Idiosyncratic Drug Reactions Research Articles

Fulminant type 1 diabetes mellitus caused by drug hypersensitivity syndrome with human herpesvirus 6 infection

Drug hypersensitivity syndrome (DHS) is an idiosyncratic and life-threatening adverse drug reaction characterized by skin rash and multiorgan involvement. In rare cases, fulminant type1 diabetes mellitus (DM) may develop after DHS. Among proposed pathogenesis, human herpesvirus 6 (HHV-6) infections may play a role in the development of DHS. We report a case of DHS associated with HHV-6 reactivation, complicated with a rare sequela of irreversible fulminant type 1 DM. No diabetes-related autoantibodies were detected. Early detection and intervention for this serious complication should be given in patients with DHS. Fulminant type1 DM associated with DHS is reviewed. The role of HHV-6 in DHS associated with fulminant type 1 DM is also discussed.

Unique Gene Expression and Hepatocellular Injury in the Lipopolysaccharide-Ranitidine Drug Idiosyncrasy Rat Model: Comparison with Famotidine

Rats cotreated with lipopolysaccharide (LPS) and ranitidine (RAN) but not LPS and famotidine (FAM) develop hepatocellular injury in an animal model of idiosyncratic drug reactions. Evaluation of liver gene expression in rats given LPS and/or RAN led to confirmation that the hemostatic system, hypoxia, and neutrophils (PMNs) are critical mediators in LPS/RAN-induced liver injury. We tested the hypothesis that unique gene expression changes distinguish LPS/RAN-treated rats from rats given LPS or RAN alone and from those cotreated with LPS/FAM. Rats were treated with a nonhepatotoxic dose of LPS (44.4 x 10(6) endotoxin units/kg, iv) or its vehicle. Two hours thereafter they were given RAN (30 mg/kg, iv), FAM (either 6 mg/kg, a pharmacologically equi-efficacious dose, or 28.8 mg/kg, an equimolar dose, iv), or vehicle. They were killed 2 or 6 h after drug treatment for evaluation of hepatotoxicity (2 and 6 h) and liver gene expression (2 h only). At a time before the onset of hepatocellular injury, hierarchical clustering distinguished rats treated with LPS/RAN from those given LPS alone. 205 probesets were expressed differentially to a greater or lesser degree only in LPS/RAN-treated rats compared to LPS/FAM or LPS alone, which did not develop liver injury. These included VEGF, EGLN3, MAPKAPK-2, BNIP3, MIP-2, COX-2, EGR-1, PAI-1, IFN-gamma, and IL-6. Expression of these genes was confirmed by real-time PCR. Serum concentrations of MIP-2, PAI-1, IFN-gamma, and IL-6 correlated with their respective gene expression patterns. Overall, the expression of several gene products capable of controlling requisite mediators of injury (i.e., hemostasis, hypoxia, PMNs) in this model were enhanced in livers of LPS/RAN-treated rats. Furthermore, enhanced expression of MAPKAPK-2 in RAN-treated rats and its target genes in LPS/RAN-treated rats suggests that p38/MAPKAPK-2 signaling is a regulation point for enhancement of LPS-induced gene expression by RAN.

Evaluation of Which Reactive Metabolite, If Any, Is Responsible for a Specific Idiosyncratic Reaction

Reactive metabolites are believed to be responsible for most idiosyncratic drug reactions. It is often assumed that if a reactive metabolite is found, it must be responsible for the idiosyncratic reactions associated with that drug. However, the evidence linking reactive metabolites and idiosyncratic reactions is circumstantial at best, and in many cases we have virtually no evidence. Furthermore, it is common for a drug to form several reactive metabolites, so it can be difficult to determine which, if any, is responsible for a given idiosyncratic reaction. Although the reactive metabolite hypothesis is logical, it has important implications for drug development, and we need to develop ways to test the hypothesis for specific drugs rigorously. Valid animal models are a powerful tool for testing whether a specific reactive metabolite is responsible for a specific adverse reaction and for studying further the mechanism by which it may induce such reactions; however, such models are rare.

