Centre for Human Drug Research - CHDR.nl http://www.chdr.nl Het laatste nieuws van CHDR Copyright 2010CHDR 2010-02-17T10:53:56+02:00 Newsletter spring 2010 http://www.chdr.nl/default.asp?id=778&nieuwsid=105 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. 
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.

]]> 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. 
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.

]]> 2010-02-17T10:53:56+02:00 Novel mixed Phosphodiesterase 3/4 inhibitor http://www.chdr.nl/default.asp?id=778&nieuwsid=107  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.
This nebulized PDE3/4 inhibitor did not produce adverse events in healthy subjects, allergic asthmatics or allergic rhinitics.
In asthmatics, the PDE3/4 inhibitor induced a statistically and clinically significant bronchodilation. The drug also induced a statistically and clinically significant bronchoprotection against methacholine challenge.
In the allergic rhinitis group, the same single dose of the PDE3/4 inhibitor reduced the percentage of inflammatory cells (eosinophils and neutrophils) obtained from the nose 7 hours after allergen challenge. However, this reduction in inflammatory cells failed to reach statistical significance, possibly due to the large variability in the eosinophil counts and a limited population size. These findings warrant further studies with multiple and/or higher doses of this PDE3/4 inhibitor in larger study populations.

More info

]]>  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.
This nebulized PDE3/4 inhibitor did not produce adverse events in healthy subjects, allergic asthmatics or allergic rhinitics.
In asthmatics, the PDE3/4 inhibitor induced a statistically and clinically significant bronchodilation. The drug also induced a statistically and clinically significant bronchoprotection against methacholine challenge.
In the allergic rhinitis group, the same single dose of the PDE3/4 inhibitor reduced the percentage of inflammatory cells (eosinophils and neutrophils) obtained from the nose 7 hours after allergen challenge. However, this reduction in inflammatory cells failed to reach statistical significance, possibly due to the large variability in the eosinophil counts and a limited population size. These findings warrant further studies with multiple and/or higher doses of this PDE3/4 inhibitor in larger study populations.

More info

]]> 2010-02-16T10:53:56+02:00 Immunopharmacology http://www.chdr.nl/default.asp?id=778&nieuwsid=104

Within this project, emphasis will be on gaining a better understanding of the mechanisms of action underlying successful immunological response of vaccines either alone or in combination therapies in humans based upon pre-clinical findings. This truly translational research area will use existing state-of the-art immunomonitoring and even improve it, such that it can also deliver more generic applicable strategies to be used in evaluating immunotherapeutics in general.  Hélène van Meir (MD) has been appointed to work full-time in this emerging, but also challenging research area that shows a lot of promise, but has many unanswered questions. She will be supported by a team of immunologists, gynaecologists, oncologists and clinical pharmacologists.

Prof. Dr G. Kenter et al - NEJM 2009; 361: 1838-1847

 ]]>

Within this project, emphasis will be on gaining a better understanding of the mechanisms of action underlying successful immunological response of vaccines either alone or in combination therapies in humans based upon pre-clinical findings. This truly translational research area will use existing state-of the-art immunomonitoring and even improve it, such that it can also deliver more generic applicable strategies to be used in evaluating immunotherapeutics in general.  Hélène van Meir (MD) has been appointed to work full-time in this emerging, but also challenging research area that shows a lot of promise, but has many unanswered questions. She will be supported by a team of immunologists, gynaecologists, oncologists and clinical pharmacologists.

Prof. Dr G. Kenter et al - NEJM 2009; 361: 1838-1847

 ]]> 2010-02-11T10:53:56+02:00 Newsletter winter 2009 http://www.chdr.nl/default.asp?id=778&nieuwsid=103

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

Exciting research & student exchange with the University of Adelaide
Newly signed agreements will promote the collaborative research between CHDR and the School of Medical Sciences, University of Adelaide in Australia. The agreement will encourage research collaboration such as the shared utilisation of the NeuroCart.
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 Medical Sciences are eligible to participate in a research exchange program and receive credit for their studies.
More info 

Leiden Bio Science Park best business park 2009
Leiden Bio Science Park was awarded best business park of the Netherlands in 2009. Leiden won the prize for its daring choice to specialize in biomedical life science and making a success out of it.
Leiden Bio Science Park is celebrating her 25th anniversary this year. Since 1984, the park has grown into the largest biomedical life science park in the Netherlands, hosting approximately 60 companies. These companies range from listed multinationals to young start-ups that are involved in the development of innovative medicines, therapies and medical devices.
More info  

