British journal of clinical pharmacology
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Br J Clin Pharmacol · Jun 2018
Randomized Controlled Trial Multicenter StudyExposure-response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose-ranging phase 2 trial.
Tofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose-ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC. ⋯ Exposure-response characterization demonstrated the potential of tofacitinib 10 and 15 mg twice daily as induction therapy for UC without monitoring of plasma drug concentrations for dose optimization.
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Br J Clin Pharmacol · Feb 2018
Randomized Controlled TrialDemonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models.
Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models, and the present study aimed to investigate the pharmacodynamics of this first-in-class molecule in humans. ⋯ The study demonstrated, for the first time, the translation of nonclinical effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan-Trk inhibitor.
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Br J Clin Pharmacol · Feb 2018
Randomized Controlled TrialIs tranexamic acid exposure related to blood loss in hip arthroplasty? A pharmacokinetic-pharmacodynamic study.
Tranexamic acid (TXA) is an antifibrinolytic agent, decreasing blood loss in hip arthroplasty. The present study investigated the relationship between TXA exposure markers, including the time above the in vitro threshold reported for inhibition of fibrinolysis (10 mg l-1 ), and perioperative blood loss. ⋯ In hip arthroplasty, TXA plasma concentrations were maintained above 10 mg l-1 during surgery and for a minimum of 3 h with a preoperative TXA dose of 1 g. Keeping TXA concentrations above this threshold up to 16 h conferred no advantage with regard to blood loss.
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Br J Clin Pharmacol · Dec 2017
Randomized Controlled Trial Comparative StudyTicagrelor mitigates ischaemia-reperfusion induced vascular endothelial dysfunction in healthy young males - a randomized, single-blinded study.
Animal data suggest that ticagrelor but not clopidogrel protects against tissue injury. It is unclear if this effect of ticagrelor is also detectable in humans. We studied the effect of ticagrelor and clopidogrel at standard clinical doses on endothelial dysfunction in an experimental model of forearm vascular ischaemia-reperfusion (IR) injury. ⋯ Our data indicate that ticagrelor treatment exerts a greater vascular salutary effect than clopidogrel during reperfusion after an acute vascular occlusion. IR-induced vascular injury cannot be prevented completely by administration of these antiplatelet agents at standard clinical doses.
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Br J Clin Pharmacol · Oct 2017
Randomized Controlled Trial Multicenter StudyTreatment of spontaneous preterm labour with retosiban: a phase II pilot dose-ranging study.
The aims of the present study were to investigate the maternal, fetal and neonatal safety and tolerability, pharmacodynamics and pharmacokinetics of intravenous (IV) retosiban in pregnant women with spontaneous preterm labour (PTL) between 340/7 and 356/7 weeks' gestation. ⋯ Intravenous retosiban has a favourable safety and tolerability profile and might prolong pregnancies in women with PTL. The study provides the rationale and dosing strategy for further evaluation of the efficacy of retosiban in the treatment of PTL.