Efficacy and safety of immunosuppressive drugs approved in EU through the centralised procedure.

INTRODUCTION: The aim of the present work is to evaluate the efficacy and safety data used by the European Medicines Agency (EMEA) between 1995 and June 2006 to approve new immunosuppressive drugs with indications in solid organ transplantation. MATERIALS AND METHODS: The information about the approval of new agents was retrieved mainly from the European Public Assessment Report (EPAR) and Summary of Product Characteristics (SPC) on the EMEA web site. The design, type of control, primary endpoints, duration of follow-up, and safety profile of pivotal trials were examined. RESULTS: Four immunosuppressive drugs belonging to three different therapeutic classes, with different clinical uses, were identified. Not all pivotal clinical trials compared the investigational agent with cyclosporin/corticosteroid/azathioprine triple therapy, which was the best therapeutic option available at the time of approval. Acute rejection, graft survival and efficacy failure at 6 months or 1 year post-transplant were the most frequent endpoints. Although some of the new agents reduce calcineurin inhibitor-associated nephrotoxicity, their adverse cardiovascular profile is of particular concern. DISCUSSION: Recent improvements in the short-term efficacy of immunosuppressive therapy make short-term outcome measures inadequate for predicting long-term clinical benefit. Clinical outcomes such as 3- or 5-year graft and patient survival should be used in clinical trials in order to take into account non-immunosuppressive-related morbidity and to assess better whether the therapeutic advantage of the new agents over standard therapy is maintained in the long term.

Fish oil and mental health: the role of n-3 long-chain polyunsaturated fatty acids in cognitive development and neurological disorders.

Epidemiological and experimental studies have indicated that consumption of more n-3 long-chain polyunsaturated fatty acids may reduce the risk for a variety of diseases, including cardiovascular, neurological and immunological disorders, diabetes and cancer. This article focuses on the role of marine n-3 long-chain polyunsaturated fatty acids in brain functions, including the development of the central nervous system and neurological disorders. An overview of the major animal studies and clinical trials is provided here, focusing on fatty acid supplementation during pregnancy and infancy, and prevention and management of Alzheimer's disease, schizophrenia, depression and attention deficit hyperactive disorder. Although an optimal balance in n-3/n-6 long-chain polyunsaturated fatty acid ratio is important for proper neurodevelopment and cognitive functions, results from randomized controlled trials are controversial and do not confirm any useful effect of supplementation on development of preterm and term infants. The relationship between fatty acid status and mental disorders is confirmed by reduced levels of n-3 long-chain polyunsaturated fatty acids in erythrocyte membranes of patients with central nervous system disorders. Nevertheless, there are very little data supporting the use of fish oil in those patients. The only way to verify whether n-3 long-chain polyunsaturated fatty acids are a potential therapeutic option in the management and prevention of mental disorders is to conduct a large definitive randomized controlled trials similar to those required for the licensing of any new pharmacological treatment.