British journal of clinical pharmacology
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Br J Clin Pharmacol · Jul 2014
ReviewExploring the link between pholcodine exposure and neuromuscular blocking agent anaphylaxis.
Neuromuscular blocking agents (NMBAs) are the most commonly implicated drugs in IgE-mediated anaphylaxis during anaesthesia that can lead to perioperative morbidity and mortality. The rate of NMBA anaphylaxis shows marked geographical variation in patients who have had no known prior exposure to NMBAs, suggesting that there may be external or environmental factors that contribute to the underlying aetiology and pathophysiology of reactions. Substituted ammonium ions are shared among NMBAs and are therefore thought to be the main allergenic determinant of this class of drugs. ⋯ This link has prompted the withdrawal of pholcodine in some countries, with an ensuing fall in the observed rate of NMBA anaphylaxis. While such observations are compelling in their suggestion of a relationship between pholcodine exposure and NMBA hypersensitivity, important questions remain regarding the mechanisms by which pholcodine is able to sensitize against NMBAs and whether there are other, as yet unidentified, agents that can elicit similar hypersensitivity reactions. This review aims to explore the evidence linking pholcodine exposure to NMBA hypersensitivity and discuss the implications for our understanding of the pathophysiology of these reactions.
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Br J Clin Pharmacol · Jul 2014
Randomized Controlled Trial Multicenter StudyA phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes.
SRT2104 is a selective activator of SIRT1. In animal models, SRT2104 improves glucose homeostasis and increases insulin sensitivity. We evaluated the tolerability and pharmacokinetics of SRT2104, and its effects on glycaemic control, in adults with type 2 diabetes mellitus. ⋯ Treatment with SRT2104 for 28 days did not result in improved glucose or insulin control which is likely due to the observed pharmacokinetics which were not dose proportional and had large between subject variability.
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Hypersensitivity reactions including anaphylaxis have been reported for nearly all classes of therapeutic reagents and these reactions can occur within minutes to hours of exposure. These reactions are unpredictable, not directly related to dose or the pharmacological action of the drug and have a relatively high mortality risk. This review will focus on the clinical presentation, immune mechanisms, diagnosis and prevention of the most serious form of immediate onset drug hypersensitivity reaction, anaphylaxis. ⋯ Misdiagnosis of drug hypersensitivity leads to substantial patient risk and cost. Although oral provocation is often considered the gold standard of diagnosis, it can pose a potential risk to the patient. There is an urgent need to improve and standardize diagnostic testing and desensitization protocols as other diagnostic tests currently available for assessment of immediate drug allergy are not highly predictive.
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Br J Clin Pharmacol · Jul 2014
Multicenter StudyPopulation pharmacokinetics of levodopa in subjects with advanced Parkinson's disease: levodopa-carbidopa intestinal gel infusion vs. oral tablets.
Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa-carbidopa delivery through intrajejunal infusion. This study characterized the population pharmacokinetics of levodopa following a 16 h jejunal infusion of LCIG or frequent oral administration of levodopa-carbidopa tablets (LC-oral) in subjects with advanced Parkinson's disease (PD). ⋯ LCIG administration results in faster absorption, comparable levodopa bioavailability and significantly reduced intra-subject variability in levodopa concentrations relative to LC-oral administration.