Hepatology highlights

Hepatology highlights

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We thank Drs. Cholongitas, Holubek, and colleagues for their interest in our work. Drs. Holubek et al. express concern about the potential inclusion of subjects with acute viral hepatitis (A, B, or C) or a concomitant idiosyncratic drug reaction. Obtaining an accurate medication history can be difficult; however, all medical records were carefully reviewed and the patient, their caregivers, and their providers were interviewed. Our prior publication demonstrated that occult HBV infection was not present in any patients with indeterminate ALF or other identifiable causes of ALF.1 Included subjects all had negative serologies. Overall, 27 subjects were excluded from the analysis for the following reasons: insufficient data (10), possible ischemic hepatitis (5), polysubstance abuse (3), concomitant acute hepatitis A virus infection (2), recent isoflurane anesthesia (2), concomitant acute herpes simplex virus infection (1) or acute hepatitis B virus infection (1), concomitant isoniazid use (1), metastatic cancer (1), and non-acetaminophen ALF (1). In addition, all of the included acetaminophen overdose cases had a clinical phenotype consistent with severe acetaminophen hepatotoxicity. Therefore, we feel that all of the cases included in our study and the conclusions reached are valid and accurate. Lastly, we have demonstrated that presence of acetaminophen-cysteine protein adducts in the blood may be a sensitive and specific biomarker for acetaminophen-induced ALF and provide a confirmatory, objective laboratory test in cases of diagnostic uncertainty (Davern, et al.2). The data provided by Cholongitas et al. are consistent with our findings. Table 1 shows the comparison of 3 prognostic models using our dataset. The King's criteria did not predict clinical outcomes well in our population. Dr. O'Grady's editorial suggests this is because of the common use of prophylactic fresh frozen plasma (FFP) in the United States. Use of prophylactic FFP is not common in U.S. transplant/specialty centers, and we discourage its use except for active bleeding or for invasive procedures (e.g., intracranial monitor placement). About 80% of subjects in the study were transferred from other institutions, and 54% had received FFP prior to transfer. In those who did not receive FFP, the likelihood ratio of the Kings' criteria for predicting death/need for transplant was 5.3 (sensitivity 32%, specificity 94%), compared to 2.3 (sensitivity 23%, specificity 90%) for those who had received FFP. Therefore, use of FFP prior to enrollment only modestly compromised the prognostic utility of the King's criteria. In our dataset, as well as that of Cholongitas et al., prognosis was best predicted by presence of multi-organ failure rather than the disease-specific King's criteria. We did not include arterial lactate collection in the protocol when the study was started in 1998, but have subsequently begun collecting these new data. A new prognostic score including readily available laboratory tests such as arterial lactate, serum phosphate, alpha-fetoprotein, and/or Gc Globulin levels in addition to the Kings criteria or other multi-organ failure indices may prove worthwhile.3-5 In the interim, efforts at reducing the increasing incidence of unintentional acetaminophen related ALF in the United States are needed to prevent future cases of this potentially life-threatening but avoidable illness. Anne M. Larson*, Robert J. Fontana , Timothy J. Davern , William M. Lee§, * Dept. of Internal Medicine, University of Washington, Seattle, WA, Dept. of Internal Medicine, University of Michigan, Ann Arbor, MI, Dept. of Internal Medicine, UCSF, San Francisco, CA, § Dept. of Internal Medicine, UT-Southwestern, Dallas, TX.