Trials and Techniques

Translational medicine of glucose regulation
As part of a scientific collaboration with Roche, a translational medicinal project has started which, as a start, will focus on metabolic diseases.
Besides glucose regulation, (subclinical) inflammation and endothelial function will be characterized as there are clear indications that inflammatory processes play an important role in the pathology of certain metabolic diseases. The obtained data will be compared to data in healthy volunteers to obtain a translational model. Furthermore, within the project, there will be ample opportunities that may help to identify novel targets for pharmacological treatment.
This scientific partnering enhances knowledge in both clinical as well as pathology areas and are believed to be the key to success in drug development.
Marloes van Dongen

NeuroSIPE
CHDR together with its collaborative partners have been part of 2 successful STW , NeuroSIPE grants.
The programme has the aim to develop diagnostic tools for neurological disorders. The two innovative programmes involve studies focused on Pain (PAINSIGHT) and Postural Stability (BALROOM), respectively.
Justin Hay

New formulation of an SSRI
Two studies of a serotonin reuptake inhibitor will be conducted to investigate the pharmacokinetic profile of a new formulation of the antidepressant drug, the orally dispersible tablet, compared to the current formulations. Besides pharmacokinetics, the safety, tolerability and perception of the new formulation will be investigated. The benefit of the orally dispersible tablet is to overcome problems in swallowing.
Tijmen Bostoen

Publications, presentations & posters

On October 13th 2009 Amita Sandhu presented the poster: "Meta-analysis exploring covariate effects on pharmacokinetics, pharmacodynamics and adverse effects of 9-tetrahydrocannabinol (THC) in humans" during the FIGON Dutch Medicines Days 2009, Lunteren, Netherlands.

Pharmacokinetics and pharmacodynamics of the erythropoietin Mimetibody construct CNTO 528 in healthy subjects.
Perez-Ruixo JJ, Krzyzanski W, Bouman-Thio E, Miller B, Jang H, Bai SA, Zhou H, Yohrling J, Cohen A, Burggraaf J, Franson K, Davis HM.
Clin Pharmacokinet. 2009; 48: 601-613.
Anaemia is a serious comorbidity that is common in patients with renal failure or cancer. CNTO 528 is the first Mimetibody developed to mimic the effects of erythropoietin (EPO), a hormone that stimulates the production of red blood cells (RBCs). This publication shows the pharmacokinetic and pharmacodynamic model for CNTO 528 in healthy male subjects. The qualified model is deemed appropriate to conduct clinical trial simulations and to support the decision-making process for dose selection in studies of EPO-stimulating agents.

Intrathecal glycine for pain and dystonia in complex regional pain syndrome.
Munts AG, van der Plas AA, Voormolen JH, Marinus J, Teepe-Twiss IM, Onkenhout W, van Gerven JM, van Hilten JJ.
Pain. 2009; 146: 199-204.
Aims of the current study were to evaluate the safety and efficacy of intrathecal glycine (ITG) administration which may be a potential therapy for both pain and movement disorders in patients with complex regional pain syndrome (CRPS). Efficacy measures involved pain, movement disorders, activity, a clinical global impression and patient's global impression score.
Although there was a trend to worsening on both global impression scores during ITG treatment, there were no significant differences between ITG and placebo treatment in any of the outcomes. 

Central nervous system effects of alcohol at a pseudo-steady-state concentration using alcohol clamping in healthy volunteers.
Zoethout RW, Schoemaker RC, Zuurman L, van Pelt H, Dahan A, Cohen AF, van Gerven JM.
Br J Clin Pharmacol. 2009; 68: 524-534.
The aim of this study was to test a range of central nervous system (CNS) effects under pseudo-steady-state conditions. Most CNS effects of alcohol showed a trend to change over time, despite stable concentrations. Other variables remained stable under pseudo-steady-state conditions.

Key steps for integrating a basic science throughout a medical school curriculum using an e-learning approach.
Dubois EA, Franson KL.
Med Teach. 2009; 31: 822-828.
The process of integrating basic science via e-learning resembles a curricular change. The change usually begins with an idea for using e-learning to teach a basic science and establishing the need for the innovation. A project team is assembled to determine the content of the e-learning program and linking the program to existing course activities. The success of the integration is demonstrated by a positive assessment of the program including favourable cost-benefit analysis and improved student performance. Lastly, continuously updating content and evaluating the integration contribute to the prolonged survival of the e-learning program.

