Utrecht Institute for Pharmaceutical science

Utrecht, Netherlands

Utrecht Institute for Pharmaceutical science

Utrecht, Netherlands
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Vinkers C.H.,Utrecht Institute for Pharmaceutical science | Oosting R.S.,Utrecht Institute for Pharmaceutical science | van Bogaert M.J.V.,Utrecht Institute for Pharmaceutical science | Olivier B.,Utrecht Institute for Pharmaceutical science | And 2 more authors.
Biological Psychiatry | Year: 2010

Background: Early-life stress may affect 5-HT1A receptor circuitry, which could result in increased anxiety in later life. An increased anxiety phenotype in 5-HT1A receptor KO mice (1AKO) mice has been ascribed to 5-HT1A receptor absence during the early postnatal period. Thus, subtle and transient serotonergic changes during the early postnatal period may lead to an increased risk for developing stress-related disorders during adulthood. Methods: Wildtype and 1AKO mice on a Swiss-Webster (SW) background were treated during the early postnatal period with vehicle or the 5-HT1A receptor antagonist WAY-100,635. Results: Pharmacologic 5-HT1A receptor blockade during the early postnatal period induced long-lasting effects on anxiety and benzodiazepine sensitivity in adolescent and adult mice on a Swiss-Webster background and resembles the SW 1AKO phenotype. Furthermore, WAY-100,635-treated mice had increased cortical gamma-aminobutyric acid-A receptor (GABAAR) α1 and α3 subunit levels and increased hippocampal GABAAR α2 subunit levels. Conclusions: Absence of 5-HT1AR signaling during early stages of brain maturation predisposes an organism to affective dysfunction later in life. Because early-life treatment with WAY-100,635 in Swiss-Webster mice reduced diazepam sensitivity and increased GABAAR α subunit levels in the prefrontal cortex and hippocampus, our data suggest a putative link between early-life disruption of the serotonergic system and the emergence of increased anxiety and decreased benzodiazepine responsivity at adult age. Moreover, early-life 5-HT1A receptor functionality appears to be essential for the development of normal GABAAR functionality. This study may have clinical implications for psychoactive drug use during pregnancy and for the pharmacogenetic background of benzodiazepine sensitivity. © 2010 Society of Biological Psychiatry.


Stolwijk C.,Maastricht University | Essers I.,Maastricht University | van Tubergen A.,Maastricht University | Boonen A.,Maastricht University | And 3 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objective: To assess the incidence and risks of common extra-articular manifestations (EAMs), that is, acute anterior uveitis (AAU), psoriasis and inflammatory bowel disease (IBD), in patients with ankylosing spondylitis (AS) compared with population-based controls. Methods: All incident patients with AS (n=4101) from the UK Clinical Practice Research Datalink (1987-2012) were matched with up to seven control subjects without AS by year of birth, sex and practice (n=28 591). Incidence rates, cumulative incidence rates and adjusted (adj) HRs for the development of EAMs were calculated, with time-dependent adjustments for age, sex, comorbidity and medication use. Results: At diagnosis of AS, the proportion of patients with an EAM was 11.4% for AAU, 4.4% for psoriasis and 3.7% for IBD. Incidence rates of EAMs were 8.9/1000 person-years for AAU, 3.4/1000 person-years for psoriasis and 2.4/1000 person-years for IBD in AS. The 20-year cumulative incidence was 24.5%, 10.1% and 7.5%, respectively. Risks of EAMs were 1.5-fold to 16-fold increased versus controls, with an adj HR of 15.5 (95% CI 11.6 to 20.7) for AAU, adj HR of 1.5 (95% CI 1.1 to 1.9) for psoriasis and adj HR of 3.3 (95% CI 2.3 to 4.8) for IBD. For psoriasis and IBD, the highest risks were found in the 1st years after diagnosis, while developing AAU continued to be increased also 10 years after diagnosis of AS. Conclusions: The risk of, in particular AAU, but also of psoriasis and IBD, is significantly increased in patients with AS compared with controls. Hazard patterns are different for each of the EAMs. © 2014 BMJ Publishing Group Ltd & European League Against Rheumatism.


