Clinical Trials in Paediatrics — Regulatory and Methodological Aspects

The photoautotrophic cyanobacterium Synechocystis PCC6803 has received much attention as a model photosynthetic cell factory for the production of a range of important biotech products. The biomass remaining from this activity may then have further utility in processes such as metal bioremediation. In addition Synechocystis being an inhabitant of many natural aquatic environments is seen as an environmentally friendly alternative to using chemical precipitation methodologies for metal remediation. Synechocystis produces a range of extracellular polysaccharide substances (EPS) that can undergo modification as a function of culture age and growth nutrients which have been implicated in metal biosorption. Many studies have demonstrated that high levels of charged groups present in EPS are important in forming polymeric matrices with metallic ions allowing their biosorption. Genetic studies has revealed genes involved in such metal binding indicating that EPS can be modified for potential enhancement of binding or modification of the types of metals bound. The utility of metal binding to live and dead biomass of Synechocystis has been demonstrated for a range of metals including Cr(VI), Cd(II), Cu(II), Pb(II), Sb, Ni(II), Mn(II), Mn(IV), As(III), As(V), Cs and Hg. The potential of using Synechocystis as a biosorption platform is discussed

Fluvastatin and atorvastatin affect calcium homeostasis of rat skeletal muscle fibers in vivo and in vitro by impairing the sarcoplasmic reticulum/mitochondria Ca2+-release system

The mechanism by which the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) induce skeletal muscle injury is still under debate. By using fura-2 cytofluorimetry on intact extensor digitorum longus muscle fibers, here we provided the first evidence that 2 months in vivo chronic treatment of rats with fluvastatin (5 and 20 mg kg-1) and atorvastatin (5 and 10 mg kg-1) caused an alteration of calcium homeostasis. All treated animals showed a significant increase of resting cytosolic calcium [Ca2+]i, up to 60% with the higher fluvastatin dose and up to 20% with the other treatments. The [Ca2+]i rise induced by statin administration was not due to an increase of sarcolemmal permeability to calcium. Furthermore, the treatments reduced caffeine responsiveness. In vitro application of fluvastatin caused changes of [Ca2+]i, resembling the effect obtained after the in vivo administration. Indeed, fluvastatin produced a shift of mechanical threshold for contraction toward negative potentials and an increase of resting [Ca2+]i. By using ruthenium red and cyclosporine A, we determined the sequence of the statin-induced Ca2+ release mechanism. Mitochondria appeared as the cellular structure responsible for the earlier event leading to a subsequent large sarcoplasmic reticulum Ca2+ release. In conclusion, we suggest that calcium homeostasis alteration may be a crucial event for myotoxicity induced by this widely used class of hypolipidemic drug

Informed consent and assent guide for paediatric clinical trials in Europe

Objective Clinical trial sponsors spend considerable resources preparing informed consent (IC) and assent documentation for multinational paediatric clinical trial applications in Europe due to the limited and dispersed patient populations, the variation of national legal and ethical requirements, and the lack of detailed guidance. The aim of this study was to design new easy-to-use guide publicly available on European Medicines Agency's, Enpr-EMA website for all stakeholders. Methods Current EU legal, ethical and regulatory guidance for paediatric clinical trials were collated, analysed and divided into 30 subject elements in two tables. The European Network of Young Person's Advisory Group reviewed the data and provided specific comments. A three-level recommendation using 'traffic light' symbols was designed for four age groups of children, according to relevance and the requirements. Results A single guide document includes two tables: (1) general information and (2) trial-specific information. In the age group of 6-9 years old, 92% of the trial-specific subject elements can be or should be included in the IC discussion. Even in the youngest possible age group (2-5 years old children), the number of elements considered was, on average, 52%. Conclusion The EU Clinical Trial Regulation (2014) does not contain specific requirements exclusively for paediatric clinical trials. This work is the first to extensively collate all the current legal, regulatory and ethical documentation on the IC process, together with input from adolescents. This guide may increase the ethical standards in paediatric clinical trials. Young people and researchers gathered together to synthesise and rate the advice from all the EU systems they could find about paediatric clinical trials to create a simpler, patient-led, framework for information to aid meaningful trial consent discussions.Peer reviewe

Clinical Trial Application in Europe: What Will Change with the New Regulation?

International audienc

Chapter Clinical Trials in Paediatrics — Regulatory and Methodological Aspects

The photoautotrophic cyanobacterium Synechocystis PCC6803 has received much attention as a model photosynthetic cell factory for the production of a range of important biotech products. The biomass remaining from this activity may then have further utility in processes such as metal bioremediation. In addition Synechocystis being an inhabitant of many natural aquatic environments is seen as an environmentally friendly alternative to using chemical precipitation methodologies for metal remediation. Synechocystis produces a range of extracellular polysaccharide substances (EPS) that can undergo modification as a function of culture age and growth nutrients which have been implicated in metal biosorption. Many studies have demonstrated that high levels of charged groups present in EPS are important in forming polymeric matrices with metallic ions allowing their biosorption. Genetic studies has revealed genes involved in such metal binding indicating that EPS can be modified for potential enhancement of binding or modification of the types of metals bound. The utility of metal binding to live and dead biomass of Synechocystis has been demonstrated for a range of metals including Cr(VI), Cd(II), Cu(II), Pb(II), Sb, Ni(II), Mn(II), Mn(IV), As(III), As(V), Cs and Hg. The potential of using Synechocystis as a biosorption platform is discussed