Idiosyncratic Drug Reactions Research Articles

A gene expression signature for oxidant stress/reactive metabolites in rat liver

Formation of free radicals and other reactive molecules is responsible for the adverse effects produced by a number of hepatotoxic compounds. cDNA microarray technology was used to compare transcriptional profiles elicited by training and testing sets of 15 oxidant stressors/reactive metabolite treatments to those produced by approximately 85 other paradigm compounds (mostly hepatotoxicants) to determine a shared signature profile for oxidant stress-associated hepatotoxicity. Initially, 100 genes were chosen that responded significantly different to oxidant stressors/reactive metabolites (OS/RM) compared to other samples in the database, then a 25-gene subset was selected by multivariate analysis. Many of the selected genes (e.g., aflatoxin aldehyde reductase, diaphorase, epoxide hydrolase, heme oxgenase and several glutathione transferases) are well-characterized oxidant stress/Nrf-2-responsive genes. Less than 10 other compounds co-cluster with our training and testing set compounds and these are known to generate OS/RMs as part of their mechanisms of toxicity. Using OS/RM signature gene sets, compounds previously associated with macrophage activation formed a distinct cluster separate from OS/RM and other compounds. A 69-gene set was chosen to maximally separate compounds in control, macrophage activator, peroxisome proliferator and OS/RM classes. The ease with which these ‘oxidative stressor’ classes can be separated indicates a role for microarray technology in early prediction and classification of hepatotoxicants. The ability to rapidly screen the oxidant stress potential of compounds may aid in avoidance of some idiosyncratic drug reactions as well as overtly toxic compounds.

Pharmacogenetics of antiretroviral therapy: genetic variation of response and toxicity.

The application of a pharmacogenetic approach to antiretroviral drug therapy represents a significant challenge, as treatment involves multiple drugs and drug classes with the potential for significant variability in drug-host, as well as drug-drug, interactions. However, despite this inherent complexity, considerable gains have been made in understanding how genetic factors influence the efficacy and toxicity of HIV therapy. In this review the available evidence regarding genetic variation in drug disposition will be examined, including the potential for relatively polymorphic drug-metabolizing enzymes (e.g., cytochrome P450 isoforms) and drug transporters (e.g., P-glycoprotein) to influence the disposition of HIV protease inhibitor and non-nucleoside reverse transcriptase inhibitor drugs. In addition, the role of genetic variation in determining the immune response to drug-specific antigens will be considered as a potentially significant determinant of susceptibility to idiosyncratic drug reactions (e.g., major histocompatibility complex alleles associated with abacavir hypersensitivity). The current and potential clinical utility of pharmacogenetic testing in HIV management will also be emphasized.

FC‐56 Nodular and non‐nodular focal alopecia related to drug injections: a retrospective study of 32 dogs

Cutaneous manifestations of idiosyncratic adverse drug reactions are considered uncommon. These manifestations are the result of unexpected drug effects, independent of dose, and are not related to the known mechanism of action of the drug. The pathogenesis is not well understood and may occur through immunologic or nonimmunologic mechanisms. Several clinical cutaneous manifestations of drug reactions are described: anaphylaxis, immune‐complex formation with or without vasculitis, allergic contact dermatitis, erythema multiforme and injection‐site reactions. Thirty‐two dogs were recorded with focal nodular and non‐nodular alopecia. Skin biopsies were taken from 31 cases for histopathological examination. Cytology was done in the remaining case. Based on clinical information and dermatopathological findings, they were divided into five groups. Group 1 included 17 toys dogs (10 French poodles) with non‐nodular circular alopecia associated with rabies vaccination. Group 2 dogs showed a nodular focal panniculitis and included five dogs (three French poodles); three had received a multivalent vaccine and the other two a rabies vaccine. Group 3 dogs included three females (two Maltese terriers) with circular alopecia related to an injectable progestin. Group 4 included three dogs (a Pekinese, a Shih Tzu and a French poodle) that had received glucocorticoid injections. Group 5 was a miscellaneous group of four dogs; two dogs had received injectable ivermectin, another ketoconazole, and there was no clear indication that the fourth dog had received a drug injection. Funding: Self‐funded.

