A variant of GRK5 is associated with the therapeutic efficacy of repaglinide in Chinese Han patients with type 2 diabetes mellitus.

Post-Market Research We aimed to investigate the impact of G protein-coupled receptor kinase 5 (GRK5) rs10886471 polymorphism on repaglinide efficacy in Chinese patients with type 2 diabetes mellitus (T2DM). A total of 300 T2DM patients and 210 healthy controls were genotyped for GRK5 rs10886471 on a three-dimensional polyacrylamide gel-based DNA microarray. Eighty-five patients with the same genotypes of cytochrome P450 (CYP) 2C8*3 139Arg and organic anion-transporting polypeptide 1B1 (OATP1B1) 521TT were randomly selected to orally take repaglinide for eight consecutive weeks. Then, the biochemical indicators and pharmacodynamic parameters were measured before and after repaglinide treatment. The T allelic frequency of GRK5 rs10886471 was higher in T2DM patients than in healthy subjects (p < .01). T2DM patients with genotypes CC and CT at GRK5 rs10886471 had a significant reduction in terms of fasting plasma glucose (FPG) compared with those with genotype TT (p < .01). In addition, the carriers of genotypes CC and CT at GRK5 rs10886471 had higher differential values of postprandial serum insulin (PINS) compared with genotype TT carriers (p < .05). These findings suggest that GRK5 rs10886471 polymorphism may influence the therapeutic efficacy of repaglinide in Chinese Han T2DM patients.

Optimal dose of cefotaxime in neonates with early-onset sepsis: A developmental pharmacokinetic model-based evaluation.

Objective: The perspective of real-world study is especially relevant to newborns, enabling dosage regimen optimization and regulatory approval of medications for use in newborns. The aim of the present study was to conduct a pharmacokinetic analysis of cefotaxime and evaluate the dosage used in newborns with early-onset sepsis (EOS) using real-world data in order to support the rational use in the clinical practice. Methods: This prospective, open-label study was performed in newborns with EOS. A developmental pharmacokinetic-pharmacodynamic model of cefotaxime in EOS patients was established based on an opportunistic sampling method. Then, clinical evaluation of cefotaxime was conducted in newborns with EOS using real-world data. Results: A one-compartment model with first-order elimination was developed, using 101 cefotaxime concentrations derived from 51 neonates (30.1-41.3°C weeks postmenstrual age), combining current weight and postnatal age. The pharmacokinetic-pharmacodynamic target was defined as the free cefotaxime concentration above MIC during 70% of the dosing interval (70% fT > MIC), and 100% of neonates receiving the dose of 50 mg/kg, BID attained the target evaluated using the model. Additionally, only two newborns had adverse reactions possibly related to cefotaxime treatment, including diarrhea and feeding intolerance. Conclusion: This prospective real-world study demonstrated that cefotaxime (50 mg/kg, BID) had a favorable efficacy and an accepted safety profile for neonates with EOS.

A variation in KCNQ1 gene is associated with repaglinide efficacy on insulin resistance in Chinese Type 2 Diabetes Mellitus Patients.

Repaglinide is an insulin secretagogue that often exhibits considerable interindividual variability in therapeutic efficacy. The current study was designed to investigate the impact of KCNQ1 genetic polymorphism on the efficacy of repaglinide and furthermore to identify the potential mechanism of action in patients with type 2 diabetes. A total of 305 patients and 200 healthy subjects were genotyped for the KCNQ1 rs2237892 polymorphism, and 82 patients with T2DM were randomized for the oral administration of repaglinide for 8 weeks. HepG2 cells were incubated with repaglinide in the absence or presence of a KCNQ1 inhibitor or the pcDNA3.1-hKCNQ1 plasmid, after which the levels of Akt, IRS-2 and PI(3)K were determined. Our data showed that repaglinide significantly decreased HOMA-IR in patients with T2DM. Furthermore, the level of HOMA-IR was significantly reduced in those patients with CT or TT genotypes than CC homozygotes. The KCNQ1 inhibitor enhanced repaglinide efficacy on insulin resistance, with IRS-2/PI(3)K/Akt signaling being up-regulated markedly. As in our clinical experiment, these data strongly suggest that KCNQ1 genetic polymorphism influences repaglinide response due to the pivotal role of KCNQ1 in regulating insulin resistance through the IRS-2/PI(3)K/Akt signaling pathway. This study was registered in the Chinese Clinical Trial Register on May 14, 2013. (No. ChiCTR-CCC13003536).