Host determinants of antiretroviral drug activity

As physicians are confronted with a diversity of adverse events and variability in response to medication among patients, this review will focus on the available evidence regarding the impact of genetic variation on drug response. Specifically, variation in drug metabolizing enzymes such as the cytochrome P450s, drug transporters and human leucocyte antigen (for idiosyncratic drug reactions). The potential role of pharmacogenetics in the management of HIV-1 infected individuals and drug discovery will be discussed. Wide inter-individual variability of antiretroviral therapy efficacy and toxicity in HIV-infected patients has been extensively reported in the literature. Since treatment involves multiple drugs and drug classes with the potential for significant variability in drug-host as well as drug-drug interactions, antiretroviral drug therapy represents a significant challenge. Despite this inherent complexity, considerable recent advances have led to a greater understanding of interactions between genetic and host factors that influence the efficacy and toxicity of these agents. The goal of pharmacogenetics in antiretroviral therapy is to outline differences within a given population that influence drug efficacy and toxicity. Although to date, despite the numerous studies available in the literature, conclusions on how the analysis of the relationship between single nucleotide polymorphisms and drug efficacy may not always be clinically useful. Further studies are warranted to clarify the role of pharmacogenetics and antiretroviral drug management.

Microarray Analysis of Lipopolysaccharide Potentiation of Trovafloxacin-Induced Liver Injury in Rats Suggests a Role for Proinflammatory Chemokines and Neutrophils

Idiosyncratic drug toxicity refers to toxic reactions occurring in a small subset of patients and usually cannot be predicted during preclinical or early phases of clinical trials. One hypothesis for the pathogenesis of hepatic idiosyncratic drug reactions is that, in certain individuals, underlying inflammation results in sensitization of the liver, such that injury occurs from an agent that typically would not cause hepatotoxicity at a therapeutic dose. We explored this possibility by cotreating rats with nonhepatotoxic doses of bacterial lipopolysaccharide (LPS) and trovafloxacin (TVX), a drug that caused idiosyncratic hepatotoxicity in humans. The combination of LPS and TVX resulted in hepatotoxicity in rats, as determined by increases in serum alanine aminotransferase activity and hepatocellular necrosis, which were not observed with either agent alone. In contrast, treatment with LPS and levofloxacin, a fluoroquinolone without human idiosyncratic liability, did not result in these changes. Liver gene expression analysis identified unique changes induced by the combination of TVX and LPS, including enhanced expression of chemokines, suggestive of liver neutrophil (PMN) accumulation and activation. Consistent with a role for PMN in the hepatotoxicity induced by LPS/TVX, prior depletion of PMN attenuated the liver injury. The results suggest that gene expression profiles predictive of idiosyncratic liability can be generated in rats cotreated with LPS and drug. Furthermore, they identify gene expression changes that could be explored as biomarkers for idiosyncratic toxicity and lead to enhanced understanding of the mechanism(s) underlying hepatotoxicity induced by TVX.

Evidence of an Immune-Mediated Mechanism for an Idiosyncratic Nevirapine-Induced Reaction in the Female Brown Norway Rat

Previously, we reported a new animal model of an idiosyncratic drug reaction in which nevirapine causes a skin rash in some rats that has characteristics similar to the reaction that occurs in humans. Strong evidence that the reaction is immune-mediated was found; specifically, low-dose pretreatment induced tolerance, while with rechallenge, the time to onset decreased and the severity increased. Furthermore, splenocytes from rechallenged rats transferred rash susceptibility to naïve recipients. We now report the results of studies to explore the immune aspects of this reaction. T cells were found to play an important role, as demonstrated by their ability to adoptively transfer susceptibility to the skin reaction. Of these T cells, CD4+ cells are the likely effectors because they were capable of transferring susceptibility and the reaction was delayed in rats partially depleted of CD4+ T cells. In contrast, it appears that CD8+ T cells are not essential, as CD8+ T cells were unable to transfer sensitivity to a naïve animal and rats depleted of CD8+ T cells still developed skin rash. Unlike the penicillamine model, where we have demonstrated that the tolerance induced by low-dose treatment is immune-mediated, tolerance induced by low-dose nevirapine appears to be largely due to induction of metabolism as it can be overcome by inhibition of cytochrome P450. Pretreatment with the immunosuppressants, cyclosporine and tacrolimus, prevented the rash and even led to resolution of the rash during nevirapine treatment. These studies reinforce the hypothesis that the reaction in this model is similar to that which occurs in humans. In particular, the finding that CD4+ T cells may play a central role in this model fits with the observation that the incidence of idiosyncratic reactions to nevirapine in humans appears to be lower in patients with low CD4+ counts.

