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Van Den Broek M.P.H.,University Utrecht | Groenendaal F.,Wilhelmina Childrens Hospital | Egberts A.C.G.,University Utrecht | Egberts A.C.G.,Utrecht Institute for Pharmaceutical science | Rademaker C.M.A.,University Utrecht
Clinical Pharmacokinetics | Year: 2010

Examples of clinical applications of therapeutic hypothermia in modern clinical medicine include traumatic cardiac arrest, ischaemic stroke and, more recently, acute perinatal asphyxia in neonates. The exact mechanism of (neuro) protection by hypothermia is unknown. Since most enzymatic processes exhibit temperature dependency, it can be expected that therapeutic hypothermia may cause alterations in both pharmacokinetic and pharmacodynamic parameters, which could result in an increased risk of drug toxicity or therapy failure. Generalizable knowledge about the effect of therapeutic hypothermia on pharmaco-kinetics and pharmacodynamics could lead to more appropriate dosing and thereby prediction of clinical effects. This article reviews the evidence on the influence of therapeutic hypothermia on individual pharmacokinetic and pharmacodynamic parameters. A literature search was conducted within the PubMed, Embase and Cochrane databases from January 1965 to September 2008, comparing pharmacokinetic and/or pharmacodynamic parameters in hypothermia and normothermia regarding preclinical (animal) and clinical (human) studies. During hypothermia, pharmacokinetic parameters alter, resulting in drug and metabolite accumulation in the plasma for the majority of drugs. Impaired clearance is the most striking effect. Based on impaired clearance, dosages should be decreased considerably, especially for drugs with a low therapeutic index. Hypothetically, high-clearance compounds are affected more than low-clearance compounds because of the additional effect of impaired hepatic blood flow. The volume of distribution also changes, which may lead to therapy failure when it increases and could lead to toxicity when it decreases. The pH-partitioning hypothesis could contribute to the changes in the volumes of distribution for weak bases and acids, depending on their acid dissociation constants and acid-base status. Pharmacodynamic parameters may also alter, depending on the hypothermic regimen, drug target location, pharmacological mechanism and metabolic pathway of inactivation. The pharmacological response changes when target sensitivity alters. Rewarming patients to normothermia can also result in toxicity or therapy failure. The integrated effect of hypothermia on pharmacokinetic and pharmacodynamic properties of individual drugs is unclear. Therefore, therapeutic drug monitoring is currently considered essential for drugs with a low therapeutic index, drugs with active metabolites, high-clearance compounds and drugs that are inactivated by enzymes at the site of effect. Because most of the studies (74%) included in this review contain preclinical data, clinical pharmacokinetic/pharmacodynamic studies are essential for the development of substantiated dose regimens to avoid toxicity and therapy failure in patients treated with hypothermia. © 2010 Adis Data Information BV. All rights reserved.

Young J.W.,University of California at San Diego | Van Enkhuizen J.,Utrecht Institute for Pharmaceutical science | Winstanley C.A.,University of British Columbia | Geyer M.A.,University of California at San Diego
Journal of Psychopharmacology | Year: 2011

Reduced functioning of the dopamine transporter (DAT) has been linked to bipolar disorder (BD). Mice with reduced DAT functioning (knockdown, KD) exhibit a behavioral profile in the mouse Behavioral Pattern Monitor (BPM) consistent with patients with BD mania in the human BPM. Patients with BD also exhibit increased risk taking, which can be quantified using the Iowa Gambling Task (IGT). We hypothesized that DAT KD mice would exhibit increased risk-taking behavior in a novel mouse version of the IGT. DAT KD and wildtype (WT) littermates were trained in the mouse IGT. In session 1, KD mice initially made riskier choices, but later performed comparably to WT mice. Once trained to stable choice performance, DAT KD mice continued to exhibit a trend to choose the riskier options more than WT mice. Finally, we confirmed that these DAT KD mice also exhibited an exploratory profile in the BPM consistent with patients with BD mania, where risky choice behavior modestly correlated with specific exploration. These data demonstrate that DAT KD mice chose the riskier options more than WT mice, providing further support for the use of DAT KD mice as a model of BD mania. © The Author(s) 2011 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

van der Zee P.A.,University Utrecht | de Boer A.,Utrecht Institute for Pharmaceutical science
Netherlands Journal of Medicine | Year: 2014

Background: During surgical treatment of pheochro-mocytoma, haemodynamic instability may occur. To prevent this, patients receive preoperative treatment with an alpha-blocker. Nowadays, some centres use phenoxybenzamine, while others use doxazosin. The purpose of this review is to analyse the current evidence of the benefits and risks of phenoxybenzamine and doxazosin in the preoperative treatment of pheochromocytoma. Methods: The literature was reviewed by searching PubMed using the following search terms: pheochro-mocytoma, phenoxybenzamine, doxazosin and alpha-blockade. The filter was set on English language. Results: No randomised controlled trials were found. Five follow-up studies comparing phenoxybenzamine and doxazosin in the treatment of pheochromocytoma were retrieved and analysed. There was a trend that systolic arterial pressure is slightly better controlled by phenoxybenzamine. However, this resulted in more pronounced postoperative hypotension as well. The use of an alpha-blocker was often accompanied by other vasoactive agents. Phenoxybenzamine was often accompanied by a beta-blocker to control reflex tachycardia, while patients on doxazosin received significantly more additional antihypertensive medicines. Most of the studies showed that the use of vasoactive drugs and fluid infusion does not differ significantly between the two drugs. Phenoxybenzamine caused significantly more orthostatic hypotension, oedema and complaints of a stuffy nose. Conclusion: On the basis of the current evidence, there is no evidently superior alpha-blocker for the pretreatment of patients with pheochromocytoma. Perioperative haemodynamics seem to be slightly better controlled with phenoxybenzamine, at the cost of more pronounced postoperative hypotension. Side effects occurred less often in the doxazosin group. © Van Zuiden Communications B.V. All rights reserved.

de Mol N.J.,Utrecht Institute for Pharmaceutical science
Methods in molecular biology (Clifton, N.J.) | Year: 2010

Direct assay of small molecules by SPR in general is troublesome and at least tedious procedures have to be applied. Competition experiments offer an attractive alternative. A small ligand known to bind to the analyte is immobilized on an SPR sensor surface, and the binding of the larger analyte in the presence of compounds under investigation in a concentration range is assayed. The resulting inhibition curves of the equilibrium SPR signal as function of the compound concentration can be analyzed to yield thermodynamic binding constants for the interaction in solution between analyte and the compounds under investigation. An additional advantage of this method is that series of compounds can be analyzed using the same sensor surface, so there is no immobilization needed for each compound. An adaptation of the method to analyze interactions with bivalent analytes (e.g., antibodies) is also included. Some observed different affinities in solution compared to that on the SPR surface are discussed.

Fischer M.J.,Utrecht Institute for Pharmaceutical science
Methods in molecular biology (Clifton, N.J.) | Year: 2010

Surface plasmon resonance (SPR) is one of the leading tools in biomedical research. The challenge in its use is the controlled positioning of one of the components of an interaction on a carefully designed surface. Many attempts in interaction analysis fail due to the non-functional or unsuccessful immobilization of a reactant onto the complex matrix of that surface. The most common technique for linking ligands covalently to a hydrophilic solid surface is amine coupling via reactive esters. In this chapter detailed methods and problem discussions will be given to assist in fast decision analysis to optimize immobilization and regeneration. Topics in focus are different coupling techniques for small and large molecules, streptavidin-biotin sandwich immobilization, and optimizing regeneration conditions.

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