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

 

Register here to receive futur newsletters ]]>

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

Exciting research & student exchange with the University of Adelaide
Newly signed agreements will promote the collaborative research between CHDR and the School of Medical Sciences, University of Adelaide in Australia. The agreement will encourage research collaboration such as the shared utilisation of the NeuroCart.
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 Medical Sciences are eligible to participate in a research exchange program and receive credit for their studies.
More info 

Leiden Bio Science Park best business park 2009
Leiden Bio Science Park was awarded best business park of the Netherlands in 2009. Leiden won the prize for its daring choice to specialize in biomedical life science and making a success out of it.
Leiden Bio Science Park is celebrating her 25th anniversary this year. Since 1984, the park has grown into the largest biomedical life science park in the Netherlands, hosting approximately 60 companies. These companies range from listed multinationals to young start-ups that are involved in the development of innovative medicines, therapies and medical devices.
More info  

Trials and Techniques

Translational medicine of glucose regulation
As part of a scientific collaboration with Roche, a translational medicinal project has started which, as a start, will focus on metabolic diseases.
Besides glucose regulation, (subclinical) inflammation and endothelial function will be characterized as there are clear indications that inflammatory processes play an important role in the pathology of certain metabolic diseases. The obtained data will be compared to data in healthy volunteers to obtain a translational model. Furthermore, within the project, there will be ample opportunities that may help to identify novel targets for pharmacological treatment.
This scientific partnering enhances knowledge in both clinical as well as pathology areas and are believed to be the key to success in drug development.
Marloes van Dongen

NeuroSIPE
CHDR together with its collaborative partners have been part of 2 successful STW , NeuroSIPE grants.
The programme has the aim to develop diagnostic tools for neurological disorders. The two innovative programmes involve studies focused on Pain (PAINSIGHT) and Postural Stability (BALROOM), respectively.
Justin Hay

New formulation of an SSRI
Two studies of a serotonin reuptake inhibitor will be conducted to investigate the pharmacokinetic profile of a new formulation of the antidepressant drug, the orally dispersible tablet, compared to the current formulations. Besides pharmacokinetics, the safety, tolerability and perception of the new formulation will be investigated. The benefit of the orally dispersible tablet is to overcome problems in swallowing.
Tijmen Bostoen

Publications, presentations & posters

On October 13th 2009 Amita Sandhu presented the poster: "Meta-analysis exploring covariate effects on pharmacokinetics, pharmacodynamics and adverse effects of 9-tetrahydrocannabinol (THC) in humans" during the FIGON Dutch Medicines Days 2009, Lunteren, Netherlands.

Pharmacokinetics and pharmacodynamics of the erythropoietin Mimetibody construct CNTO 528 in healthy subjects.
Perez-Ruixo JJ, Krzyzanski W, Bouman-Thio E, Miller B, Jang H, Bai SA, Zhou H, Yohrling J, Cohen A, Burggraaf J, Franson K, Davis HM.
Clin Pharmacokinet. 2009; 48: 601-613.
Anaemia is a serious comorbidity that is common in patients with renal failure or cancer. CNTO 528 is the first Mimetibody developed to mimic the effects of erythropoietin (EPO), a hormone that stimulates the production of red blood cells (RBCs). This publication shows the pharmacokinetic and pharmacodynamic model for CNTO 528 in healthy male subjects. The qualified model is deemed appropriate to conduct clinical trial simulations and to support the decision-making process for dose selection in studies of EPO-stimulating agents.

Intrathecal glycine for pain and dystonia in complex regional pain syndrome.
Munts AG, van der Plas AA, Voormolen JH, Marinus J, Teepe-Twiss IM, Onkenhout W, van Gerven JM, van Hilten JJ.
Pain. 2009; 146: 199-204.
Aims of the current study were to evaluate the safety and efficacy of intrathecal glycine (ITG) administration which may be a potential therapy for both pain and movement disorders in patients with complex regional pain syndrome (CRPS). Efficacy measures involved pain, movement disorders, activity, a clinical global impression and patient's global impression score.
Although there was a trend to worsening on both global impression scores during ITG treatment, there were no significant differences between ITG and placebo treatment in any of the outcomes. 

Central nervous system effects of alcohol at a pseudo-steady-state concentration using alcohol clamping in healthy volunteers.
Zoethout RW, Schoemaker RC, Zuurman L, van Pelt H, Dahan A, Cohen AF, van Gerven JM.
Br J Clin Pharmacol. 2009; 68: 524-534.
The aim of this study was to test a range of central nervous system (CNS) effects under pseudo-steady-state conditions. Most CNS effects of alcohol showed a trend to change over time, despite stable concentrations. Other variables remained stable under pseudo-steady-state conditions.

Key steps for integrating a basic science throughout a medical school curriculum using an e-learning approach.
Dubois EA, Franson KL.
Med Teach. 2009; 31: 822-828.
The process of integrating basic science via e-learning resembles a curricular change. The change usually begins with an idea for using e-learning to teach a basic science and establishing the need for the innovation. A project team is assembled to determine the content of the e-learning program and linking the program to existing course activities. The success of the integration is demonstrated by a positive assessment of the program including favourable cost-benefit analysis and improved student performance. Lastly, continuously updating content and evaluating the integration contribute to the prolonged survival of the e-learning program.

