- show a pharmacological effect on a system that already functions optimally in healthy subjects is a so-called pharmacological challenge
- This means that the system under investigation will be artificially 'toned down'
- if a drug restores the challenged function in a dose dependent way, this is an indication that it triggers the right pharmacological mechanism
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, which were small because of low brain penetration but were not found with the drugs alone.
- The literature reports stronger suppressions 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:
- 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
- To be used for proof-of-pharmacology and dose finding studies of (α7) nicotinic agonist
The psychoactive properties of several classes of drugs can be used to induce psychomimetic symptoms in healthy volunteers as a model for psychosis and antipsychotic drug action. Previous studies have used THC for this.
A ketamine-challenge was found to be a robust method to induce psychomimetic symptoms, that could be measured by the PANSS, prepulse inhibition and VAS. The response was larger than the response found for the THC-challenge and there were no 'non-responders'.
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. We have 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.
CHDR has a long tradition in investigating THC, the active compound 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). From this instrument, CHDR has developed a repeatable, reproducible, dose dependent and clinically relevant structured interview. The positive PANSS shows highly significant dose-dependent psychotic effects of THC in a majority of healthy volunteers.
HPA axis activation models (serotonergic, vasopressinergic)
The hypo-thalamus-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.