allopurinol and Drug-Hypersensitivity

Drug hypersensitivity reactions (DHR) are heterogeneous in their pathomechanisms, clinical presentation, severity, and outcomes. Novel DHR mechanisms, phenotypes, and endotypes have been described. The key to prevention from further exposure to the culprit drugs involves correct identification of the putative drug through a combination of in vitro and/or in vivo tests, accurate drug allergy labeling and reporting, and electronic decision support systems within electronic medical records to prevent future accidental prescribing. Prescreening and premedication, the focus of this review, may be a useful adjunct to preventive measures in certain situations. After an index immediate drug hypersensitivity reaction, prescreening may be useful in perioperative anaphylaxis, and iodinated (ICM) and gadolinium-based contrast media (GCM) where the culprit and potential alternative agents are skin tested. In certain nonimmediate DHR, pharmacogenomic prescreening may be used before prescribing high-risk drugs (eg, carbamazepine and allopurinol) where specific human-leukocyte antigen genotypes are associated with severe cutaneous adverse reactions. Premedication with antihistamine and systemic corticosteroids is another therapeutic strategy to prevent infusion reactions for certain biologicals and chemotherapeutic agents, in cases of perioperative anaphylaxis, ICM and GCM DHR, and clonal mast cell disorders. Rapid drug desensitization may also be used to induce temporary tolerance in situations where there are limited alternative drugs.

Topics: Allopurinol; Contrast Media; Drug Hypersensitivity; Humans; Premedication; Skin Tests; Stevens-Johnson Syndrome

Allopurinol, a first line urate-lowering therapy, has been associated with serious cutaneous reactions that have a high mortality. A number of risk factors for these serious adverse reactions have been identified including ethnicity, HLA-B∗5801 genotype, kidney impairment, allopurinol starting dose, and concomitant diuretic use. There is a complex interplay between these risk factors, which may (albeit rarely) lead to allopurinol-related serious adverse events. Although oxypurinol, the active metabolite of allopurinol, has been implicated, there is no defined drug concentration at which the reaction will occur. There is no specific treatment other than the cessation of allopurinol and supportive care. Whether hemodialysis, which rapidly removes oxypurinol, improves outcomes remains to be determined. Strategies to help reduce this risk are therefore important, which includes screening for HLA-B∗5801 in high-risk individuals, commencing allopurinol at low dose, and educating patients about the signs and symptoms of severe cutaneous adverse reactions, and what to do if they occur.

Topics: Allopurinol; Drug Hypersensitivity; Gout; Gout Suppressants; Humans; Oxypurinol

The safety of newer xanthine oxidase inhibitor febuxostat compared to allopurinol remains unclear. To compare the risks of allopurinol hypersensitivity and febuxostat hypersensitivity and cardiovascular diseases (CVDs) in Asians, we conducted a population-based cohort study enrolling patients receiving allopurinol or febuxostat from Chang Gung Memorial Hospital Health System across Taiwan during 2012-2016 and further performed a meta-analysis incorporating two recent studies. Among the 61,539 users, a corresponding 12,007 and 5,680 patients were identified as new users. The overall incidence of febuxostat hypersensitivity was significantly lower than allopurinol hypersensitivity (0.2 vs. 2.7 per 1,000 new users; P < 0.001). There were 33 allopurinol-hypersensitivity reactions (including 18 severe cutaneous adverse drug reactions), and only one patient developed febuxostat-maculopapular exanthema. Moreover, febuxostat did not statistically increase the risk of CVD (hazard ratio (HR), 1.16; P = 0.152) and related death (HR, 1.49; P = 0.496) compared to allopurinol. The result of the meta-analysis also showed a consistent result. In conclusion, the incidence and severity of febuxostat-hypersensitivity are lower than with allopurinol. Febuxostat did not show an increased risk of CVD and related death.

Topics: Aged; Allopurinol; Asian People; Cardiovascular Diseases; Cohort Studies; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Febuxostat; Gout; Gout Suppressants; Humans; Middle Aged; Taiwan

Allopurinol hypersensitivity syndrome (AHS) is a severe and sometimes life-threatening adverse drug reaction. Although AHS is rare, the number of patients with gout requiring allopurinol is high, and there are sufficient overall cases of AHS to warrant consideration of preventive measures. Most cases occur within 8-9 weeks of commencing allopurinol, and good patient education at initiation may lead to rapid drug cessation at onset of symptoms. Pretreatment testing for HLA-B*5801 and avoidance of allopurinol when positive reduces the risk of AHS and is cost-effective in some ethnic groups. A low starting allopurinol dose may reduce AHS risk, but the relationship between maintenance dose and AHS is more controversial. Chronic kidney disease increases AHS risk, but slowly increasing the allopurinol dose in chronic kidney disease has not been associated with AHS. Alternative newer treatments are available for patients at risk of AHS, but similar adverse reactions can also occur with these.

Topics: Allopurinol; Dose-Response Relationship, Drug; Drug Hypersensitivity; Gout; Gout Suppressants; Humans

Adverse drug reactions (ADRs) affect many patients and remain a major public health problem, as they are a common cause of morbidity and mortality. It is estimated that ADRs are responsible for about 6% of hospital admissions and about 9% of hospitalization costs. Skin is the organ that is most frequently involved in ADRs. Drug-induced skin injuries vary from mild maculopapular eruptions (MPE) to severe cutaneous adverse reactions (SCARs) that are potentially life threatening. Genetic factors have been suggested to contribute to these SCARs, and most significant genetic associations have been identified in the major histocompatibility complex (MHC) genes. Common drugs associated with SCARs connected with strong genetic risk factors include antiepileptic drugs (AEDs), allopurinol, abacavir, nevirapine, sulfonamides, dapsone, non-steroidal anti-inflammatory drugs (NSAIDs), and analgesic drugs. However, genetic associations vary between different ethnic populations. Differences may in part be explained by the different prevalence of HLA (human leukocyte antigen) alleles among ethnic groups. In this review, we present and discuss the recent advances in genetic associations with ADRs in the skin. Many of these ADRs are now preventable with pharmacogenetic screening.

Topics: Alleles; Allopurinol; Anti-HIV Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression; Genetic Testing; Gout Suppressants; HLA-B Antigens; Humans; Pharmacogenetics; Skin

The observed associations of hyperuricaemia with hypertension, cardiovascular disease and kidney disease are receiving increasing interest. The potential role of urate-lowering therapy in the management of these "non-gout diseases" has been raised, and in some countries it is already recommended. However, there is no consistent definition of hyperuricaemia or asymptomatic hyperuricaemia, much remains unknown about the causal role of urate in these "non-gout diseases" and there is currently a lack of evidence about the effects of urate lowering on disease progression. In addition, there is potential for serious adverse effects associated with urate-lowering therapies with recent evidence suggesting that asymptomatic hyperuricaemia may be an independent risk factor for the potentially fatal allopurinol hypersensitivity syndrome.. Pubmed was searched in January 2016 using the search term "asymptomatic hyperuricaemia".. Herein, we discuss the issues related to treating asymptomatic hyperuricaemia, which at present seems premature.

Topics: Allopurinol; Asymptomatic Diseases; Drug Eruptions; Drug Hypersensitivity; Febuxostat; Gout Suppressants; Humans; Hyperuricemia; Probenecid; Uricosuric Agents; Urolithiasis

Adverse drug reactions are a significant cause of morbidity and mortality and represent a major burden on the healthcare system. Some of those reactions are immunologically mediated (hypersensitivity reactions) and can be clinically subdivided into two categories: immediate reactions (IgE-related) and delayed reactions (T-cell-mediated). Delayed hypersensitivity reactions include both systemic syndromes and organ-specific toxicities and can be triggered by a wide range of chemically diverse drugs. Recent studies have demonstrated a strong genetic association between human leukocyte antigen alleles and susceptibility to delayed drug hypersensitivity. Most notable examples include human leukocyte antigen (HLA)-B*57:01 allele and abacavir hypersensitivity syndrome or HLA-B*15:02 and HLA-B*58:01 alleles related to severe cutaneous reactions induced by carbamazepine and allopurinol, respectively. This review aims to explore our current understanding in the field of pharmacogenomics of HLA-associated drug hypersensitivities and its translation into clinical practice for predicting adverse drug reactions.

Topics: Allopurinol; Anticonvulsants; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Enzyme Inhibitors; Genetic Predisposition to Disease; HLA Antigens; Humans; Pharmacogenetics; Reverse Transcriptase Inhibitors

Allopurinol is the most commonly prescribed urate-lowering therapy for the management of gout. Serious adverse reactions associated with allopurinol, while rare, are feared owing to the high mortality. Such reactions can manifest as a rash combined with eosinophilia, leukocytosis, fever, hepatitis and progressive kidney failure. Risk factors for allopurinol-related severe adverse reactions include the recent introduction of allopurinol, the presence of the HLA-B(*)58:01 allele, and factors that influence the drug concentration. The interactions between allopurinol, its metabolite, oxypurinol, and T cells have been studied, and evidence exists that the presence of the HLA-B(*)58:01 allele and a high concentration of oxypurinol function synergistically to increase the number of potentially immunogenic-peptide-oxypurinol-HLA-B(*)58:01 complexes on the cell surface, thereby increasing the risk of T-cell sensitization and a subsequent adverse reaction. This Review will discuss the above issues and place this in the clinical context of reducing the risk of serious adverse reactions.

Topics: Allopurinol; Drug Hypersensitivity; Drug Hypersensitivity Syndrome; Genetic Testing; Gout; HLA-B Antigens; Kidney; Oxypurinol; Skin; T-Lymphocytes

The article reviews the immunopathogenesis and risk factors related to allopurinol-induced severe cutaneous adverse reactions (SCARs).. For years, allopurinol remains one of the leading cause for SCARs worldwide. The pathogenesis of allopurinol-induced SCARs have been discovered in recent years. HLA-B58 : 01 has been found to be strongly associated with allopurinol-SCARs with functional interactions between allopurinol/its metabolite-oxypurinol and the T-cell receptor (TCR). However, the genetic strength of HLA-B58 : 01 may vary among different ethnic populations. In addition to HLA-B58 : 01, specific T cells with preferential TCR clonotypes, which have no cross-reactivity with new xanthine oxidase inhibitors structurally different from allopurinol, are found to play a crucial role for allopurinol-induced SCARs. Furthermore, other nongenetic factors such as renal impairment are also found to be an important factor resulting in allopurinol-induced SCARs of greater severity and poorer prognosis.. There are multiple risk factors for allopurinol-induced SCARs, including genetic and nongenetic factors. Activation of specific T cells with preferential TCR and its functional interaction of HLA-B58 : 01 molecule and allopurinol/oxypurinol are involved in the immune mechanism of allopurinol-induced SCAR. Patients with allopurinol-induced SCARs with renal impairment have significantly higher risk of mortality. A structurally different new generation xanthine oxidase inhibitor can provide a safer alternative for patients intolerant to allopurinol.

Topics: Allergens; Allopurinol; Animals; Drug Hypersensitivity; Enzyme Inhibitors; Ethnicity; Genetic Predisposition to Disease; HLA-B Antigens; Humans; Kidney; Receptors, Antigen, T-Cell; Risk Factors; Skin; T-Lymphocytes; Xanthine Oxidase

Immune-mediated (IM) adverse drug reactions (ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B cell-mediated and primary T cell-mediated IM-ADRs. In this review we summarize the role of host genetics, microbes, and drugs in IM-ADR development; expand on the existing models of IM-ADR pathogenesis to address multiple unexplained observations; discuss the implications of this work in clinical practice today; and describe future applications for preclinical drug toxicity screening, drug design, and development.

Topics: Allopurinol; B-Lymphocytes; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression Regulation; Genetic Loci; HLA Antigens; Humans; Models, Immunological; Pharmacogenetics; Stevens-Johnson Syndrome; T-Lymphocytes; Virus Diseases

Over the past decade, there have been significant advances in our understanding of the immunopathogenesis and pharmacogenomics of severe immunologically-mediated adverse drug reactions. Such T-cell-mediated adverse drug reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug-induced liver disease (DILI) and other drug hypersensitivity syndromes have more recently been shown to be mediated through interactions with various class I and II HLA alleles. Key examples have included the associations of HLA-B*15:02 and carbamazepine induced SJS/TEN in Southeast Asian populations and HLA-B*57:01 and abacavir hypersensitivity. HLA-B*57:01 screening to prevent abacavir hypersensitivity exemplifies a successful translational roadmap from pharmacogenomic discovery through to widespread clinical implementation. Ultimately, our increased understanding of the interaction between drugs and the MHC could be used to inform drug design and drive pre-clinical toxicity programs to improve drug safety.

Topics: Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Genotype; HLA-B Antigens; Humans; Nevirapine; Pharmacogenetics; Protein Conformation; Stevens-Johnson Syndrome

Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings.

Topics: Alleles; Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Azetidines; Benzylamines; Carbamazepine; Chemical and Drug Induced Liver Injury; Diclofenac; Dideoxynucleosides; Drug Hypersensitivity; Floxacillin; Genetic Markers; HLA Antigens; HLA-A Antigens; HLA-B Antigens; HLA-DQ alpha-Chains; Humans; Lapatinib; Pharmacogenetics; Quinazolines; Skin; Stevens-Johnson Syndrome; Ticlopidine

Allopurinol is the primary therapy for the management of chronic gout. Utilization of allopurinol has increased in tandem with the growing prevalence of gout globally. This exposes more patients to the risk of allopurinol hypersensitivity (AH), a rare adverse reaction characterised by a spectrum of cutaneous reactions and systemic manifestations. Severe forms of AH have been associated with high mortality. The pathophysiology underlying this reaction remains unknown, but several risk factors have been proposed.. The aim of this study was to review all published cases of AH documented in the literature in order to better understand the constellation of factors predisposing to this reaction, building on previous reviews by Lupton and Odom, Singer and Wallace and Arellano and Sacristan.. A literature search was conducted in MEDLINE and EMBASE to identify relevant articles published between January 1950 and December 2012, with no language restrictions imposed. Articles that were included reported either allopurinol-induced cutaneous manifestations alone or satisfied the diagnostic criteria for AH as defined by Singer and Wallace.. Nine hundred and one patients (overall AH cohort) were identified from 320 publications. Of these patients, 802 satisfied the Singer and Wallace criteria ('Singer and Wallace' cohort) while 99 patients had only mild cutaneous manifestations ('non-Singer and Wallace' cohort). Data were often incomplete; hence the results reported reflect the fractions of the subsets of the cohort where the data in question were available. In the overall AH cohort, 58 % (416/722) were male. The majority (73 %; 430/590) of patients were Asian. Renal impairment (48 %; 182/376) and hypertension (42 %; 160/376) were the most common chronic conditions; accordingly, diuretics (45 %; 114/252) and antihypertensives (39 %; 99/252) were the most prevalent concomitant medications. Allopurinol was prescribed for approved indications (chronic gout and chemoprophylaxis) in only 40 % (186/464) of patients. The median allopurinol dose was 300 mg/day (range 10-1,000 mg/day) and was taken by 50 % (168/338). There was no significant association between a higher dose (>300 mg/day) and an increased risk of severe cutaneous manifestations [odds ratio (OR) 1.76; 95 % CI 0.73-4.22; p = 0.23]. Approximately 90 % (489/538) of patients developed AH within 60 days of initiating allopurinol therapy. Serum oxypurinol (the active metabolite of allopurinol) concentration was only recorded in six patients, four of whom had levels within the putative therapeutic range of 30-100 μmol/L. The HLA-B*5801 allele was present in 99 % (166/167) of patients tested, with the majority (147/166) being of Asian ancestry. The all-cause mortality rate was 14 % (109/788) with 94 AH-related deaths, all of which occurred in the cohort meeting the Singer and Wallace criteria.. The publications included in this review utilized different laboratory reference ranges to classify the non-cutaneous manifestations of AH; this may have introduced some variation in the cases identified as AH. A majority of the articles included in this analysis consisted of case reports and series--publication types that are not recognized as best-quality evidence; this thus limited the conclusions we could draw about the many risk factors we were interested in evaluating.. Risk factors associated with AH, such as concomitant diuretic use, pre-existing renal impairment and recent initiation of allopurinol, were commonly present in AH patients; however, their role in the mechanism of AH remains to be established. A clear risk factor was the HLA-B*5801 status; this was especially relevant in Asian populations where there is a higher carriage rate of the allele. High allopurinol dose, previously suggested to be a risk factor, was not confirmed as such. The paucity of well-documented case reports and studies of AH render it difficult to draw more concrete conclusions or construct a meticulous profile of patients at risk of AH. Future case reports of AH need to be better documented to contribute to understanding the risks for, and mechanisms of, AH.