Kinetics of tienilic acid bioactivation and functional generation of drug–protein adducts in intact rat hepatocytes

Drug-induced autoimmune hepatitis is among the most severe hepatic idiosyncratic adverse drug reactions. Considered multifactorial, the disease combines immunological and metabolic aspects, the latter being to date much better known. As for many other model drugs, studies on tienilic acid (TA)-induced hepatitis have evidenced the existence of bioactivation during the hepatic oxidation of the drug, allowing the identification of the neoantigen of anti-LKM2 autoantibodies and the pathway responsible for its formation. However, most of these results are based on the use of microsomal fractions whose relevance to the liver in vivo still needs to be established. In the more complex intact cell environment, several endogenous processes may play a significant role on triggering the reaction and should therefore be considered. In this work we have characterised the kinetics of TA biotransformation in metabolically competent hepatocytes, the influence of TA bioactivation on physiological GSH levels, and the qualitative and quantitative profile of drug–protein conjugates generated in situ, as a function of exposure time. Results confirm that intact hepatocytes reproduce in vitro the metabolic sequence that leads to the functional generation of drug–protein adducts, in conditions that simulate clinical human exposure to TA. Metabolically competent cultured hepatocytes appear as a very promising approach to investigate the early preimmunological events of drug-induced autoimmune hepatitis, adequate to identify the conditions that may modulate the formation and specificity of drug–protein adducts in vivo, to study the hepatic disposition of the TA-protein targets, and to define the specific role of the hepatocyte in the origin of this adverse reaction.

Toxic epidermal necrolysis: current evidence, practical management and future directions

Toxic epidermal necrolysis (TEN) is a rare disorder characterized by extensive epidermal death. Almost all cases appear to be caused by an idiosyncratic drug reaction. Proposed pathogenic mechanisms are conflicting, and the evidence for the benefits of individual treatments is inadequate, and in some cases contradictory. The mortality rate remains high. We review the literature pertaining to the pathogenesis of TEN and drug reactions in general. The rationale for therapeutic interventions, together with reported evidence of efficacy, are considered. We present a composite model of TEN, based on previous work and suggested pathogeneses of TEN, mechanisms of drug reactions and reported cytotoxic lymphocyte (CTL) cytolytic pathways. In this system, TEN, like some other cutaneous drug eruptions, is an HLA class I-restricted, specific drug sensitivity, resulting in clonal expansion of CD8+ CTLs. Cytotoxicity is mediated by CTL granzyme and possibly death receptor (DR) ligand (DR-L), probably Fas ligand (FasL). Particular to TEN, there is then an amplification sequence involving further DR-L expression. FasL is likely to be particularly important but tumour necrosis factor (TNF) may well contribute, via the TNF receptor 1 (TNF-R1) death pathway. Alternatively, we suggest the possibility of upregulation of an antiapoptotic TNF-R1-nuclear factor kappaB pathway, which would proscribe treatments which downregulate this pathway. None of the published data on individual treatment efficacies is sufficiently strong to suggest a definitive single treatment. Currently a multifaceted regimen appears indicated, targeting various likely intermediary mechanisms, including elimination of residual drug, immunosuppression, inhibition of DR pathways, general antiapoptotic strategies, and aggressive supportive care. Particular attention has been directed at avoiding potential conflicts between different treatments and avoiding agents that theoretically might have a net proapoptotic rather than antiapoptotic effect. Nursing on a specialized unit is of paramount importance.

