CHDR has grown over the past 30 years with a strategy of thorough functional testing for pharmacological effects in early clinical drug research. An important tool to look for pharmacological effects, even in healthy subjects, are various pharmacological challenges. We have an experienced CNS research group, with a self funded research line focusing on development and validation of models that help to answer important research questions of our sponsors.

Summary

Showing a pharmacological effect on a system that already functions optimally in healthy subjects is a so-called pharmacological challenge. By subjecting a volunteer to a pharmacological challenge, the system that is under investigation will be artificially 'toned down' in this volunteer. If a drug restores the challenged function in a dose dependent way, this is an indication that it triggers the right pharmacological mechanism. Pharmacological challenges are thus a great tool to look for pharmacological effects, even in healthy subjects

Scopolamine model

In some cases, a pharmacological challenge test is needed for unequivocal proof-of-pharmacological-activity. CHDR has thoroughly validated a range of pharmacological challenge tests, including the muscarinic receptor antagonist scopolamine. The scopolamine model was able to show CNS-effects of glycine reuptake inhibitors. These effects were small because of low brain penetration, but were not found with the inhibitors alone, indicating the importance of a challenge test. The literature reports stronger suppression of scopolamine effects with muscarinic and nicotinic agonists.

Nicotinic anti-cholinergic challenge (mecamylamine)

For proof-of-pharmacology studies with receptor specific agonists, CHDR has developed an anti-cholinergic pharmacological challenge with the nicotinic antagonist mecamylamine. Some results of the validation study:

  • Mecamylamine was well tolerated and had linear pharmacokinetics over the dose range tested.
  • Mecamylamine gives a nicotinic ACh receptor specific, reproducible pattern of cognitive disturbances.
  • Contrary to scopolamine, mecamylamine did not have significant effects on parameters for sedation

This model can be used for proof-of-pharmacology and dose finding studies of (α7) nicotinic agonists.

Mecamylamine challenge

THC challenge

CHDR has a long tradition in investigating THC, the primary psychoactive constituent of cannabis, which resulted in a robust PK/PD model. THC induces psychomimetic symptoms that closely resemble core aspects of acute clinical psychosis. In clinical research, psychotic symptoms are often quantified with the Positive and Negative Syndrome Scale (PANSS). The PANSS is a clinically validated scale to longitudinally measure changes in psychotic symptoms and is based on a structured clinical interview. It is subdivided into three subscales: positive, negative and general. From this instrument, CHDR has developed a repeatable, reproducible, dose dependent and clinically relevant structured interview. Our data indicates that the positive PANSS shows highly significant dose-dependent psychotic effects of THC in a majority of healthy volunteers.

Clinical pharmacology of cannabinoids in early phase drug development

Ketamine challenge

Like THC, the psychoactive properties of several other classes of drugs can be used to induce psychomimetic symptoms in healthy volunteers as a model for psychosis and antipsychotic drug action. A ketamine challenge was also found to be a robust method to induce psychomimetic symptoms. The effect of ketamine could be measured by the Positive and Negative Syndrome Scale (PANSS), prepulse inhibition of the startle reflex (PPI) and an extensive test battery for cns effects (CHDR's NeuroCart) consisting of several Visual Analogue Scales (VAS). The response to the ketamine challenge was larger than the response found for the THC challenge and there were no 'non-responders'.  

Drug induced psychomimetic effects as a model for psychosis

Mitochondrial function challenge (statin induced)

Evidence has shown that dysfunction of mitochondria plays an important role in age related diseases, such as diabetes mellitus type 2, sarcopenia, and most neurodegenerative diseases. CHDR has validated a model for statin-induced mitochondrial dysfunction in healthy subjects, which can be used to evaluate the pharmacodynamic effects of drugs that potentially enhance mitochondrial function.

Mitochondrial function challenge

HPA axis activation models (serotonergic, vasopressinergic)

The hypothalamic-pituitary-adrenal (HPA) axis is the most important functional regulator of the neuroendocrine response during stress. Pituitary hormones are sensitive to altered central neurotransmission. Changes in peripheral hormone concentrations are frequently observed. They may be used as primary read-out parameters for neurotransmitter activation (with challenge-tests using 5-HTP, metoclopramine or desmopressin) or modulation of central neurotransmission, or to assess general neuroendocrine effects of novel drugs.

The LPS challenge

There is increasing evidence for the beneficial effects of inflammasome inhibition on various diseases, ranging from autoimmune diseases (arthritis, atherosclerosis) to metabolic disorders (diabetes mellitus) and neurodegenerative disease (Alzheimer’s disease). Therefore, CHDR aims to develop and characterize human inflammasome challenges to support the clinical development of investigational compounds that suppress inflammasome or caspase activity and/or IL-1β and IL-18 production. Our research indicates that an ex vivo LPS+ATP challenge and an in vivo intradermal LPS challenge may be valuable models for future clinical trials investigating the effects of inflammasome/caspase inhibitors. We will continue to further validate these models.

Contact Research Director Translational Biomarkers Matthijs Moerland for more information: MMoerland@chdr.nl

Ex vivo and in vivo models for inflammasome activation

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