The natural history of Vigabatrin associated visual field defects in patients electing to continue their medication.

To determine the natural history of visual field defects in a group of patients known to have Vigabatrin-associated changes who elected to continue the medication because of good seizure control. All patients taking Vigabatrin alone or in combination with other antiepileptic drugs for at least 5 years (range 5-12 years) were entered into a visual surveillance programme. Patients were followed up at 6-monthly intervals for not less than 18 months (range 18-43 months). In all, 16 patients with unequivocal defects continued the medication. Following already published methodology (Eye 2002; 16;567-571) monocular mean radial degrees (MRDs) to the I/4e isopter on Goldmann perimetry was calculated for the right eye at the time of discovery of a visual field defect and again after not less than 18 months follow-up. Mean right eye MRD at presentation was 36.98 degrees (range 22.25-51.0), compared to 38.40 degrees (range 22.5-49.75) after follow-up; P=0.338 unpaired t-test. Only one patient demonstrated a deterioration in visual field during the study period and discontinued treatment. Established visual field defects presumed to be due to Vigabatrin therapy did not usually progress in spite of continuing use of the medication. These data give support to the hypothesis that the pathogenesis of Vigabatrin-associated visual field defects may be an idiosyncratic adverse drug reaction rather than dose-dependent toxicity.

Anticonvulsant hypersensitivity syndrome associated with bellamine s, a therapy for menopausal symptoms

Anticonvulsant hypersensitivity syndrome (AHS) is a rare, potentially fatal, idiosyncratic drug reaction characterized by fever, morbilliform rash, lymphadenopathy, hepatitis, and hematologic abnormalities. Aromatic antiepileptic agents, such as phenytoin, carbamazepine, and phenobarbital are the most frequent causes of this syndrome. We report a case of a previously healthy, postmenopausal woman who developed anticonvulsant hypersensitivity syndrome while taking Bellamine S (belladonna alkaloids; ergotamine; phenobarbital) for hot flashes. Although combinations of belladonna, ergotamine, and phenobarbital have been used for medical treatment of menopausal symptoms since the 1960s, this is the first known case report of its association with anticonvulsant hypersensitivity syndrome. Given the current debate about the risks of hormonal replacement therapy, more women are seeking alternative therapies for menopausal symptoms. Dermatologists need to be aware of this potential serious reaction to this phenobarbital-containing therapy for hot flashes.

Tolerance induced by low dose D-penicillamine in the brown Norway rat model of drug-induced autoimmunity is immune-mediated.

Most patients taking drugs associated with idiosyncratic drug reactions tolerate the drug and do not develop adverse reactions. Understanding the mechanism of tolerance to drugs is important as it could provide insight into why some patients develop idiosyncratic reactions and others do not. The Brown Norway rat model of D-penicillamine-induced autoimmunity was used as a model of idiosyncratic drug-induced autoimmunity. Two weeks of low dose (5 mg/day) D-penicillamine pretreatment completely prevented all clinical signs of autoimmunity normally seen in 60-80% of rats treated with high dose (20 mg/day) D-penicillamine. Low dose pretreatment also prevented the increase in IgE and IL-4 mRNA characteristic of the response to high dose D-penicillamine. Experiments were conducted to determine whether low dose tolerance is metabolic or immunological. It was found that low dose tolerance possesses key characteristics of immune-mediated tolerance: memory, splenocytes that adoptively transfer tolerance, and regulatory cytokine production. To provide an understanding of the factors that can prevent or reverse established tolerance, the conditions for inducing and maintaining tolerance were investigated. Tolerance induction was investigated by manipulating the immune system during the period of low dose exposure. The induction of tolerance was partially prevented by depleting the macrophage subset of antigen presenting cells with clodronate-filled liposomes or by inhibiting T cells with tacrolimus during the period of low dose exposure. As well, the induction of tolerance was completely prevented by repeatedly stimulating the immune system throughout the period of low dose pretreatment with poly I:C. To investigate the permanence of tolerance, the immune system was stimulated after tolerance induction in an attempt to break tolerance. Both LPS and poly I:C reversed tolerance in a dose-dependent manner. These results demonstrate that immune tolerance to D-penicillamine autoimmunity can be induced by short-term low dose pretreatment.