Neuroleptic malignant syndrome due to three atypical antipsychotics in a child

Neuroleptic Malignant Syndrome (NMS) is a rare, potentially fatal and idiosyncratic drug reaction. It is characterized by a sudden loss of body temperature control, renal and respiratory failure, muscle rigidity, loss of consciousness and impairment of autonomic nervous system. Although NMS was previously associated with the use of classical high-potency neuroleptics, cases have started to emerge with atypical neuroleptics. This article discusses the first case of NMS in a child, induced by the use of risperidone, olanzapine and quetiapine.

Gene Expression Profiling in a Model of d-Penicillamine-Induced Autoimmunity in the Brown Norway Rat: Predictive Value of Early Signs of Danger

Idiosyncratic drug reactions (IDRs) cause significant morbidity and mortality. In an animal model of IDRs, 50-80% of Brown Norway rats exposed to D-penicillamine develop an autoimmune syndrome after several weeks of treatment. The symptoms of the IDR are similar to that observed in humans who take D-penicillamine. The mechanism of this reaction is unknown, and no effective biomarkers have been identified to predict susceptibility. We postulate that cell stress caused by drugs is required to initiate the response. We used a high-throughput approach to identify factors that might represent danger signals by profiling hepatic gene expression 6 h after dosing with D-penicillamine (150 mg/kg). Our results show that the drug-treated animals cluster into two distinct groups. One group exhibits substantial expression changes relative to control animals. The most significantly altered transcripts have a role in stress, energy metabolism, acute phase response, and inflammation. We used quantitative reverse transcriptase polymerase chain reaction to measure transcript levels in liver biopsies of 33 rats and found that resistant animals cluster together. This "resistant" cluster of animals contains 87.5% (7/8) resistant animals but only 48% (12/25) "sensitive" animals. This separation is statistically significant at the p = 0.01 level.

Portal Vein Arterialization: A New Surgical Option Against Acute Liver Failure?

Survival rates of patients with acute liver failure (ALF) without transplantation are poor. Supporting these patients until an organ becomes available or until their own liver is able to regenerate itself, avoiding transplantation, is a major goal in the treatment of ALF. We report our clinical experience of portal vein arterialization in one case of massive liver necrosis after liver transplantation and in two patients with ALF caused by idiosyncratic drug reaction and mushroom intoxication. Portal vein arterialization, at least in two cases, was a turning point in the course of the disease since a close temporal association between surgery and clinical improvement was clearly evident. We believe that this novel approach, which should promote liver regeneration by providing an additional oxygen supply to the liver, may disclose a new possibility in the treatment of ALF and prompt new clinical and experimental research.

A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups

The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligatory event in the etiology of many drug-induced adverse reactions. Therefore, a thorough examination of the biochemical reactivity of functional groups/structural motifs in all new drug candidates is essential from a safety standpoint. A major theme attempted in this review is the comprehensive cataloging of all of the known bioactivation pathways of functional groups or structural motifs commonly utilized in drug design efforts. Potential strategies in the detection of reactive intermediates in biochemical systems are also discussed. The intention of this review is not to "black list" functional groups or to immediately discard compounds based on their potential to form reactive metabolites, but rather to serve as a resource describing the structural diversity of these functionalities as well as experimental approaches that could be taken to evaluate whether a "structural alert" in a new drug candidate undergoes bioactivation to reactive metabolites.

