Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries.
TL;DR: In this paper, a new method for drug causality assessment is described and applied to reports of acute liver injuries, using reports with positive rechallenge as external standard.
About: This article is published in Journal of Clinical Epidemiology.The article was published on 1993-11-01. It has received 1291 citations till now. The article focuses on the topics: Adverse drug reaction.
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1,564 citations
TL;DR: Findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.
Abstract: Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 x 10(-33)) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 x 10(-8)). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.
949 citations
TL;DR: Clinical guidance is provided with regard to the detection, evaluation, and possible prevention of drug-related hepatotoxicity in patients exposed to hepatotoxic effects of new medication.
Abstract: Given its rarity, drug-related hepatotoxicity may not be seen during the initial clinical trials of a new medication. After approval, when many more patients are exposed, toxic effects that are very infrequent may emerge. This review explains the difficulties in identifying the cause of hepatotoxic effects in such situations and provides clinical guidance with regard to the detection, evaluation, and possible prevention of drug-related hepatotoxicity.
944 citations
TL;DR: The current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans.
Abstract: The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the most frequent cause of post-marketing warnings and withdrawals This review examines the clinical signatures of this problem, signals predictive of its occurrence (particularly of more frequent, reversible, low-grade injury) and the role of monitoring in prevention by examining several recent examples (for example, troglitazone) In addition, the failure of preclinical toxicology to predict idiosyncratic reactions, and what can be done to improve this problem, is discussed Finally, our current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans
926 citations
TL;DR: Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation, and amoxicillin-clavulanate stands out as the most common drug related to DILI.
811 citations
References
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Journal Article•
846 citations
TL;DR: It is concluded that adverse drug reaction reports with a positive rechallenge can provide a standard for validation of causality assessment methods, and RUCAM applied to drug-induced liver injuries has been validated.
494 citations
TL;DR: An algorithm is developed that provides detailed operational criteria for ranking the probability of causation when ADR is suspected between a drug and a clinical manifestation.
Abstract: Despite widespread clinical and epidemiologic attention to adverse drug reactions (ADRs), their clinical identification has been a nonreproducible act of unspecified subjective judgment; adequate operational criteria have not been available for diagnostic decisions about the cause of an observed untoward clinical manifestation. To improve scientific precision in the diagnosis of ADRs, we have developed an algorithm that provides detailed operational criteria for ranking the probability of causation when ADR is suspected between a drug and a clinical manifestation. The algorithm provides a scoring system for six axes of decision strategy: previous general experience with the drug, alternative etiologic candidates, timing of events, drug levels and evidence of overdose, dechallenge, and rechallenge. The sum of the scores is ordinally partitioned to rate the candidate ADR as definite, probable, possible, or unlikely. (JAMA242:623-632, 1979)
460 citations
TL;DR: A decision table algorithm approach is presented toward the development of an operational system for the identification of adverse drug reactions that incorporates an estimate of the certainty of the link between the untoward clinical event and the suspect drug, and examines the underlying causes of the identified drug reactions.
Abstract: The evaluation of adverse drug reactions in clinical practice is somewhat arbitrary and is characterized by considerable differences of opinion. This report presents a decision table algorithm approach toward the development of an operational system for the identification of adverse drug reactions. The algorithm incorporates an estimate of the certainty of the link between the untoward clinical event and the suspect drug, and examines the underlying causes of the identified drug reactions. Use of such a system is a first step toward reducing ambiguity in the evaluation of adverse drug reactions.
443 citations
TL;DR: Six alternative criteria are described that attempt to address a potential user's main concerns--the need to know whether to believe the results in general and in a particular case and focus on the internal structure of a method rather than its output.
80 citations