Suchergebnisse

In this paper we discuss the consensus view on the use of qualifying biomarkers in drug safety, raised within the frame of the XXIV meeting of the Spanish Society of Clinical Pharmacology held in Málaga (Spain) in October, 2011. The widespread use of biomarkers as surrogate endpoints is a goal that scientists have long been pursuing. Thirty years ago, when molecular pharmacogenomics evolved, we anticipated that these genetic biomarkers would soon obviate the routine use of drug therapies in a way that patients should adapt to the therapy rather than the opposite. This expected revolution in routine clinical practice never took place as quickly nor with the intensity as initially expected. The concerted action of operating multicenter networks holds great promise for future studies to identify biomarkers related to drug toxicity and to provide better insight into the underlying pathogenesis. Today some pharmacogenomic advances are already widely accepted, but pharmacogenomics still needs further development to elaborate more precise algorithms and many barriers to implementing individualized medicine exist. We briefly discuss our view about these barriers and we provide suggestions and areas of focus to advance in the field. ; The work in the author's laboratory is financed by Grants PS09/00943, PS09/00469, PS09/01384, FIS-FEDER-PI081913, RETICS RIRAAF RD07/0064/0016, REDINSCOR RD06/0003/0015, TERCEL RD06/010/0017, RTA RD06/0001/1009, CIBERehD and CIBERobn from Instituto de Salud Carlos III, Madrid, Spain, and by Grants SAF10/16549 from Ministerio de Ciencia y Tecnología, CTS-6470 from Consejeria de Salud, Junta de Andalucía, Spain, and GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union. IMI-JU is partly funding the research activities under the SAFE-T project (Grant Agreement No 115003). ; Peer reviewed ; Peer Reviewed

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download ; Drug-induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)-containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti-TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti-TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans-ethnic meta-analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA-B*52:01 was significant (meta-analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63-4.37, P = 9.4 × 10-5 ). For N-acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57-0.83, P = 0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84-4.22, P = 0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered. ; International Serious Adverse Events Consortium Abbott Laboratories Amgen Daiichi Sankyo Company Limited GlaxoSmithKline Merck & Company Novartis Pfizer Roche Holding Sanofi-Aventis Takeda Pharmaceutical Company Ltd Wellcome Trust National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit NIHR Nottingham Biomedical Research Centre at the Nottingham University Hospitals NHS Trust University of Nottingham Instituto de Salud Carlos III European Union (EU) Instituto de Salud Carlos III Swedish Medical Products Agency Swedish Society of ...

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download ; Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation. ; European Union (EU) European Union (EU) Instituto de Salud Carlos III Medical Research Council UK (MRC) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of Allergy & Infectious Diseases (NIAID) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of General Medical Sciences (NIGMS) Swedish Heart-Lung Foundation Swedish Research Council MRC Centre for Drug Safety Science International Serious Adverse Events Consortium (iSAEC) National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research ...