British journal of anaesthesia
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Variability is high in predicted propofol concentrations during clinical anaesthesia titrated by target-controlled infusion (TCI) to maintain a processed EEG parameter (bispectral index [BIS]) within a specified range. We have shown that the potential for improving the pharmacokinetic model is minimal. The drug titration paradox revealed that titration challenges the classical relationship between drug dose and effect in both individuals and the population. We hypothesised that dynamic factors during surgery beyond the static genetic, epigenetic, and other factors such as age, height, and weight affect the necessary dose. We compared the variability of measured end-tidal sevoflurane concentrations with predicted effect-site propofol concentrations when titrated to a BIS range of 40-60, with the hypothesis that the variability in measured sevoflurane concentrations would not be less than the variability in estimated propofol concentrations. ⋯ Improvements in prediction accuracy of pharmacokinetic models beyond that of those already in clinical use are unlikely to reduce variability in target anaesthetic concentrations across patients in clinical practice.
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Neuropathic pain impairs quality of life, is widely prevalent, and incurs significant costs. Current pharmacological therapies have poor/no efficacy and significant adverse effects; safe and effective alternatives are needed. Hyperpolarisation-activated cyclic nucleotide-regulated (HCN) channels are causally implicated in some forms of peripherally mediated neuropathic pain. Whilst 2,6-substituted phenols, such as 2,6-di-tert-butylphenol (26DTB-P), selectively inhibit HCN1 gating and are antihyperalgesic, the development of therapeutically tolerable, HCN-selective antihyperalgesics based on their inverse agonist activity requires that such drugs spare the cardiac isoforms and do not cross the blood-brain barrier. ⋯ These findings provide a proof-of-concept demonstration that anchor-tethered drugs are a new chemotype for treatment of disorders involving membrane targets.