As the sale of the land with Leiden has been signed and the building construction will start soon, CHDR will start to sell the current building at Zernikedreef 10 on the BioSiencePark Leiden. This building, constructed by cepezed has a netto floor surface of 1.788 m². The asked price is € 3.350.000. The smart design of this multifunctional building offers many possibilities for different kind of users. A film of the building is shown on  YouTube .

Wanted: Interns
The student training at CHDR is open to any student with a (bio-) medical/ scientific background. The training program primarily aims to teach knowledge, learn skills and applications of state-of-the-art methodology in human drug studies. It provides a unique opportunity to get insight in the intriguing process of drug or method development. In addition, the CHDR provides a board-certified education program in clinical pharmacology that is open for trainees.
To apply for a training period at the CHDR, please contact us.

Trials and techniques

PK model in Plasma and Saliva
As blood sampling is undesirable in children in the setting of a non-therapeutic study, saliva samples are a suitable alternative to measure the drug concentration. By combining these data with pharmacokinetic data in blood, a PK model can be build that provides us with estimated plasma drug levels in children needed for population PK/PD analysis. A randomized, open-label study has been performed to elucidate pharmacokinetic plasma and saliva profiles and to describe the relationship between plasma and saliva concentrations and use for the analysis of data obtained in children.
Lenneke Schrier

Presentations, Publications and Posters

WorldPharma
Come and visit us at the WorldPharma congress in Copenhagen, July 17-23.
Abstracts

• Effects of caffeine on central and autonomous nervous system parameters in adolescents (oral), Koos Burggraaf et al
• Whole blood challenge tests as translational tools for early assessment of anti-inflammatory/ immunosuppressive effects of drugs (poster), Andrea Kales et al
• The effect of olanzapine on THC induced psychomimetic symptoms (poster), Kleinloog D. et al
• Modulation of vasoactivity and platelet aggregation by 5-HT antagonism (poster), Matthijs Moerland et al
• Evaluation of the EndoPAT as a tool to assess endothelial function (poster), Matthijs Moerland et al
• Evaluation of a glucagon challenge test as a tool in diabetes research (poster), Marloes van Dongen et al
• Pharmacological resting state fMRI study using THC (poster), Linda Klumpers et al

CINP
Our visit to the CINP conference June 6-10 in Hong Kong was a large success. CHDR was the most publishing output unit of the 3500 participants. Please find the overview and downloads of our posters here.

The reduction of hepatic glucagon receptor (GCGR) expression with antisense oligonucleotides (ASO) was tested in a SAD and MAD design in healthy subjects. The subjects underwent a glucagon-challenge procedure at baseline and at the end of treatment to determine the pharmacological efficacy. The ASO treatment significantly blunted both the glucagon-induced increase in plasma glucose and hepatic glucose and showed a consistent PK-PD relationship with preclinical data. In conclusion, the results support further evaluation of the GCGR antisense approach in patients with T2DM.

Sputum induction with hypertonic saline reduces fractional exhaled nitric oxide in chronic smokers and non-smokers.
Zuiker RG, Boot JD, Calderon C, Piantone A, Petty K, de Kam M, Diamant Z.
Respir Med. 2010; 104: 917-920
The objective of the study was to evaluate the reproducibility and differences in fractional exhaled NO (FeNO) values in asymptomatic chronic smokers and healthy, non-smoking controls and to test the effect of hypertonic saline sputum induction on FeNO levels in both study groups. Our data extend previous findings in asthmatics and healthy controls to asymptomatic chronic smokers.

• A meta-analysis of pharmacodynamic testing of central nervous system drug effects with the NeuroCart in early phase drug development
  Hay J. et al
• The effect of olanzapine on THCinduced psychomimetic symptoms
  Kleinloog D. et al
• Novel method in pharmacology research: resting state-functional Magnetic Resonance Imaging study using delta 9-Tetrahydrocannabidiol
  Klumpers L. et al
• Pharmacokinetics and pharmacodynamics of the novel fast-dissociating dopamine D2 receptor antagonist JNJ-37822681
  te Beek E. et al
• In vivo quantification of striatal dopamine D2 receptor occupancy by JNJ-37822681 using [11C]raclopride and positron emission tomography
  te Beek E. et al
• Central nervous system effects of the interaction between single doses of risperidone and repeated daily doses of the 5-HT6 antagonist SB742457 in healthy male volunteers
  Liem-Moolenaar M. et al
• A review of biomarkers for the acute effects of alcohol on the central nervous system in healthy volunteers
  Zoethout R. et al
• Hypothalamic glutamate levels following serotonergic stimulation: a pilot study using 7 Tesla magnetic resonance spectroscopy in healthy volunteers
  Jacobs G. et al
• The selective central nervous system (CNS) effects of two different GABAA alpha2,3 subtypeselective agonists compared to lorazepam
  Chen X. et al
• Pharmacodynamic response profiles of anxiolytic drugs
  Chen X. et al

