Mechanistic Investigations Support Liver Safety of Ubrogepant.

Small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated therapeutic efficacy for the treatment of migraine. However, previously investigated CGRP receptor antagonists, telcagepant and MK-3207, were discontinued during clinical development because of concerns about drug-induced liver injury. A subsequent effort to identify novel CGRP receptor antagonists less likely to cause hepatotoxicity led to the development of ubrogepant.

Liver and muscle glycogen oxidation and performance with dose variation of glucose-fructose ingestion during prolonged (3 h) exercise.

Purpose: This study investigated the effect of small manipulations in carbohydrate (CHO) dose on exogenous and endogenous (liver and muscle) fuel selection during exercise.

Method: Eleven trained males cycled in a double-blind randomised order on 4 occasions at 60% [Formula: see text] for 3 h, followed by a 30-min time-trial whilst ingesting either 80 g h or 90 g h or 100 g hC-glucose-C-fructose [2:1] or placebo. CHO doses met, were marginally lower, or above previously reported intestinal saturation for glucose-fructose (90 g h).

Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways.

Drug induced thyroid effects were evaluated in organotypic models utilizing either a rat thyroid lobe or human thyroid slices to compare rodent and human response. An inhibition of thyroid peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and release pathways. The clinically used thiourea drugs, methimazole (MMI) and 6-n-propyl-2-thioruacil (PTU), were used to evaluate thyroid drug response in these models.

Sensitivity and proportionality assessment of metabolites from microdose to high dose in rats using LC-MS/MS.

Background: The objective of this study was to evaluate the sensitivity requirement for LC-MS/MS as an analytical tool to characterize metabolites in plasma and urine at microdoses in rats and to investigate proportionality of metabolite exposure from a microdose of 1.67 µg/kg to a high dose of 5000 µg/kg for atorvastatin, ofloxacin, omeprazole and tamoxifen.

Results: Only the glucuronide metabolite of ofloxacin, the hydroxylation metabolite of omeprazole and the hydration metabolite of tamoxifen were characterized in rat plasma at microdose by LC-MS/MS.