- Synthesis and molecular modeling of novel non-sulfonylureas as hypoglycemic agents and selective ALR2 inhibitors. [Journal Article]
- BMBioorg Med Chem 2019 Jun 13
- Novel non-sulfonylureas derivatives bearing an acetamide linker between a spirohydantoin scaffold and a phenyl ring were prepared and their hypoglycemic activity was estimated in vivo. Their abilitie…
Novel non-sulfonylureas derivatives bearing an acetamide linker between a spirohydantoin scaffold and a phenyl ring were prepared and their hypoglycemic activity was estimated in vivo. Their abilities to discriminate in vitro between aldehyde reductase (ALR1) and aldose reductase (ALR2) were determined. The molecular docking and the in silico prediction studies were performed to rationalize the obtained biological results and to predict the physicochemical properties and drug-likeness scores of the new compounds. N-(2,4-Dichlorophenyl)-2-(2',4'-dioxospiro[fluorene-9,5'-imidazolidine]-3'-yl)acetamide (3e) displayed an 84% reduction in blood glucose level superior to that of repaglinide 66% and showed an IC50 value of 0.37 μM against ALR2 that is superior to that of sorbinil 3.14 µM. Compound (3e) was selective 96 fold towards ALR2 which is closely related to serious diabetic complications. Based on the identification of this hit candidate, a new generation of safe and effective antidiabetic agents could be designed.
- Risk of Hypoglycemia and Concomitant Use of Repaglinide and Clopidogrel:A Population-Based Nested Case-Control Study. [Journal Article]
- CPClin Pharmacol Ther 2019 Jun 19
- This nested case-control study evaluated the potential interaction between repaglinide and clopidogrel. Cases were defined by inpatient admissions or emergency room visits due to hypoglycemia. Concom…
This nested case-control study evaluated the potential interaction between repaglinide and clopidogrel. Cases were defined by inpatient admissions or emergency room visits due to hypoglycemia. Concomitant use of repaglinide and clopidogrel within 3 days before the hypoglycemic event was the exposure of interest. For each case, up to four controls were randomly selected and matched by age, sex, type of glinide used (repaglinide or nateglinide), and time since cohort entry to the index date. Hypoglycemic risk was estimated by conditional logistic regressions. Concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared to repaglinide alone (AOR: 2.42 95% CI: 1.75, 3.35). No significant associations were found with the two negative control object drug concomitants: nateglinide and clopidogrel and repaglinide and aspirin (without clopidogrel use). Our study suggests drug interaction between clopidogrel and repaglinide is clinically relevant and could increase the risk for hypoglycemia. This article is protected by copyright. All rights reserved.
- Improved oral bioavailability of repaglinide, a typical BCS Class II drug, with a chitosan-coated nanoemulsion. [Journal Article]
- JBJ Biomed Mater Res B Appl Biomater 2019 Jun 12
- The aim of the present study was to develop modified nanoemulsions to improve the oral bioavailability and pharmacokinetics of a poor water-soluble drug, repaglinide (RPG). The repaglinide-loaded nan…
The aim of the present study was to develop modified nanoemulsions to improve the oral bioavailability and pharmacokinetics of a poor water-soluble drug, repaglinide (RPG). The repaglinide-loaded nanoemulsions (RPG-NEs) were prepared from olive oil as internal phase, span 80, tween 80, and poloxamer 188 as emulsifiers, using homogenization technique. The mean droplet size, zeta potential, and entrapment efficiency of RPG-NEs were 86.5 ± 3.4 nm, -33.8 ± 2.1 mV, and 96.3 ± 2.3%, respectively. The chitosan-coated RPG-NEs (Cs-RPG-NEs) showed an average droplet size of 149.3 ± 3.9 nm and a positive zeta-potential of +31.5 ± 2.8 mV. Drug release profile of RPG-NEs was significantly higher than free drug in the simulated gastrointestinal fluids (p < .005). The in vivo study revealed 3.51- and 1.78-fold increase in the AUC0-12h and Cmax of the drug, respectively, in RPG-NEs-receiving animals in comparison to the free drug. The pharmacokinetic analysis confirmed that Cs-RPG-NEs were more efficient than uncoated ones for the oral delivery of RPG. Cs-RPG-NEs showed a longer t1/2 and higher AUC0-∞ compared to control group. The relative bioavailability of Cs-RPG-NEs was higher than that of uncoated RPG-NEs and free drug. Collectively, these findings suggest that chitosan-coated nanoemulsions are promising carrier for improving the oral bioavailability of RPG.
- Physiologically Based Pharmacokinetic Models for Prediction of Complex CYP2C8 and OATP1B1 (SLCO1B1) Drug-Drug-Gene Interactions: A Modeling Network of Gemfibrozil, Repaglinide, Pioglitazone, Rifampicin, Clarithromycin and Itraconazole. [Journal Article]
- CPClin Pharmacokinet 2019 May 25
- CONCLUSIONS: Whole-body PBPK models of gemfibrozil, repaglinide, and pioglitazone have been built and qualified for DDI and DGI prediction. PBPK modeling is applicable to investigate complex interactions between multiple drugs and genetic polymorphisms.
- The Importance of Precision Medicine in Type 2 Diabetes Mellitus (T2DM): From Pharmacogenetic and Pharmacoepigenetic Aspects. [Journal Article]
- EMEndocr Metab Immune Disord Drug Targets 2019 Feb 27
- CONCLUSIONS: Taken everything into the consideration, there is an extreme need to determine the genetic status of T2DM patients in some known genetic region before planning the medication strategies.