Trials and techniques

Improved detection of suspicious colorectal lesions
A FIH study has started to determine the optimal dose and optimal timing between dosing and examination of a single ascending dose of a new biological compound in healthy volunteers and subsequently in subjects with high suspicion of colorectal cancer (CRC). The study aims to detect areas with high suspicion of CRC using conventional and innovative colonoscopy. Associations between biopsy-based histopathological assessment of suspected lesions and the appearance on colonoscopy will also be investigated. The study will be conducted in collaboration with Dr. J. Hardwick from the Department of Gastroenterology of Leiden University Medical Center.
Andrea Kales

Analgesic research
In collaboration with prof. dr. Dahan from the Anesthesiology Department of the LUMC, the safety and efficacy of a new analgesic compound will be investigated and compared to fentanyl. The study will assess respiratory depressant effects using the dynamic end-tidal forcing technique and the analgesic effects using an electrical pain test. Subsequently a PK/PD model of the respiratory and analgesic effects of the drugs will be developed.
Justin Hay

Acute effects of THC on metabolic parameters
In an upcoming study, serum taken from healthy males and females who are dosed with THC or placebo, will be used to investigate the effects of THC on leptin, glucose, triglycerides and HDL-cholesterol.
Although cannabinoid receptor type I (CB1) ligand development often relates to the treatment of obesity and metabolic diseases, only the long term effect of CB1 ligands are tested. Therefore, in this study acute effects on metabolic parameters will be studied by using the most well-known CB1-agonist, THC.
Linda Klumpers

Measuring drug-related effects using subjective tests
Visual Analogue Scale as described by Bond and Lader (VAS Bond and Lader) appeared sensitive enough to indicate drug-related effects. This was concluded from an analysis which was performed on 13 clinical trials at CHDR during the past eight years involving CNS depressing compounds with different receptor binding mechanisms.



The VAS Bond and Lader is a generally used method to measure drug-related sedative effects subjectively. Standardized procedures implementing this subjective test have improved the quality of the data and lead to far better and more accurate results of how different types of drugs affect the subjective feelings.
Daniel Kleinloog

Presentations, Publications and Posters

Come and visit us at the CINP world congress in Hong Kong, June 6-10.

Abstracts

• A meta-analysis of pharmacodynamic testing of central nervous system drug effects with the NeuroCart in early phase drug development, Hay J. et al
• The selective central nervous system (CNS) effects of two different GABAA alpha2,3 subtypeselective agonists compared to lorazepam Chen X. et al
• Pharmacodynamic response profiles of anxiolytic drugs, Chen X. et al
• Pharmacokinetics and pharmacodynamics of the novel fast-dissociating dopamine D2 receptor antagonist JNJ-37822681, te Beek E. et al
• In vivo quantification of striatal dopamine D2 receptor occupancy by JNJ-37822681 using [11C]raclopride and positron emission tomography, te Beek E. et al
• Central nervous system effects of the interaction between single doses of risperidone and repeated daily doses of the 5-HT6 antagonist SB742457 in healthy male volunteers, Liem-Moolenaar M. et al
• A review of biomarkers for the acute effects of alcohol on the central nervous system in healthy volunteers, Zoethout R. et al
• Hypothalamic glutamate levels following serotonergic stimulation: a pilot study using 7 Tesla magnetic resonance spectroscopy in healthy volunteers, Jacobs G. et al

Hypothalamic glutamate levels following serotonergic stimulation: a pilot study using 7-Tesla magnetic resonance spectroscopy in healthy volunteers.
Jacobs GE, der Grond J, Teeuwisse WM, Langeveld TJ, van Pelt J, Verhagen JC, de Kam ML, Cohen AF, Zitman FG, van Gerven JM.
Prog Neuropsychopharmacol Biol Psychiatry. 2010; 34: 486-491.
This exploratory study shows that Functional proton magnetic resonance spectroscopy (MRS) is capable of detecting neuronal activation following functional stimulation of a targeted brain area.
We studied the effect of the administration of the serotonin precursor 5-hydroxytryptophan function test in healthy volunteers on hypothalamic levels of glutamate/glutamine, choline, N-acetyl-aspartate and creatine using 7-Tesla MRS, and adrenocorticotropic hormone and cortisol in peripheral blood.

