Replicative ageing of fibroblasts has often been used as a model for organismal ageing. The general assumption that the ageing process is mirrored by cellular senescence in vitro is based on lower... Show moreReplicative ageing of fibroblasts has often been used as a model for organismal ageing. The general assumption that the ageing process is mirrored by cellular senescence in vitro is based on lower replicative capacity of human fibroblasts from donors of higher chronological age, but these inverse relations have not been reported unequivocally. The relation between chronological age and fibroblast growth characteristics was assessed in nonagenarian subjects of the Leiden 85+ Study. A high remaining replicative capacity impressively showed that even in the very elderly a crucial number of cells with high mitotic capacity are left to give rise to fibroblast strains with the capacity for more than 100 population doublings. During the course of fibroblast growth in vitro, beta-galactosidase activity has been shown to be a reliable biomarker for replicative senescence. In myoblast cultures the relation between mixed cultures and clonal cultures was studied, showing marked heterogeneity between clonal cultures that all had a significantly lower replicative capacity when compared to mixed cultures, indicating heterogeneity of cells within one tissue compartment in their in vivo history. In a formal review on the replicative capacity of fibroblasts from patients suffering from accelerated ageing syndromes, age related diseases and donor age it was found that except for premature ageing syndromes, the replicative capacity of fibroblasts in vitro does not mirror key characteristics of human life histories. 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
