Quantum Dot Nanomedicine Formulations Dramatically Improve Pharmacological Properties and Alter Uptake Pathways of Metformin and Nicotinamide Mononucleotide in Aging Mice.

Orally administered Ag2S quantum dots (QDs) rapidly cross the small intestine and are taken up by the liver. Metformin and nicotinamide mononucleotide (NMN) target metabolic and aging processes within the liver. This study examined the pharmacology and toxicology of QD-based nanomedicines as carriers of metformin and NMN in young and old mice, determining if their therapeutic potency and reduced effects associated with aging could be improved. Pharmacokinetic studies demonstrated that QD-conjugated metformin and NMN have greater bioavailability, with selective accumulation in the liver following oral administration compared to unconjugated formulations. Pharmacodynamic data showed that the QD-conjugated medicines had increased physiological, metabolic, and cellular potency compared to unconjugated formulations (25× metformin; 100× NMN) and highlighted a shift in the peak induction of, and greater metabolic response to, glucose tolerance testing. Two weeks of treatment with low-dose QD-NMN (0.8 mg/kg/day) improved glucose tolerance tests in young (3 months) mice, whereas old (18 and 24 months) mice demonstrated improved fasting and fed insulin levels and insulin resistance. High-dose unconjugated NMN (80 mg/kg/day) demonstrated improvements in young mice but not in old mice. After 100 days of QD (320 µg/kg/day) treatment, there was no evidence of cellular necrosis, fibrosis, inflammation, or accumulation. Ag2S QD nanomedicines improved the pharmacokinetic and pharmacodynamic properties of metformin and NMN by increasing their therapeutic potency, bypassing classical cellular uptake pathways, and demonstrated efficacy when drug alone was ineffective in aging mice.

Genome-wide association study identifies new susceptibility loci for diabetic nephropathy in Korean patients with type 2 diabetes mellitus.

Genetic factors are considered to be important in the pathogenesis of diabetic nephropathy (DN). Despite several genome-wide association studies (GWASs) demonstrating that specific polymorphisms of candidate genes were associated with DN, there were some limitations in previous studies. We conducted a GWAS using customized DNA chips to identify novel susceptibility loci for DN in Korean. We analyzed a total of 414 DN cases and 474 normoalbuminuric diabetic hyper-controls across two stages using customized DNA chips containing 98 667 single nucleotide polymorphisms (SNPs). We explored the associations between SNPs and DN in samples from 87 DN cases, mostly confirmed by renal biopsy, and 104 diabetic hyper-controls, and replicated these associations in independent cohort samples with 327 DN cases and 370 diabetic hyper-controls. The top significant SNPs from the discovery samples were selected for replication in the independent cohort. rs3765156 in PIK3C2B was significantly associated with DN in the replication cohort after multiple test. The SNPs identified in our study provide new insights into the pathogenesis of DN in the Korean population. Additional studies are needed to determine biological effects and clinical utility of our findings.

Efficacy, safety and albuminuria-reducing effect of gemigliptin in Korean type 2 diabetes patients with moderate to severe renal impairment: A 12-week, double-blind randomized study (the GUARD Study).

AIMS: This multicentre, randomized, double-blind study investigated the efficacy and safety of gemigliptin in Korean type 2 diabetes mellitus (T2DM) patients with moderate to severe renal impairment (RI). METHODS: The study comprised a 12-week main part and a 40-week extension. We report here the results from the main part. In total, 132 patients were randomized to receive gemigliptin (n = 66) or placebo (n = 66). Changes in glycated haemoglobin (HbA1c; primary endpoint), other glycaemic control parameters (fasting plasma glucose, glycated albumin and fructosamine), lipid profiles, renal function parameters and safety profiles were evaluated. RESULTS: Baseline characteristics were comparable between the groups (mean HbA1c, 8.4% [68 mmol/mol]; age, 62.0 years; duration of type 2 diabetes, 16.3 years; estimated glomerular filtration rate, 33.3 mL/min/1.73 m2 ). At Week 12, the adjusted mean change ± standard error in HbA1c with gemigliptin was -0.82% ± 0.14% (-8.9 ± 1.5 mmol/mol), whereas it was 0.38% ± 0.14% (4.2 ± 1.5 mmol/mol) with placebo (significant between-group difference, P < .001). Other glycaemic control parameters showed beneficial changes as well. Body weight change (gemigliptin, -0.3 kg; placebo, -0.2 kg) was not significant. In the gemigliptin group, the mean decrease in urinary albumin creatinine ratio (UACR) was significant, both in patients with microalbuminuria (-41.9 mg/g creatinine, P = .03) and macroalbuminuria (-528.9 mg/g creatinine, P < .001). Drug-related adverse events were similar with gemigliptin and placebo (15% and 12%, respectively). CONCLUSIONS: A 12-week treatment with gemigliptin improved glycaemic control and provided UACR reduction in T2DM patients with moderate to severe RI. Gemigliptin was well tolerated, with no additional risk of hypoglycaemia and change in body weight.

Pharmacokinetic effect of voriconazole on cyclosporine in the treatment of aspergillosis after renal transplantation.

Azole antifungal agents are essential drugs in the treatment of fungal infections in renal transplant patients. As azoles, these antifungal agents are inhibitors of CYP3A4 and P-glycoprotein (P-gp); and thus therapeutic drug monitoring is important. We evaluated a patient with cutaneous and pulmonary aspergillosis who was successfully treated with voriconazole and a low cyclosporine trough level (3.2 - 27.9 ng/ml) for 3 months. During that period, the patient showed good allograft function with the co-administration of voriconazole and cyclosporine. We measured the patient's genotype of MDR1, CYP3A4, CYP3A5 and CYP2C19 enzymes in addition to the intracellular concentration of cyclosporine in peripheral blood mononuclear cells (PBMCs). The intracellular concentration of cyclosporine in PBMC is 3.2 times higher with no functionally defected alleles in MDR1, CYP3A4, CYP3A5 or CYP2C19 enzymes when cyclosporine is co-administered with voriconazole ex vivo. Although other confounding factors causing immunological modulation may exist, it is plausible that low serum and high intracellular cyclosporine concentrations, due to the inhibition of P-gp activity by voriconazole, also contribute to an immunosuppressive state.