Characterization of a potential animal model of an idiosyncratic drug reaction: nevirapine-induced skin rash in the rat.

Idiosyncratic drug reactions are difficult to study in humans due to their unpredictability. Unfortunately, this characteristic also hinders the development of animal models needed for mechanistic studies. Nevirapine, used to treat human immunodeficiency virus (HIV) infections, results in a severe idiosyncratic skin rash in some patients. We found that nevirapine can also cause a significant rash in some strains of rats. At a dose of 150 mg/kg/day, the incidence in female Sprague-Dawley rats was 6/28 (21%), in female Brown Norway rats 32/32 (100%), and in female Lewis rats 0/6 (0%) while no male Sprague-Dawley or Brown Norway rats developed a rash. Female SJL mice 0/7 also did not develop nevirapine-induced skin lesions. The first sign of a reaction in Brown Norway rats was red ears at days 7-10 followed by a rash with scabbing mainly on the back; this was a shorter time to onset than in Sprague-Dawley rats. Light microscopy of the skin revealed a primarily mononuclear inflammatory infiltrate and lesions typical of self-trauma. Immunohistochemistry results suggest that the infiltrate was composed of CD4 and CD8 T cells as well as macrophages. A lower dose of either 40 or 75 mg/kg/day did not lead to a rash and, in fact, 2 weeks of the lower doses induced tolerance to the 150 mg/kg/day dose in female Brown Norway rats. A dose of 100 mg/kg/day resulted in rash in 2/4 (50%) of female Brown Norway rats. Rechallenge of Brown Norway rats that had been allowed to recuperate after a nevirapine-induced rash led to red ears in less than 24 h followed by hair loss and occasional skin lesions. Although the skin rash was less evident on rechallenge, microscopically, the cellular infiltrate was more prominent, especially surrounding the hair follicles. Moreover, there were lesions of interface dermatitis with apoptosis and satellitosis, indicative of a cell-mediated immune attack on the epidermis. While systemic signs of illness did not accompany the rash on primary exposure, on rechallenge, the animals appeared generally unwell and this forced sacrifice after 2 weeks or less of treatment. Importantly, splenocytes isolated from rechallenged animals were able to transfer susceptibility to nevirapine-induced skin rash to naïve female Brown Norway recipients, which was illustrated by a faster time to onset of rash in the recipients. The characteristics of this adverse reaction are similar to that seen in humans; that is, it is idiosyncratic in that it only occurs in some strains of animals, is delayed in onset, is more common in females, is dose-dependent, and appears to be immune-mediated. Therefore, it may represent a good animal model for the study of idiosyncratic drug reactions.

The danger hypothesis applied to idiosyncratic drug reactions.

Idiosyncratic drug reactions pose a significant clinical threat and hamper drug development. The idiosyncratic nature of these reactions has made mechanistic studies exceedingly difficult, and yet without a better understanding of the mechanisms involved it is unlikely that much progress can be made in dealing with the problem. Several working hypotheses have been used to study these reactions, but none fits all of the characteristics that are observed. Borrowed from immunology, the danger hypothesis has most recently been used to explain several characteristics of these reactions. The present review describes the danger hypothesis and compares it with previous hypotheses to determine how well each fits with the observed characteristics of the reactions. Slow progress in the field continues and it is important to use new observations, such as identifying T cells that recognize drugs in the absence of reactive metabolite formation, to test and refine the working hypotheses. However, the development of animal models of idiosyncratic drug reactions as well as progress in basic immunology and genomics are likely to accelerate progress in this area in the near future. No one model fits the characteristics of all idiosyncratic drug reactions; however, the danger model provides a new perspective and suggests avenues of research that have the potential to increase our ability to predict and prevent such reactions significantly.

Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats.

