oxadiazoles and Hypoglycemia

G protein-coupled receptor 119 (GPR119) is a promising target for the treatment of type 2 diabetes mellitus (T2DM), as both insulin and glucagon-like peptide-1 secretion can be promoted with a single drug. We compared the efficacy and safety of the GPR119 agonist DS-8500a with placebo and sitagliptin 50 mg in Japanese patients with T2DM.. DS-8500a demonstrated dose-dependent HbA1c lowering compared with placebo at week 12: change from baseline - 0.23% (p = 0.0173), - 0.37% (p = 0.0001), and - 0.44% (p < 0.0001) in the 25-mg, 50-mg, and 75-mg groups, respectively. At 50- and 75-mg doses, DS-8500a significantly lowered FPG, glucose AUC. DS-8500a was well tolerated and demonstrated significant glucose-lowering effects and favorable changes in lipid profiles up to 12 weeks in Japanese patients with T2DM.. Daiichi Sankyo Co. Ltd.

Topics: Adult; Aged; Benzamides; Cyclopropanes; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Japan; Male; Middle Aged; Oxadiazoles; Receptors, G-Protein-Coupled; Sitagliptin Phosphate; Treatment Outcome

Deficiency of carnitine palmitoyltransferase 1A (CPT1A) results in impaired hepatic long-chain fatty acid oxidation and ketogenesis. We have previously described a patient with a severe CPT1A phenotype who is homozygous for the nonsense mutation 478 C > T (R160X). It has been known for some time that gentamicin can promote readthrough of nonsense codons. Recently, a new compound (PTC124) with less clinical toxicity than gentamicin has been indicated as a therapy for patients with nonsense mutations for multiple genetic diseases. The study is designed to investigate whether PTC124 can promote readthrough of the R160X CPT1A mutation and increase normal sized CPT1 protein expression and activity in the patient's skin fibroblasts. Our study demonstrated that after both PTC 124 and gentamicin treatment, there was an increase in CPT1 activity in patient fibroblasts to levels that are similar to that of the mild Inuit P479L variant. Our results provide additional evidence for proof of principle that PTC124 is a potential therapeutic agent for treating patients with any genetic condition that results from a nonsense mutation.

Topics: Carnitine O-Palmitoyltransferase; Child, Preschool; Codon; Codon, Nonsense; Fatty Acids; Female; Fibroblasts; Gentamicins; Homozygote; Humans; Hyperammonemia; Hypoglycemia; Ketones; Liver Diseases; Mutation; Oxadiazoles; Oxygen; Phenotype; Skin