The thesis describes the use of extensive pharmacodynamic effect profiling to characterise the clinical pharmacology of classic and non-classical analgesia. Analgesic drugs that modulate widespread... Show moreThe thesis describes the use of extensive pharmacodynamic effect profiling to characterise the clinical pharmacology of classic and non-classical analgesia. Analgesic drugs that modulate widespread targets in the nervous system can be expected to affect numerous CNS functions, which requires multimodal characterisation of pain processing and neurocognition. This is illustrated on the basis of two case studies of pharmacological agents that target cannabinoid CB1 and GABA-ergic GABAA receptors: two of the most widely distributed systems of receptors and neurotransmitters that are involved in a myriad of physiological functions. The distribution of receptors throughout the central nervous system render an oral formulation of ∆9-THC and a positive allosteric modulator of α2/3/5 subunit-containing GABAA receptors, ideal candidates for extensive neurophysiological and analgesic effect profiling in early phase clinical research. Profiling human pharmacology with a strong focus on pharmacodynamics may help to better understand the therapeutic potential and safety limitations of a compound before selection of doses and patient populations for phase II proof-of-concept studies. Show less
Although cannabis is especially known for its recreational use as a __soft drug__, its potential therapeutic properties have been recognized for hundreds of years. Since the isolation of THC from... Show moreAlthough cannabis is especially known for its recreational use as a __soft drug__, its potential therapeutic properties have been recognized for hundreds of years. Since the isolation of THC from Cannabis sativa L, the discovery of cannabinoid receptors and their natural ligands (endocannabinoids) the interest in the development of novel cannabinoids as medicine is accelerating. This thesis describes useful cannabis-biomarkers and the clinical pharmacology of some cannabinoid agonists and antagonists in early phase drug development. This includes a novel mode of pure intrapulmonary THC administration that can be used as a benchmark for novel CB1/CB2-agonists, or to demonstrate inhibitory activity of CB1-antagonists. In addition, the pharmacodynamics and pharmacokinetics of two novel CB1/CB2 agonists are evaluated and compared with the pharmacodynamic effect profile of THC. The clinical trials carried out for this research were performed at the Centre for Human Drug Research, Leiden, The Netherlands. Show less