Warnier M.J.,University Utrecht | Warnier M.J.,Utrecht Institute for Pharmaceutical science | Van Riet E.E.S.,University Utrecht | Rutten F.H.,University Utrecht | And 2 more authors.
European Respiratory Journal | Year: 2013

Smoking cessation is the cornerstone of treatment of chronic obstructive pulmonary disease (COPD) patients. This systematic review evaluates the effectiveness of behavioural and pharmacological smoking cessation strategies in COPD patients. MEDLINE was searched from January 2002 to October 2011. Randomised controlled trials evaluating the effect of smoking cessation interventions for COPD patients, published in English, were selected. The methodological quality of included trials was assessed using the Delphi list by two reviewers independently. The relative risks of smoking cessation due to the intervention, compared with controls, were calculated. Eight studies met the inclusion criteria. Heterogeneity was observed for study population, the intervention strategy, the follow-up period and the outcome. According to the Delphi list methodological quality scores, five studies were considered to be of acceptable quality. Pharmacological therapy combined with behavioural counselling was more effective than each strategy separately. In COPD patients, the intensity of counselling did not seem to influence the results, nor did the choice of drug therapy make a difference. This systematic review makes clear that in COPD patients, pharmacological therapy combined with behavioural counselling is more effective than each strategy separately. Neither the intensity of counselling nor the type of anti-smoking drug made a difference.


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 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.


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 Kivit S.,Utrecht Institute for Pharmaceutical science | Kraneveld A.D.,Utrecht Institute for Pharmaceutical science | Garssen J.,Danone Inc. | Willemsen L.E.M.,Utrecht Institute for Pharmaceutical science
European Journal of Pharmacology | Year: 2011

The intestinal mucosa is constantly exposed to the luminal content, which includes micro-organisms and dietary components. Prebiotic non-digestible oligosaccharides may be supplemented to the diet to exert modulation of immune responses in the intestine. Short chain galacto- and long chain fructo-oligosaccharides (scGOS/lcFOS), functionally mimicking oligosaccharides present in human milk, have been reported to reduce the development of allergy through modulation of the intestinal microbiota and immune system. Nonetheless, the underlying working mechanisms of scGOS/lcFOS are unclear. Intestinal epithelial cells lining the mucosa are known to express carbohydrate (glycan)-binding receptors that may be involved in modulation of the mucosal immune response. This review aims to provide an overview of glycan-binding receptors, in particular galectins, which are expressed by intestinal epithelial cells and immune cells. In addition, their involvement in health and disease will be addressed, especially in food allergy and inflammatory bowel disease, diseases originating from the gastro-intestinal tract. Insight in the recognition of glycans in the intestinal tract may open new avenues for the treatment of intestinal inflammatory diseases by either nutritional concepts or pharmacological intervention. © 2011 Elsevier B.V. All rights reserved.


Mets M.A.J.,Utrecht Institute for Pharmaceutical science | Volkerts E.R.,Utrecht Institute for Pharmaceutical science | Olivier B.,Utrecht Institute for Pharmaceutical science | Verster J.C.,Utrecht Institute for Pharmaceutical science
Sleep Medicine Reviews | Year: 2010

Background: Disturbed body balance and standing steadiness are problematic for those who wake up at night or in the morning after using hypnotic drugs. As a result, falls and hip fractures are frequently reported in patients using sleep medication. Methods: A literature search was performed to identify double blind, placebo-controlled clinical trials that examined body balance and standing steadiness. Drugs that were searched were nitrazepam, triazolam, lorazepam, temazepam, loprazolam, flunitrazepam, flurazepam, and the Z-drugs zopiclone, zolpidem and zaleplon. Results: A total of 57 studies were eligible for inclusion. Results showed that both benzodiazepine hypnotics and the Z-drugs significantly impair body balance and standing steadiness after single dose administration. Impairments correlate significantly with blood plasma levels and are greatest at peak plasma concentrations, but are sometimes still present upon awakening. Balance problems were dose-related and most pronounced in elderly. Co-administration of alcohol aggravated the impairment. After repeated daily use of hypnotic drugs partial tolerance develops to the impairing effects on standing steadiness. Conclusion: Single dose administration of benzodiazepine hypnotics and Z-drugs significantly impair body balance in a dose-dependent manner. Zolpidem and zopiclone produced similar significant impairment as benzodiazepine hypnotics. Zaleplon significantly impaired balance up to 2 h after intake. Partial tolerance develops after repeated daily use. In conclusion, patients should be warned about the possible risk of imbalance and falls due to the use of sleep medication. © 2009 Elsevier Ltd. 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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