Topics: Allopurinol; Drug Hypersensitivity; Drug Utilization; Gout; Gout Suppressants; Humans

The human leukocyte antigen (HLA) genes are the most polymorphic in the human genome and are critical in regulating specific immunity, hence their historical discovery as "immune response" genes. HLA allotypes are also implicated in unwanted immune reactions, including drug hypersensitivity syndrome, in which small therapeutic drugs interact with antigenic peptides to drive T cell responses restricted by host HLA. Abacavir, allo-purinol, and carbamazepine are three commonly used drugs that cause a T cell-mediated hypersensitivity that is HLA linked, with each drug exhibiting striking specificity for presentation by defined HLA allotypes. Recent findings have begun to unearth the mechanistic basis for these HLA associations, and here we review recent advances in the field of HLA-associated drug hypersensitivities.

Topics: Alleles; Allopurinol; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; HLA Antigens; Humans; Major Histocompatibility Complex; Pharmacogenetics; Polymorphism, Genetic; T-Lymphocytes

The human leucocyte antigen (HLA) system is well known for its association with certain diseases such as ankylosing spondylitis, celiac disease and many others. More recently, severe and even fatal drug hypersensitivity reactions linked to particular HLA alleles have been discovered. The significance of these discoveries has led the European Medicines Agency (EMA) and its member state agencies to recommend HLA gene testing before initiation of drug treatment. To date, the following drugs have been identified as causing significant drug hypersensitivity reactions in patients who have the following HLA alleles: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02/A*31:01 and finally allopurinol and HLA-B*58:01. This review will outline and discuss these three drugs and their associated HLA alleles as well as examine the pathogenesis of the drug hypersensitivity reactions.

Topics: Alleles; Allopurinol; Anti-HIV Agents; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Frequency; Genetic Testing; HLA-B Antigens; HLA-B15 Antigen; Humans; Pharmacogenetics; Stevens-Johnson Syndrome

Recent publications have shown that certain human leukocyte antigen (HLA) alleles are strongly associated with hypersensitivity to particular drugs. As HLA molecules are a critical element in T-cell stimulation, it is no surprise that particular HLA alleles have a direct functional role in the pathogenesis of drug hypersensitivity. In this context, a direct interaction of the relevant drug with HLA molecules as described by the p-i concept appears to be more relevant than presentation of hapten-modified peptides. In some HLA-associated drug hypersensitivity reactions, the presence of a risk allele is a necessary but incomplete factor for disease development. In carbamazepine and HLA-B*15:02, certain T-cell receptor (TCR) repertoires are required for immune activation. This additional requirement may be one of the 'missing links' in explaining why most individuals carrying this allele can tolerate the drug. In contrast, abacavir generates polyclonal T-cell response by interacting specifically with HLA-B*57:01 molecules. T cell stimulation may be due to presentation of abacavir or of altered peptides. While the presence of HLA-B*58:01 allele substantially increases the risk of allopurinol hypersensitivity, it is not an absolute requirement, suggesting that other factors also play an important role. In summary, drug hypersensitivity is the end result of a drug interaction with certain HLA molecules and TCRs, the sum of which determines whether the ensuing immune response is going to be harmful or not.

Topics: Alleles; Allopurinol; Carbamazepine; Drug Hypersensitivity; HLA Antigens; HLA-B Antigens; Humans; Receptors, Antigen, T-Cell; T-Lymphocytes

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions, usually induced by drugs. The reactions, which are characterized by extensive necrosis and detachment of the epidermis, followed by erosions of the skin and mucous membranes, are associated with high rates of mortality. There is growing evidence that SJS and TEN are a single disease with common causes and mechanisms. The present article summarizes recent updates and innovations related to the etiology, pathogenesis, genetic background, prognosis and treatment of these reactions. Among high-risk drugs associated with SJS/TEN, allopurinol is the most common cause of SJS/TEN in Europe and Israel. The prognosis of SJS/TEN can be predicted by a scoring system based on seven clinical and laboratory parameters. Founded on the genetic background of SJS/TEN, predictive tests can be used prior to starting high-risk medications. Treatment is still controversial, and further controlled studies are necessary.

Topics: Allopurinol; Drug Hypersensitivity; Humans; Israel; Stevens-Johnson Syndrome

Allopurinol, the first-line drug for serum urate-lowering therapy in gout, is approved by the US Food and Drug Administration for a dose up to 800 mg/d and is available as a low-cost generic drug. However, the vast majority of allopurinol prescriptions are for doses < or = 300 mg/d, which often fails to adequately treat hyperuricemia in gout. This situation has been promoted by longstanding, non-evidence-based guidelines for allopurinol use calibrated to renal function (and oxypurinol levels) and designed, without proof of efficacy, to avoid allopurinol hypersensitivity syndrome. Severe allopurinol hypersensitivity reactions are not necessarily dose-dependent and do not always correlate with serum oxypurinol levels. Limiting allopurinol dosing to < or = 300 mg/d suboptimally controls hyperuricemia and fails to adequately prevent hypersensitivity reactions. However, the long-term safety of elevating allopurinol dosages in chronic kidney disease requires further study. The emergence of novel urate-lowering therapeutic options, such as febuxostat and uricase, makes timely this review of current allopurinol dosing guidelines, safety, and efficacy in gout hyperuricemia therapy, including patients with chronic kidney disease.

Topics: Allopurinol; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Hypersensitivity; Gout; Gout Suppressants; Health Care Costs; Humans; Hyperuricemia; Kidney; Kidney Function Tests; Oxypurinol; Practice Guidelines as Topic

The present article reviews the recent literature on the identification of human leukocyte antigen (HLA) alleles as major susceptible genes for drug hypersensitivity and discusses the clinical implications.. Several recent studies have reported strong genetic associations between HLA alleles and susceptibility to drug hypersensitivity. The genetic associations can be drug specific, such as HLA-B*1502 being associated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), HLA-B*5701 with abacavir hypersensitivity and HLA-B*5801 with allopurinol-induced severe cutaneous adverse reactions. A genetic association can also be phenotype-specific, as B*1502 is associated solely with carbamazepine-SJS/TEN, and not with either maculopapular eruption or hypersensitivity syndrome. Furthermore, a genetic association can also be ethnicity specific; carbamazepine-SJS/TEN associated with B*1502 is seen in south-east Asians but not in whites, which may be explained by the different allele frequencies.. The strong genetic association suggests a direct involvement of HLA in the pathogenesis of drug hypersensitivity when the HLA molecule presents an antigenic drug for T cell activation. The high sensitivity/specificity of some markers provides a plausible basis for developing tests to identify individuals at risk for drug hypersensitivity. Application of HLA-B*1502 genotyping as a screening tool before prescribing carbamazepine could be a valuable tool in preventing carbamazepine-induced SJS/TEN in south-east Asian countries.

Topics: Allopurinol; Carbamazepine; Dideoxynucleosides; Drug Eruptions; Drug Hypersensitivity; Genetic Predisposition to Disease; HLA Antigens; HLA-B Antigens; Humans; Pharmacogenetics; Stevens-Johnson Syndrome

Topics: Allopurinol; Anticonvulsants; Carbamazepine; Drug Eruptions; Drug Hypersensitivity; Herpesvirus 6, Human; Humans; Solvents; Sulfasalazine; Syndrome; T-Lymphocytes; Trichloroethylene; Virus Activation

Hyperuricemia is present in approximately 5% of the population, the vast majority of whom are asymptomatic and at no clinical risk. Complications, including renal calculi, uric acid nephropathy and gout, occur in a small proportion of patients. Allopurinol, an analog of hypoxanthine, has been widely used in clinical practice for over 30 years for the treatment of hyperuricemia and gout. Two percent of patients taking this medication develop a mild exanthema. A syndrome characterized by exfoliative dermatitis, hepatitis, interstitial nephritis and eosinophilia has been described previously. Termed allopurinol hypersensitivity syndrome, its etiology is related to the accumulation of one of the allopurinol metabolites, oxypurinol; clearance of oxypurinol is decreased in the setting of renal insufficiency and the use of thiazide diuretics. The term DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) was recently introduced to describe a disorder associated with various drugs or viral infections and characterized by similar features. The pathophysiology of allopurinol-induced hypersensitivity, clinical presentation and treatment are reviewed.

Topics: Allopurinol; Drug Hypersensitivity; Gout; Gout Suppressants; Humans

The manifestations of gout can be abolished permanently by lifelong urate-lowering therapy maintaining serum urate levels under 360 mmol/l, as this ensures dissolution of pathogenic crystals of monosodium urate monohydrate. Benzbromarone has been withdrawn from the market, leaving allopurinol as the only urate-lowering drug readily available in France. Allopurinol may induce unacceptable side effects, and in patients with dose-limiting renal failure it may not be sufficiently effective. Because allopurinol can induce serious side effects when given concomitantly with purine antimetabolites, it is contraindicated in organ transplant recipients. In patients who cannot tolerate allopurinol, dietary treatment, discontinuation of diuretic agents, and use of losartan or fenofibrate to treat concomitant hypertension or dyslipidemia, respectively, may ensure adequate control of serum urate levels. Desensitization to allopurinol can be attempted in patients with mild cutaneous hypersensitivity reactions but is difficult to perform and rarely used. Uricosuric agents may be helpful in patients with normal or diminished urate excretion. Probenecid is available in France from hospital pharmacies, and benzbromarone can be prescribed via a time-limited authorization procedure. Rasburicase, an Aspergillus urate oxidase produced by genetic engineering, is indicated to prevent acute hyperuricemia induced by chemotherapy for hematological malignancies. Factors that limit the use of rasburicase include the absence of a marketing authorization, the need for parenteral administration, and the absence of validated treatment schedules. Patients with renal failure precluding the use of effective allopurinol dosages are good candidates for benzbromarone therapy. Organ transplant recipients can be given benzbromarone, within the current restrictions to its use; alternatively, mycophenolate mofetil can be substituted for calcineurin inhibitors, which elevate serum urate levels, or for azathioprine, which contraindicates the use of allopurinol.

Topics: Allopurinol; Drug Hypersensitivity; Drug Resistance; Gout; Gout Suppressants; Humans

Topics: Allopurinol; Anticonvulsants; Drug Hypersensitivity; Gout Suppressants; Humans; Sulfonamides; Time Factors

A major obstacle to the treatment of hyperuricemia in patients allergic to allopurinol is the limited availability of suitable, equally effective, alternative, urate-lowering drugs. Conventional uricosuric drugs, including probenecid and sulfinpyrazone, are recommended for allopurinol- intolerant patients with gout and "underexcretion" hyperuricemia who have normal renal function and no history of nephrolithiasis. Therapeutic options in those in whom traditional uricosuric drugs are contraindicated, ineffective, or poorly tolerated include slow oral desensitization to allopurinol and cautious administration of oxipurinol. Allopurinol desensitization is useful particularly in those who have failed other treatment modalities. If available (as in Europe, South Africa, and Japan), benzbromarone may be tried in patients with gout and mild-to-moderate renal insufficiency. Recombinant urate oxidase can be used in the short-term prophylaxis and treatment of chemotherapy- associated hyperuricemia in patients with lymphoproliferative and myeloproliferative disorders. Hyperuricemia and gout occur with increased frequency in cyclosporine-treated allograft transplant recipients. The management of gout in these patients is complicated by two main factors: cyclosporine-induced renal impairment, and interactions with medications used to preserve the allograft.

Topics: Allopurinol; Drug Hypersensitivity; Gout; Gout Suppressants; Humans; Kidney; Transplantation, Homologous; Uric Acid; Uricosuric Agents

Allopurinol hypersensitivity syndrome (AHS) is a severe reaction which is potentially lethal. Exanthematous rash, fever, eosinophilia, and other severe reactions such as toxic epidermal necrolysis, acute vasculitis, and severe hepatic and renal dysfunctions are manifestations of this syndrome. The authors report a case of lethal massive hepatic necrosis due to allopurinol in a patient with the asymptomatic hyperuricemia. They also describe the risk factors most frequently associated with the development of AHS and the strategy for its prevention and consequent reduction of the mortality associated with this syndrome.

Topics: Aged; Aged, 80 and over; Allopurinol; Drug Hypersensitivity; Fatal Outcome; Gout; Gout Suppressants; Humans; Liver; Male; Necrosis

Hypersensitivity syndromes are severe drug induced side effects with skin rashes, fever and/or multiorgan-system abnormalities which are not pharmacologically related. They are well known in relation to allopurinol, anticonvulsants and sulfonamides, but only rarely described with other drugs. These reactions are considered to be immune-mediated but the precise mechanisms are not completely understood. Clinical features, which resemble an EBV infection, and some immunological studies suggest that T-cell mediated immunity is involved in the pathogenesis of this rare disease. In the literature, allopurinol and anticonvulsant hypersensitivity syndromes are clinically well characterized entities, while the definition of hypersensitivity syndrome elicited by other drugs is rather confusing. We present two patients, one with sulfamethoxazole- and one with allopurinol-induced hypersensitivity syndrome. In both cases a lymphocyte transformation test (LTT) was performed and we analyzed the T-cell activation parameters CD25 and HLA-DR on CD4- and CD8- T-cells to demonstrate in vivo activation of T-cells during the active disease. Both patients show increased activation of T-cells with elevated levels of HLA-DR on CD8+ cells. The T-cell activation correlated with the clinical course. Our data support an immunological pathogenesis for hypersensitivity syndromes and the concept that drug specific T-cells are involved in hypersensitivity syndromes.

Topics: Adult; Aged; Allopurinol; CD8 Antigens; Drug Eruptions; Drug Hypersensitivity; Female; HLA-DR Antigens; Humans; Lymphocyte Activation; Sulfamethoxazole; Syndrome; T-Lymphocytes

Allopurinol is a drug of wide clinical use and good tolerance. Some patients develop severe hypersensitivity due to immunologic reaction to the drug. A new case which fulfills all the diagnostic criteria of the syndrome of allopurinol hypersensitivity with associated clinical manifestations of multiple mononeuritis and evidence of granulomas and vasculitis in liver biopsy as the most significant data is reported. The syndrome was favorably resolved following withdrawal of the drug without need for corticoid therapy. The characteristics of the cases described in the Spanish literature over the last few years are globally reviewed. The absence of mortality is of note. The inconvenience of prescribing allopurinol to patients with asymptomatic hyperuricemia is emphasized.

