British journal of clinical pharmacology
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Br J Clin Pharmacol · Jul 2013
ReviewDrug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice.
There has been an increasing focus on drug induced QT prolongation including research on drug development and QT prolongation, following the removal of drugs due to torsades de pointes (TdP). Although this has improved our understanding of drug-induced QT prolongation there has been much less research aimed at helping clinicians assess risk in individual patients with drug induced QT prolongation. This review will focus on assessment of drug-induced QT prolongation in clinical practice using a simple risk assessment approach. ⋯ The nomogram has an 'at risk' line and QT-HR pairs above this line have been shown in a systematic study to be associated with TdP and the line is more sensitive and specific than Bazett's QTc of 440 ms or 500 ms. Plotting the QT-HR pair for patients on drugs suspected or known to cause QT prolongation allows assessment of the QT interval based on normal population QT variability. This risk assessment then allows the safer commencement of drugs therapeutically or management of drug induced effects in overdose.
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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 · 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
A phase 1 study of prasugrel in patients with sickle cell disease: pharmacokinetics and effects on ex vivo platelet reactivity.
Prasugrel is a novel thienopyridine P2Y12 adenosine diphosphate (ADP) receptor antagonist that inhibits ADP-mediated platelet activation and aggregation. Accordingly, it may be useful in reducing platelet-related ischaemia in sickle cell disease (SCD). Exposure to prasugrel's active metabolite (Pras-AM) and its antiplatelet activity in SCD have not been investigated. ⋯ Results demonstrate that in response to prasugrel, patients with SCD and healthy subjects have similar degrees of platelet inhibition and exposure to Pras-AM, and provide a basis for further study of prasugrel in patients with SCD.