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
The muscular dystrophies are a group of neuromuscular disorders characterized by progres_sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular... Show moreThe muscular dystrophies are a group of neuromuscular disorders characterized by progres_sive muscle weakness and wasting. Although the underlying genetic defects of a large number of muscular dystrophies are now know, the molecular mechanisms resulting in the devastating effects of the disease are not yet clear. Furthermore, the muscular dystrophies differ in clinical presentation and severity. The processes responsible for this di_vergence are largely unknown as well. In this thesis, gene expression profiling has been applied to study the molecular and cellular mechanisms and subsequent biological processes that play a role in muscular dystrophy. To characterize the processes associated with regeneration, we have compared gene expression levels in hindlimb muscle tissue of mdx and control mice in a temporal study. Additionally, we have determined the gene expression profiles of dif_ferentiating human myoblasts in vitro, since regeneration processes recapitulate myogenesis. We also set out to compare gene expression levels of different mouse models for muscular dystrophy to find common and distinct molecular mechanisms that underlie different forms of muscular dystrophy. Accordingly, we first had to determine the effects of genetic background variation between inbred mouse strains, and to study the feasibility of alternative experimental designs. Show less
