Herbal Hepatotoxicity: Challenges and Pitfalls of Causality Assessment Methods.

Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods.

World J Gastroenterol. 2013 May 21; 19(19): 2864-2882
Teschke R, Frenzel C, Schulze J, Eickhoff A

The diagnosis of herbal hepatotoxicity or herb induced liver injury (HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation. At the day HILI is suspected in a patient, physicians should start assessing the quality of the used herbal product, optimizing the clinical data for completeness, and applying the Council for International Organizations of Medical Sciences (CIOMS) scale for initial causality assessment. This scale is structured, quantitative, liver specific, and validated for hepatotoxicity cases. Its items provide individual scores, which together yield causality levels of highly probable, probable, possible, unlikely, and excluded. After completion by additional information including raw data, this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation. The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases, compared to numerous other causality assessment methods, which are inferior on various grounds. Among these disputed methods are the Maria and Victorino scale, an insufficiently qualified, shortened version of the CIOMS scale, as well as various liver unspecific methods such as the ad hoc causality approach, the Naranjo scale, the World Health Organization (WHO) method, and the Karch and Lasagna method. An expert panel is required for the Drug Induced Liver Injury Network method, the WHO method, and other approaches based on expert opinion, which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician. In conclusion, HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale, avoiding pitfalls commonly observed with other approaches. HubMed – drug

Atrial fibrillation and the ‘other drug problem’: reducing non-adherence with technology.

Eur Heart J. 2013 May 22;
Nerini E, Grip L, Camm AJ, Giugliano RP

HubMed – drug

Genetic Variation in Aldo-keto Reductase 1D1 (AKR1D1) Affects the Expression and Activity of Multiple Cytochrome P450s (CYPs).

Drug Metab Dispos. 2013 May 23;
Chaudhry AS, Thirumaran RK, Yasuda K, Yang X, Fan Y, Strom SC, Schuetz EG

Human liver gene regulatory (Bayesian) network analysis (Yang et al., 2010) was previously used to identify a cytochrome P450 gene subnetwork with AKR1D1 as a key regulatory driver of this subnetwork. This study assessed the biological importance of AKR1D1 (a key enzyme in the synthesis of bile acids, ligand activators of FXR, PXR and CAR – known transcriptional regulators of CYPs) to hepatic CYP expression. Over-expression of AKR1D1 in primary human hepatocytes led to increased expression of CYP3A4, 2C8, 2C9, 2C19, and 2B6. Conversely, AKR1D1 knockdown significantly decreased expression of these CYPs. We resequenced AKR1D1 from 98 donor livers and identified a 3′-UTR (rs1872930) single nucleotide polymorphism (SNP) significantly associated with higher AKR1D1 mRNA expression. AKR1D1 3′-UTR-luciferase reporter studies showed that the variant allele resulted in higher luciferase activity, suggesting the SNP increases AKR1D1 mRNA stability and/or translation efficiency. Consistent with AKR1D1’s putative role as a driver of the CYP subnetwork, the AKR1D1 3′-UTR SNP was significantly associated with increased hepatic mRNA expression of multiple CYPs (CYP3A4, 2C8, 2C9, 2C19, and 2B6) and CYP3A4, CYP2C8, CYP2C19 and CYP2B6 activities. After adjusting for multiple testing the association remained significant for AKR1D1, CYP2C9 and CYP2C8 mRNA expression and CYP2C8 activity. These results provide new insights into the variation in expression and activity of CYPs that can account for interindividual differences in drug metabolism/ efficacy and adverse drug events. In conclusion, we provide the first experimental evidence supporting a role for AKR1D1 as a key genetic regulator of the CYP network. HubMed – drug

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