Drug idiosyncrasy is an adverse event of unknown etiology that occurs in a small fraction of people taking a drug. Some idiosyncratic drug reactions may occur from episodic decreases in the threshold for drug hepatotoxicity. Previous studies in rats have shown that modest underlying inflammation triggered by bacterial lipopolysaccharide (LPS) can decrease the threshold for xenobiotic hepatotoxicity. The histamine-2 (H2)-receptor antagonist ranitidine (RAN) causes idiosyncratic reactions in people, with liver as a usual target. We tested the hypothesis that RAN could be rendered hepatotoxic in animals undergoing a modest inflammatory response. Male rats were treated with a nonhepatotoxic dose of LPS (44 x 10(6) endotoxin units/kg i.v.) or its vehicle and then 2 h later with a nonhepatotoxic dose of RAN (30 mg/kg i.v.) or its vehicle. Liver injury was evident only in animals treated with both RAN and LPS as estimated by increases in serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase activities within 6 h after RAN administration. LPS/RAN cotreatment resulted in midzonal liver lesions characterized by acute necrosuppurative hepatitis. Famotidine (FAM) is an H2-antagonist for which the propensity for idiosyncratic reactions is far less than RAN. Rats given LPS and FAM at a dose pharmacologically equipotent to that of RAN did not develop liver injury. In vitro, RAN sensitized hepatocytes to killing by cytotoxic products from activated neutrophils, whereas FAM lacked this ability. The results indicate that a response resembling human RAN idiosyncrasy can be reproduced in animals by RAN exposure during modest inflammation.

Adverse drug reactions, transcription factors and transcriptomics

It is currently believed that most idiosyncratic adverse drug reactions arise because of enzymatic modification of the parent drug structure to produce reactive chemical intermediates. However, there is very little direct evidence that can link the formation of a reactive metabolite with a particular idiosyncratic adverse drug reaction. Further study is required to understand the relationship between metabolic bioactivation, induction of oxidative stress and the particular pathways underlying the biological response. In particular, an understanding of the early processes in cellular signalling and defensive manifestations after oxidative insult may help determine the final outcome, i.e. recovery or toxicity. A stress response is initiated when the reductive capacity of a cell, or specialised compartment within a cell, becomes compromised. This could be via depletion of the first line of cellular defences such as glutathione or ascorbate, or by oxidation of critical sulphydryl groups on the surface of redox-sensitive proteins. Once detected, the cell activates the expression of genes involved in antioxidant response. This `switching-on' of gene expression is performed by transcription factors that encode for specific groups of genes that contain the particular transcriptional response element within the promoter region of the gene. Through the profiling of transcription factors and the subsequent genetic regulation, after oxidative insult or exposure to reactive chemical species, we will gain an insight into the underlying biological pathways. Using this information we can identify areas for potential therapeutic modulation as well as obtaining more detailed and predictive toxicity fingerprints for informative decision-making during the drug development process.

Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.

Because acute liver failure is rare, related data have been sparse. Studies have suggested that viral hepatitis is the most common underlying cause of this condition. To describe the clinical features, presumed causes, and short-term outcomes of acute liver failure. Prospective cohort study. 17 tertiary care centers participating in the U.S. Acute Liver Failure Study Group. 308 consecutive patients with acute liver failure, admitted over a 41-month period. Detailed clinical and laboratory data collected during hospitalization, including outcome 3 weeks after study admission. 73% of patients were women; median age was 38 years. Acetaminophen overdose was the most common apparent cause of acute liver failure, accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of cases, and 17% of cases were of indeterminate cause. Overall patient survival at 3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and 43% survived without transplantation. Short-term transplant-free survival varied greatly, from 68% for patients with acetaminophen-related liver failure to 25% and 17% for those with other drug reactions and liver failure of indeterminate cause, respectively. Coma grade at admission appeared to be associated with outcome, but age and symptom duration did not. Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent apparent causes of acute liver failure. Apparent cause and coma grade at admission were associated with outcome. Although transplantation may improve patient survival, it was unavailable or unnecessary for most patients.

