British journal of clinical pharmacology
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Br J Clin Pharmacol · Jul 2013
Comparative StudySafety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers.
The purpose of this study was to establish safety and tolerability of a single intravenous (IV) infusion of a p38 mitogen-activated protein kinase inhibitor, losmapimod, to obtain therapeutic levels rapidly for a potential acute coronary syndrome indication. Pharmacokinetics (PK) following IV dosing were characterized, and pharmacokinetic/pharmacodynamic (PK/PD) relationships between losmapimod and phosphorylated heat shock protein 27 (pHSP27) and high-sensitivity C-reactive protein were explored. ⋯ A single IV infusion of losmapimod in healthy volunteers was safe and well tolerated, and may potentially serve as an initial loading dose in acute coronary syndrome as rapid exposure is achieved.
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Br J Clin Pharmacol · Jul 2013
Validation of suicide and self-harm records in the Clinical Practice Research Datalink.
The UK Clinical Practice Research Datalink (CPRD) is increasingly being used to investigate suicide-related adverse drug reactions. No studies have comprehensively validated the recording of suicide and nonfatal self-harm in the CPRD. We validated general practitioners' recording of these outcomes using linked Office for National Statistics (ONS) mortality and Hospital Episode Statistics (HES) admission data. ⋯ The CPRD recording of suicide using Read codes is unreliable, with significant inaccuracy (over- and under-reporting). Future CPRD suicide studies should use linked ONS mortality data. The under-reporting of self-harm appears to be less marked.
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Br J Clin Pharmacol · Jul 2013
Randomized Controlled TrialSurinabant, a selective cannabinoid receptor type 1 antagonist, inhibits Δ9-tetrahydrocannabinol-induced central nervous system and heart rate effects in humans.
Cannabinoid receptor type 1 (CB1 ) antagonists have been developed for the treatment of obesity and associated risk factors. Surinabant is a high affinity CB1 antagonist in vitro. The aim of this study was to assess the magnitude of inhibition by surinabant of CNS effects and heart rate induced by Δ(9) -tetrahydrocannabinol (THC) in humans. ⋯ The dose-related inhibition by surinabant, without any effect of its own, suggests that this compound behaves as a CB1 receptor antagonist in humans at these concentrations. A single surinabant dose between 5 to 20 mg and above was able to antagonize THC-induced effects in humans.
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Br J Clin Pharmacol · Jun 2013
Randomized Controlled TrialGrapefruit juice markedly increases the plasma concentrations and antiplatelet effects of ticagrelor in healthy subjects.
This study examined the effects of grapefruit juice on the new P2Y12 inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein. ⋯ Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice-ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.
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Br J Clin Pharmacol · Jun 2013
The Val158Met polymorphism of the COMT gene is associated with increased pain sensitivity in morphine-treated patients undergoing a painful procedure after cardiac surgery.
The catechol-O-methyltransferase (COMT) Val158Met polymorphism affected pain sensitivity of healthy volunteers upon application of experimental pain stimuli. The relevance of these findings in morphine-treated postoperative cardiac patients undergoing painful healthcare procedures is unknown; therefore, the aim of this study was to investigate whether the COMT Val158Met polymorphism increases pain sensitivity in morphine-treated patients undergoing an unavoidable painful routine procedure after cardiac surgery. ⋯ Our results show that the COMT Val158Met polymorphism contributes to variability in pain sensitivity after cardiac surgery of morphine-treated patients in the intensive care unit, because Met-allele carriers were more sensitive to overall pain and procedure-related pain.