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

 

Register here to receive futur newsletters ]]> 2009-12-11T10:53:56+02:00 Exciting new research & student exchange agreement with the University of Adelaide http://www.chdr.nl/default.asp?id=778&nieuwsid=102

 

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 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.

 

]]> 2009-11-19T10:53:56+02:00 Bridging studies http://www.chdr.nl/default.asp?id=778&nieuwsid=101 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.

 

]]> 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.

 

]]> 2009-11-17T10:53:56+02:00 Leiden Bio Science Park best businesspark 2009 http://www.chdr.nl/default.asp?id=778&nieuwsid=100 Nettie Buitelaar, managing director of the Leiden Bio Science Park foundation, perceives the award to be a great stimulus for continuing the chosen direction.

Leiden Bio Science Park is celebrating her 25th anniversary this year. Since 1984, the park has grown into the largest biomedical life science park in the Netherlands, hosting approximately 60 companies. These companies range from listed multinationals to young start-ups that are involved in the development of innovative medicines, therapies and medical devices.

Double celebration
Marc Witteman, alderman of the city of Leiden states: ‘Obviously, this is a dream for every alderman of Economic Affairs. For 25 years, many people - from the University of Leiden, but also entrepreneurs, researchers and the local authorities - have put a lot of energy in the development of Leiden Bio Science Park. We are the largest life science cluster of the Netherlands, and we rank number 5 in Europe. As from today we can add that we are the best business park of the Netherlands. And all of this in Leiden too - the city that is key to discovery - that is tremendous!’

Election
A selection of 121 business parks in total contested for the award for Best Business Park in the Netherlands. Three of them were nominated in the category ‘Existing Business Park’; Industrial park Moerdijk, Business park Borchwerf in Roosendaal and Leiden Bio Science Park. On October 8th the winner was announced at the National Business park Congress in Venlo by Jérome Verhagen, director of the NV Industrial Bank Liof.

Keeping the backs straight
The jury praised the fact that Leiden chose for a specialization in the biomedical sciences 25 years ago, a time when segmentation of business parks was not common yet. Specializing a business park was a daring choice, which has consequently been sustained for all those years. Since only life science companies are allowed to set up their company at the park , tough decisions have to be made every now and then. Keeping the backs straight has resulted in a strongly specialized cluster, and an attractive place for establishing new businesses.

Leiden Bio Science Park

]]> Nettie Buitelaar, managing director of the Leiden Bio Science Park foundation, perceives the award to be a great stimulus for continuing the chosen direction.

Leiden Bio Science Park is celebrating her 25th anniversary this year. Since 1984, the park has grown into the largest biomedical life science park in the Netherlands, hosting approximately 60 companies. These companies range from listed multinationals to young start-ups that are involved in the development of innovative medicines, therapies and medical devices.

Double celebration
Marc Witteman, alderman of the city of Leiden states: ‘Obviously, this is a dream for every alderman of Economic Affairs. For 25 years, many people - from the University of Leiden, but also entrepreneurs, researchers and the local authorities - have put a lot of energy in the development of Leiden Bio Science Park. We are the largest life science cluster of the Netherlands, and we rank number 5 in Europe. As from today we can add that we are the best business park of the Netherlands. And all of this in Leiden too - the city that is key to discovery - that is tremendous!’

Election
A selection of 121 business parks in total contested for the award for Best Business Park in the Netherlands. Three of them were nominated in the category ‘Existing Business Park’; Industrial park Moerdijk, Business park Borchwerf in Roosendaal and Leiden Bio Science Park. On October 8th the winner was announced at the National Business park Congress in Venlo by Jérome Verhagen, director of the NV Industrial Bank Liof.

Keeping the backs straight
The jury praised the fact that Leiden chose for a specialization in the biomedical sciences 25 years ago, a time when segmentation of business parks was not common yet. Specializing a business park was a daring choice, which has consequently been sustained for all those years. Since only life science companies are allowed to set up their company at the park , tough decisions have to be made every now and then. Keeping the backs straight has resulted in a strongly specialized cluster, and an attractive place for establishing new businesses.

