Pharmacology Research & Perspectives最新文献

Considering the importance of pain and stress, we decided to investigate the intra-anterior cingulate cortex (ACC) microinjection of histamine and mepyramine alone and concurrently on acute pain induced by hot plate following restraint stress in male rats. 24-gauge, 10 mm stainless steel guide cannula was implanted over the ACC in the incised scalp of 4 groups. Restraint stress in healthy rats produced a significant increase (p < .05) in the pain threshold. The simultaneous microinjection of 4 μg/side histamine and 8 μg/side mepyramine as a histaminergic system inverse agonist in healthy nonrestraint animals did not affect the pain threshold. Although Histamine decreased the threshold of pain meaningfully, mepyramine elevated it in a significant manner (p < .05). In the restrained animals, intra-ACC microinjection of histamine produced no significant impact on the pain threshold. However, intra-ACC microinjection of mepyramine before histamine, significantly (p < .01) altered the result and enhanced the threshold of pain. The results of our study demonstrated that histaminergic neurons have an important role in the processing of pain in the ACC following restraint stress.

Ulotaront (SEP-363856) is a TAAR1 agonist, with 5-HT1A agonist activity, currently in clinical development for the treatment of schizophrenia. In vitro studies indicate ulotaront is an OCT2-specific inhibitor with IC₅₀ of 1.27 μM. The primary objective of this study is to determine if a single dose of ulotaront affects the PK of metformin, an index substrate of OCT2, in subjects with schizophrenia. In a randomized, single-blind, 2-period crossover study, 25 adults with schizophrenia received a single dose of metformin-HCl 850 mg (approximately 663 mg metformin) with and without coadministration of 100 mg ulotaront. The plasma samples were analyzed by fully validated LC-MS/MS methods. The primary PK endpoints for metformin were AUC_inf, AUC_last, C_max, and t_max. The highest-anticipated clinical dose of ulotaront (100 mg) had no statistically significant effect on the PK of a single dose of metformin based on C_max and AUC_inf. Geometric least squares mean ratios were 89.98% and 110.63%, respectively, with the 90% confidential interval (CI) for each parameter contained within 80%-125%. Median t_max was comparable across the treatments. Ulotaront does not act as a perpetrator of OCT2-mediated DDI against metformin. Co-administration of ulotaront is not expected to require dose adjustment of metformin or other drugs cleared by OCT2.

We investigated the metabolism and disposition of vornorexant, a novel dual orexin receptor antagonist, in rats and dogs, and clarified in vitro metabolite profiles in humans. Furthermore, we investigated the pharmacokinetics of active metabolites in rats and dogs and their CNS distribution in rats to elucidate its contribution to drug efficacy. [¹⁴ C]vornorexant was rapidly and mostly absorbed after the oral administration in rats and dogs. The drug-derived radioactivity, including metabolites, was distributed to major organs such as the liver, kidneys in rats, and was almost eliminated within 24 h post-dose in both species. Metabolite profiling revealed that main clearance mechanism of vornorexant was metabolism via multiple pathways by oxidation. The major circulating components were the cleaved metabolites (M10, M12) in rats, and the unchanged form in dogs, followed by M1, and then M3. Incubation with human hepatocytes resulted in formation of metabolites, including M1, M3, M10, and M12. The metabolic pathways were similar in all tested species. Resulting from the PK and CNS distribution of active metabolites (M1 and M3) with weaker pharmacological activity, the concentration of the unchanged form was higher than that of active metabolites in rat CSF and dog plasma, suggesting that the unchanged form mainly contributed to the drug efficacy. These findings demonstrate that vornorexant is absorbed immediately after administration, and vornorexant and its metabolites are rapidly and completely eliminated in rats and dogs. Thus, vornorexant may have favorable pharmacokinetic profiles as a hypnotic drug to provide rapid onset of action and minimal next-day residual effects in humans.