Topics: Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Granuloma; Humans; Liver Diseases; Male; Neuritis; Spain; Syndrome; Vasculitis

To review the pathophysiology, pathology, and clinical findings of allopurinol hypersensitivity syndrome (AHS), an infrequent but life-threatening adverse effect of allopurinol therapy.. A MEDLINE search (key terms hepatitis, interstitial nephritis, severe hypersensitivity, severe toxicity, vasculitis, toxic epidermal necrolysis, Lyell's syndrome, erythema multiforme, and Stevens-Johnson syndrome) was used to identify cases reported in the literature through the end of 1990.. All cases evaluated met Singer and Wallace's diagnostic criteria for AHS.. We extracted data from 101 cases of AHS reported in the literature. The following information, when available, was analyzed: (1) patient data (age, gender, medical history), (2) treatment data (daily dosage of allopurinol, duration of treatment, indications, concomitant medications, and (3) adverse-event data.. Patients were mostly middle-aged men with hypertension and/or renal failure receiving excessive doses of allopurinol primarily for asymptomatic hyperuricemia. Cutaneous rash and fever were the most common clinical findings.. Although the pathophysiologic pathway leading to the development of AHS is unknown, it probably involves an immunologic mechanism following allopurinol accumulation in patients with poor renal function. Our findings suggest that the accepted diagnostic criteria for AHS may be too broad, and we recommend the application of more restrictive criteria. There is no effective treatment for AHS. The use of allopurinol only for accepted indications and in dosages adjusted for a patient's renal function may be the only means of minimizing the incidence of AHS.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Female; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Risk Factors; Skin Diseases

A severe adverse drug effect secondary to allopurinol ingestion has been described, characterized by fever, eosinophilia, cutaneous rash, hepatic lesion and renal failure, with a high mortality (21-26%) and unknown ethiopathogenicity. In many cases patients had a previous disorder on their renal function (53%) and more than half received allopurinol due to asymptomatic hyperuricemia. We present two new cases and review other 18 patients diagnosed in the last nine years, analyzing the ethiopathogenicity, epidemiological, clinical, therapeutical and preventive aspects.

Topics: Aged; Allopurinol; Drug Hypersensitivity; Female; Humans; Male; Middle Aged

Topics: Adult; Allopurinol; Child; Drug Hypersensitivity; Drug Interactions; Gout; Humans; Iron; Kidney Diseases; Nucleic Acids; Purines; Pyrimidines; Tryptophan; Uric Acid; Urinary Calculi; Xanthines

To investigate the efficacy and tolerability of allopurinol as the first-choice antihyperuricaemic treatment for gout, and compare the efficacy and tolerability of benzbromarone and probenecid as second-choice treatment.. Prospective, multicentre, open-label, two-stage randomised controlled trial in gout patients with normal renal function. Enrolled patients were given 300 mg allopurinol for 2 months (stage 1). Those patients who could not tolerate allopurinol or who did not attain the target serum urate concentration (sUr) < or=0.30 mmol/l (5.0 mg/dl), which was defined as successful, were randomised to benzbromarone 200 mg/day or probenecid 2 g/day for another 2 months (stage 2).. 96 patients were enrolled in stage 1. 82 patients (85%) were eligible for the analysis at the end of stage 1: there was a mean (SD) decrease in sUr concentration of 35 (11)% from baseline; 20 patients (24%) attained target sUr < or=0.30 mmol/l; and 9 patients (11%) stopped allopurinol because of adverse drug reactions. 62 patients were enrolled in stage 2. 27 patients received benzbromarone (3 patients not eligible for analysis) and 35 received probenecid (4 patients not eligible for analysis). Treatment with benzbromarone was successful in 22/24 patients (92%) and with probenecid in 20/31 patients (65%) (p = 0.03 compared with benzbromarone). Compared with baseline values, there was a mean (SD) decrease of sUr concentration of 64 (9)% with benzbromarone and 50 (7)% with probenecid (p<0.001).. This study showed that allopurinol 300 mg/day has a poor efficacy and tolerability profile when used to attain a biochemical predefined target level of sUr < or =0.30 mmol/l, following 2 months of treatment. In stage 2, benzbromarone 200 mg/day was more effective and better tolerated than probenecid 2 g/day.

Topics: Aged; Allopurinol; Benzbromarone; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Hypersensitivity; Female; Gout; Gout Suppressants; Humans; Male; Middle Aged; Probenecid; Prospective Studies; Treatment Failure; Uric Acid

HLA-B*58:01 allele was strongly associated with allopurinol induced severe cutaneous adverse drug reaction (SCAR). However, HLA-B genotype is not sufficient to predict the occurrence of allopurinol-induced SCAR.. To discover DNA methylation markers for allopurinol-induced SCAR which may improve the prediction accuracy of genetic testing.. The study was designed as a retrospective case-control clinical study in multicenter hospitals across Taiwan, Mainland China, Malaysia and Canada. 125 cases of allopurinol-induced SCAR patients and 139 cases of allopurinol tolerant controls were enrolled in this study during 2005 to 2021.. The results of genome-wide DNA methylation assay of 62 patients revealed that ITGB2 showed strong discriminative ability of allopurinol-induced SCAR in both HLA-B*58:01 positive and negative patients with AUC value of 0.9364 (95% CI 0.8682-1.000). In validation study, significant hypermethylation of ITGB2 were further validated in allopurinol-induced SCAR patients compared to tolerant controls, especially in those without HLA-B*58:01(AUC value of 0.8814 (95% CI 0.7121-1.000)). Additionally, the methylation levels of 2 sites on ITGB2 were associated with SCAR phenotypes. Combination of HLA-B*58:01 genotyping and ITGB2 methylation status could improve the prediction accuracy of allopurinol-induced SCAR with the AUC value up to 0.9387 (95% CI 0.9089-0.9684), while the AUC value of HLA-B*58:01 genotyping alone was 0.8557 (95% CI 0.8030-0.9083).. Our study uncovers differentially methylated genes between allopurinol-induced SCAR patients and tolerant controls with positive or negative HLA-B*58:01 allele and provides the novel epigenetic marker that improves the prediction accuracy of genetic testing for prevention of allopurinol-induced SCAR.

Topics: Allopurinol; DNA Methylation; Drug Hypersensitivity; HLA-B Antigens; Humans; Retrospective Studies; Stevens-Johnson Syndrome

Topics: Allopurinol; Disease Progression; Drug Hypersensitivity; Drug Hypersensitivity Syndrome; Gout Suppressants; Humans

Allopurinol, widely used in the treatment of hyperuricemia and gout, has been shown to cause severe cutaneous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as systemic reactions such as DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). The HLA-B*5801 allele is known to be a risk factor for severe cutaneous manifestations of hypersensitivity to allopurinol, mostly in Asian populations.. We report the observation of a 47-year-old Chinese patient, with no previous medical history, carrying the HLA-B*5801 allele, who developed an isolated allopurinol hypersensitivity necrotizing renal vasculitis without cutaneous manifestations.. . The identification of this allele should be proposed before prescribing allopurinol in patients originating from certain regions of Asia, and the imputability of allopurinol should be evoked in case of necrotizing renal vasculitis, even without associated cutaneous involvement.

Topics: Allopurinol; China; Drug Hypersensitivity; Drug Hypersensitivity Syndrome; Gout Suppressants; HLA-B Antigens; Humans; Kidney Diseases; Middle Aged; Stevens-Johnson Syndrome; Vasculitis

Immune-mediated drug hypersensitivity reactions are an important source of iatrogenic morbidity and mortality. Human leukocyte antigen (HLA)-B*57:01, HLA-B*15:02, HLA-A*31:01, and HLA-B*58:01 constitute established risk factors and preemptive genotyping of these HLA alleles in patients prior to the initiation of abacavir, carbamazepine, and allopurinol-based therapies can prevent toxicity and improve patient outcomes. However, the cost-effectiveness of preemptive HLA testing has only been evaluated in the United States and few countries in Europe and Asia. In this study, we consolidated HLA genotypes from 3.5-6.4 million individuals across up to 74 countries and modeled the country-specific cost-effectiveness of genetic testing. We find major ethnogeographic differences in risk allele prevalence, which translated into pronounced differences in the number of patients needed to test to prevent one case of severe hypersensitivity reactions between countries and populations. At incremental cost-effectiveness ratio thresholds of $40,000, testing of HLA-B*57:01 in patients initiating abacavir was cost-effective in the majority of countries with potential exceptions of East Asia, Saudi Arabia, Ghana, and Zimbabwe. For carbamazepine, preemptive genotyping of HLA-B*15:02 is only cost-effective across most of East and South Asia, whereas HLA-A*31:01 testing is likely to be cost-effective globally. Testing of HLA-B*58:01 is more likely to be cost-effective throughout Africa and Asia compared with Europe and the Americas. We anticipate that this data set can serve as an important resource for clinicians and health economists to guide clinical decision making and inform public healthcare strategies.

Topics: Alleles; Allopurinol; Asia; Carbamazepine; Cost-Benefit Analysis; Dideoxynucleosides; Drug Hypersensitivity; Europe; Genetic Testing; Genotype; HLA Antigens; Humans; Pharmacogenetics; Pharmacogenomic Testing

Allopurinol, a common medication to treat gout, is associated with severe cutaneous adverse reactions, and the occurrence is highly predicted by an individual's HLA-B*58:01 carrier status. Guidelines endorse preemptive testing in select Asian populations before initiating allopurinol. The Hmong, an Asian subpopulation originally from China who now live dispersed around the world, have a 2.5-fold higher risk of gout when compared to non-Hmong in Minnesota. Given the concern for severe cutaneous adverse reactions when prescribing allopurinol, we quantified the carrier status of HLA-B*58:01 in Hmong from two independent cohorts in Minnesota. Using a community-based participatory research approach, HLA-B*58:01 carrier status was determined in 49 US-born Hmong without a history of gout or allopurinol use. Further, 47 Hmong patients undergoing clinical evaluation to receive gout pharmacotherapy were also tested. The frequency of HLA-B*58:01 positive carrier status in these two cohorts were compared to published data from a Han Chinese (n = 2910) and a Korean cohort (n = 485) using a Fisher's exact test with a Bonferroni-corrected P-value <0.025 for significance. With one uninterpretable result, we identified two out of 95 people (2.1%) who carried HLA-B*58:01. This 2.1% incidence in these Hmong adults is notably lower than Han Chinese (19.6%, P < 0.0001) and Korean (12.2%, P = 0.0016) populations. Though commonly understood to be of Chinese descent, the lower prevalence within the Hmong underscores the risk of generalizing genotypic findings from Chinese to Asian subpopulations. We suggest no change to the current guidelines recommending which populations should be tested for HLA-B*58:01 before allopurinol use until further validation.

Topics: Adolescent; Adult; Allopurinol; China; Drug Hypersensitivity; Female; Genetic Markers; Genotyping Techniques; HLA-B Antigens; Humans; Male; Middle Aged; Minnesota; Prevalence; Republic of Korea; Young Adult

To assess the risk of hypersensitivity reactions (HSRs) with allopurinol and febuxostat in a population-based study.. We used the 5% Medicare beneficiary sample (≥65 years) from 2006 to 2012 to identify people with a newly filled prescription for allopurinol, febuxostat or colchicine. We used multivariable-adjusted Cox regression analyses to compare the hazard ratio (HR) of incident HSRs with allopurinol or febuxostat use versus colchicine use; separate analyses were done in people exposed to allopurinol. Propensity-matched analyses (5:1) compared hazards with allopurinol versus febuxostat.. Crude incidence rates of HSRs were as follows: allopurinol, 23.7; febuxostat, 30.7; and colchicine, 25.6 per 1000 person-years. Compared with colchicine, allopurinol, febuxostat and febuxostat+colchicine were associated with significantly higher HRs of HSRs, 1.32 (95% CI: 1.10 to 1.60) and 1.54 (95% CI: 1.12 to 2.12) and 2.17 (95% CI: 1.18 to 3.99), respectively. In propensity-matched analyses, febuxostat did not significantly differ from allopurinol; HR for HSRs was 1.25 (95% CI: 0.93 to 1.67). Compared with allopurinol start dose <200 mg/day, allopurinol start dose ≥300 mg/day, diabetes and female sex were associated with significantly higher hazard of HSRs, 1.27 (95% CI: 1.12 to 1.44), 1.21 (95% CI: 1.00 to 1.45) and 1.32 (95% CI: 1.17 to 1.48), respectively. The majority (69%) of HSRs occurred in the outpatient setting.. Compared with colchicine, allopurinol and febuxostat similarly increased the risk of HSRs. Allopurinol and febuxostat did not differ from each other. In allopurinol users, starting dose, female sex and diabetes increased this risk, findings that need further study.

Topics: Age Factors; Aged; Aged, 80 and over; Allopurinol; Colchicine; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Hypersensitivity; Drug Therapy, Combination; Febuxostat; Female; Gout Suppressants; Humans; Incidence; Male; Medicare; Multivariate Analysis; Propensity Score; Proportional Hazards Models; Sex Factors; United States

Hypersensitivity adverse drug reactions (ADRs) are usually serious, unpredictable, and associated with high morbidity and mortality. This study describes cases of hypersensitivity ADRs spontaneously reported in Central Portugal.. Spontaneous reports (SRs) of ADRs received between 2010 and 2017 were reviewed to identify cases of hypersensitivity reactions, using a Standardized MedDRA Query (SMQ). Seriousness, expectedness, and causality were assessed. Descriptive statistics were used to analyze data.. Among 2050 SRs, 598 (29.2%) contained 726 hypersensitivity ADRs: 657 (90.5%) serious, 569 (78.4%) unexpected, and 469 (64.6%) certainly related to drug exposure. Anaphylactic reactions (n = 93; 12.8%), rash maculopapular (n = 82; 11.3%), rash (n = 67; 9.2%) and DRESS (n = 54; 7.4%) were the most common reactions. Frequently implicated drug classes comprised antibiotics (n = 150; 23.0%), antineoplastic agents (n = 124; 19.0%), antigout preparations (n = 54; 8.3%), and anti-inflammatories (n = 44; 6.8%). Top-causative drugs were allopurinol (n = 54; 8.3%), docetaxel (n = 46; 7.1%), and trimethoprim/sulfamethoxazole (n = 26; 4.0%).. Most hypersensitivity ADRs were serious, unexpected, and with strong causal relationship with suspected drugs. Allopurinol was the top-causative drug. Besides antibiotics and anti-inflammatories, antineoplastic agents were frequently cited. These results deserve further investigation.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Allopurinol; Child; Child, Preschool; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Infant; Male; Middle Aged; Pharmacovigilance; Portugal; Retrospective Studies; Young Adult

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Asian People; Drug Hypersensitivity; Female; Genetic Predisposition to Disease; Genotype; Genotyping Techniques; HLA-B Antigens; Humans; Male; Middle Aged; Practice Guidelines as Topic

The prevention and confirmation of drug-induced severe cutaneous adverse reactions (SCARs) are difficult.. To determine the benefit of HLA-B allele prescreening and the measurement of drug-specific IFN-γ-releasing cells in the prevention and identification of the culprit drug in patients with SCARs.. A total of 160 patients with SCARs were recruited from 6 university hospitals in Thailand over a 3-year period. HLA-B alleles were genotypically analyzed. The frequencies of drug-specific IFN-γ-releasing cells in patients with SCARs were also measured.. The drugs commonly responsible for SCARs were anticonvulsants, allopurinol, beta-lactams, antituberculosis agents, and sulfonamides. If culprit drugs had been withheld in patients carrying known HLA-B alleles at risk, it would have prevented 21.2% of SCAR cases, mainly allopurinol- and carbamazepine-related SCARs. Culprit drug-specific IFN-γ-releasing cells could be identified in 45.7% (53 of 116) of patients with SCARs caused by 5 major drug groups, particularly in patients diagnosed with drug reactions with eosinophilia and systemic symptoms (DRESS) (50.0%), followed by Stevens-Johnson syndrome/toxic epidermal necrolysis (46.0%), and acute generalized exanthematous pustulosis (31.3%). According to our study, high frequencies of drug-specific IFN-γ-releasing cells were significantly demonstrated in patients who suffered from DRESS phenotype, having anticonvulsants or the drugs belonging to the "probable" category based on the Naranjo algorithm scale, as the culprit drugs.. HLA-B prescreening would succeed in preventing only a minority of SCAR victims. Drug-specific IFN-γ-releasing cells are detectable in almost half of patients. Better strategies are required for better SCAR prevention and culprit drug confirmation.