Minimising the potential for metabolic activation in drug discovery

Investigations into the role of bioactivation in the pathogenesis of xenobiotic-induced toxicity have been a major area of research since the link between reactive metabolites and carcinogenesis was first reported in the 1930s. Circumstantial evidence suggests that bioactivation of relatively inert functional groups to reactive metabolites may contribute towards certain drug-induced adverse reactions. Reactive metabolites, if not detoxified, can covalently modify essential cellular targets. The identity of the susceptible biomacromolecule(s), and the physiological consequence of its covalent modification, will dictate the resulting toxicological response (e.g., covalent modification of DNA by reactive intermediates derived from procarcinogens that potentially leads to carcinogenesis). The formation of drug–protein adducts often carries a potential risk of clinical toxicities that may not be predicted from preclinical safety studies. Animal models used to reliably predict idiosyncratic drug toxicity are unavailable at present. Furthermore, considering that the frequency of occurrence of idiosyncratic adverse drug reactions (IADRs) is fairly rare (1 in 1000 to 1 in 10,000), it is impossible to detect such phenomena in early clinical trials. Thus, the occurrence of IADRs during late clinical trials or after a drug has been released can lead to an unanticipated restriction in its use and even in its withdrawal. Major themes explored in this review include a comprehensive cataloguing of bioactivation pathways of functional groups commonly utilised in drug design efforts with appropriate strategies towards detection of corresponding reactive intermediates. Several instances wherein replacement of putative structural alerts in drugs associated with IADRs with a latent functionality eliminates the underlying liability are also presented. Examples of where bioactivation phenomenon in drug candidates can be successfully abrogated via iterative chemical interventions are also discussed. Finally, appropriate strategies that aid in potentially mitigating the risk of IADRs are explored, especially in circumstances in which the structural alert is also responsible for the primary pharmacology of the drug candidate and cannot be replaced.

Neutrophilic dermatitis and immunemediated haematological disorders in a dog: suspected adverse reaction to carprofen

This report describes the clinical and pathological findings of a suspected idiosyncratic adverse drug reaction in a young dog. The patient presented with sudden onset, severe skin lesions together with episodes of collapse. Investigations revealed a neutrophilic dermatitis with vasculitis, immune-mediated haemolytic anaemia and thrombocytopenia. Similar pathology has been described in human cases of Sweet's syndrome. The chronology of events suggested an adverse drug reaction to carprofen, although two antibiotics had been prescribed within the dog's recent history. Lymphocyte transformation tests were performed and tended to exclude both antibiotics as the cause of the reaction. To the authors' knowledge, lymphocyte transformation tests have not previously been described with regard to drug hypersensitivity assessment in the veterinary literature, and this is the first peer-reviewed case report of neutrophilic dermatitis and vasculitis with immune-mediated haemolytic anaemia and thrombocytopenia occurring as a suspected adverse drug reaction to carprofen in the dog.

Fulminant hepatic failure

Abstract Analysis of the first 150 cases collected from 73 centers reporting to the Fulminant Hepatic Failure Surveillance Study showed that 80 patients had presumable viral hepatitis, of whom 62 died. Of 41 patients who had recent surgery, 36 died. In 35 patients massive liver necrosis developed less than three weeks after halothane anesthesia, and 27 (77 per cent) of these had multiple exposures to halothane. The risk from halothane is small, but this complication was present in nearly one quarter of the cases reported in our study. When the use of halothane is desired, multiple exposure should be avoided, if possible. Moreover, postoperative fever after exposure to halothane, otherwise "unexplained," is an important warning sign, and should be thoroughly investigated and taken into consideration when further exposure to this anesthetic is contemplated. The physician prescribing halothane must balance need against risk.

Investigating the Role of 2-Phenylpropenal in Felbamate-Induced Idiosyncratic Drug Reactions

