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The transition from rolling to firm adhesion is a key element of neutrophil activation and essential to the inflammatory response. Although the molecular mediators of rolling and firm adhesion are known to be selectins and beta2 -integrins, respectively, the precise dynamic mechanism by which these ligands facilitate neutrophil arrest remains unknown.(More)
STUDY OBJECTIVES Suvorexant (MK-4305) is an orexin receptor antagonist being developed for the treatment of insomnia. This report describes the effects of nighttime administration of suvorexant on polysomnography (PSG) sleep parameters in healthy young men. DESIGN Randomized, double-blind, placebo-controlled, 4-period crossover PSG study, followed by an(More)
Recently, the US Food and Drug Administration and European Medicines Agency have issued new guidance for industry on drug interaction studies, which outline comprehensive recommendations on a broad range of in vitro and in vivo studies to evaluate drug–drug interaction (DDI) potential. This paper aims to provide an overview of these new recommendations and(More)
INTRODUCTION Doravirine is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor exhibiting a robust safety and efficacy profile in combination with other antiretrovirals. While existing data do not suggest that doravirine delays cardiac repolarization, the aim of this trial was to evaluate the effects of a supratherapeutic dose of doravirine on the(More)
OBJECTIVE To assess the antiviral activity, pharmacokinetics, and safety of doravirine in nonnucleoside reverse transcriptase inhibitor-naïve, HIV-infected men. DESIGN Double-blind, randomized, two-panel, dose-escalation study. METHODS In two sequential panels, 18 individuals received doravirine [25 mg (Panel A) or 200 mg (Panel B)] or matching placebo(More)
Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound’s mechanism(More)
Although in vitro-in vivo correlations (IVIVCs) are commonly pursued for modified-release products, there are limited reports of successful IVIVCs for immediate-release (IR) formulations. This manuscript details the development of a Multiple Level C IVIVC for the amorphous solid dispersion formulation of suvorexant, a BCS class II compound, and its(More)
Orexin neuropeptides regulate sleep/wake through orexin receptors (OX1R, OX2R); OX2R is the predominant mediator of arousal promotion. The potential for single OX2R antagonism to effectively promote sleep has yet to be demonstrated in humans. MK-1064 is an OX2R-single antagonist. Preclinically, MK-1064 promotes sleep and increases both rapid eye movement(More)
Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1(More)
INTRODUCTION Doravirine, a non-nucleoside reverse-transcriptase inhibitor in development for the treatment of patients with human immunodeficiency virus-1 infection, has potential to be used concomitantly in antiretroviral therapy with dolutegravir, an integrase strand transfer inhibitor. The pharmacokinetic interactions between these drugs were therefore(More)