Supercritical carbon dioxide extracts of small cardamom and yellow mustard seeds have fasting hypoglycaemic effects: diabetic rat, predictive iHOMA2 models and molecular docking study.

In the present investigation, the supercritical carbon dioxide (SC-CO2) extracts of small cardamom (SC) and yellow mustard (YM) seeds have been investigated for their efficacies in combating type 2 diabetes in streptozotocin-induced Wistar albino rats. Fasting blood glucose (FBG) levels in the rats were monitored on days 8, 15 and 21. On day 15, FBG level reduced appreciably by 31·49 % in rats treated with SC seed extract and by 32·28 % in rats treated with YM seed extract, comparable to metformin (30·70 %) and BGR-34 (a commercial polyherbal drug) (31·81 %) administered rats. Either extract exhibited desirable effects on hepatic glucose-6-phosphatase, glucose-6-phosphate dehydrogenase (G6PD) and catalase activities in controlling diabetes. A molecular docking exercise was conducted to identify specific compounds in the extracts which possessed augmenting effect on G6PD. The results revealed that all the bioactive compounds in the extracts have binding affinities with the enzyme and contributed to the antidiabetic efficacies of the extracts as G6PD augmenters. The effects of the extracts on insulin sensitivity and glucose uptake were investigated using non-invasive modelling by iHOMA2 software. This in vitro approach indicated that extract administration resulted in increased both insulin sensitivity of the liver and glucose uptake in the gut. The findings of the present study attest these SC-CO2 extracts of the spices as safe alternatives of metformin and BGR-34 in combating type 2 diabetes and could be safely subjected to clinical studies. These extracts could also be employed in designing proactive food supplements in mitigating the metabolic disorder.

Nanoliposomes of Supercritical Carbon Dioxide Extract of Small Cardamom Seeds Redresses Type 2 Diabetes and Hypercholesterolemia.

BACKGROUND & OBJECTIVES: In our previous investigation, oral administration of 1,8- cineole-rich supercritical carbon dioxide extract of small cardamom seeds in Wistar albino rats resulted in achieving normal fasting blood glucose (FBG) and serum cholesterol levels. The objective of this study was to further protect the aforesaid extract and to enhance its in vivo therapeutic efficacies in redressing type 2 diabetes and hypercholesterolemia, by encapsulating it as nanoliposomes. Patents related to nanoliposomes have been revised thoroughly. METHODS: PEGylated nanoliposomes of the aforesaid extract were formulated using soya phosphatidylcholine and Tween 80 by probe-sonication. These nanoliposomes were subjected to in vitro characterizations and were orally administered to Wistar albino rats at three different doses viz. 550, 175 and 55 mg/kg b.w. for detailed investigation of their antidiabetic and hypocholesterolemic efficacies. RESULTS: FT-IR, DSC and XRD analyses, HLB value (16), entrapment efficiency (84%) and release kinetics (obeying Higuchi model) revealed that the nanoliposomes were o/w type and were hydrophilic. They exhibited appreciable in vitro antioxidant potency (59% DPPH scavenging activity) owing to a synergistic consortium of antioxidants present therein. Oral administration of the liposomes in rats at 550 mg/kg b.w. could restore their normal FBG levels and serum lipid profiles on day 35, with desirable up-down regulations of related key enzymes. The iHOMA2 model could successfully predict the effects of nanoliposomes on insulin sensitivity and glucose uptake in rat liver and brain, respectively. CONCLUSION: Nanoliposome of 1,8-cineole rich extract of small cardamom seeds is a new biotherapeutic in redressing type 2 diabetes and hypercholesterolemia.

LC-MS/MS assay for quantitation of enalapril and enalaprilat in plasma for bioequivalence study in Indian subjects.

BACKGROUND: Enalapril (EPL) is an angiotensin-converting enzyme inhibitor for the treatment of hypertension and chronic heart failure. Enalaprilat (EPLT) is an active metabolite that contributes to the overall activity of EPL. AIM: To quantitate EPL along with its metabolite EPLT using LC-MS/MS, a bioanalytical method was developed and validated with tolbutamide in human plasma using a protein precipitation technique. RESULTS: The sensitive and selective method has an LLOQ of 1 ng/ml with a linearity range of 1-500 ng/ml for both EPL and EPLT using 300 µl of plasma without any matrix effect. CONCLUSION: Linearity, specificity, accuracy, precision and stability, as well as its application to the analysis of plasma samples after oral administration of 20 mg of EPL maleate in healthy volunteers demonstrate applicability to bioavailability/bioequivalence studies.

Pharmacokinetics, pharmacodynamics and toxicity of a combination of metoprolol succinate and telmisartan in Wistar albino rats: safety profiling.

Metoprolol succinate (MET), a cardioselective ß blocker and telmisartan (TEL), an angiotensin receptor blocker were administered orally, both individually and in combination to Wistar albino rats for evaluation of their pharmacokinetics, pharmacodynamics and repeated dose oral toxicity (28 days). Pharmacokinetic study was performed by analyzing drug concentration in plasma by a developed and validated LC-MS/MS method following oral administration of MET and TEL at 2.5 mg/kg and 2.0 mg/kg dose, respectively, both individually and in combination. Antihypertensive activity of MET and TEL in above dose and manner was evaluated on artificially induced hypertension on laboratory animals. In repeated dose oral toxicity study, MET (60, 120 and 240 mg/kg/day) and/or TEL (12, 24 and 48 mg/kg/day) were administered to animals for 28 days followed by a recovery period of 14 days. Pharmacokinetic data revealed the probable absence of any pharmacokinetic interaction when co-administered. Improved blood pressure lowering effect was observed by combination therapy. Moreover, toxic effects obtained at high dose level of each treatment groups were transient and reversible and no evidence of additive toxic effects were observed due to concomitant administration. So, this combination can primarily be stated as safe which will be confirmed after clinical interaction studies in humans.

Convulsant activity and pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effect of gemifloxacin in rats.

A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to investigate the epileptogenic activity of gemifloxacin as a representative antibiotic with concentration-dependent antimicrobial activity. Rats received an intravenous infusion of gemifloxacin at a rate of 4 mg kg of body weight(-1) min(-1) over 50 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. An important delay was observed between concentrations of gemifloxacin in plasma and the EEG effect; this effect was accompanied by tremors and partial seizures. Indirect effect models failed to describe these data, which were successfully fitted by using an effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site. The robustness of the PK-PD model was then assessed by keeping the dose constant but increasing the duration of infusion to 100 and 200 min. Although this was accompanied by PK modifications, PD parameters did not vary significantly, and the PK-PD model still applied. In conclusion, the successful PK-PD modeling of the gemifloxacin EEG effect in rats should be considered to predict and reduce the epileptogenic risk associated with this antibiotic as a representative fluoroquinolone.