Felbamate (2-phenyl-1,3-propanediol dicarbamate, FBM) can cause aplastic anemia and hepatotoxicity. The mechanism of FBM-induced toxicities is unknown; however, it has been proposed that 2-phenylpropenal, a reactive metabolite of FBM, is responsible. The pathway leading to this metabolite involves hydrolysis of FBM to 2-phenyl-1,3-propandiol monocarbamate (MCF), oxidation to 3-carbamoyl-2-phenylpropionaldehyde (CBMA), and spontaneous loss of carbon dioxide and ammonia. We made a polyclonal antibody against 2-phenylpropenal bound to protein and confirmed its specificity using ELISA. We attempted to develop an animal model of FBM-induced aplastic anemia and/or hepatotoxicity, and we also used the antibody to try to detect covalent binding of 2-phenylpropenal using immunoblotting. However, none of the animals developed evidence of bone marrow or liver toxicity, and we were unable to detect covalent binding, possibly because significantly less 2-phenylpropenal is formed in rodents than in humans. As this type of idiosyncratic drug reaction is believed to be immune-mediated, we also studied the potential of FBM and its metabolites to stimulate an immune response using the reporter antigen popliteal lymph node assay in female Balb/c mice. We found that neither FBM nor MCF induced an immune response in popliteal lymph nodes (PLNs). However, CBMA treatment appeared immunogenic, causing footpad inflammation, hardening, scab formation, and an increase in thickness. The PLN cell count in CBMA-treated mice increased 8-fold as compared to control, FBM-, or MCF-treated mice. Immunohistochemical analysis of the CBMA-exposed PLNs revealed germinal center formation, indicating B cell proliferation, later confirmed by flow cytometry. Most of the cells expressing the activation surface marker CD54 were B cells. We also found that CBMA treatment caused an increase in the production of IgM and IgG1 antibodies as well as IL-4 and IFN-gamma cytokines. Our findings indicate that 2-phenylpropenal is a very potent immunogen, supporting its possible involvement in the FBM-induced hepatotoxicity and aplastic anemia.

Fulminant Hepatic Failure and the Potential Role of Liver Dialysis

Fulminant hepatic failure (FHF) carries a high mortality. We aimed to review the prognostic factors and explore the potential role of Liver Dialysis (LD). Fifty-two patients were reviewed. The etiologies were acetaminophen toxicity (33%), viral hepatitis (18%), autoimmune (10%), idiosyncratic drug reactions (8%), others (6%) and undetermined (25%). Patients with acetaminophen had a significantly higher survival compared to the non-acetaminophen group (p=0.04). Patients with grade 3 encephalopathy had a mortality of 68%, among 5 patients with grade IV encephalopathy, 2 survived and both had had treatment with LD. Chi-square with Fisher's exact test was used for statistical analysis. Our study confirmed that the diagnosis of non-acetaminophen induced FHF and reduced initial serum factor V level are associated with fatal outcome. Timely OLT significantly improved the survival. The role of LD in hepatic regeneration or as a bridge to OLT needs to be further studied with prospective control trials.

Animal models of idiosyncratic drug reactions

Idiosyncratic drug reactions represent a major problem. In most cases the mechanisms of these reactions are unknown, but circumstantial evidence points to the involvement of reactive metabolites and the characteristics of the reactions suggest involvement of the immune system. If progress is to be made in dealing with these adverse reactions it is essential that we have a better understanding of their mechanisms, and it is hard to imagine testing mechanistic hypotheses without good animal models. Unfortunately, idiosyncratic reactions are also idiosyncratic in animals so few good models exist. The best models, in which a rodent develops a clinical syndrome similar to that which occurs in humans, appear to be penicillamine-induced autoimmunity in Brown Norway rats and nevirapine-induced skin rash in rats. Sulfamethoxazole-induced hypersensitivity in dogs and propylthiouracil-induced autoimmunity in cats are also similar to adverse reactions that occur in people, but they have practical limitations. Halothane-induced liver toxicity in guinea pigs and amodiaquine-induced bone marrow and liver toxicity in rats represent models in which there is an immune response and mild, reversible toxicity. It is possible that the development of immune tolerance is what limits the toxicity in these models, and if this is true, interventions that prevent tolerance might lead to good models. Although the history of developing animal models of idiosyncratic drug reactions is mostly one of failure, such models are essential. A better understanding of immune tolerance may greatly facilitate the development of better models; transgenic technology may also provide an important tool.