Mechanisms of idiosyncratic drug reactions: the case of felbamate

Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicological outcome. As the name implies, IDR are unpredictable and ofter result in the post marketing failure of otherwise useful therapies. Examples of drugs, which have failed as a result of IDR in recent years, include trovafloxacin, zileuton, troglitazone, tolcapone and felbamate. To date there exists no pre-clinical model to predict these adverse drug reactions and a mechanistic understanding of these toxicities remains limited. In an attempt to better understand this class of drug toxicities and gain mechanistic insight, we have studied the IDR associated with a model compound, felbamate. Our studies with felbamate are consistent with the theory that compounds which cause IDR undergo bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo. In additon, our data suggest that under normal physiological conditions glutathione plays a protective role in preventing IDR during felbamate therapy, further emphasizing a correlation between reactive metabolite formation and a toxic outcome. Clinical studies with felbamate have been able to demonstrate an association between reactive metabolite formation and a clinically relevant toxicity; however, additonal research is required to more fully understand the link between reactive metabolite formation and the events which elicit toxicity. Going forward, it seems reasonable that screening for reactive metabolite formation in early drug discovery may be an important tool in eliminating the post-marketing failure of otherwise useful therapies.

Hypocaloric jejunal feeding is better than total parenteral nutrition in acute pancreatitis: results of a randomized comparative study

OBJECTIVES: The aims of this study were to define the indications for, and to evaluate the cost-effectiveness of, nutritional support in patients with acute pancreatitis. METHODS: All admissions during the 12-month period from January through December 2000, were entered into a common management protocol consisting of an initial 48-h fast with i.v. fluids and analgesics. After 48 h, those patients who were improving were restarted on oral feeding (group O). The remaining patients were randomized to receive naso-jejunal (group EN) or parenteral feeding (group TPN). The randomization study was continued until 50 patients had been accrued. Outcomes in the three groups were compared with respect to length of hospital stay, duration of feeding, complications, and hospital costs. RESULTS: A total of 156 admissions were evaluated in the first 12 months. Of these, 87% patients had mild disease, 10% moderate, and 3% severe; 62% were related to alcohol abuse, 18% gallstones, and 8% idiosyncratic drug reactions. Of the patients, 75% improved on 48 h bowel rest and i.v. fluids, and were discharged within 4 days. The remainder were randomized to jejunal elemental (n = 26) or parenteral (n = 27) feeding. Duration of feeding was shorter with EN (6.7 vs 10.8 days, p < 0.05) and nutrition costs were lower, representing an average cost saving of $2362.00 per patient fed. EN was less effective in meeting estimated nutritional requirements (54 vs 88%, p < 0.0001), but metabolic ( p < 0.003) and septic complications ( p = 0.01) were lower. Subgroup analysis of patients with severe disease showed similar findings. CONCLUSION: Despite concerns that metabolic expenditure is increased and that food-stimulated pancreatic secretion might exacerbate the disease process, hypocaloric enteral feeding seems to be safer and less expensive than parenteral feeding and bowel rest in patients with acute pancreatitis.

Vigabatrin associated visual field loss: a clinical audit to study prevalence, drug history and effects of drug withdrawal.

To survey clinical visual function including quantitative manual perimetry results in a group of patients taking vigabatrin; to assess the severity of any field defects; to tabulate cumulative and daily doses of medication and to assess possible changes in visual function over time. A prevalence study of 100 out of 183 patients currently attending a tertiary referral epilepsy centre who were taking or had recently discontinued vigabatrin (duration 83-3570 days; mean 1885 days) as part of combination anticonvulsant therapy. Complete neuro-ophthalmic examination including Goldmann kinetic perimetry was performed and monocular mean radial degrees (MRD) to the I/4e isopter calculated. Patients were followed up at 6-monthly intervals for not less than 18 months. Acuity and colour vision remained stable in all patients regardless of changes in visual fields. Twenty per cent of patients had significant constriction of their visual field defined as a monocular MRD of 30 degrees or less. Males were significantly more likely to be severely affected than females (P < 0.01). Twenty one patients were followed after discontinuing vigabatrin treatment. Only three of these showed a change in MRD of 10 degrees or more with two deteriorating and one improving. No correlation between treatment duration or cumulative dosage/kg and the severity of defects could be demonstrated. Earlier reports of a high prevalence of both moderate and more serious field defects were confirmed in patients taking vigabatrin but not in epileptic patients taking other anti-convulsants. We found no evidence of progression or resolution of visual field defects on discontinuing the drug, and no relationship between dose history and visual deficit field loss. An idiosyncratic drug reaction within the neurosensory retina may underlie the pathogenesis of the visual field loss in some patients.

Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system.

Drug-induced adverse reactions, especially type B reactions, represent a major clinical problem. They also impart a significant degree of uncertainty into drug development because they are often not detected until the drug has been released onto the market. Type B reactions are also termed idiosyncratic drug reactions by many investigators due to their unpredictable nature and our lack of understanding of the mechanisms involved. It is currently believed that the majority of these reactions are immune-mediated and are caused by immunogenic conjugates formed from the reaction of a reactive metabolite of a drug with cellular proteins. It has been shown that most drugs associated with idiosyncratic reactions form reactive metabolites to some degree. Covalent binding of reactive metabolites to cellular proteins has also been shown in many cases. However, studies to reveal the role of reactive metabolites and their protein-adducts in the mechanism of drug-induced idiosyncratic reactions are lacking. This review will focus on our current understanding and speculative views on how a reactive metabolite of a drug might ultimately lead to immune-mediated toxicity.

Xenobiotic acyl glucuronides and acyl CoA thioesters as protein-reactive metabolites with the potential to cause idiosyncratic drug reactions.

Some carboxylic acid-containing drugs have been implicated in rare but serious adverse reactions. These compounds can be bioactivated via two distinct pathways: by UDP-glucuronosyltransferase-catalyzed conjugation with glucuronic acid, resulting in the formation of acyl glucuronides, or by acyl-CoA synthetase-catalyzed formation of acyl-CoA thioesters. This review compares the two types of potentially reactive metabolites with respect to their stability, protein-reactivity, target selectivity, and disposition in the liver, and summarizes the evidence which links acyl glucuronide and acyl-CoA thioester formation with downstream toxicologic effects. While with increasing drug concentration the acyl glucuronide pathway may prevail, CoA intermediates may be more reactive. Both metabolites are electrophilic species which can acylate target proteins if they escape inactivation by S-glutathione-thioester formation. A crucial factor is the up-concentration of acyl glucuronides in hepatocytes and the biliary tree, due to vectorial transport by conjugate export pumps, where they may selectively acylate canalicular membrane proteins. Furthermore, positional isomers, which are avidly formed by acyl migration, can glycate proteins in the liver and at more distal sites. In contrast, acyl-CoA esters may be more rapidly hydrolysed or further metabolized in hepatocytes, and their hepatobiliary transport has not been well explored. While there is accumulating evidence that acyl glucuronides can alter cellular function by various mechanisms, including haptenation of peptides, critical protein acylation or glycation, or direct stimulation of neutrophils and macrophages, the role of acyl-CoA intermediates is less clear. More work is needed to provide a causal link between protein-reactive acyl glucuronides and acyl-CoA thioesters and the rare and unpredictable idiosyncratic drug reactions in humans.

On the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics.

The unexpected occurrence of idiosyncratic drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use or failure to release/withdrawal. This leads to considerable uncertainty in drug development and has led to attempts to try to predict a drug's potential to cause such reactions. The biotransformation of relatively inert drugs to highly reactive metabolites, commonly referred to as "bioactivation", is now recognized to be an obligatory step in several kinds of drug-induced adverse reactions. Reactive metabolites can be formed by most, if not all, of the enzymes that are involved in drug metabolism. A major theme explored in this review includes the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics including drugs. A variety of Phase I enzymes including P450, MAO, and peroxidases bioactivate nitrogen-containing xenobiotics via direct oxidations on the nitrogen atom leading to reactive intermediates or by oxidation at an alternate site in the molecule; for the metabolite to be reactive via the latter sequence nitrogen participation in required. Examples of direct oxidations on nitrogen include the N-oxidation of aromatic amines (e.g. procainamide), single electron N-oxidation of imides (e.g. phenytoin), or alpha-carbon oxidations of arylalkyl- or alkylamines (e.g. mianserin), to reactive nitroso, nitrogen free radical and iminium species, respectively. Examples of indirect bioactivation are highlighted with aromatic amines (e.g. diclofenac) that undergo p-hydroxylation resulting in the formation of p-aminophenols, two-electron oxidation of which results in the formation of reactive quinoneimines. Potential strategies that could be utilized in the screening of novel bioactivation pathways are also discussed.