Topics: Adult; Aged; Alleles; Allopurinol; Anticonvulsants; beta-Lactams; Cells, Cultured; Drug Hypersensitivity; Drug Hypersensitivity Syndrome; Drug-Related Side Effects and Adverse Reactions; Enzyme-Linked Immunospot Assay; Female; Genetic Association Studies; Genotype; HLA-B Antigens; Humans; Interferon-gamma; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Polymorphism, Genetic; Skin Diseases; Thailand

Although HLA-B*58:01 is a well-known risk factor for the development of allopurinol-induced severe cutaneous adverse reactions (SCARs), most of the HLA-B*58:01 carriers do not suffer from SCARs despite a long-term use of allopurinol. This suggests that there are other risk factors that determine the fate of HLA-B*58:01 carriers.. The aim of this study was to investigate the additional genetic factors that increase the risk of allopurinol-induced SCARs in HLA-B*58:01 carriers.. The incidence of allopurinol-induced SCARs was investigated according to coexisting HLA alleles in all subjects with HLA-B*58:01 who took allopurinol between 2003 and 2017. The allopurinol tolerant group was defined as a group who took allopurinol for more than 60 days without developing hypersensitivity and was compared with the allopurinol-induced SCAR group.. Among the retrospective cohort consisting of 367 HLA-B*58:01 carriers treated with allopurinol, 11 (3.0%) were diagnosed with allopurinol-induced SCARs. When HLA-B75, DR13 homozygosity, or DR14 was present, the incidence of SCARs increased up to 22.2% (odds ratio [OR], 19.568; P = .015), 20.0% (OR, 38.458; P = .001), and 10.7% (OR, 19.355; P = .004), respectively. Among the 153 HLA-B*58:01 carriers with chronic renal insufficiency (CRI), the incidence of SCARs doubled to 6.5% and further increased to 40%, 30%, and 37.5% in the presence of HLA-B75, DR13 homozygosity, or DR14, respectively.. Secondary screening with HLA-B75, DR13 homozygosity, and DR14 in addition to primary screening with HLA-B*58:01 would enable a more accurate prediction of SCAR occurrence, especially in patients with CRI.

Topics: Adult; Allergens; Allopurinol; Cohort Studies; Drug Hypersensitivity; Female; HLA-B Antigens; HLA-DR Serological Subtypes; Homozygote; Humans; Incidence; Korea; Male; Middle Aged; Retrospective Studies; Risk; Skin

Thus far, human leukocyte antigen (HLA)-B. To determine the usefulness of prospective screening for the HLA-B. We prospectively enrolled 542 patients with chronic renal insufficiency (CRI) from 10 hospitals nationwide and performed DNA genotyping to determine whether they carried the HLA-B. Nineteen patients in the prospective cohort developed mild and transient adverse reactions but none showed allopurinol-induced SCARs. By contrast, we identified 38 patients with allopurinol-induced SCARs (0.95%) in the historical control. The difference in the incidence of allopurinol-induced SCARs between the prospective cohort and historical control was statistically significant (0% vs 0.95%, respectively; P = .029).. The present study demonstrated the clinical usefulness of the HLA-B

Topics: Aged; Allergens; Allopurinol; Drug Hypersensitivity; Febuxostat; Female; Genotype; Histocompatibility Testing; HLA-B Antigens; Humans; Korea; Male; Mass Screening; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Risk; Skin

To assess delayed-type cutaneous reactions (DTCRs) related to drugs, using a case-control approach to qualify drug risks.. The study used the Tunisian pharmacovigilance database of Monastir. The association between drugs and DTCRs was assessed using a case/non-case method. Drugs were grouped according to the ATC Classification System. Patients were defined as "cases" if they have developed DTCRs regardless of the causality assessment. All other reports were "non-cases". Association between reactions and drugs was calculated using the reporting odds ratio (ROR) with 95% confidence intervals (CIs). A p value < 0.05 was considered significant.. The analysis was carried out on 1798 reports, of which 867 concerned DTCRs (cases) and 931 concerned non-cases. The calculated risk estimates were significant for cefotaxime (ROR 2.1; 95% CI 1.5 to 3), pristinamycin (ROR 4; 95% CI 2 to 7.9), sulfamethoxazole (ROR 4.4; 95% CI 1.6 to 11.7), oxacillin (ROR 2.2; 95% CI 1.2 to 3.8), doxycycline (ROR 10.8; 95% CI 1.4 to 84.9), carbamazepine (ROR 3.3; 95% CI 1.7 to 6.2), phenobarbital (ROR 2.3; 95% CI 1.03 to 5.1), allopurinol (ROR 3.6; 95% CI 1.8 to 7.2), furosemide (ROR 2.4; 95% CI 1.3 to 6.3), hydrochlorothiazide(ROR 2.9; 95% CI 1.3 to 6.3) and candesartan (ROR 4.7; 95% CI 1.3 to 16.6).. Our findings corroborate risks for a number of drugs, such as antibacterials, antiepileptics and allopurinol in inducing DTCRs. Given the widespread use of these drug classes, awareness should be raised among patients and prescribers about these risks.

Topics: Adolescent; Adult; Aged; Allopurinol; Anti-Bacterial Agents; Anticonvulsants; Case-Control Studies; Drug Hypersensitivity; Female; Humans; Hypersensitivity, Delayed; Male; Middle Aged; Pharmacovigilance; Tunisia; Young Adult

Preventive efforts for serious immunologically mediated adverse drug reactions (IM-ADRs) have been fueled by discovery of strong class I human leukocyte antigen (HLA) associations; however, the low positive predictive value of HLA for IM-ADRs has limited translation. Studies were undertaken to explain why most patients carrying an HLA risk allele do not develop IM-ADR on exposure to the risk drug. Tissue-specific approaches defined the T-cell receptor (TCR) repertoire and phenotype of the pathogenic T cells found in the skin and blister fluid of IM-ADRs. Dominant CD8+ T cell clonotypes representing >50% of total TCRαβ sequences among CD8+ CD137+ T cells were identified in tissue to identify the pathogenic activated T cells. Identification of the specific molecular and cellular signatures of the antigen-driven pathogenic T cells will facilitate more specific mechanisms to determine the small percentage of individuals carrying an HLA risk allele who are likely to develop an IM-ADR before drug exposure.

Topics: Aged; Allopurinol; Animals; Drug Eruptions; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Female; Genetic Predisposition to Disease; Gout Suppressants; HLA Antigens; Humans; Lymphocyte Activation; Phenotype; Receptors, Antigen, T-Cell; Risk Assessment; Risk Factors; T-Lymphocytes

This study was conducted to evaluate the usefulness of human leukocyte antigen (HLA) typing in preventing allopurinol-induced severe cutaneous adverse reactions (SCARs) through the application of an allopurinol tolerance induction protocol or prescription of other alternative medications in high-risk patients.. HLA typing was performed in patients with chronic renal insufficiency who needed allopurinol. HLA-B*58:01-negative patients were prescribed the usual dose of allopurinol. For HLA-B*58:01-positive patients, administration of either allopurinol based on a 28-day tolerance induction protocol or alternative medications was initiated. Hypersensitivity reactions were surveyed for 90 days and compared with the result of a previous retrospective cohort study.. Among a total of 401 study subjects, no SCARs were noted in HLA-B*58:01-positive patients with application of the tolerance induction protocol (n = 30) or alternative medications (n = 16), nor were any SCARs observed in HLA-B*58:01-negative patients who started allopurinol at the usual dose (n = 355). Compared with the previous retrospective cohort study, a significant reduction in SCARs was observed in HLA-B*58:01-positive patients (0 vs. 18%; P = 0.002).. This study shows the usefulness of HLA-B*58:01 screening in identifying patients at high risk for the development of allopurinol-induced SCARs and suggests that application of a tolerance induction protocol or alternative medications could be an effective strategy to prevent allopurinol-induced SCARs in HLA-B*58:01-positive patients.

Topics: Adult; Aged; Alleles; Allopurinol; Desensitization, Immunologic; Drug Hypersensitivity; Female; Histocompatibility Antigens; Histocompatibility Testing; HLA-B Antigens; Humans; Immune Tolerance; Incidence; Male; Middle Aged; Risk Factors

Topics: Allopurinol; Drug Hypersensitivity; Female; Gout Suppressants; Humans; Hyperuricemia; Male

Allopurinol, a first-line drug used for treating gout, is increasingly prescribed worldwide to patients with asymptomatic hyperuricemia and comorbid renal or cardiovascular diseases. Nevertheless, allopurinol use has been associated with fatal hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The overall risks of allopurinol use remain unclear.. To investigate the incidence of, risk factors for, and mortality associated with allopurinol hypersensitivity in new users of allopurinol.. A retrospective nationwide population study was conducted using data from the Taiwan National Health Insurance Research Database, which includes detailed medical records of more than 23 million insured enrollees. Data were collected from January 1, 2005, through December 31, 2011, using the Anatomical Therapeutic Chemical classification system and International Classification of Diseases, Ninth Revision, Clinical Modification codes. Among 1,613,719 patients receiving allopurinol prescriptions, 495,863 were identified as new users.. Allopurinol hypersensitivity was identified within 3 months since the first prescription. The period for measuring related hospitalizations was 1 month since the episode, and the period for measuring renal complications or mortality was 2 months since the episode. Poisson regression test and multivariable logistic regression analysis were performed, and P < .01 was considered statistically significant.. Among the more than 23 million insured enrollees, the annual incidence rates were 4.68 per 1000 new users for allopurinol hypersensitivity, 2.02 per 1000 new users for related hospitalization, and 0.39 per 1000 new users for related mortality. The annual incidence of allopurinol hypersensitivity rose statistically significantly during the study period (P < .001). Risk factors for allopurinol hypersensitivity included female sex, age 60 years or older, initial allopurinol dosage exceeding 100 mg/d, renal or cardiovascular comorbidities, and use for treating asymptomatic hyperuricemia. Patients with asymptomatic hyperuricemia and renal or cardiovascular diseases had statistically significantly increased risk of allopurinol hypersensitivity (odds ratio [OR], 1.61; 95% CI, 1.33-1.94; P < .001 for renal diseases and OR, 1.52; 95% CI, 1.19-1.93; P < .001 for cardiovascular diseases). They also had statistically significantly increased risk of mortality (OR, 5.59; 95% CI, 2.61-11.94; P < .001 for renal diseases and OR, 3.57; 95% CI, 2.31-5.51; P < .001 for cardiovascular diseases).. The use of allopurinol in patients with asymptomatic hyperuricemia accompanied by renal or cardiovascular diseases statistically significantly increased the risk of hypersensitivity reactions. Physicians should be cautious when prescribing allopurinol to high-risk populations and should consider the potential risks of fatal adverse reactions.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Cardiovascular Diseases; Child; Child, Preschool; Drug Hypersensitivity; Female; Gout Suppressants; Hospitalization; Humans; Hyperuricemia; Incidence; Infant; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Risk Factors; Taiwan; Young Adult

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Desensitization, Immunologic; Drug Hypersensitivity; Female; Humans; Male; Middle Aged

Topics: Allopurinol; Drug Hypersensitivity; Female; Gout Suppressants; Humans; Hyperuricemia; Male

Topics: Allopurinol; Asian People; Drug Hypersensitivity; Gout Suppressants; Humans; Hyperuricemia; Risk Factors

A strong association between the human leucocyte antigen (HLA)-B*58:01 allele and allopurinol-associated severe cutaneous adverse reactions (SCAR) has been reported. A screening for HLA-B*58:01 before allopurinol has been suggested in guidelines for management of gout. HLA-B*58:01 screening is generally based on molecular biology methods that may be not suitable for wide application. We have retrospectively evaluated the performance on a rapid flow cytometry (FCM) test, based on the use of a monoclonal antibody specific for HLA-B17, an antigen that can be split into HLA-B*57 and -B*58 alleles by molecular biology testing, which is used to screen for HLA-B*57:01 before prescription of the antiretroviral agent abacavir in HIV-positive patients. Among 475 samples that were analysed by FCM and by molecular biology test as gold standard, 2 out of 89 false negative tests for HLA-B*58:01 were found. The sensitivity was 97.8% and the negative predictive value was 98.9%. We have shown that a FCM test can identify almost all HLA-B*58:01 positive individuals. As FCM laboratories are more widely available than molecular biology ones, this approach could be used to reduce the risk for allopurinol-induced SCAR. Where both facilities are available, a two-step strategy (FCM as screening, molecular biology for confirmation) may reduce the cost of the screening.

Topics: Alleles; Allopurinol; Antibodies, Monoclonal; Dideoxynucleosides; Drug Hypersensitivity; False Negative Reactions; Flow Cytometry; HLA-B Antigens; Humans; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Skin Diseases

Topics: Aged, 80 and over; Allopurinol; Asymptomatic Diseases; Drug Hypersensitivity; Fatal Outcome; Female; Gout Suppressants; Health Services Misuse; Humans; Hyperuricemia

Topics: Allopurinol; Antimetabolites; Desensitization, Immunologic; Drug Hypersensitivity; Humans; Leukemia, Myeloid; Male; Young Adult

The aims of this study are to evaluate prevalence and characteristics of adverse drug reactions (ADRs) and to evaluate the potential contribution of specific medications, therapeutic categories and drug-drug interactions (DDIs) in older adults.. All ADR reporting forms of persons aged 65+ years collected by the pharmacovigilance of one of the main hospitals in Italy during 2013 were evaluated. DDIs were analysed by a computerized prescription system (INTERCheck) and based on the interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri. DDIs were classified according to their clinical relevance as contraindicated, major, and moderate.. Amongst all the ADR reporting forms (n=1014) collected during 2013, 343 affected older adults. The most frequent ADRs were: haemorrhages (n=122, 35.5%), allergic reactions (n=56, 16.3%), and elevated International Normalized Ratio (INR>6, n=54, 15.7%). The specific medications that contributed to ADRs were warfarin (42.5%), acenocumarol (9%), and allopurinol (8.5%); while the therapeutic categories were haematological agents (67%) and proton pump inhibitors (13%). A total of 912 DDIs were found; one third of them were contraindicated or major and 31.5% of them potentially contributed to ADRs; of these, the most frequent were: warfarin and heparin (contraindicated, n=5); warfarin and a statin (major, n=38); warfarin and a proton pump inhibitor (moderate, n=40). At least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%).. DDIs significantly contribute to the onset of ADRs in older adults and intervention programmes, e.g., the employment of a computerized system, may reduce the burden of iatrogenic illnesses in the elderly.