Typical example of the MRS planning. The white rectangles represent the borders of the MRS voxel that contains the hypothalamus.

Inhibition of THC-induced effects on the central nervous system and heart rate by a novel CB1 receptor antagonist AVE1625.
Zuurman L, Roy C, Schoemaker RC, Amatsaleh A, Guimaeres L, Pinquier JL, Cohen AF, van Gerven JM.
J Psychopharmacol. 2010; 24: 363-371
This study shows a useful method for studying the effects of CB1 antagonists which are potentially useful in the treatment of obesity, smoking cessation and cognitive impairment. Proof of pharmacological action of AVE1625 in the brain is given by antagonising the effects of delta-9-tetrahydrocannabinol (THC), a CB1/CB2 agonist, as 20 mg AVE1625 inhibited most of THC-induced effects.

Mean time profile of feeling high-
time profiles with SD as error bars.
Arrows indicate drug administration.

Contact info
Marieke van den Bosch
Business Development Manager
+31 - 71 - 5246 487
bd@chdr.nl
www.chdr.nl 

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. 
More info

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.
More info

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.

More info

Newsletter CHDR Winter 2009

 Bridging studies
A longstanding relation between the Japan Clinical Pharmacology Network for Global Trials (J-CLIPNET) and CHDR was formalized by signing a Memorandum of Understanding on Nov 16 2009 which emphasizes the commitment of both organisations and the contribution of mutual research and education.
Within the J-CLIPNET consortium, CHDR has performed highly efficient bridging studies using the same protocol in both countries simultaneously. Also, several Japanese pharmacologists received their training at CHDR.
More info

Creating a culture of thoughtful prescribing.
Franson KL, Dubois EA, de Kam ML, Burggraaf J, Cohen AF.
Med Teach. 2009; 31: 415-419.
This publication describes the development of the Individualized Therapy Evaluation and Plan (ITEP) for therapeutic decision-making and communication based on the subjective objective assessment and plan note. The aim of ITEP is to introduce a structured format for creating and communicating therapeutic plans and to provide for students opportunities practice and feedback on their abilities. 

Contact info
Marieke van den Bosch
Business Development Manager
+31 - 71 - 5246 487
bd@chdr.nl
www.chdr.nl

The research collaboration will encourage academic exchange and co-operation between the research staff in the area of clinical pharmacology. Benefits already include the agreement to share methodologies, including providing the University of Adelaide with CHDR's NeuroCart. This will allow the two institutes to use the same methodologies, facilitating collaborative research, especially in the area of CNS research.

Furthermore, a Student Exchange Program has been set up where research projects in the field of clinical pharmacology are offered.

Students enrolled in the Schools of Medicine, Biomedical And Biopharmaceutical Sciences (Leiden University) and the School of Medical Sciences (University of Adelaide) are eligible to participate in a research exchange program and receive credit for their studies. Research projects are provided at the Centre for Human Drug Research (NL) and the School of Medical Sciences (AUS) in the field of clinical pharmacology.

The Japan Clinical Pharmacology Network for Global Trials (J-CLIPNET) is a network consisting of six of the most prestigeous Japanese university hospitals and clinical trial centers in Korea, China, and the Netherlands all with extensive experience in human pharmacology and clinical trials.

Within the J-CLIPNET consortium, CHDR has performed highly efficient bridging studies using the same protocol in both countries simultaneously. Also, several Japanese pharmacologists received their training at CHDR.

For this occasion prof. dr. Kyoichi Ohashi, J-CLIPNET representative, and our CEO prof. dr. Adam Cohen have signed a ceremonial letter of understanding which emphasizes the commitment of both organisations and the contribution of mutual research and education. This collaboration offers yet another unique opportunity for our clients to combine top-level science and excellent operational activities in a full service model, this time allowing to build the difficult bridges between trials in US/Europe and Asia.

Please contact our business development office who will be delighted to arrange a meeting in any of the J CLIPNET countries.