Leiden Bio Science Park

]]> 2009-10-23T10:53:56+02:00 Newsletter Autumn 2009 http://www.chdr.nl/default.asp?id=778&nieuwsid=99 Newsletter CHDR Autumn 2009



Collaboration Erasmus MC
CHDR and the Erasmus Medical Centre in Rotterdam have announced last week that they will join forces to provide translational studies in the field of allergy and pulmonology.
This collaboration will combine the facilities of CHDR for early phase drug development with the clinical facilities of one of the major European academic medical centers, for subsequent clinical studies, under supervision of Dr Zuzana Diamant, research director Respiratory & Allergy.
More info 

New director of education
Since September 7th, Daniël Dresden has joined CHDR as a new director of education. Daniël was trained at the Academic Medical Center in medical biology and medicine.
Before joining CHDR, Daniël worked as a physician at the department of internal medicine. The last two years, he was responsible for an online and offline platform of Elsevier Healthcare (editing and e-learning for cardiology, diabetes and neurology, e.g. journals, web, TV broadcast and e-interviews). At CHDR, he will coordinate and give medical education for students and others.

Wanted: pragmatic statistician
We are looking for a statistician who likes being involved in pharmacological research. This person wants to develop, execute and evaluate statistical analyses together with a team of researchers.  Programming skills in a statistical package and a desire to get the most out of the research are recommended, but a lot of enthusiasm for research is even more important.
More info (in Dutch) or contact Marieke de Kam (E: mdekam@chdr.nl or T: +31-71-5246458)

Biologics Research Platform Leiden
Along with many companies at the Leiden Bio Science Park, CHDR has become a partner in the Biologics Research Platform Leiden (BRPL). Its mission is to foster scientific collaborations between academia and industry with the aim to design and develop biologics as innovative drugs.
The BRPL also organises seminars and courses in the field of pharmaceutical biotechnology ("from clone to clinic"), which are primarily intended for PhD students, postdoctoral fellows and industrial (junior) scientists. Secondly, the BRPL aims to conduct pre-competitive and competitive research on the development of biologics as innovative drugs.
More info

Trials & Techniques

A first in human study with a novel anti-fibrotic protein
Currently, a phase 1 dose escalation study is being conducted of a new anti-fibrotic compound in healthy subjects. This recombinant form of human Serum Amyloid P has demonstrated a reduction of fibrosis in multiple tissues, organs, and disease models, by modulating cells of the innate immune system and decreasing the differentiation of fibrocytes. Besides safety, tolerability and pharmacokinetics we explore the pharmacodynamic parameters of the compound.
Maya Levi

Study of an anti-asthma/allergy drug
We have just successfully completed a safety and proof-of-concept study with a novel drug for the treatment of asthma and allergic rhinitis. This study was conducted according an innovative combined step-up dose-design, combining efficacy data from animal studies with safety data in healthy volunteers for a dose-finding stage in patients with asthma. The effective dose was subsequently used in two placebo-controlled cross-over studies in patients with asthma and patients with allergic rhinitis, respectively. This first-in-humans study showed an excellent safety and tolerability profile, and provided evidence for the drug’s potential in the treatment of asthma and/or allergic rhinitis.
Zuzana Diamant

Alcohol interaction study
To investigate whether the psychomotor and cognitive effects of alcohol are exacerbated by a tachykinin modulator in healthy subjects, a 2-period crossover trial has started. Approximately 20 subjects will be administered with a single oral dose of the modulator or matching placebo, while alcohol is administered intravenously according to the clamping paradigm of Zoethout et el. Pharmacodynamic tests and pharmacokinetic sampling for the tachykinin modulator will be conducted.
Erik te Beek

Chronopharmacology of midazolam kinetics
Various drugs show circadian variability in kinetics and/or dynamics. Despite growing interest in this topic, little is known on the exact cause of circadian PK variations. This is important, as time-dependent changes may proceed from 24h changes in absorption, distribution, metabolism and/or excretion.
In collaboration with the dept's of Neurophysiology and Clinical Pharmacy of Leiden University Medical Centre we have started a trial in which midazolam is used as a model drug to study circadian variability. By using a novel approach of drug administration (at six different time points throughout the 24h cycle) we will be able to study the relative contribution of all important factors contributing to overall PK of the compound and its possible circadian variability.
Floor van Oosterhout

Publications, Presentations & Posters

Thesis defence Diderik Boot
On September 10th Diderik Boot has defended his PhD-thesis: Non-invasive sampling methods of inflammatory biomarkers in asthma and allergic rhinitis (promotores Prof Adam Cohen/Prof Peter Sterk; copromotor Dr Zuzana Diamant). This thesis evaluates the feasibility and applicability of several non-invasive sampling methods and quantification techniques for the assessment of inflammatory biomarkers in clinical trials of allergic asthma and allergic rhinitis.
More info