Topics: Acenocoumarol; Age Factors; Aged; Allopurinol; Drug Hypersensitivity; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Hematologic Agents; Hemorrhage; Humans; International Normalized Ratio; Italy; Male; Prevalence; Proton Pump Inhibitors; Warfarin

A 41 year old patient started treatment with 300 mg/d allopurinol for asymptomatic hyperuricaemia (9,2 mg/dl).. 4 weeks later he developed exfoliative skin lesions with haemorrhage, fever, eosinophilia and acute liver and renal failure, typical for an allopurinol hypersensitivity syndrome (AHS).An orthotopic liver-transplantation was performed.. The AHS is a serious iatrogenic disease. 2 % of the treated patients develop a skin rash. 0,4 % of these patients experience suddenly and unforeseen a severe hypersensitivity with a mortality of 14-30 %. An early diagnosis is often very difficult. In the pathogenesis different causes are discussed. A hereditary component is involved. Of essential importance is the amount of the starting dose, the kidney function and concomitant drugs. In an asymptomatic hyperuricaemia the application of allopurinol is not indicated. If strong indications are present, the allopurinol therapy has to start with the lowest dose (100 mg/d). If required this dose should be increased under consequent supervision only.

Topics: Adult; Allopurinol; Amoxicillin; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Hypersensitivity; Drug Interactions; Drug Therapy, Combination; Follow-Up Studies; Humans; Hyperuricemia; Kidney Failure, Chronic; Liver Transplantation; Male; Risk Factors; Scarlet Fever; Stevens-Johnson Syndrome

The liver is the most commonly involved internal organ in drug-induced systemic hypersensitivity. However, data obtained from these patients have yet to be analyzed in depth with respect to liver injury.. The medical records of 136 patients who developed delayed-type drug hypersensitivity were reviewed at a tertiary referral hospital. Culprit drugs, the pattern and degree of liver injury, and the effect of systemic corticosteroids were evaluated in the group of patients with drug-induced systemic hypersensitivity and liver dysfunction (aspartate aminotransferase or alanine aminotransferase ≥80 IU/L). Clinical characteristics of patients with drug-induced systemic hypersensitivity and liver injury were analyzed.. Among the 61 patients with drug-induced systemic hypersensitivity and liver dysfunction, the clinical phenotypes were drug reaction with eosinophilia and systemic symptoms (n = 29, 48%), Stevens-Johnson syndrome/toxic epidermal necrolysis (n = 11, 18%), and maculopapular rash (n = 17, 28%). Antibiotics (n = 27, 44%) were the most common cause of drug-induced systemic hypersensitivity with liver dysfunction. Whereas patients with Stevens-Johnson syndrome/toxic epidermal necrolysis had mild hepatocellular-type liver injury of relatively brief duration, those with drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome had more severe and prolonged hepatocellular injury in addition to moderate to severe cholestatic-type liver injury. The use of systemic corticosteroids did not significantly affect either recovery from liver injury or mortality.. This study was retrospective and the number of subjects was small.. The results suggest that the severity, pattern, and duration of liver injury differ according to the drug-hypersensitivity phenotype. Further studies are needed to evaluate the role of systemic corticosteroids in drug-induced systemic hypersensitivity and liver injury.

Topics: Adrenal Cortex Hormones; Adult; Aged; Alanine Transaminase; Allopurinol; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Enzyme Inhibitors; Eosinophilia; Female; Humans; Male; Middle Aged; Retrospective Studies; Stevens-Johnson Syndrome

The objective of this study was to estimate the association between adverse drug reactions (ADRs) and exposure to allopurinol maintenance doses higher than those in the 1984 suggested limits of Hande et al. adjusted for level of renal function.. We conducted a retrospective review of electronic health records of patients prescribed allopurinol from January 1, 2004, to June 30, 2011, to identify those who had a definite or possible ADR to allopurinol. The associations of ADRs with maintenance doses of allopurinol 1 to 1.5 times and more than 1.5 times the suggested limits of Hande et al. compared with doses within the suggested limits of Hande et al. were estimated using logistic regression models.. Of 4755 patients prescribed allopurinol, 2946 had a serum creatinine measured within 6 months of starting allopurinol, and of these, 1268 patients' records were reviewed. Forty-eight patients had a definite ADR to allopurinol, 2 of which were allopurinol hypersensitivity syndrome. The odds ratios of definite ADRs with maintenance doses of allopurinol 1.0 to 1.5 times and more than 1.5 times suggested compared with doses within suggested limits were, respectively, 1.42 (95% confidence interval [CI], 0.66-3.04) and 2.04 (95% CI, 0.87-4.77). Among those with an allopurinol maintenance dose more than 1.5 times suggested limits, the proportion of patients with a definite ADR was 2.6% (95% CI, 1.0%-5.2%).. There is no significant association of high maintenance doses of allopurinol with ADRs, and the absolute risk of ADRs at doses higher than 1.5 times the 1984 suggested limits of Hande et al. is low. Cautious, gradual increases in allopurinol maintenance doses above the suggested limits of Hande et al. are warranted if necessary to achieve a serum uric acid level less than 6 mg/dL.

Topics: Aged; Allopurinol; Creatinine; Diarrhea; Dose-Response Relationship, Drug; Drug Hypersensitivity; Eosinophilia; Female; Fever; Gout Suppressants; Humans; Logistic Models; Male; Middle Aged; Nausea; Retrospective Studies; Sex Factors; Stevens-Johnson Syndrome; Thrombocytopenia; Transaminases; Vomiting

Topics: Allopurinol; Drug Hypersensitivity; Gout Suppressants; Humans; Oxypurinol; T-Lymphocytes

Allopurinol is a main cause of severe cutaneous adverse reactions (SCAR). How allopurinol induces hypersensitivity remains unknown. Pre-disposing factors are the presence of the HLA-B*58:01 allele, renal failure and possibly the dose taken.. Using an in vitro model, we sought to decipher the relationship among allopurinol metabolism, HLA-B*58:01 phenotype and drug concentrations in stimulating drug-specific T cells.. Lymphocyte transformation test (LTT) results of patients who had developed allopurinol hypersensitivity were analysed. We generated allopurinol or oxypurinol-specific T cell lines (ALP/OXP-TCLs) from allopurinol naïve HLA-B*58:01(+) and HLA-B*58:01(-) individuals using various drug concentrations. Their reactivity patterns were analysed by flow cytometry and (51) Cr release assay.. Allopurinol allergic patients are primarily sensitized to oxypurinol in a dose-dependent manner. TCL induction data show that both the presence of HLA-B*58:01 allele and high concentration of drug are important for the generation of drug-specific T cells. The predominance of oxypurinol-specific lymphocyte response in allopurinol allergic patients can be explained by the rapid conversion of allopurinol to oxypurinol in vivo rather than to its intrinsic immunogenicity. OXP-TCLs do not recognize allopurinol and vice versa. Finally, functional avidity of ALP/OXP-TCL is dependent on both the induction dose and HLA-B*58:01 status.. This study establishes the important synergistic role of drug concentration and HLA-B*58:01 allele in the allopurinol or oxypurinol-specific T cell responses. Despite the prevailing dogma that Type B adverse drug reactions are dose independent, allopurinol hypersensitivity is primarily driven by oxypurinol-specific T cell response in a dose-dependent manner, particular in the presence of HLA-B*58:01 allele.

Topics: Adult; Aged; Aged, 80 and over; Aldehyde Oxidase; Alleles; Allopurinol; Cross Reactions; Dose-Response Relationship, Drug; Drug Hypersensitivity; Gout Suppressants; HLA-B Antigens; Humans; Lymphocyte Activation; Middle Aged; Oxypurinol; T-Lymphocytes; Xanthine Dehydrogenase

Allopurinol, a common medication for gout treatment, can cause rare but life-threatening severe cutaneous adverse reactions. A strong pharmacogenetic association of human leucocyte antigen (HLA)-B*58:01 with allopurinol-induced drug hypersensitivity has been reported, especially in the Han Chinese population.. To develop a rapid and simple loop-mediated isothermal amplification (LAMP) assay of HLA-B*58:01 and evaluate its feasibility in predicting allopurinol-induced drug hypersensitivity.. Two sets of LAMP primers targeting exons 2 and 3 of HLA-B*58:01 were designed. DNA extracted from 20 clinical blood samples of patients with gout was used to evaluate the effectiveness of the two LAMP primer sets for the detection of HLA-B*58:01.. The results were compared with routine clinical genotyping methods. All extracted DNA samples tested with the HLA-B*58:01 LAMP assay showed agreement with the routine genotyping results. No amplifications were observed when unextracted blood samples were tested.. The HLA-B*58:01 LAMP assay was confirmed to be simple, rapid and specific for the detection of HLA-B*58:01, and therefore of potential value in the diagnosis of allopurinol-induced hypersensitivity.

Topics: Allopurinol; Cost-Benefit Analysis; Drug Hypersensitivity; Feasibility Studies; Gene Frequency; Genetic Predisposition to Disease; Gout Suppressants; HLA-B Antigens; Humans; Nucleic Acid Amplification Techniques; Sensitivity and Specificity

Allopurinol, an analog of hypoxanthine has been worldwide used for the treatment of hyperuricemia and gout for over 40 years. Unfortunately some patients assuming this medication have developed hypersensitivity reactions ranging from mild cutaneous eruption to more severe clinical manifestations such as allopurinol hypersensitivity syndrome or Steven-Johnson syndrome and lethal toxic epidermal necrolysis. Various strategies of slow desensitization have been elaborated to reintroduce allopurinol in a part of these patients, mainly patients affected by mild skin reactions as fixed drug eruption or exanthema. However, several new uricosuric therapies have been recently introduced. Actually drugs as recombinant urate oxidase and febuxostat are under post-marketing surveillance to control potential adverse effects related to their immunogenicity even.

Topics: Allopurinol; Animals; Desensitization, Immunologic; Drug Hypersensitivity; Febuxostat; Gout; Humans; Hyperuricemia; Product Surveillance, Postmarketing; Recombinant Proteins; Skin; Thiazoles; Urate Oxidase

Allopurinol hypersensitivity (AH) can rarely be manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) that have high mortality rates. Less serious, but still significant, skin and systemic hypersensitivity reactions form part of the AH spectrum. One hundred per cent of Han Chinese with SJS/TEN due to allopurinol have been found to be at least heterozygous for HLA-B*5801, the carriage rate for this allele in the Han Chinese population being about 15%. The association has been found to be weaker in Caucasians whose HLA-B*5801 carriage rate is less than 6%. We examined the relationship between the different skin hypersensitivity reactions to allopurinol and the HLA-B locus in Australian patients.. We examined 23 patients referred with AH.. Five of six Australian SJS/TEN patients were heterozygous for HLA-B*5801 and four were of South-East Asian origin. Five AH patients without SJS/TEN were all Caucasian and only one of these was positive for HLA-B*5801. Twelve patients with allopurinol-induced maculopapular exanthema were negative for HLA-B*5801, including one South-East Asian.. Cases of AH manifesting as SJS/TENS in Australians are more likely to be in those of Asian heritage. The place of routine testing for HLA-B*5801 prior to commencing allopurinol therapy requires further investigation. However, Han Chinese origin patients commencing allopurinol might be informed of the test and may elect to have it performed as there are alternative hypouricaemic medicines, such as probenecid thereby reducing the risk of a catastrophic reaction to allopurinol.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Asian People; Australia; Drug Hypersensitivity; Female; Genetic Predisposition to Disease; HLA Antigens; HLA-B Antigens; Humans; Male; Middle Aged; Stevens-Johnson Syndrome

Topics: Adult; Allopurinol; Antitubercular Agents; Drug Eruptions; Drug Hypersensitivity; Humans; Isoniazid; Lymphocyte Activation; Male; Patch Tests; Syndrome

Topics: Acute Kidney Injury; Allopurinol; Chemical and Drug Induced Liver Injury; Delayed Diagnosis; Drug Hypersensitivity; Female; Gout Suppressants; Humans; Middle Aged; Necrosis; Time Factors

Allopurinol is an effective urate lowering drug, which is usually well-tolerated with no adverse effects in most cases, but about 2% of the treated patients develop a skin rash, and patients may experience severe allopurinol-induced hypersensitivity syndrome.. The aim of the authors was to summarize and present the clinical manifestations of allopurinol-induced hypersensitivity in patients treated at the Department of Dermatology and Allergology, University of Szeged in order to identify potential associations with this syndrome.. Retrospective review of all patients who were referred to the department with allopurinol-induced hypersensitivity syndrome in the last four years.. During four years, 11 patients were treated with allopurinol-induced hypersensitivity syndrome. The average age was 70.3 years. Before the initiation of allopurinol therapy, 36% of patients had already suffered from various degrees of renal impairment, and 72% of them had been taking thiazide diuretics. Cutaneous manifestations were mainly generalized, erythematous, maculopapular exanthemas (9 patients, 82%), and two patients showed signs of erythema multiforme (18%). Asymptomatic hyperuricemia was the indication for allopurinol therapy in all patients.. Allopurinol-induced hypersensitivity syndrome is a severe, life-threatening disease. Administration of allopurinol should be initiated with clear indications in appropriate dose. Old age, underlying renal impairment and concomitant thiazide diuretic intake should be considered as potential risk factors for developing hypersensitivity syndrome.

