Summary
A pharmacological challenge allows the demonstration of a pharmacological effect on a system that already functions optimally in healthy subjects. When a volunteer is subjected to a pharmacological challenge, the system that is under investigation is artificially hampered. If a given drug restores the challenged function in a dose-dependent way, this is an indication that it triggers the right pharmacological mechanism. In this way, pharmacological challenges enable the investigation of pharmacological effects in healthy subjects.
Scopolamine model
In some cases, a pharmacological challenge test is needed to provide 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 anticholinergic challenge (mecamylamine)
For proof-of-pharmacology studies with receptor-specific agonists, CHDR has developed an anticholinergic pharmacological challenge with the nicotinic antagonist mecamylamine. Results of the validation study showed not only that mecamylamine was well tolerated and had linear pharmacokinetics over the dose range tested, but also that 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 challengeTHC challenge
CHDR's long tradition in the investigation of THC, the primary psychoactive constituent of cannabis, has yielded 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 for the longitudinal measurement of changes in psychotic symptoms, based on a structured clinical interview. It is subdivided into three subscales: positive, negative and general. Using this instrument, CHDR has developed a repeatable, reproducible, dose-dependent and clinically-relevant structured interview. Our data indicate that the positive PANSS shows highly significant dose-dependent psychotic effects of THC in the majority of healthy volunteers.
Clinical pharmacology of cannabinoids in early phase drug development
Ketamine challenge
The psychoactive properties of several classes of drugs can be used to induce psychomimetic symptoms in healthy volunteers, offering a model for psychosis and antipsychotic drug action. Besides THC (above), 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 (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’ among the subjects.
Mitochondrial function challenge (statin-induced)
Evidence has shown that dysfunction of mitochondria plays an important role in age-related diseases, such as type 2 diabetes mellitus, 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.
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 readout 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.
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 diseases (Alzheimer’s disease). CHDR aims to develop and characterise 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 continue to work on further validation of these models.
