 Newsletter CHDR Feb 2010
 Human Immunopharmacology
CHDR's human immunopharmacology research line is now really underway. The focus of this truly translational project is to describe in detail the immunological responses of immunologicals alone or in combination therapies using state-of the-art immunomonitoring in patients with malignancies. The project is designed such that it deliver more generic applicable strategies to be used in the development of immunotherapeutics in general.
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Trials and techniques
Identifying biomarkers for psychostimulants in adolescents
Recently, a study was performed in 16 healthy adolescents to measure objective, quantitative CNS effect measures with a common CNS-stimulant using CHDR's NeuroCart test battery. To complete this study took only 4 weeks. This successful endeavour was possible thanks to the extensive involvement of the participants, their parents and the school, and the recognition by the ethical reviewers of the importance of this research project. The preliminary results appear promising across several different functional CNS-domains, even in these optimally performing healthy young subjects. The results confirm the sensitivity of the NeuroCart to provide meaningful information about the effect profiles of CNS-active drugs. Furthermore, this approach opens possibilities to investigate such profiles in children and adolescents and helps to reduce the lack of knowledge in this field.
Lenneke Schrier
 Serotonin-induced platelet aggregation
We have developed a method that can be used to study the relative contribution of (a low concentration) collagen and serotonin (5-HT) to platelet aggregation. The availability of the method is of interest as 5-HT is involved in both platelet aggregation and vasoconstriction, rendering it a promising therapeutic target. The method can be used to study selective 5-HT antagonists that can potentially be used to minimise the sequelae of erosion and rupture of atherosclerotic plaques.
Matthijs Moerland
A novel mixed Phosphodiesterase 3/4 inhibitor for the treatment of allergic asthma and allergic rhinitis
A combined phase I/IIa study has been performed to evaluate the safety and efficacy of a novel mixed phosphodiesterase (PDE) 3/4 inhibitor for the treatment of allergic asthma and allergic rhinitis. The study was designed to ascertain whether a safe dose of this PDE3/4 inhibitor, given by inhalation to a group of clinically stable, mild asthmatic patients that were not on maintenance anti-asthma therapy, produced bronchodilation (relaxation of airways) as well as bronchoprotection (protection against the airway stimulant methacholine). In a separate group of asymptomatic patients with allergic rhinitis who were not on maintenance therapy, the effects of the drug on the inflammatory cellular responses to a nasal allergen challenge were tested.
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A novel CB1 antagonist
This spring a study will be executed investigating the tolerability, PK ánd PD parameters of a new CB1 antagonist. In a five-way cross over study, the impact of the antagonist on the effects of the CB1 agonist THC will be compared to placebo and to another CB1 antagonist that will be used as a control. CB1 receptor antagonists have beneficial effects on appetite and metabolic parameters, and are promising compounds for the treatment of obesity and metabolic disorders. However, CB1-antagonists have been associated with adverse CNS effects. This new compound is expected to be devoid of such effects. In this study, the effects on different metabolic and central nervous system parameters will be closely measured.
Linda Klumpers
Preliminary results fMRI study
Recently, a study was completed that examined the effects of THC on resting state functional magnetic resonance imaging (fMRI). Twelve healthy male and female subjects inhaled multiple rising doses THC during repeated measurements of resting state MRI scans. THC administration decreased functional connectivity in most standard brain networks, including cerebellum, cuneus and different cortical regions. The subjective effects of THC were associated with changes in the brainstem, cerebellum, medial frontal gyrus and parietal lobe. Not all THC-related decreases in connectivity correlated with subjective effect scores. Future analyses will determine whether a dose-response relationship is present.
Linda Klumpers
Presentations, Publications and Posters
Sleep disorders in neurology: a practical approach.
Ruigt G, Van Gerven JMA. Sleep pharmacology. In Overeem S, Reading P (eds): Chapter 22. Wiley-Blackwell, London, 2010.
Enhanced tolerability of the 5-hydroxytryptophane challenge test combined with granisetron.
Jacobs G, Kamerling I, de Kam M, Derijk R, van Pelt J, Zitman F, van Gerven J.
J Psychopharmacol. 2010; 24: 65-72.
A recently developed oral serotonergic challenge test consisting of 5-Hydroxytryptophane (5-HTP) combined with carbidopa (CBD) exhibited dose-related neuroendocrine responsiveness and predictable pharmacokinetics. However, its applicability is limited by nausea and vomiting. A four-way crossover trial was performed in 12 healthy male volunteers in which the 5-HTP/CBD-challenge was combined with two oral anti-emetics (granisetron or domperidone). Addition of granisetron to the combined 5-HTP/CBD challenge suppresses nausea and vomiting without influencing the neuroendocrine response or pharmacokinetics, enhancing its clinical applicability in future psychiatric research and drug development.
Psychomotor and cognitive effects of a single oral dose of talnetant (SB223412) in healthy volunteers compared with placebo or haloperidol.
Liem-Moolenaar M, Gray F, de Visser S, Franson K, Schoemaker R, Schmitt J, Cohen A, van Gerven J.
J Psychopharmacol. 2010; 24: 73-82.
Central Nervous System (CNS) effects of 200 mg talnetant, an NK-3 antagonist in development for schizophrenia, were compared to those of 3 mg haloperidol and placebo in a three-way crossover study. Twelve healthy males participated and a large variety of CNS function tests were assessed. Haloperidol effects were predominantly CNS-depressant, while those of talnetant were slightly stimulatory. The results suggest that talnetant penetrates the brain, but it remains to be established whether this dose is sufficient and whether the observed effect profile is class-specific for NK3-antagonists.
Acute psychomotor effects of MDMA and ethanol (co-) administration over time in healthy volunteers.
Dumont G, Schoemaker R, Touw Dj, Sweep F, Buitelaar J, van Gerven J, Verkes R.
J Psychopharmacol. 2010; 24: 155-164
 The aim of the present study was to assess the acute psychomotor and subjective effects of co- administration of 3,4-methylenedioxymethamphetamine (MDMA) and ethanol over time and in relation to the pharmacokinetics. In a four-way crossover study, 16 healthy volunteers were administered 100 mg MDMA orally while blood alcohol concentration was maintained at pseudo-steady state levels. Co-administration of ethanol and MDMA improved psychomotor speed but impaired psychomotor accuracy compared with placebo and reversed ethanol-induced sedation.
Ethanol co-administration moderates MDMA effects on human physiology.
Dumont G, Kramers C, Sweep F, Willemsen J, Touw Dj, Schoemaker R, van Gerven J, Buitelaar J, Verkes R.
J Psychopharmacol. 2010; 24: 165-174.
Both alcohol and MDMA affect cardiovascular function, hydration and temperature regulation, but may have partly opposing effects. The present study aims to assess the acute physiologic effects of co-administration of MDMA and ethanol over time in a four-way crossover study with 16 healthy volunteers. Co-administration of ethanol with MDMA did not affect cardiovascular function compared to the MDMA alone condition, but attenuated the effects of MDMA on fluid retention and showed a trend for attenuation of MDMA-induced temperature increase. |