Topics: Age Factors; Aged; Aged, 80 and over; Allopurinol; Dermatitis, Exfoliative; Drug Eruptions; Drug Hypersensitivity; Erythema Multiforme; Exanthema; Female; Gout Suppressants; Humans; Male; Middle Aged; Parapsoriasis; Renal Insufficiency; Retrospective Studies; Risk Factors; Sodium Chloride Symporter Inhibitors

Allopurinol is the most commonly used urate-lowering therapy in gout. Allopurinol hypersensitivity syndrome (AHS) is a rare but potentially fatal adverse event. Dosing guidelines based on creatinine clearance have been proposed based on the recognition that dosages of ≥300 mg/day may be associated with AHS, particularly in patients with renal impairment. However, the relationship between the allopurinol starting dose and AHS is unknown. This study was undertaken to determine the relationship between allopurinol dosing and AHS.. A retrospective case-control study of patients with gout who developed AHS between January 1998 and September 2010 was undertaken. For each case, 3 controls with gout who were receiving allopurinol but did not develop AHS were identified. Controls were matched with cases for sex, diuretic use at the time of initiating allopurinol, age (±10 years), and estimated glomerular filtration rate (estimated GFR). Starting dose and dose at the time of the reaction in cases were compared between cases and controls.. Fifty-four AHS cases and 157 controls were identified. There was an increase in the risk of AHS as the starting dose of allopurinol corrected for the estimated GFR increased. For the highest quintile of starting dose per estimated GFR, the odds ratio was 23.2 (P < 0.01). Receiver operating characteristic analysis indicated that 91% of AHS cases and 36% of controls received a starting dose of allopurinol of ≥1.5 mg per unit of estimated GFR (mg/ml/minute).. Our findings indicate that starting allopurinol at a dose of 1.5 mg per unit of estimated GFR may be associated with a reduced risk of AHS. In patients who tolerate allopurinol, the dose can be gradually increased to achieve the target serum urate level.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Case-Control Studies; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Glomerular Filtration Rate; Gout; Gout Suppressants; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; ROC Curve; Syndrome; Uric Acid

Drug hypersensitivity reactions are an immune-mediated reaction to otherwise innocuous antigens derived from drugs. These reactions can affect many different organs, with the skin being the commonest. Skin involvement can range in severity with hypersensitivity syndrome (or DRESS) and the blistering reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), also termed serious cutaneous adverse drug reactions, being the most severe and most feared. There is increasing evidence for the role of the immune system in the pathogenesis of these reactions, with drug-specific T cells having been identified in many patients. Until recently, very little was known about the predisposition to these reactions. However, the availability of more accurate molecular typing methods, and the ability to analyse the whole genome in an unbiased fashion, has led to some remarkable findings of the role of the HLA genes as genomic biomarkers of predisposition. The 'revolution' started with abacavir where the predisposition to hypersensitivity was linked to HLA-B*57:01, which was confirmed in a clinical trial, and where its implementation has shown to reduce the incidence of hypersensitivity in a cost-effective manner. Since then, associations have also been shown for allopurinol (HLA-B*58:01)- and carbamazepine (HLA-B*1502 and HLA-A*3101)-induced serious cutaneous adverse drug reactions. The latter is interesting since the association with HLA-B*1502 is present in certain South-Eastern Asian populations, and the predisposition is phenotype specific (only for SJS/TEN). The utility of this biomarker has been shown in a prospective cohort study performed in Taiwan. By contrast, the association with HLA-A*3101 is seen in more diverse ethnic groups, and predisposes to mild as well more severe cutaneous reactions associated with carbamazepine. It is important to note that strong HLA associations have also been shown with a number of drugs that cause liver injury including flucloxacillin, lumiracoxib, lapatinib and ximelagatran, indicating that the immune system is also important in the pathogenesis of other forms of drug-induced organ toxicity. The crucial question as to whether these HLA alleles are truly causative or acting as surrogate markers of predisposition, however, is still unclear, and will require further investigations in larger patient cohorts, through the use of bioinformatic techniques, fine mapping using next generation sequencing technologies and functional stud

Topics: Allopurinol; Anti-Bacterial Agents; Anti-HIV Agents; Anticonvulsants; Antimetabolites; Biomarkers; Carbamazepine; Chemical and Drug Induced Liver Injury; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genome-Wide Association Study; HLA Antigens; HLA-A Antigens; HLA-B Antigens; Humans; Immune System; Predictive Value of Tests; Stevens-Johnson Syndrome

Topics: Allopurinol; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Drug Hypersensitivity; Drug Interactions; Humans; Intravitreal Injections; Male; Middle Aged; Syndrome

Allopurinol hypersensitivity syndrome(AHS) is a severe form of cutaneous adverse reaction that is associated with significant morbidity and mortality. We report a case of AHS with the cutaneous manifestation of acute generalised exanthematous pustulosis(AGEP). A 47 year old gentleman, with no previous skin disease, presented with a generalized mildly pruritic erythematous rash on the trunk and all 4 limbs, with patches of superficial non-follicular pustules. Our patient fulfilled both criteria for AGEP and AHS.

Topics: Acute Generalized Exanthematous Pustulosis; Allopurinol; Drug Hypersensitivity; Gout Suppressants; Humans; Male; Middle Aged

Although allopurinol is a very effective urate-lowering drug for complicated hyperuricemia, in some patients, it can induce severe cutaneous adverse reactions (SCARs). Recent investigations suggest that HLA-B*5801 is a very strong marker for allopurinol-induced SCARs, especially in the population with a high frequency of HLA-B*5801. Korea is one of the countries with a high frequency of HLA-B*5801 which is the only subtype of HLA-B58 in the Korean population. Objective. This study was conducted to find out the incidence of allopurinol-induced hypersensitivity on patients with chronic renal insufficiency (CRI) according to HLA-B58 and the clinical implications of HLA-B58 as a risk marker for the development of allopurinol-induced hypersensitivity.. We retrospectively reviewed the medical records of patients with CRI who took allopurinol and carried out serologic human leukocyte antigen (HLA) typing for kidney transplantation between January 2003 and May 2010.. Among a total of 448 patients with CRI, 16 (3.6%) patients experienced allopurinol hypersensitivity. Nine of these patients (2.0%) were diagnosed with SCARs (two Stevens-Johnson syndrome and seven allopurinol hypersensitivity syndrome) and seven patients (1.6%) had simple maculopapular rashes. The HLA-B58 allele was present in all patients with allopurinol-induced SCARs, while the frequency of HLA-B58 was only 9.5% in allopurinol-tolerant patients (P < 0.05). The incidence of allopurinol-induced SCARs in CRI shows a wide disparity according to HLA-B58 [18% in HLA-B58 (+) versus 0% in HLA-B58 (-)]. Among patients without HLA-B58, most (98.2%) of the CRI patients were tolerant to allopurinol and only 1.8% experienced simple rashes after taking allopurinol.. In this study, the incidence of allopurinol-induced SCARs was considerably high in CRI patients with HLA-B58. This finding indicates that the presence of HLA-B58 may increase the risk of allopurinol-induced SCARs. Screening tests for HLA-B58 in CRI patients will be clinically helpful in preventing severe allopurinol hypersensitivity reactions.

Topics: Adolescent; Adult; Allopurinol; Biomarkers; Drug Hypersensitivity; Female; Follow-Up Studies; Gout Suppressants; HLA-B Antigens; Humans; Male; Middle Aged; Prognosis; Renal Insufficiency, Chronic; Republic of Korea; Retrospective Studies; Stevens-Johnson Syndrome; Young Adult

Topics: Adult; Alleles; Allopurinol; Anticonvulsants; Asian People; Carbamazepine; China; Cyclosporine; Drug Hypersensitivity; Genetic Predisposition to Disease; Genetic Testing; Gout Suppressants; HLA-B Antigens; Humans; Immunization, Passive; Immunosuppressive Agents; Keratoconjunctivitis; Male; Stevens-Johnson Syndrome; Urethritis

In some patterns of cutaneous adverse drug reactions, and depending on the culprit drug, patch testing has been helpful in confirming its cause. Its value in Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) has not been established in a large cohort of patients.. The aim of the present study is to evaluate the safety and usefulness of patch testing in DRESS.. Between January 1998 and December 2008, we studied 56 patients with DRESS induced by antiepileptic agents in 33 patients (59%), allopurinol in 19 (34%) and sulfasalazine, cotrimoxazole, tenoxicam, and amoxicillin in 1 patient each (7%).. A positive patch test reaction was observed in 18 patients (32.1%), of which 17 were with antiepileptics and 1 with tenoxicam. In the antiepileptic group, carbamazepine alone was responsible for 13 of 17 positive reactions (76.5%). Patch tests with allopurinol and its metabolite were negative in all cases attributed to this drug.. In this study, patch testing was a safe and useful method in confirming the culprit drug in DRESS induced by antiepileptic drugs, whereas it had no value in DRESS induced by allopurinol. The pathogenesis of DRESS is not yet entirely clarified, but positive patch tests suggest a drug-dependent delayed hypersensitivity mechanism.

Topics: Allopurinol; Amoxicillin; Anticonvulsants; Drug Hypersensitivity; Eosinophilia; Exanthema; Female; Humans; Male; Middle Aged; Patch Tests; Sulfasalazine; Syndrome; Trimethoprim, Sulfamethoxazole Drug Combination

The present report describes the case of a 67-year-old patient who developed an allopurinol-induced hypersensitivity syndrome (AHS) with toxic epidermal necrolysis and subsequently died of septic multiorgan failure. Considering the increasing prescription rate of allopurinol, the present case report intends to demonstrate the underestimated threat of AHS.

Topics: Aged; Allopurinol; Diagnosis, Differential; Drug Hypersensitivity; Fatal Outcome; Gout; Humans; Kidney Failure, Chronic; Male; Multiple Organ Failure; Recurrence; Stevens-Johnson Syndrome

Topics: Allopurinol; Drug Hypersensitivity; General Practice; Gout; Gout Suppressants; Guideline Adherence; Humans; Practice Patterns, Physicians'; Risk Factors; Time Factors; Treatment Failure; Uric Acid

Topics: Allopurinol; Drug Hypersensitivity; Gastritis; Gout; Gout Suppressants; Humans; Male; Middle Aged; Probenecid; Uric Acid; Uricosuric Agents

Drug-induced hypersensitivity syndrome (DIHS/DRESS) is a severe adverse systemic reaction. Reactivation of human herpesvirus (HHV) family members other than HHV-6 has been reported in patients with DIHS. Reactivation of HHV family members is generally characterized by increased serum antibody titers against the virus. By contrast, clinical symptoms caused by viral reactivation are relatively rare.. We report a case of DIHS with intractable genital ulcers from reactivation of herpes simplex virus (HSV) in accordance with reactivation of HHV-6 and cytomegalovirus (CMV).. Twenty-two days after the onset of the rash, the patient developed intractable genital ulcers that were resistant to treatment. Histological examination of the ulcers revealed necrotic degeneration in the epidermal cells, with giant cells containing inclusion bodies and marked lymphocytic infiltration in the upper dermis. Immunohistochemical staining with antibodies reactive to HSV or CMV showed that these giant cells were positive for HSV but negative for CMV.. Genital herpes is a common skin disease. However, our case was considered to be a DIHS-associated symptom, not an accidental complication, as the symptoms were severe and resistant to treatment.

Topics: Aged, 80 and over; Allopurinol; Drug Hypersensitivity; Gout Suppressants; Herpes Genitalis; Humans; Hyperuricemia; Male; Skin Ulcer; Virus Activation

Topics: Adult; Allopurinol; Amoxicillin; Anti-Bacterial Agents; Anticonvulsants; Carbamazepine; Drug Hypersensitivity; Enzyme Inhibitors; Eosinophilia; Exanthema; Humans; Male; Middle Aged

Topics: Adolescent; Adrenal Cortex Hormones; Allopurinol; Drug Hypersensitivity; Female; Histamine Antagonists; Humans

A 83-years-old Japanese woman visited our hospital, complaining of fever, erythema over the entire body and erosion on the lips after taking allopurinol for a month. Laboratory examinations showed liver dysfunction and renal failure. The histological study showed dense lymphocytic and eosinophilic perivascular infiltrations in the upper dermis at the erythematous lesion. We withdrew administration and started steroid pulse therapy. The eruption subsided after a week, but liver dysfunction was not controlled by treatment with corticosteroid (PSL 15 mg/day). She suffered from sepsis and DIC, and despite of intensive therapy, she died of the disease. We measured blood concentration of allopurinol and oxypurinol after stopping drug administration. Blood concentration of oxypurinol was high for nine days at that time. We diagnosed this case as DIHS due to allopurinol because of a significant increase of anti HHV-6 and CMV IgG titer.

Topics: Aged, 80 and over; Allopurinol; Drug Hypersensitivity; Fatal Outcome; Female; Humans; Hyperuricemia

Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Aged; Allopurinol; Angioedema; Diuretics; Drug Hypersensitivity; Exanthema; Gout; Histamine Antagonists; Humans; Hypertension; Hyperuricemia; Liver Failure, Acute; Male; Oxygen Inhalation Therapy; Renal Insufficiency

Topics: Allopurinol; Drug Hypersensitivity; Gout; Gout Suppressants; Humans; Monitoring, Physiologic; Nephrology; Risk; Treatment Outcome

Topics: Alleles; Allopurinol; Anticonvulsants; Asian People; Carbamazepine; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Gout Suppressants; HLA-B Antigens; Humans; Japan; Stevens-Johnson Syndrome; Syndrome; Virus Activation

Topics: Aged; Allopurinol; Drug Eruptions; Drug Hypersensitivity; Female; Gout Suppressants; Humans; Skin

Allopurinol is a widely-prescribed urate-lowering agent. Allopurinol hypersensitivity syndrome, a severe form of cutaneous adverse reaction, is associated with significant mortality and morbidity. The aim of this study was to document the clinical presentation of allopurinol hypersensitivity in a local population, examine the indications for urate-lowering therapy and to identify potential associations with such a syndrome.. Retrospective review was done for all patients who were referred to the dermatology unit of a tertiary hospital for allopurinol hypersensitivity syndrome over a four-year period.. Over four years, there were 28 patients with allopurinol hypersensitivity syndrome, of which there were 27 (96 percent) Chinese and one (four percent) Malay. The average age was 69 years. At baseline, 24 patients (86 percent) had renal impairment, and 21 patients (75 percent) had higher dosages of allopurinol. The cutaneous manifestation included generalised maculopapular exanthem (22 patients, 79 percent), Stevens Johnson/toxic epidermal necrolysis overlap (two patients, seven percent) and Stevens-Johnson syndrome (two patients, seven percent) and generalised exfoliative dermatitis (one patient, four percent). Mortality rate was 18 percent. Indications for allopurinol therapy were clear in ten patients (36 percent).. Allopurinol hypersensitivit y syndrome is a life-threatening cutaneous adverse reaction. Allopurinol should be initiated under clear indications with appropriate dosages. Potential associations with this syndrome include the Chinese race, the elderly, and patients with underlying renal impairment.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Drug Hypersensitivity; Female; Gout Suppressants; Humans; Male; Middle Aged; Retrospective Studies

Topics: Aged; Aged, 80 and over; Alleles; Allopurinol; Drug Eruptions; Drug Hypersensitivity; Follow-Up Studies; Gout; HLA-B Antigens; Humans; Male; Middle Aged; Risk Assessment; Sampling Studies; Stevens-Johnson Syndrome; Syndrome

Topics: Allopurinol; Drug Hypersensitivity; Drugs, Generic; Humans; Male; Middle Aged; Parapsoriasis

Allopurinol is frequently used for the treatment of hyperuricemia and gout. Sometimes, a life-threatening reaction develops, as is illustrated by the following case report. We describe a 60-year-old male patient who was treated with allopurinol because of asymptomatic hyperuricemia, and he was presented with fever, skin rash, eosinophilia, worsening renal function and vanishing bile duct syndrome. In this report, we discussed vanishing bile duct syndrome as a serious side effect of allopurinol, and we briefly reviewed the etiology, prevention, and treatment modalities for vanishing bile duct syndrome.

Topics: Allopurinol; Bile Duct Diseases; Drug Hypersensitivity; Gout Suppressants; Humans; Male; Middle Aged

A 62-year-old male was sent to the emergency room due to a high fever and generalized skin rash after taking allopurinol for 9 days. Physical examination was normal except for the generalized skin rash presenting with erythematous macules. Complete blood count showed leukocytosis with eosinophilia. Blood biochemistry showed impaired renal and hepatic function. Pathologic examination concluded that the skin rash was erythema multiforme. These findings met the diagnostic criteria for allopurinol-induced hypersensitivity syndrome (AHS). Our patient not only had the most common skin lesion but soon developed acute renal failure that required intermittent hemodialysis, despite rapid discontinuation of allopurinol and adequate hydration and steroid therapy. No other causes of acute renal failure were found. Renal impairment was the worst part of the patient's condition and he never completely recovered. AHS should be considered in the differential diagnosis of acute renal and hepatic failure in patients with evidence of allergy and recent use of allopurinol.