Japanese and Dutch medicine tradition
Embedded in the cultural activities of Japan@Leiden, Leiden Bio Science Park has organised, in cooperation with Astellas, Sieboldhuis, CHDR, LUMC and Leiden University, a scientific symposium to celebrate the 400 years of relations between the two countries: '400 years of health(y) cooperation between Japan and the Netherlands’.
More info 


Cleaved secretory leucocyte protease inhibitor as a biomarker of chymase activity in allergic airway disease.
Belkowski SM, Boot JD, Mascelli MA, Diamant Z, de Garavilla L, Hertzog B, Polkovitch D, Towers M, Batheja A, D'Andrea MR.
Clin Exp Allergy 2009; 39: 1179-1186.
Chymase in an important mediator of allergic airways disease, but it is difficult to directly measure chymase activity. In this study we show data that the cleaved portion of Secretory leukocyte protease inhibitor (cSLPI) reflects chymase activity in AR and asthma in vivo, and hence, may serve as a biomarker for clinical and research purposes.

Figure: Sputum cSLPI/SLPI ratios

Pharmacokinetics and pharmacodynamics of the erythropoietin Mimetibody construct CNTO 528 in healthy subjects.
Pérez-Ruixo JJ, Krzyzanski W, Bouman-Thio E, Miller B, Jang H, Bai SA, Zhou H, Yohrling J, Cohen A, Burggraaf J, Franson K, Davis HM.
Clin Pharmacokinet. 2009; 48: 601-613
A PK/PD model for CNTO 528 was developed to describe the serum concentration versus time profile and the pharmacological responses of percentage of reticulocytes, total red blood cell counts and haemoglobin concentration after a single intravenous administration of CNTO 528. CNTO 528 is the first Mimetibody developed to mimic the effects of erythropoietin, a hormone that stimulates the production of red blood cells.

Comparison of biomarkers between allergic rhinitis only and allergic rhinitis with concomitant asthma.
Wang WY, Boot JD, Mascelli MA, Gerth van Wijk R, Diamant Z.
Allergy 2009; 64: 1102-1103.
Despite many similarities, evidence suggests different phenotypes within the allergic airways syndrome. This post hoc analysis suggests distinct immunologic profiles in patients with allergic rhinitis only and patients with allergic rhinitis & allergic asthma phenotypes.

Physiological thyroid hormone levels regulate numerous skeletal muscle transcripts.
Visser WE, Heemstra KA, Swagemakers SM, Ozgür Z, Corssmit EP, Burggraaf J, van Ijcken WF, van der Spek PJ, Smit JW, Visser TJ.
J Clin Endocrinol Metab. 2009; 94: 3487-3496.
We examined the effects of l-thyroxine on human skeletal muscle transcriptome and performed a microarray analysis of transcript levels using skeletal muscle biopsies from patients under euthyroid and hypothyroid conditions. We identified the genes that are regulated by physiological TH levels which may provide the molecular basis of clinical effects in subjects with different TH status.

Cannabis Coadministration Potentiates the Effects of "Ecstasy" on Heart Rate and Temperature in Humans.
Dumont G, Kramers C, Sweep F, Touw D, van Hasselt J, de Kam M, van Gerven J, Buitelaar J, Verkes R.
Clin Pharmacol Ther. 2009; 86: 160-166.
Acute physiologic effects like PK and cardiovascular, temperature, and catecholamine responses over time of (co)administration of THC and MDMA or "ecstasy" has been studied. The results show that THC mediates heart rate increase independent of sympathetic (catecholaminergic) activity, probably through direct cannabinoid receptor type 1 agonism in cardiac tissue. Furthermore, THC coadministration did not prevent MDMA-induced temperature increase, but it delayed the onset and prolonged the duration of temperature elevation.

Figure: Average heart rate per 5 min (arrows indicate THC administration)

Contact info:
Marieke van den Bosch
Business Development Manager
+31 - 71 - 5246 400
bd@chdr.nl
www.chdr.nl

]]> Newsletter CHDR Autumn 2009



Collaboration Erasmus MC
CHDR and the Erasmus Medical Centre in Rotterdam have announced last week that they will join forces to provide translational studies in the field of allergy and pulmonology.
This collaboration will combine the facilities of CHDR for early phase drug development with the clinical facilities of one of the major European academic medical centers, for subsequent clinical studies, under supervision of Dr Zuzana Diamant, research director Respiratory & Allergy.
More info 

New director of education
Since September 7th, Daniël Dresden has joined CHDR as a new director of education. Daniël was trained at the Academic Medical Center in medical biology and medicine.
Before joining CHDR, Daniël worked as a physician at the department of internal medicine. The last two years, he was responsible for an online and offline platform of Elsevier Healthcare (editing and e-learning for cardiology, diabetes and neurology, e.g. journals, web, TV broadcast and e-interviews). At CHDR, he will coordinate and give medical education for students and others.

