Comparison of in vitro and in vivo biological effects of trabectedin,lurbinectedin (PM01183) and Zalypsis® (PM00104)

This study: (i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (ii) evaluated their in vivo antitumor activity against a series of murine tumors and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumor lines were very similar. Nucleotide Excision Repair (NER) deficient cells were approximately fourfold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in non‐homologous end joining (NHEJ), MRN complex and translesion synthesis (TLS) were slightly more sensitive to the three compounds (approximately fivefold) while cells deficient in homologous recombination (HR) were markedly more sensitive (150–200‐fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumors and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host‐mediated effects are involved in the in vivo pharmacological effects.     

Clinical utility of novel biomarkers for cardiovascular disease risk stratification

Over the past few decades, a number of coronary artery disease (CAD) and cardiovascular disease (CVD) risk factors have been identified. The predictive power of “conventional” risk factors have been validated by observational, prospective and intervention studies. Nevertheless, all attempts to exactly predict the individual risk for CAD have failed, biased by a large number of incorrectly risk-classified subjects. To improve cardiovascular (CV) risk prediction, a large number of genetic and/or non-genetic biomarkers have been discovered and tested against the “classical” risk factors for their power to predict CV risk. Only few of them had a significant improvement over the predictive models. In this paper, the most investigated biomarkers will be discussed and the evidence of their use as predictors of CV will be questioned.     

Development of a spray-drying method for the formulation of respirable microparticles containing ofloxacin–palladium complex

The purpose of this study was to produce low-releasing spray-dried polymeric microparticles (MP) useful to target alveolar macrophages in tuberculosis (TB) inhalation therapy.