MATERIALS AND METHODS: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2- period crossover study with a washout period of 7 days. All 28 adult male subjects were required to fast for at least 10 hours prior to drug administration and they were given access to water ad libitum during this period. Thirty minutes prior to dosing, all subjects were served with a standardized high-fat and high-calorie breakfast with a total calorie of 1000 kcal which was in accordance to the EMA Guideline on the Investigation of Bioequivalence. Subsequently, subjects were administered either the test or reference preparation with 240mL of plain water in the first trial period. During the second trial period, they received the alternate preparation. Plasma levels of glibenclamide and metformin were analysed separately using two different high performance liquid chromatography methods.

RESULTS: The 90% confidence interval (CI) for the ratio of the AUC0-t, AUC0-∞, and Cmax of the test preparation over those of the reference preparation were 0.9693-1.0739, 0.9598- 1.0561 and 0.9220 - 1.0642 respectively. Throughout the study period, no serious drug reaction was observed. However, a total of 26 adverse events (AE)/side effects were reported, including 24 that were definitely related to the study drugs, namely giddiness (n=17), while diarrheoa (n=3), headache (n=2) and excessive hunger (n=2) were less commonly reported by the subjects.

MATERIALS AND METHODS: Analysis of metformin and sildenafil (SIL) from rat plasma was done by high performance liquid chromatography. Optimum chromatographic separation and quantification of MET, SIL and Cetirizine was achieved on Phenomenex EVO C18 column with triethyl amine (0.3%): Methanol: Acetonitrile (70:05:25 v/v) as mobile phase maintaining flow rate of 1 ml/min, the detector was tuned at 224 nm. The extraction of MET and sildenafil from rat plasma was achieved by solid-phase extraction using Strata-X cartridges. The method was validated as per the ICH guidelines. For docking studies, the crystal structure of organic cation transporter 1 (OCT1) protein and multidrug and toxin extrusion (MATE) protein (5XJJ) were downloaded from the PubChem database. The docking study was performed by PyRx virtual screening software, and the results were analyzed by BIOVIA Discovery Studio.

RESULTS: The validation of HPLC method was done, intraday and interday precision study of HPLC method demonstrated %RSD values less than 5%, the extraction recovery for MET and SIL were near to 80 % for low, medium and high QC samples. The plasma stability of MET and SIL showed % RSD values <10% for low, medium, and high QC samples. A sensitivity study for MET and SIL in rat plasma suggested a lower limit of quantification values of 8 and 10 ng/mL, respectively. The pharmacokinetic parameters were recorded, Cmax of experimental and control rats was 611.2 and 913.2 ng/mL; t1/2 1.66 and 1.98, AUC (0-t) 1637.5 and 2727.24, AUC (0-∞) 1832.38 and 2995.24 for MET. The results suggested that the Cmax of MET in experimental rats (MET + SIL) was 33.07% lower than the control (MET only) and also the t1/2 was 0.32 h shorter. Docking analysis suggested a higher binding affinity of sildenafil with MATE protein (5XJJ) compared to OCT1, suggesting possible involvement of MATE family proteins for pharmacokinetic alterations of MET.

METHODS: Subjects (n = 121) received oral repaglinide (4 mg). Blood samples were taken at 0, 30, 60, 120, 180 and 240 min and serum concentrations of repaglinide were determined using high-performance liquid chromatography. Subjects were also genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for CYP3A4*4, *5 and*18 and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles.

RESULTS: The allele frequencies of CYP2C8*1, *2, *3, *4 and *5 were 95.04, 0.40, 0.40, 0 and 4.13%, respectively. The frequencies of the CYP3A4*1, *4, *5 and *18 alleles were 97.93, 0, 0 and 2.07%, respectively. CYP2C8 and CYP3A4 genotypes were not significantly associated with repaglinide's blood glucose-lowering effect. However, the CYP3A4 genotype significantly influenced some of repaglinide's pharmacokinetics, where the mean elimination rate constant was 44.0% lower (p = 0.04) and the mean half-life was 33.8% higher (p = 0.04) in subjects with the CYP3A4*1/*18 genotype as compared to those with the normal CYP3A4*1/*1 genotype. This result confirms that CYP3A4 plays a large role in metabolizing repaglinide.

AIM OF THE REVIEW: The present review aims to compile an up-to-date information on the progress made in the protective role of swertiamarin in cardiac and metabolic diseases with the objective of providing a guide for future research on this bioactive molecule.

MATERIALS AND METHODS: Information on the swertiamarin was collected from major scientific databases (Pubmed, Springer, google scholar, and Web of Science) for publication between1974-2016. In this review, the protective role of swertiamarin on cardiac and metabolic diseases was discussed.

RESULTS: Swertiamarin reported to exhibit a wide range of biological activities such as anti-atherosclerotic, antidiabetic, anti-inflammatory and antioxidant effects. These activities were mainly due to its effect on various signaling pathways associated with cardiac remodeling events such as inhibition of NF-kB expression, LDL oxidation, apoptosis, inflammatory and lipid peroxidation markers and stimulation of antioxidant enzymes.