Proyectos

Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs.

 Building a Spanish-Latin American network on Drug Induced Liver Injury: much to get from a joint collaborative initiative.

Annals of Hepatology 2012; 11 (4): 544-549 IF 2011: 1.811 (Q3). http://www.imbiomed.com.mx/1/1/articulos.php?method=showDetail&id_articulo=84330&id_seccion=3563&id_ejemplar=8306&id_revista=215

Bessone Fernando, Hernández Nelia, Dávalos Moscol Milagros, Paraná Raymundo, Schinoni Maria Isabel, Lizarzabal Maribel, Kershenobich Stalnikowitz David, et al .

INTRODUCTION

Latin America lacks a centralized database registry capable of reliably accounting for the incidence and particular characteristics of drug-induced liver damage within the region. Collaborative efforts, consensus-based diagnostic criteria and a standardized nomenclature are the essential components to perform this task. The present work focuses on the steps taken by Latin American countries to tackle their present isolation and set up a collaborative network together with Spain in order to further understand and investigate the complex underlying mechanism of drug-induced liver injury (DILI).

  Editorial. Prescripción de fármacos en pacientes con hepatopatía crónica: reglas para dosificación y más allá.

 Case definition and phenotype standardization in Drug-Induced Liver Injury.

Clin Pharmacol Ther. 2011; 89 (6):806-15. IF 2011: 6.043 (Q1). http://www.ncbi.nlm.nih.gov/pubmed/21544079

Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, Hunt CM, Wilke RA, Avigan M, Kaplowitz N, Bjornsson E, Daly AK.

Abstract. Drug-induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH).

 Hepatotoxicity in 2011--advancing resolutely.

Rev Esp Enferm Dig. 2011; 103 (9): 472-9.  IF 2011: 1.548  (Q3). http://www.ncbi.nlm.nih.gov/pubmed/21951116 

Lozano-Lanagrán M, Robles M, Lucena MI, Andrade RJ.

Introduction: Liver toxicity from drugs, and also from alternative medicine products such as herbalist’s remedies and dietary supplements, is currently an increasingly relevant health issue. A great majority of hepatic adverse reactions seen in clinical practice are unpredictable (unrelated to a drug’s pharmacological characteristics) and basically result from an interaction of three circumstances: a drug with potential to generate hepatotoxic radicals in a genetically susceptible individual under certain environmental factors.

 Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and class II alleles

Gastroenterology 2011, doi:10.1053/j.gastro.2011.04.001. IF 2011:  11.675 (Q1)

Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, Day CP, Ruiz-Cabello F, Donaldson PT, Stephens C, Pirmohamed M, Romero-Gomez M, Navarro JM, Fontana RJ, Miller M, Groome M, Bondon-Guitton E, Conforti A, Stricker BH, Carvajal A, Ibanez L, Yue QY, Eichelbaum M, Floratos A, Pe'er I, Daly MJ, Goldstein DB, Dillon JF, Nelson MR, Watkins PB, Daly AK; Spanish Dili Registry, EUDRAGENE, DILIN, DILIGEN, and International SAEC.

BACKGROUND & AIMS: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI (DILI following AC administration [AC-DILI]), but little is understood about genetic susceptibility to this adverse reaction...

Human leucocyte antigen class II genotype in susceptibilityand resistance to co-amoxiclav-induced liver injury. Journal of Hepatology 2010 53(6):1049-53.

Peter T. Donaldson, Ann K. Daly, Jill Henderson, Julia Graham, Munir Pirmohamed,
William Bernal, Christopher P. Day, Guruprasad P. Aithal

Background & Aims: Co-amoxiclav is one of the most common causes of drug-induced liver injury (DILI). Although there are previous reports of genetic associations between HLA class II and coamoxiclav-related DILI, studies to date have been based on very small numbers from single centres only. In order to address this problem we have investigated the role of HLA class II DRB1 and DQB1 in 61 cases of co-amoxiclav DILI as part of a UK-wide multicentre study...

  A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nat Genet. 2010 Aug;42(8):650-1.