Wanted: pragmatic statistician
We are looking for a statistician who likes being involved in pharmacological research. This person wants to develop, execute and evaluate statistical analyses together with a team of researchers.  Programming skills in a statistical package and a desire to get the most out of the research are recommended, but a lot of enthusiasm for research is even more important.
More info (in Dutch) or contact Marieke de Kam (E: mdekam@chdr.nl or T: +31-71-5246458)

Biologics Research Platform Leiden
Along with many companies at the Leiden Bio Science Park, CHDR has become a partner in the Biologics Research Platform Leiden (BRPL). Its mission is to foster scientific collaborations between academia and industry with the aim to design and develop biologics as innovative drugs.
The BRPL also organises seminars and courses in the field of pharmaceutical biotechnology ("from clone to clinic"), which are primarily intended for PhD students, postdoctoral fellows and industrial (junior) scientists. Secondly, the BRPL aims to conduct pre-competitive and competitive research on the development of biologics as innovative drugs.
More info

Trials & Techniques

A first in human study with a novel anti-fibrotic protein
Currently, a phase 1 dose escalation study is being conducted of a new anti-fibrotic compound in healthy subjects. This recombinant form of human Serum Amyloid P has demonstrated a reduction of fibrosis in multiple tissues, organs, and disease models, by modulating cells of the innate immune system and decreasing the differentiation of fibrocytes. Besides safety, tolerability and pharmacokinetics we explore the pharmacodynamic parameters of the compound.
Maya Levi

Study of an anti-asthma/allergy drug
We have just successfully completed a safety and proof-of-concept study with a novel drug for the treatment of asthma and allergic rhinitis. This study was conducted according an innovative combined step-up dose-design, combining efficacy data from animal studies with safety data in healthy volunteers for a dose-finding stage in patients with asthma. The effective dose was subsequently used in two placebo-controlled cross-over studies in patients with asthma and patients with allergic rhinitis, respectively. This first-in-humans study showed an excellent safety and tolerability profile, and provided evidence for the drug’s potential in the treatment of asthma and/or allergic rhinitis.
Zuzana Diamant

Alcohol interaction study
To investigate whether the psychomotor and cognitive effects of alcohol are exacerbated by a tachykinin modulator in healthy subjects, a 2-period crossover trial has started. Approximately 20 subjects will be administered with a single oral dose of the modulator or matching placebo, while alcohol is administered intravenously according to the clamping paradigm of Zoethout et el. Pharmacodynamic tests and pharmacokinetic sampling for the tachykinin modulator will be conducted.
Erik te Beek

Chronopharmacology of midazolam kinetics
Various drugs show circadian variability in kinetics and/or dynamics. Despite growing interest in this topic, little is known on the exact cause of circadian PK variations. This is important, as time-dependent changes may proceed from 24h changes in absorption, distribution, metabolism and/or excretion.
In collaboration with the dept's of Neurophysiology and Clinical Pharmacy of Leiden University Medical Centre we have started a trial in which midazolam is used as a model drug to study circadian variability. By using a novel approach of drug administration (at six different time points throughout the 24h cycle) we will be able to study the relative contribution of all important factors contributing to overall PK of the compound and its possible circadian variability.
Floor van Oosterhout

Publications, Presentations & Posters

Thesis defence Diderik Boot
On September 10th Diderik Boot has defended his PhD-thesis: Non-invasive sampling methods of inflammatory biomarkers in asthma and allergic rhinitis (promotores Prof Adam Cohen/Prof Peter Sterk; copromotor Dr Zuzana Diamant). This thesis evaluates the feasibility and applicability of several non-invasive sampling methods and quantification techniques for the assessment of inflammatory biomarkers in clinical trials of allergic asthma and allergic rhinitis.
More info

Japanese and Dutch medicine tradition
Embedded in the cultural activities of Japan@Leiden, Leiden Bio Science Park has organised, in cooperation with Astellas, Sieboldhuis, CHDR, LUMC and Leiden University, a scientific symposium to celebrate the 400 years of relations between the two countries: '400 years of health(y) cooperation between Japan and the Netherlands’.
More info 


Cleaved secretory leucocyte protease inhibitor as a biomarker of chymase activity in allergic airway disease.
Belkowski SM, Boot JD, Mascelli MA, Diamant Z, de Garavilla L, Hertzog B, Polkovitch D, Towers M, Batheja A, D'Andrea MR.
Clin Exp Allergy 2009; 39: 1179-1186.
Chymase in an important mediator of allergic airways disease, but it is difficult to directly measure chymase activity. In this study we show data that the cleaved portion of Secretory leukocyte protease inhibitor (cSLPI) reflects chymase activity in AR and asthma in vivo, and hence, may serve as a biomarker for clinical and research purposes.

