbal formulation when compared with the co-administration. The maximum plasma concentration of Quercetin from coadministration and polyherbal formulation was 165.3 ± 31.9 and 90.8 ± 21.4 ng/mL, respectively, whereas in the case of Rutin it was 61.1 ± 29.3 and 121.7 ± 19.2 ng/mL. After polyherbal formulation administration to rats the AUC0-24, AUC0-∞ and AUMC0-∞ of both Quercetin and Rutin significantly increased when compared to co-administration. The above results proved that inter and intra herb pharmacokinetic interactions between Quercetin and Rutin. Possible interactions of the other constituents with hydrolyzing enzymes in the formulation enhances the oral bioavailability of Rutin. Accordingly besides the drug herb interactions, inter and intra herb interaction might be brought into view with the wide use of herbal remedies.