Jonathan B Singer, Steve Lewitzky, Elisabeth Leroy, Fan Yang, Xiaojun Zhao, Lloyd Klickstein, Timothy M Wright, Joanne Meyer & Charles A Paulding

Lumiracoxib is a selective cyclooxygenase-2 inhibitor developed for the symptomatic treatment of osteoarthritis and acute pain1. Concerns over hepatotoxicity have contributed to the withdrawal or non-approval of lumiracoxib in most major drug markets worldwide. We performed a case-control genome-wide association study on 41 1 lumiracoxib-treated patients with liver injury (cases) and 1 176 matched lumiracoxib-treated patients without liver injury (controls). Several SNPs from the MHC class II region showed strong evidence of association (the top SNP was rs9270986 with P = 2.8 × 1 10−10). These findings were replicated in an independent set of 98 lumiracoxib-treated cases and 405 matched lumiracoxib-treated controls (top SNP rs3129900, P = 4.4 × 1 10−12). Fine mapping identified a strong association to a common HLA haplotype (HLA-DRB1*1501-HLA-DQB1*0602-HLA-DRB5*0101-HLA-DQA1*0102, most significant allele
P = 6.8 × 1 10−25, allelic odds ratio = 5.0, 95% CI 3.6–7.0). These results offer the potential to improve the safety profile of lumiracoxib by identifying individuals at elevated risk for liver injury and excluding them from lumiracoxib treatment.

   Preempting and preventing Drug-Induced Liver Injury. Nat Genet. 2010 Aug;42(8):711-4

Guruprasad P Aithal & Ann K Daly

A new study reports that susceptibility to drug-induced liver injury by the cyclooxygenase 2 (COX-2) inhibitor lumiracoxib is associated with a human lymphocyte antigen (HLA) class II haplotype. This finding suggests that those at risk of hepatotoxicity can be identified by HLA genotyping, raising the possibility that lumiracoxib can be resurrected as a useful drug.

Three-dimensional culture of hepatocytes for prediction of drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol. 2010 Jun;6(6):733-46
 

Meng Q.
Zhejiang University, Department of Chemical and Biochemical Engineering, 38 Zheda Road, Hangzhou, Zhejiang 310027, PR China +86 571 87953193 ; +86 571 87951227 ; This email address is being protected from spambots. You need JavaScript enabled to view it..

Abstract
Importance of the field: Hepatotoxicity is the most frequent reason for the withdrawal of an approved drug from the market. Monolayer culture of hepatocyte in two-dimension, which is relatively inexpensive, convenient and easy to use, serves a traditional hepatocyte-based high-content screening for identifying hepatotoxic side effects of tested drugs. However, two-dimensional methods have their limitations in lack of insensitivity on reflection of drug hepatotoxicity. Three-dimensional (3D) cultures of hepatocytes in sandwich, spheroid and gel entrapment provide a microenvironment for high expression of liver-specific functions and are being proposed for prediction of drug hepatotoxicity. Areas covered in this review: This review addressed the reliability of 3D culture models on screening hepatotoxic drugs with particular emphasis on gel entrapment culture model due to its more systematic data on drug testing. What the reader will gain: The reader will gain a comprehensive understanding of the improved prediction efficacy of 3D culture models. Take home message: Hepatocytes in 3D cultures, although in need of further standardization required by the throughput operation, show great potential in attempts to ensure the efficacy on prediction of drug hepatotoxicity.

 Successful Treatment With Erlotinib After Gefitinib-Related Severe Hepatotoxicity. J Thorac Oncol. 2010 Jul;5(7):1103-4.

Takeda M, Okamoto I, Fukuoka M, Nakagawa K. Department of Medical Oncology, Kinki University School of Medicine, Osaka, Japan.

Nuclear receptors as drug targets in cholestasis and drug-induced hepatotoxicity. Pharmacol Ther. 2010 Jun;126(3):228-43.

Zollner G, Wagner M, Trauner M.
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Austria.

Abstract
Nuclear receptors are key regulators of various processes including reproduction, development, and metabolism of xeno- and endobiotics such as bile acids and drugs. Research in the last two decades provided researchers and clinicians with a detailed understanding of the regulation of these processes and, most importantly, also prompted the development of novel drugs specifically targeting nuclear receptors for the treatment of a variety of diseases. Some nuclear receptor agonists are already used in daily clinical practice but many more are currently designed or tested for the treatment of diabetes, dyslipidemia, fatty liver disease, cancer, drug hepatotoxicity and cholestasis. The hydrophilic bile acid ursodeoxycholic acid is currently the only available drug to treat cholestasis but its efficacy is limited. Therefore, development of novel treatments represents a major goal for both pharmaceutical industry and academic researchers. Targeting nuclear receptors in cholestasis is an intriguing approach since these receptors are critically involved in regulation of bile acid homeostasis. This review will discuss the general role of nuclear receptors in regulation of transporters and other enzymes maintaining bile acid homeostasis and will review the role of individual receptors as therapeutic targets. In addition, the central role of nuclear receptors and other transcription factors such as the aryl hydrocarbon receptor (AhR) and the nuclear factor-E2-related factor (Nrf2) in mediating drug disposition and their potential therapeutic role in drug-induced liver disease will be covered. Copyright © 2010. Published by Elsevier Inc.