- A Variation in the ABCC8 gene is Associated with Type 2 Diabetes Mellitus and Repaglinide Efficacy in Chinese Type 2 Diabetes Mellitus Patients. [Journal Article]
- IMIntern Med 2019 May 22
- Background Previous studies have suggested that variations in the ABCC8 gene may be closely associated with T2DM susceptibility and repaglinide response. However, these results have not been entirely…
Background Previous studies have suggested that variations in the ABCC8 gene may be closely associated with T2DM susceptibility and repaglinide response. However, these results have not been entirely consistent, and there are no related studies in a Chinese population, suggesting the need for further exploration. Objective The current study investigated the associations of the ABCC8 rs1801261 polymorphism with type 2 diabetes mellitus (T2DM) susceptibility and repaglinide therapeutic efﬁcacy in Chinese Han T2DM patients. Methods A total of 234 T2DM patients and 105 healthy subjects were genotyped for ABCC8 rs1801261 polymorphism by a polymerase chain reaction-restriction fragment length polymorphism assay. A total of 70 patients with the same genotypes of CYP2C8*3 139Arg and OATP1B1 521TT were randomized to orally take 3 mg repaglinide per day (1 mg each time before meals) for 8 consecutive weeks. The pharmacodynamic parameters of repaglinide and biochemical indicators were then determined before and after repaglinide treatment. Results The frequency of ABCC8 rs1801261 allele was higher in T2DM patients than in the control subjects (22.6% vs.11.0%, p<0.01). After repaglinide treatment, T2DM patients carrying genotype CT showed a signiﬁcantly attenuated efﬁcacy on FPG (p<0.01) and HbA1c (p<0.01) compared with those with genotype CC. Conclusion These results suggested that the ABCC8 rs1801261 polymorphism might inﬂuence T2DM susceptibility and the therapeutic effect of repaglinide in Chinese Han T2DM patients. This study was registered in the Chinese Clinical Trial Register on May 14, 2013 (No. ChiCTR-CCC13003536).
- Short-term efficacy and safety of repaglinide versus glimepiride as augmentation of metformin in treating patients with type 2 diabetes mellitus. [Journal Article]
- DMDiabetes Metab Syndr Obes 2019; 12:519-526
- CONCLUSIONS: These results indicated that the repaglinide plus metformin might have some advantages over glimepiride plus metformin in the short-term treatment of patients with T2DM, and should be further explored.
- Comparison of mortality and cardiovascular event risk associated with various insulin secretagogues: A nationwide real-world analysis. [Journal Article]
- DRDiabetes Res Clin Pract 2019; 152:103-110
- CONCLUSIONS: For patients with diabetes taking an insulin secretagogue, glimepiride was associated with the best clinical outcome, showing the lowest mortality and cardiovascular event risk.
- An Investigation into the Role of P-Glycoprotein in the Intestinal Absorption of Repaglinide: Assessed by Everted Gut Sac and Caco-2 Cell Line. [Journal Article]
- IJIran J Pharm Res 2019; 18(1):102-110
- The present study aimed at exploring the potential of the P-glycoprotein (P-gp) transporters as a barrier to the repaglinide (REG) epithelial permeability. In-vitro intestinal absorption models, the …
The present study aimed at exploring the potential of the P-glycoprotein (P-gp) transporters as a barrier to the repaglinide (REG) epithelial permeability. In-vitro intestinal absorption models, the everted gut sac, and Caco-2 cell line, were used to study the possible role of P-gp in intestinal transport of REG. In the everted gut sacs, apparent permeability coefficients showed cargo concentration dependency transport over the concentration of 40 µM, indicating involvement of a saturable mechanism in REG absorption (Papp were 1.23 × 10 -5 and 3.29 × 10 -5 at drug concentrations of 40 and 100 μM, respectively). Adding verapamil (100 μM), valspodar (5 μM) and ketoconazole (10 μM) significantly enhanced the permeability of REG across mucosal to serosal in the rat jejunum (P < 0.05) suggesting role of CYP 3A4 and/or efflux transporters in oral bioavailability of REG. However, the results of Caco-2 cell experiments indicated low efflux ratios (less than 2) and insignificant involvement of P-gp efflux pumps in REG intestinal transport. Given that Caco-2 cells do not express adequate level of CYP 3A4, the current study suggests that the presystemic metabolism by cytochrome P450 (and not ejection by P-gp) may play a significant role in limiting the oral absorption of REG in small intestine.
New Search Next
- Targeting the neuronal calcium sensor DREAM with small-molecules for Huntington's disease treatment. [Journal Article]
- SRSci Rep 2019 May 13; 9(1):7260
- DREAM, a neuronal calcium sensor protein, has multiple cellular roles including the regulation of Ca2+ and protein homeostasis. We recently showed that reduced DREAM expression or blockade of DREAM a…
DREAM, a neuronal calcium sensor protein, has multiple cellular roles including the regulation of Ca2+ and protein homeostasis. We recently showed that reduced DREAM expression or blockade of DREAM activity by repaglinide is neuroprotective in Huntington's disease (HD). Here we used structure-based drug design to guide the identification of IQM-PC330, which was more potent and had longer lasting effects than repaglinide to inhibit DREAM in cellular and in vivo HD models. We disclosed and validated an unexplored ligand binding site, showing Tyr118 and Tyr130 as critical residues for binding and modulation of DREAM activity. IQM-PC330 binding de-repressed c-fos gene expression, silenced the DREAM effect on KV4.3 channel gating and blocked the ATF6/DREAM interaction. Our results validate DREAM as a valuable target and propose more effective molecules for HD treatment.