British journal of clinical pharmacology
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Br J Clin Pharmacol · Apr 2016
Randomized Controlled TrialThe haemodynamic effects of intravenous paracetamol (acetaminophen) in healthy volunteers: a double-blind, randomized, triple crossover trial.
The haemodynamic effects of intravenous paracetamol have not been systematically investigated. We compared the physiological effects of intravenous mannitol-containing paracetamol, and an equivalent dosage of mannitol, and normal saline 0.9% in healthy volunteers. ⋯ I.v. paracetamol caused a transient decrease in blood pressure immediately after infusion. These effects were not seen with mannitol or normal saline. The physiological mechanism was consistent with vasodilatation. This study provides plausible physiological data in a healthy volunteer setting, supporting transient changes in haemodynamic variables with i.v. paracetamol and justifies controlled studies in the peri-operative and critical care setting.
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Br J Clin Pharmacol · Apr 2016
EditorialImplications of the BIA-102474-101 study for review of first-into-human clinical trials.
Over the past 10 years, thousands of first-into-human (FIH) clinical trials have been performed in Europe, with few severe adverse events (SAEs). Each has received detailed prior safety review at both the local clinical research facility and at national drug regulatory authority level. The recent fatal SAE in the BIA-102474-101 clinical trial shows the limitations of this process. ⋯ In the meantime, reviewers and clinical researchers should always ask for information on drug and target interactions and full reports of preclinical toxicity studies, and plan sequential dosing with longer delays between patients and cohorts, particularly if late SAEs might be anticipated. The use of individual patient pharmacokinetic and dynamic data should guide sequential dosing. A process for systematic risk assessment, like that currently used in the Netherlands, should be applied routinely to all trials with novel compounds.
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Br J Clin Pharmacol · Apr 2016
Review Meta AnalysisThe risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: a systematic review and meta-analysis.
The aim of this study was to perform an up-to-date meta-analysis on the risk of cardiac malformations associated with gestational exposure to paroxetine, taking into account indication, study design and reference category. ⋯ Paroxetine use during the first trimester of pregnancy is associated with an increased risk of any major congenital malformations and cardiac malformations. The increase in risk is not dependent on the study method or population.
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Br J Clin Pharmacol · Apr 2016
Clinical TrialParacetamol decreases steady-state exposure to lamotrigine by induction of glucuronidation in healthy subjects.
Patients receiving lamotrigine therapy frequently use paracetamol concomitantly. While one study suggests a possible, clinically relevant drug-drug interaction, practical recommendations of the concomitant use are inconsistent. We performed a systematic pharmacokinetic study in healthy volunteers to quantify the effect of 4 day treatment with paracetamol on the metabolism of steady-state lamotrigine. ⋯ Paracetamol statistically significantly induced steady-state lamotrigine glucuronidation, resulting in a 20% decrease in total systemic exposure and a 25% decrease in trough value of lamotrigine. This interaction may be of clinical relevance in some patients.