Current Issue : April - June Volume : 2019 Issue Number : 2 Articles : 5 Articles
The purpose of this study was to investigate the effect of red ginseng extract on the\npharmacokinetics (PK) and efficacy of metformin in streptozotocin-induced diabetic rats. The diabetes\nmellitus rat model was established by intraperitoneally administering multiple doses of streptozotocin\n(30 mg/kg, twice on day 1 and 8), and diabetic rats received metformin 50 mg/kg with or without\nsingle or multiple administration of Korean red ginseng extract (RGE, 2 g/kg/day, once or for 1 week).\nRGE administration did not affect the plasma concentration and renal excretion of metformin. Further,\ndiabetic rats were administered metformin (50 mg/kg) and RGE (2 g/kg) alone or concomitantly for\n5 weeks, and both regimens decreased the fasting blood glucose and glycated hemoglobin (Hb-A1c)\nlevels. Furthermore, fasting blood glucose levels were reduced by metformin or RGE administered\nalone but recovered to the control level following co-administration, suggesting that the effect was\nadditive. However, triglyceride and free fatty acid levels were not different with metformin and\nRGE treatment alone or in combination. Biochemical parameters such as alanine aminotransferase\n(ALT), aspartate aminotransferase (AST), triglycerides, total cholesterol, high-density lipoprotein\n(HDL) cholesterol, low-density lipoprotein (LDL) cholesterol levels were not different among the\nthree treatment groups. In conclusion, RGE and metformin showed an additive effect in glycemic\ncontrol. However, the co-administration of RGE and metformin did not cause PK interactions or affect\nbiochemical parameters including the free fatty acid, triglyceride, AST, ALT, or cholesterol levels....
Paclitaxel (PTX) is an anticancer agent that is used to treat many cancers but it has a very low\noral bioavailability due, at least in part, to the drug efflux transporter, P-glycoprotein (P-gp). Therefore,\nthis study was performed to enhance oral bioavailability of PTX. In this study, we investigated the\neffects of several piperazine derivatives on P-gp function in vitro. Compound 4 was selected as the\nmost potent P-gp inhibitor from the in vitro results for examining the pharmacokinetic (PK) changes\nof PTX in rats. Compound 4 increased the AUCinf of PTX without alterations in the Cmax value.\nThe elimination half-life was extended and the oral clearance decreased. Additionally, the Tmax was\ndelayed or widened in the treatment groups. Therefore, the bioavailability (BA) of PTX was improved\n2.1-fold following the co-administration of 5 mg/kg of the derivative. A piperazine derivative,\ncompound 4, which was confirmed as a substantial P-gp inhibitor in vitro increased the BA of PTX\nup to 2-fold by a lingering absorption, in part due to inhibition of intestinal P-gp and a low oral\nclearance of PTX. These results suggest that co-administering compound 4 may change the PK profile\nof PTX by inhibiting P-gp activity in the body....
Background: 2-Hydroxybenzylamine (2-HOBA) is a selective scavenger of dicarbonyl electrophiles that protects\nproteins and lipids from being modified by these electrophiles. It is currently being developed for use as a\nnutritional supplement to help maintain good health and protect against the development of conditions associated\nwith dicarbonyl electrophile formation, such as the cognitive decline associated with Mild Cognitive Impairment\nand Alzheimerâ??s disease.\nMethods: In this first-in-human study, the safety, tolerability, and pharmacokinetics of six ascending single oral\ndoses of 2-HOBA acetate were tested in eighteen healthy human volunteers.\nResults: Reported adverse events were mild and considered unlikely to be related to 2-HOBA. There were no\nclinically significant changes in vital signs, ECG recordings, or clinical laboratory parameters. 2-HOBA was fairly\nrapidly absorbed, with a tmax of 1â??2 h, and eliminated, with a t1/2 of approximately 2 h. Both tmax and t1/2 were\nindependent of dose level, while Cmax and AUC increased proportionally with dose level.\nConclusions: 2-HOBA acetate was safe and well-tolerated at doses up to 825 mg in healthy human volunteers,\npositioning it as a good candidate for continued development as a nutritional supplement.\nTrial registration: This study is registered at ClinicalTrials.gov (NCT03176940)....
Biologicals are important ocular drugs that are be delivered using monthly and bimonthly\nintravitreal injections to treat retinal diseases, such as age-related macular degeneration. Long acting\ndelivery systems are needed for prolongation of their dosing interval. Intravitreal biologicals are\neliminated from the eye via the aqueous humor outflow. Thus, the anterior and posterior segments are\nexposed to the drug. We utilized a kinetic simulation model to estimate protein drug concentrations\nin the vitreous and aqueous humor after bolus injection and controlled release administration to the\nvitreous. The simulations predicted accurately the experimental levels of 5 biologicals in the vitreous\nand aqueous humor. The good match between the simulations and experimental data demonstrated\nalmost complete anterior segment bioavailability, and major dose sparing with ocular controlled\nrelease systems. Overall, the model is a useful tool in the design of intraocular delivery of biologicals...
Background: Several tyrosine kinase inhibitors (TKIs) developed as anti-cancer drugs, also have anti-viral activity\ndue to their ability to disrupt productive replication and dissemination in infected cells. Consequently, such drugs\nare attractive candidates for â??repurposingâ? as anti-viral agents. However, clinical evaluation of therapeutics against\ninfectious agents associated with high mortality, but low or infrequent incidence, is often unfeasible. The United\nStates Food and Drug Administration formulated the â??Animal Ruleâ? to facilitate use of validated animal models for\nconducting anti-viral efficacy studies.\nMethods: To enable such efficacy studies of two clinically approved TKIs, nilotinib, and imatinib, we first conducted\ncomprehensive pharmacokinetic (PK) studies in relevant rodent and non-rodent animal models. PK of these agents\nfollowing intravenous and oral dosing were evaluated in C57BL/6 mice, prairie dogs, guinea pigs and Cynomolgus\nmonkeys. Plasma samples were analyzed using an LC-MS/MS method. Secondarily, we evaluated the utility of\nallometry-based inter-species scaling derived from previously published data to predict the PK parameters, systemic\nclearance (CL) and the steady state volume of distribution (Vss) of these two drugs in prairie dogs, an animal model\nnot tested thus far.\nResults: Marked inter-species variability in PK parameters and resulting oral bioavailability was observed. In general,\nelimination half-lives of these agents in mice and guinea pigs were much shorter (1â??3 h) relative to those in larger\nspecies such as prairie dogs and monkeys. The longer nilotinib elimination half-life in prairie dogs (i.v., 6.5 h and\noral, 7.5 h), facilitated multiple dosing PK and safety assessment. The allometry-based predicted values of the Vss\nand CL were within 2.0 and 2.5-fold, respectively, of the observed values.\nConclusions: Our results suggest that prairie dogs and monkeys may be suitable rodent and non-rodent species to\nperform further efficacy testing of these TKIs against orthopoxvirus infections. The use of rodent models such as\nC57BL/6 mice and guinea pigs for assessing pre-clinical anti-viral efficacy of these two TKIs may be limited due to\nshort elimination and/or low oral bioavailability. Allometry-based correlations, derived from existing literature data,\nmay provide initial estimates, which may serve as a useful guide for pre-clinical PK studies in untested animal\nmodels....
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