Topics: Acute Kidney Injury; Allopurinol; Antimetabolites; Drug Hypersensitivity; Exanthema; Humans; Hyperuricemia; Male; Middle Aged; Oliguria; Renal Dialysis; Steroids; Treatment Outcome

Topics: Allopurinol; Anti-Inflammatory Agents; Benzbromarone; Chronic Disease; Colchicine; Drug Hypersensitivity; Gout; Humans; Uric Acid; Uricosuric Agents

To report a rare case of combined hypersensitivity syndrome and pure red cell aplasia (PRCA) following allopurinol therapy.. A 43-year-old woman with underlying mesangioproliferative glomerulonephritis developed fever, generalized morbilliform rash, leukocytosis with marked eosinophilia, and hepatic dysfunction 3 weeks after starting allopurinol therapy (300 mg/day for 3 days followed by 200 mg/day) for hyperuricemia and arthritis. The clinical findings were judged to be a probable drug reaction according to the Naranjo probability scale. The drug-induced hypersensitivity syndrome (DHS) resolved after withdrawal of allopurinol and initiation of systemic corticosteroid therapy. However, there was progressive worsening of anemia with reticulocytopenia; PRCA was suspected. PRCA was judged to be a possible drug reaction according to the Naranjo probability scale. The patient refused blood transfusion and bone marrow biopsy. Recombinant human erythropoietin was initiated in addition to prednisolone 15 mg daily. Eleven days later (approximately 7 wk after allopurinol withdrawal), both the hemoglobin level and reticulocyte count began to rise. The patient consented to a bone marrow study at that time, which confirmed the presence of dysplasia involving only the erythroid lineage.. Allopurinol may induce DHS, aplastic anemia, and, in rare instances, PRCA. We report the first case of PRCA concurrent with allopurinol-induced DHS in a patient with chronic kidney disease. Discontinuation of allopurinol is the first step in the treatment of such cases. The slow recovery of PRCA might be partly attributed to her underlying chronic kidney disease.. To minimize serious DHS, proper indications for treatment and dosage adjustment should be closely observed when starting allopurinol therapy in patients with chronic kidney disease.

Topics: Adult; Allopurinol; Antimetabolites, Antineoplastic; Drug Eruptions; Drug Hypersensitivity; Female; Glomerulonephritis, Membranoproliferative; Humans; Hyperuricemia; Kidney Failure, Chronic; Red-Cell Aplasia, Pure

Topics: Aged; Aged, 80 and over; Allopurinol; Drug Hypersensitivity; Fatal Outcome; Gout; Gout Suppressants; Humans; Hyperuricemia; Male; Syndrome

Oral desensitization with allopurinol presents a problem for patients with allopurinol hypersensitivity and gout that needs to be controlled rapidly. To our knowledge, only 1 case report of intravenous (i.v.) desensitization has been previously published.. To present a case report of a patient with cutaneous reactions to allopurinol who underwent i.v. allopurinol desensitization.. Intravenous infusion of allopurinol was performed using an escalating, 19-dose protocol.. No adverse reactions were precipitated by 2 i.v., escalating dose procedures, allowing continuation of effective treatment of the patient's hyperuricemia.. This case of safe and effective desensitization with allopurinol by the i.v. route should emphasize the need for a trial of this protocol in additional patients in whom rapid desensitization would be advantageous.

Topics: Allopurinol; Cardiomyopathies; Desensitization, Immunologic; Drug Hypersensitivity; Female; Gout; Heart Transplantation; Humans; Infusions, Intravenous; Middle Aged

Minor hypersensitivity reactions to allopurinol presenting as skin rash occur in approximately 2% of patients. A more severe, albeit rare, hypersensitivity reaction with fever, eosinophilia, dermatitis, renal failure, vasculitis and hepatic dysfunction carries a mortality of up to 20%. The incidence of this severe reaction can probably be reduced by adjusting the dose of allopurinol in patients with impaired renal function. Azathioprine and mercaptopurine are metabolised by xanthine oxidase, the enzyme that is inhibited by allopurinol. Concomitant administration can result in life-threatening neutropenia unless the dose of allopurinol is reduced by approximately 75%. The uricosuric agent benzbromarone has recently been withdrawn from the market because of several cases of fulminant hepatic failure with subsequent death of the patient or liver transplantation.

Topics: Allopurinol; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Eruptions; Drug Hypersensitivity; Drug Interactions; Gout; Humans; Stevens-Johnson Syndrome; Uricosuric Agents; Vasculitis, Leukocytoclastic, Cutaneous

Allopurinol is generally considered to be a safe and well tolerated drug. We report one patient with a serious effect from allopurinol, a serious exfoliative rash and signs of allopurinol hypersensitivity syndrome. Only after considerable diagnostic delay and patient morbidity, signs and symptoms were associated with the drug. The patient recovered when the medication was withdrawn. Data from the Norwegian reporting system for side effects of drugs for the period 1973-2003 show a wide range of side effects of allopurinol and even some fatalities. The indication for treatment must be carefully considered. Impaired renal function, ampicillin and thiazide diuretics increase the risk of serious hypersensitivity reactions.

Topics: Aged; Allopurinol; Drug Eruptions; Drug Hypersensitivity; Enzyme Inhibitors; Female; Gout Suppressants; Humans

Hypersensitivity syndrome is one of the most severe forms of drug eruption, and is characterized by a severe, potentially lethal, multiorgan involvement. Recently, reactivation of human herpesvirus 6 (HHV-6) has been suggested to be involved in this syndrome, although the exact role of HHV-6 remains elusive. In addition to exanthem subitum, neurological illnesses, such as infantile febrile illness without rash and encephalitis in immunocompromised patients have been attributed to HHV-6. A 51-year-old man developed a generalized erythematous eruption during treatment with allopurinol. Prednisolone improved his condition, but after the dose of prednisolone was reduced neurological abnormalities such as mental deterioration and positive meningeal signs developed. HHV-6 DNA in his blood by PCR analysis was positive. Furthermore, we detected HHV-6 DNA in the cerebrospinal fluid. The titers of anti-HHV-6-IgG increased during the course. His neurological symptoms gradually improved and no neurological sequelae were noted. Neurological abnormalities associated with hypersensitivity syndrome are very rare. However, the detection of HHV-6 DNA in the cerebrospinal fluid strongly indicates an involvement of reactivated HHV-6 in encephalitis.

Topics: Allopurinol; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Drug Hypersensitivity; Encephalitis, Herpes Simplex; Gout Suppressants; Herpesvirus 6, Human; Humans; Male; Middle Aged; Prednisolone; Recurrence

Association of drug-induced hypersensitivity syndrome with viral infection is debated. Human herpesvirus 6 (HHV-6) reactivation has been the most frequently reported infection associated with this syndrome. However, a case of cytomegalovirus (CMV) infection was recently described associated with anticonvulsant-induced hypersensitivity syndrome. We report a case of severe allopurinol-induced hypersensitivity syndrome with pancreatitis associated with Epstein-Barr virus (EBV) infection. Active EBV infection was demonstrated in two consecutive serum samples by the presence of anti-EBV early antigen (EA) IgM antibodies and an increase in anti-EBV EA IgG antibodies, whereas no anti-EBV nuclear antigen IgG antibodies were detected. EBV DNA was detected by polymerase chain reaction (PCR) in peripheral blood mononuclear cells. Reactivation of HHV-6 was suggested only by the presence of anti-HHV-6 IgM antibodies, but HHV-6 DNA was not detected by PCR in the serum. Other viral investigations showed previous infection (CMV, rubella, measles, parvovirus B19), immunization after vaccination (hepatitis B virus), or absence of previous infection (hepatitis C virus, human immunodeficiency virus). We suggest that EBV infection may participate in some cases, as do the other herpesviruses HHV-6 or CMV, in the development of drug-induced hypersensitivity syndrome.

Topics: Adult; Allopurinol; Antimetabolites; Drug Hypersensitivity; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Herpesvirus 6, Human; Humans; Male; Pancreatitis; Roseolovirus Infections; Syndrome; Virus Activation

Stevens-Johnson syndrome (SJS) is an extreme, systemic allergic reaction with potentially morbid ocular complications. The main ocular complications include severe dry eyes, corneal scarring, symblepharon, and keratopathy.. Stevens-Johnson syndrome developed in a 69-year old man as a result of a hypersensitivity reaction to the drug allopurinol three years before his referral to our clinic. He had been treated, but was left with corneal scarring, hyperemia, and sore, chronic dry eyes, which necessitated continuous lubrication. The patient was fit with RGP sealed scleral contact lenses of high oxygen permeability, which produced a remarkable improvement of his signs and symptoms and allowed him to completely cease the use of artificial tears.. Stevens-Johnson syndrome is a serious systemic condition in which the foremost ocular complication is severe dry eyes. This report shows that it can be managed successfully with RGP sealed scleral lenses of high permeability.

Topics: Aged; Allopurinol; Contact Lenses; Drug Hypersensitivity; Dry Eye Syndromes; Enzyme Inhibitors; Gout Suppressants; Humans; Male; Prosthesis Fitting; Stevens-Johnson Syndrome

Topics: Aged; Allopurinol; Diagnosis, Differential; Drug Hypersensitivity; Gout Suppressants; Humans; Male

Allopurinol hypersensitivity syndrome is an idiosyncratic drug reaction characterised by an acute and severe multiorgan disease. It usually begins 2 to 6 weeks after starting allopurinol. The most important and critical characteristics are the presence of visceral involvement and haematological abnormalities; hepatitis, interstitial nephritis and eosinophilia are most frequently seen. However, cardiac involvement has not been previously reported.. Two previously well young Chinese men presented with fever, rash and hepatitis 3 weeks after taking allopurinol. The clinicopathological presentation was typical of allopurinol hypersensitivity syndrome.. Both men received systemic corticosteroid therapy and had full recovery. A few months later, they each had an acute myocardial infarction with a fatal outcome, despite minimal cardiac risk factors and no family history of coronary artery disease.. The immunologic process in allopurinol hypersensitivity syndrome may have caused coronary vasculitis and subsequent myocardial infarct. Alternatively, the idiosyncratic reaction may have damaged myocardium, with the resultant myocarditis masquerading as coronary artery disease. Patients with allopurinol hypersensitivity syndrome should be followed up for cardiac involvement.

Topics: Adult; Allopurinol; Drug Hypersensitivity; Fatal Outcome; Gout Suppressants; Humans; Male; Myocardial Infarction; Myocarditis; Syndrome; Vasculitis

Topics: Allopurinol; Diabetes Mellitus, Type 1; Drug Hypersensitivity; Enzyme Inhibitors; Female; Humans; Hypertension; Middle Aged; Pancreatic Diseases

Topics: Aged; Allopurinol; Diagnosis, Differential; Drug Eruptions; Drug Hypersensitivity; Gout Suppressants; Guillain-Barre Syndrome; Humans; Male; Severity of Illness Index

A 43-year-old man developed fever, skin rash, eosinophillia, and severe renal and liver dysfunction following treatment with allopurinol. The patient died after 3 months of hospitalization. Autopsy revealed systemic cytomegalovirus infection and bacteremia.

Topics: Adult; Allopurinol; Anti-Bacterial Agents; Antiviral Agents; Bacteremia; Cytomegalovirus Infections; Drug Hypersensitivity; Drug Therapy, Combination; Ganciclovir; Gout Suppressants; Humans; Kidney Failure, Chronic; Male; Skin; Skin Ulcer

Because serious adverse reactions to allopurinol have been related to a reduce creatinine clearance rate and prolonged half life of oxypurinol, it has been recommended that the dose should be adjusted according to the rate of creatinine clearance. However, in some patients with gout the dose is not sufficient to reduce serum levels of uric acid (< or =390 micromol/l) and to halt disease progression.. To determine the prevalence of adverse reactions attributable to allopurinol in patients with primary gout according to dose and creatinine clearance rate.. Data on 120 patients with gout receiving allopurinol, in whom the starting dose was adjusted according to creatinine clearance rate and later increased in some patients to control the disease, were retrospectively reviewed. Two groups were compared: group A, 52 patients receiving creatinine clearance adjusted maintenance doses of allopurinol and group B, 68 patients receiving non-adjusted higher maintenance doses of allopurinol.. During follow up 57% required higher allopurinol doses than those recommended according to their creatinine clearance rate. Only five (4%) of 120 consecutive patients developed allopurinol related adverse reactions: four minor skin reactions and one allopurinol hypersensitivity syndrome (AHS). Three of these (including the case of AHS) occurred in group A and two in group B (p=NS). The duration of allopurinol treatment was the same in both groups (group A: 2.3 (3.3) years; group B: 3.7 (4.8) years). No patient in group A, but 44% in group B had a creatinine clearance rate of <50 ml/min. None of the patients received concomitant diuretics, ampicillin, or azathioprine.. No increase was seen in the prevalence of adverse reactions to allopurinol in patients who received higher allopurinol maintenance doses than those recommended according to creatinine clearance rate.

Topics: Adult; Aged; Allopurinol; Creatinine; Drug Eruptions; Drug Hypersensitivity; Female; Gout; Gout Suppressants; Humans; Kidney; Kidney Function Tests; Male; Middle Aged; Retrospective Studies

Topics: Aged; Allopurinol; Drug Hypersensitivity; Gout Suppressants; Humans; Male; Syndrome

A 86-year-old woman with chronic renal failure was treated with allopurinol for asymptomatic hyperuricemia. After one week she developed quickly progressive exanthema, bullous eruptions, epidermolysis, fever of 39.1; C and dyspnoea at rest.. The diagnosis of an allopurinol-induced hypersensitivity syndrome with toxic epidermal necrolysis was made from the history, the typical clinical picture and a skin biopsy. Initial therapy starts with steroids. Because of a lack of clinical improvement therapy was changed to immunoglobulins. In addition, systemic analgesia and cardiocirculatory supportive therapy were given. Because of increasing somnolence and severe pain intubation and controlled artificial ventilation were initiated. Despite intensive therapy progressive multi- organ failure developed and the patient died 3 weeks after start of symptoms.. The life threatening hypersensitivity syndrome with fever, eosinophilia, hepatitis, renal failure and skin eruptions as severe as epidermal necrolysis is the most dangerous complication of therapy with allopurinol. The trigger seems to be oxipurinol, the main metabolite of allopurinol, which particularly accumulates in patients with renal failure and concomitant therapy with thiazides. There is no specific treatment of the disease. The use of allopurinol in patients with asymptomatic hyperuricaemia is not indicated in most cases. Dose adjustment according to the clearance of creatinine is mandatory.

