Degenerative diseases of the nervous system, such as Alzheimer's, Parkinson's and ALS, are severe, progressive and ultimately fatal. Most existing drugs for these neurodegenerative diseases only... Show moreDegenerative diseases of the nervous system, such as Alzheimer's, Parkinson's and ALS, are severe, progressive and ultimately fatal. Most existing drugs for these neurodegenerative diseases only temporarily relieve symptoms, increase mobility or relieve pain, but do not slow disease progression.This dissertation describes a method to efficiently carry out the development of new drugs that could inhibit disease progression in neurodegenerative diseases. Namely, by using pharmacodynamic biomarkers. These are signaling substances to measure the magnitude of a drug response.These biomarkers can be used in early clinical-pharmacological studies in healthy volunteers or small groups of patients to select the best drug candidates and their expected therapeutic doses as early as possible in the development stage. This helps to make informed choices to advance a potential new drug into large and expensive phase 2 and 3 (registration) studies, or conversely to discontinue development of a non-potential drug as early as possible. This biomarker method was applied in this dissertation to investigate 2 new drugs that could potentially slow disease progression in Alzheimer's and ALS (a RIPK1 inhibitor) or Parkinson's disease (a LRRK2 inhibitor). The research results from multiple early clinical-pharmacological studies in healthy volunteers and patients described in this thesis form the basis for larger phase 2 and 3 follow-up studies that have now been initiated with ALS patients and Parkinson's disease patients. Both with the goal of confirming whether these agents can indeed slow disease progression, which would represent a major breakthrough in the treatment of these conditions. Show less
Pharmacological challenges with psychomimetic drugs may not fully represent the complexity of (chronic) schizophrenia, but constitute a useful model for psychosis and antipsychotic drug action.... Show morePharmacological challenges with psychomimetic drugs may not fully represent the complexity of (chronic) schizophrenia, but constitute a useful model for psychosis and antipsychotic drug action. This thesis describes the use of THC and ketamine as models and explores different outcome measurements that can be used to quantify psychomimetic effects, in particular VAS-scales and fMRI. The phenomenological and pharmacological basis of psychomimetic challenge models were discussed. Well-controlled circumstances and repeated measurement of drug concentrations and effect greatly benefit the use of pharmacological challenges in drug development. Show less