Figure: Sputum cSLPI/SLPI ratios

Pharmacokinetics and pharmacodynamics of the erythropoietin Mimetibody construct CNTO 528 in healthy subjects.
Pérez-Ruixo JJ, Krzyzanski W, Bouman-Thio E, Miller B, Jang H, Bai SA, Zhou H, Yohrling J, Cohen A, Burggraaf J, Franson K, Davis HM.
Clin Pharmacokinet. 2009; 48: 601-613
A PK/PD model for CNTO 528 was developed to describe the serum concentration versus time profile and the pharmacological responses of percentage of reticulocytes, total red blood cell counts and haemoglobin concentration after a single intravenous administration of CNTO 528. CNTO 528 is the first Mimetibody developed to mimic the effects of erythropoietin, a hormone that stimulates the production of red blood cells.

Comparison of biomarkers between allergic rhinitis only and allergic rhinitis with concomitant asthma.
Wang WY, Boot JD, Mascelli MA, Gerth van Wijk R, Diamant Z.
Allergy 2009; 64: 1102-1103.
Despite many similarities, evidence suggests different phenotypes within the allergic airways syndrome. This post hoc analysis suggests distinct immunologic profiles in patients with allergic rhinitis only and patients with allergic rhinitis & allergic asthma phenotypes.

Physiological thyroid hormone levels regulate numerous skeletal muscle transcripts.
Visser WE, Heemstra KA, Swagemakers SM, Ozgür Z, Corssmit EP, Burggraaf J, van Ijcken WF, van der Spek PJ, Smit JW, Visser TJ.
J Clin Endocrinol Metab. 2009; 94: 3487-3496.
We examined the effects of l-thyroxine on human skeletal muscle transcriptome and performed a microarray analysis of transcript levels using skeletal muscle biopsies from patients under euthyroid and hypothyroid conditions. We identified the genes that are regulated by physiological TH levels which may provide the molecular basis of clinical effects in subjects with different TH status.

Cannabis Coadministration Potentiates the Effects of "Ecstasy" on Heart Rate and Temperature in Humans.
Dumont G, Kramers C, Sweep F, Touw D, van Hasselt J, de Kam M, van Gerven J, Buitelaar J, Verkes R.
Clin Pharmacol Ther. 2009; 86: 160-166.
Acute physiologic effects like PK and cardiovascular, temperature, and catecholamine responses over time of (co)administration of THC and MDMA or "ecstasy" has been studied. The results show that THC mediates heart rate increase independent of sympathetic (catecholaminergic) activity, probably through direct cannabinoid receptor type 1 agonism in cardiac tissue. Furthermore, THC coadministration did not prevent MDMA-induced temperature increase, but it delayed the onset and prolonged the duration of temperature elevation.

Figure: Average heart rate per 5 min (arrows indicate THC administration)

Contact info:
Marieke van den Bosch
Business Development Manager
+31 - 71 - 5246 400
bd@chdr.nl
www.chdr.nl

]]> 2009-09-23T10:53:56+02:00 Symposium on Japanese and Dutch medicine tradition http://www.chdr.nl/default.asp?id=778&nieuwsid=98 ]]> ]]> 2009-09-11T10:53:56+02:00 Thesis defense Diderik Boot http://www.chdr.nl/default.asp?id=778&nieuwsid=94 Non-invasive sampling methods of inflammatory biomarkers in asthma and allergic rhinitis

by J. Diderik Boot


This thesis evaluates the feasibility and applicability of several non-invasive sampling methods and quantification techniques for the assessment of inflammatory biomarkers in allergic asthma and allergic rhinitis.

 

To download the thesis please visit the University Leiden system or after registration here.

 

For more information, feel free to contacting us:

CHDR, Leiden, The Netherlands
Tel: +31.71.5246400
E-mail: info@chdr.nl

]]> Non-invasive sampling methods of inflammatory biomarkers in asthma and allergic rhinitis

by J. Diderik Boot


This thesis evaluates the feasibility and applicability of several non-invasive sampling methods and quantification techniques for the assessment of inflammatory biomarkers in allergic asthma and allergic rhinitis.

 

To download the thesis please visit the University Leiden system or after registration here.

 

For more information, feel free to contacting us:

CHDR, Leiden, The Netherlands
Tel: +31.71.5246400
E-mail: info@chdr.nl

]]> 2009-09-10T10:53:56+02:00