Topics: Aged; Aged, 80 and over; Allopurinol; Antimetabolites; Drug Hypersensitivity; Fatal Outcome; Female; Humans; Stevens-Johnson Syndrome; Uric Acid

We investigated the relationship between the toxic effect of allopurinol and pyrimidine metabolism in mice. Allopurinol-induced increases in plasma transaminase levels in dinitrofluorobenzene (DNFB)-sensitized mice were not affected by uridine. In contrast, plasma creatinine and BUN tended to decrease 18 hr after the last injection of uridine. Both plasma and urinary orotidine (OD) were detected in DNFB-sensitized mice after administration of a single dose of allopurinol. In contrast, TEI-6720, a newly synthesized xanthine oxidase/xanthine dehydrogenase inhibitor, caused neither pyrimidine metabolism abnormality nor renal impairment in DNFB-sensitized mice. Also, normal mice administered high doses of allopurinol showed abnormal pyrimidine metabolism together with renal toxicity which could be ameliorated by uridine, indicating that allopurinol essentially causes pyrimidine metabolism abnormality leading to renal impairment. In DNFB-sensitized mice, allopurinol increased urinary OD excretion to an extent similar to that in normal mice administered the same dose of allopurinol. However, renal impairment by allopurinol was more striking in DNFB-sensitized mice than in normal mice. Histopathological observations showed that allopurinol induced calculus formation in the collecting tubules and papillary duct. Calculus formation was increased by DNFB and decreased by uridine. These observations indicate that the enhancement of the renal toxicity of allopurinol by DNFB-sensitization may be due to some biological interactions between DNFB and allopurinol. In humans, it is possible that there are some biological interactions which serve to enhance the toxicity of allopurinol, resulting in the development of allopurinol hypersensitivity syndrome (AHS). In contrast, TEI-6720, had no effect on pyrimidine metabolism and showed no toxic effect.

Topics: Allopurinol; Animals; Antimetabolites; Dinitrofluorobenzene; Drug Hypersensitivity; Drug Interactions; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred BALB C; Pyrimidines; Uridine

Topics: Allopurinol; Drug Hypersensitivity; Humans; Male; Middle Aged; Recurrence; Renal Insufficiency

Topics: Administration, Oral; Aged; Allopurinol; Chronic Disease; Desensitization, Immunologic; Drug Hypersensitivity; Female; Gout; Gout Suppressants; Heart Diseases; Humans; Kidney Failure, Chronic; Urea

To describe an allopurinol desensitization that failed on the first attempt but was successful on the second attempt, resulting in the management of crippling tophaceous gout.. A 64-year-old white man with a history of gouty nephropathy requiring hemodialysis developed a severe cutaneous reaction from exposure to allopurinol. The first desensitization attempt was unsuccessful, and the gouty nephropathy caused chronic cellulitus and urate microcrystal deposition on the patient's hands and feet. Continuous ambulatory peritoneal dialysis and hemodialysis were used to treat the patient's severe symptoms and increase uric acid clearance. This method, however, was ineffective. Severe tissue ischemia, requiring bilateral below-the-knee amputations, prompted the second desensitization attempt four years later. The second attempt, administered differently and with more caution, was successful and did not cause further complications.. Allopurinol is the only agent available to effectively reduce uric acid concentrations in those who are over-producers. Hypersensitivity-type reactions have been reported with its use, and desensitization is the only viable therapeutic option. Few cases of desensitization to allopurinol have been reported in the literature. This article describes a failure and a subsequent success in desensitization to allopurinol.. Although desensitization to allopurinol poses potential risks, the benefits can outweigh the risks of therapy. Desensitization requires close monitoring; if failure does occur, subsequent attempts can be successful, as this case report demonstrates.

Topics: Allopurinol; Desensitization, Immunologic; Drug Hypersensitivity; Gout; Gout Suppressants; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

Topics: Allopurinol; Drug Hypersensitivity; Gout; Gout Suppressants; Humans; Male; Middle Aged; Penicillin G; Penicillins; Risk Factors

A 76 year-old otherwise healthy man was treated with allopurinol after a single episode of gout. He developed allopurinol hypersensitivity syndrome with epidermal necrolysis, dermal vasculitis, impaired renal function, fever, gastrointestinal bleeding, and possibly pulmonary vasculitis. The outcome was lethal. Controlling allopurinol therapy according to renal function is emphasized.

Topics: Aged; Allopurinol; Drug Hypersensitivity; Fatal Outcome; Gout; Gout Suppressants; Humans; Kidney; Male; Stevens-Johnson Syndrome; Vasculitis, Leukocytoclastic, Cutaneous

Topics: Allopurinol; Desensitization, Immunologic; Drug Hypersensitivity; Gout Suppressants; Humans; Male; Middle Aged; Uric Acid

We studied purine metabolism in gouty patients from three categories: primary gout, familial juvenile hyperuricaemic nephropathy (FJHN) and partial HPRT deficiency.

Topics: Adolescent; Adult; Aged; Allopurinol; Benzbromarone; Creatinine; Drug Hypersensitivity; Gout; Gout Suppressants; Humans; Hypoxanthine Phosphoribosyltransferase; Kidney Failure, Chronic; Male; Middle Aged; Purine-Pyrimidine Metabolism, Inborn Errors; Uric Acid

We describe a 61-year-old male patient who was treated with allopurinol and developed fever, a skin rash, eosinophilia and severe renal and liver dysfunction. We discuss the allopurinol hypersensitivity syndrome as a serious complication of the use of allopurinol, and briefly review the aetiology, prevention and treatment modalities.

Topics: Acute Kidney Injury; Allopurinol; Anti-Inflammatory Agents; Diagnosis, Differential; Drug Hypersensitivity; Gout; Gout Suppressants; Humans; Male; Middle Aged; Prednisone; Syndrome

Allopurinol is a xanthine oxidase inhibitor widely used to control plasma uric acid levels. Episodes of hypersensitivity to the drug are not rare. A severe form of this with a generalized exanthem, fever and liver involvement has been termed the allopurinol hypersensitivity syndrome (AHS). Patch testing and lymphocyte stimulation testing (LST) are not helpful in confirming this sensitivity. Allopurinol works as a substrate of xanthine oxidase, and is rapidly oxidized into oxypurinol in vivo. Therefore, the biological half-life of oxypurinol is markedly longer than that of allopurinol. In addition, conspicuous pre-existing renal impairment has been noted in many AHS patients. Thus, it is possible that AHS is a manifestation of hypersensitivity to oxy-, not allopurinol. Here, we now report three cases of AHS in which there were significant lymphoproliferative reactions to oxypurinol but not allopurinol.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Cystitis; Drug Hypersensitivity; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Oxypurinol; Xanthine Oxidase

Topics: Acute Kidney Injury; Aged; Allopurinol; Drug Hypersensitivity; Erythema Multiforme; Fatal Outcome; Gout Suppressants; Humans; Male; Middle Aged

A 45-year-old man developed cerebral vasculitis associated with a systemic hypersensitivity response shortly after commencing treatment with allopurinol. The illness settled on withdrawal of the drug and no other cause was found.

Topics: Allopurinol; Cerebrovascular Disorders; Drug Hypersensitivity; Enzyme Inhibitors; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Magnetic Resonance Imaging; Male; Middle Aged; Vasculitis; Xanthine Oxidase

The authors describe a case of drug-induced cytolytic hepatitis probably secondary to hypersensitivity to allopurinol which was prescribed incorrectly for secondary hyperuricaemia during treatment with pyrazinamide. The diagnosis was reviewed in view of the late occurrence of hepatitis in relation to the onset of the antituberculous treatment, the absence of a viral aetiology and the presence of clinical manifestations, biological and histological features which were compatible with hypersensitivity to allopurinol. The authors recalled that the type of uricaemia induced by pyrazinamide is most often asymptomatic and does not require any treatment with uric acid lowering drugs. Cessation of pyrazinamide is justified in cases of symptomatic hyperuricaemia but when the indications for pyrazinamide are imperative, treatment with an eliminator of uric acid is indicated. Allopurinol is contra-indicated in association with pyrazinamide on account of its inhibitory reaction to xanthine oxidase. Xanthine oxidase decreases the level pyrazinoic acid, a metabolite of pyrazinamide, which is responsible for the inhibition of the tubular secretion of uric acid.

Topics: Adult; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Hypersensitivity; Drug Interactions; Humans; Male; Pyrazinamide; Tuberculosis, Pulmonary; Uric Acid

Topics: Acute Kidney Injury; Adult; Allopurinol; Drug Hypersensitivity; Female; Humans; Skin Diseases, Papulosquamous

Topics: Aged; Allopurinol; Drug Hypersensitivity; Fatal Outcome; Female; Gout; Humans; Kidney Failure, Chronic; Male; Middle Aged; Syndrome

Allopurinol may induce severe hypersensitivity characterized by hepatitis, interstitial nephritis, and skin rash. The mechanisms for this hypersensitivity syndrome are incompletely elucidated. Immunologic studies were performed on tissue and peripheral blood lymphocytes from a patient with allopurinol hypersensitivity. Immunohistochemistry was performed on sections of the liver biopsy utilizing monoclonal antibodies for T and B lymphocytes. Peripheral blood lymphocyte immunophenotyping by flow cytometry and peripheral blood lymphocyte stimulation studies with either allopurinol or oxypurinol measured as tritiated thymidine uptake were performed in the hypersensitive patient and compared to a group of six patients treated with allopurinol without hypersensitivity and eight normal control patients. Additional single- and dual-color immunophenotyping by flow cytometry of oxypurinol-stimulated lymphocytes was performed in the hypersensitive patient and compared to normal controls. The liver biopsy demonstrated predominantly a T lymphocyte infiltrate. The number of peripheral blood lymphocytes expressing activation antigens was significantly greater in the hypersensitive patient compared to that of both control groups. Lymphocytes from the hypersensitive patient were moderately stimulated by allopurinol and markedly stimulated by oxypurinol compared to both control groups. Oxypurinol-stimulated lymphocytes from the hypersensitive patient demonstrated enhanced expression of activation antigens compared to unstimulated lymphocytes from this patient and normal controls. These studies suggest that cell-mediated immunity directed toward allopurinol and more importantly to its oxypurinol metabolite is involved in the pathogenesis of allopurinol-induced hypersensitivity.

Topics: Acute Disease; Allopurinol; Drug Hypersensitivity; Female; Hepatitis; Humans; Immunity, Cellular; Immunophenotyping; Lymphocyte Activation; Middle Aged

Allopurinol hypersensitivity syndrome (AHS) is an infrequent but life-threatening adverse reaction of allopurinol therapy. The records of 38 patients with the allopurinol hypersensitivity syndrome evaluated at the Veterans General Hospital-Taipei were reviewed. The clinical pictures included fever, rash, leukocytosis, eosinophilia, impaired renal function and hepatocellular injury. Nine patients died (24%) and the major cause of death was infection. The use of corticosteroids increased neither survival nor mortality rate. Twenty-six percent of patients were treated with allopurinol for asymptomatic hyperuricemia, which was not an established indication of the drug, should be avoided. The most important factor of mortality was toxic epidermal necrolysis (TEN) (p < 0.001 compared with other skin lesions). As there is no way to identify the risk group of patients or to make effective treatment for AHS, the only means of minimizing the incidence of AHS is to limit the allopurinol therapy to accepted indications and to adjust the dosage for the patient's renal function.

Topics: Adrenal Cortex Hormones; Adult; Aged; Allopurinol; Antimetabolites; Drug Hypersensitivity; Enzyme Inhibitors; Female; Humans; Male; Middle Aged

An in vitro canine tibia model was used to assess the effects of 48 h of hypothermic (4 degrees C) ischemia on bone vascular resistance and on responsiveness of intraosseous blood vessels to circulating norepinephrine. Three groups of bones were studied: Group I (n = 11), 48 h hypothermic ischemia; Group II (n = 11), 48 h hypothermic ischemia with pretreatment with allopurinol and oxypurinol; and Group III (n = 10), no ischemia. Resting vascular resistance in both ischemic groups (79 and 74 mmHg/ml/min) was significantly higher (p less than 0.0001) than in the nonischemic group (22 mmHg/ml/min). Effects of norepinephrine on vascular resistance were significantly greater in both ischemic groups (p less than 0.004). In all three groups, acetylcholine infusion attenuated the increases in perfusion pressure caused by norepinephrine. This demonstrates secretion of endothelial-mediated relaxing factors (EDRF) and prostaglandin for up to 48 h of hypothermic ischemia. As no significant differences were detected between the two ischemic groups, this study failed to demonstrate any protective effect of xanthine oxidase inhibitors.

Topics: Acetylcholine; Allopurinol; Animals; Cold Temperature; Disease Models, Animal; Dogs; Drug Hypersensitivity; Ischemia; Nitric Oxide; Norepinephrine; Oxypurinol; Regional Blood Flow; Reperfusion Injury; Tibia; Vascular Resistance; Xanthine Oxidase

Sensitivity to allopurinol, which occurs in 10-15% of patients, can seriously limit the drug's use in chronic tophaceous gout. Oral allopurinol desensitization has been advocated for sensitive patients in whom use of the drug is warranted. We report the successful use of intravenous allopurinol desensitization in a patient with chronic tophaceous gout in whom oral desensitization had previously failed.

Topics: Administration, Oral; Allopurinol; Chronic Disease; Desensitization, Immunologic; Drug Hypersensitivity; Gout; Humans; Injections, Intravenous; Male; Middle Aged

Topics: Aged; Allopurinol; Catatonia; Drug Hypersensitivity; Female; Gout; Humans

Topics: Allopurinol; Drug Hypersensitivity; Humans

Monitoring of plasma oxypurinol has been proposed to prevent allopurinol side effects. An 89-year-old man developed a severe desquamative rash, fever, eosinophilia, hepatocellular injury and renal failure after allopurinol administration. Eight hours after the last dose, plasma allopurinol was undetectable and plasma oxypurinol was 50 mumol/l. This is the first case in which severe allopurinol hypersensitivity occurred despite a simultaneous plasma oxypurinol concentration within recommended levels (below 100 mumol/l).

Topics: Aged; Aged, 80 and over; Allopurinol; Chemical and Drug Induced Liver Injury; Dermatitis, Exfoliative; Drug Eruptions; Drug Hypersensitivity; Humans; Kidney Failure, Chronic; Male; Oxypurinol; Pyrimidines

Topics: Aged; Aged, 80 and over; Allopurinol; Drug Hypersensitivity; Humans; Male; Metabolism, Inborn Errors; Oxypurinol; Pyrimidines; Uric Acid

Deoxycoformycin (dCF) is a promising new antineoplastic agent in the treatment of lymphoid malignancies, particularly hairy cell leukemia (HCL). Skin toxicity in the form of a maculopapular eruption has previously been reported but has not clearly been associated with idiosyncratic reactions. We present five cases of dCF-related hypersensitivity reactions in which additional systemic manifestations indicated an allergic etiology. The value of dCF in treating lymphoid neoplasms suggests that further study of the treatment of these reactions is indicated.

Topics: Adult; Aged; Allopurinol; Antineoplastic Agents; Coformycin; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Pentostatin; Ribonucleosides; Skin

Topics: Adenocarcinoma; Aged; Allopurinol; Arteritis; Coformycin; Drug Hypersensitivity; Humans; Lung Neoplasms; Male; Necrosis; Pentostatin; Ribonucleosides

Two patients developed severe hypersensitivity reactions to allopurinol. Both patients required long-term corticosteroid therapy to control their symptoms. We make recommendations on the use of allopurinol.

Topics: Aged; Allopurinol; Drug Hypersensitivity; Female; Humans

Topics: Allopurinol; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Male; Middle Aged

A patient with coexistent Klinefelter's syndrome, systemic lupus erythematosus (SLE) and chronic tophaceous gouty arthritis developed allopurinol hypersensitivity. The drug was reinstituted by a schedule of gradually increasing doses. Gout should be considered in the differential diagnosis of patients with SLE who present with acute arthritis and/or subcutaneous nodules particularly in those with longstanding stable nephritis who are receiving diuretics for concomitant hypertension.

Topics: Adult; Allopurinol; Arthrography; Drug Hypersensitivity; Fingers; Gout; