Safety, Tolerability, and Pharmacokinetics of a Novel Oral Phosphodiesterase 4 Inhibitor, ME3183: First-in-Human Phase 1 Study.

A novel, oral phosphodiesterase 4 (PDE4) inhibitor, ME3183, is under development for the treatment of psoriasis, atopic dermatitis, and other inflammatory diseases. To evaluate its safety, tolerability, and pharmacokinetics, double-blind, placebo-controlled, single ascending dose (SAD), and multiple ascending dose (MAD) phase 1 studies were conducted in 126 healthy adults. The food effect was evaluated in a randomized, open-label, crossover manner (n = 5).

ME3183, a novel phosphodiesterase-4 inhibitor, exhibits potent anti-inflammatory effects and is well tolerated in a non-clinical study.

Phosphodiesterase 4 (PDE4) inhibitors are expected to exhibit efficacy against inflammatory diseases due to their broad pharmacological activity. The launched PDE4 inhibitors apremilast, crisaborole, and roflumilast have not exhibited sufficient inhibitory potential due to poor margins of effectiveness and tolerability. In this report, we describe the non-clinical efficacy, brain translocation, and vomit-inducing effects of ME3183 compared with apremilast.

Formation of reactive metabolites of benzbromarone in humanized-liver mice.

Benzbromarone, a uricosuric drug, has the potential to cause serious hepatotoxicity. Several studies have shown the formation of reactive metabolites of benzbromarone and their association with hepatotoxicity in mice. However, it is unknown whether those reactive metabolites are generated in humans in vivo.

Selection of the candidate compound at an early stage of new drug development: retrospective pharmacokinetic and metabolic evaluations of valsartan using common marmosets.

Valsartan is an antihypertensive drug that was developed using common marmosets () in pivotal toxicity studies as a non-rodent species. The aim of the present study was to investigate the utility of marmosets in the candidate selection of this drug from a pharmacokinetic and metabolic viewpoint.Valsartan, as well as three other angiotensin II type-I receptor blockers, assumed as competitive candidates, were administered to common marmosets.

Empirical and theoretical approaches for the prediction of human hepatic clearance using chimeric mice with humanised liver: the use of physiologically based scaling, a novel solution for potential overprediction due to coexisting mouse metabolism.

Chimeric mice are immunodeficient mice in which the majority of the hepatic parenchymal cells are replaced with human hepatocytes.Following intravenous administration of 24 model compounds to control and chimeric mice, human hepatic clearance (CL) was predicted using the single-species allometric scaling (SSS) method. Predictability of the chimeric mice was better than that of the control mice.

Association of a reactive intermediate derived from 1',6-dihydroxy metabolite with benzbromarone-induced hepatotoxicity.

Treatment with benzbromarone can be associated with liver injury, but the detailed mechanism remains unknown. Our recent studies demonstrated that benzbromarone was metabolized to 1',6-dihydroxybenzbromarone and followed by formation of reactive intermediates that were trapped by glutathione, suggesting that the reactive intermediates may be responsible for the liver injury. The aim of this study was to clarify whether the reactive intermediates derived from 1',6-dihydroxybenzbromarone is a risk factor of liver injury in mice.

Identification of novel glutathione adducts of benzbromarone in human liver microsomes.

Benzbromarone (BBR) is a potent uricosuric drug that can cause serious liver injury. Our recent study suggested that 1'-hydroxy BBR, one of major metabolites of BBR, is metabolized to a cytotoxic metabolite that could be detoxified by glutathione (GSH). The aim of this study was to clarify whether GSH adducts are formed from 1'-hydroxy BBR in human liver microsomes (HLM).