Mechanistic perspectives on sulfonamide-induced cutaneous drug reactions.

Idiosyncratic drug reactions continue to limit the therapeutic utility of sulfonamide drugs because of their associated morbidity and mortality. Cutaneous reactions are the predominant reasons for withdrawal of such drugs from use in patients. As a consequence of the recognized metabolic and immunologic capability of the skin, an understanding of the pathogenic role of this tissue in the development of sulfonamide-induced cutaneous drug reactions may provide insight into the mechanisms and risk factors for these and other adverse drug events. In the present review we discuss currently available mechanistic information, including issues related to drug bioactivation and adduct formation, immunoresponsiveness, and immune dysregulation, for the development of sulfonamide-induced (delayed-type) cutaneous drug reactions. The potential application of findings from several related areas of research are also discussed within the context of the pathogenesis of these cutaneous reactions. Despite progress, numerous unresolved issues support the testing of novel hypotheses, the search for additional risk factors, and the need for a global approach, including links between laboratory and clinical paradigms. These issues must be addressed if we are to gain an understanding of the mechanistic bases for these cutaneous drug reactions.

The danger hypothesis—potential role in idiosyncratic drug reactions

Idiosyncratic or type B reactions are characterised by their unpredictability and lack of simple dose-dependency. They occur in a small proportion of patients, and usually the predisposing factors are unknown. A proportion of, but not all, idiosyncratic reactions are immune-mediated. Our understanding of immune-mediated reactions is based on the hapten hypothesis, which requires drug bioactivation, covalent binding to proteins, followed by uptake, antigen processing and a polyclonal immune response. The recently proposed ‘danger hypothesis’ can be considered to be additive to the hapten hypothesis. The hypothesis states that the immune system only responds when it detects danger. If no danger is detected, tolerance results. Thus, stimulation of an immune response to a drug-protein conjugate (signal 1) requires the presence of co-stimulatory signals and cytokines (signals 2 and 3), which propagate and determine the type of immune response. The nature of the danger signal is poorly defined, and has been proposed to include different forms of stress including chemical, physical and viral. Indeed, there are several examples where the frequency of drug hypersensitivity is increased in the presence of a viral infection, most notably in HIV disease. Nevertheless, this clinical evidence has to be regarded as being circumstantial and more direct experimental evidence is required to understand the role of ‘danger’ in the overall pathogenesis of drug hypersensitivity reactions.

N-OXIDATION OF DRUGS ASSOCIATED WITH IDIOSYNCRATIC DRUG REACTIONS

Circumstantial evidence strongly suggests that most idiosyncratic drug reactions are due to reactive metabolites of drugs rather than due to the drugs themselves. Many of the drugs that are associated with idiosyncratic drug reactions contain nitrogen. There are many possible reasons for this association. One is simply that many drugs, especially CNS active drugs, contain nitrogen. In addition, nitrogen is relatively easy to oxidize because of its lone pair of electrons and many nitrogen-containing compounds readily undergo redox cycling, which can generate reactive oxygen species. There are several nitrogen-containing function groups that are especially associated with adverse reactions. These include aromatic amines, nitro compounds (nitro compounds are reduced to the same reactive intermediates as are formed by oxidation of the corresponding aromatic amine), hydrazines and compounds that can be oxidized to iminoquinone and related compounds. A greater attention to the issue of reactive metabolites during drug development would likely lead to safer drugs; however, not all drugs that form reactive metabolites are associated with a high incidence of idiosyncratic drug reactions. In addition to the presence of such a group, other factors, such as dose and electron density of the compound, appear to play a role in whether the drug containing such functional groups will be associated with a relatively high incidence of idiosyncratic drug reactions.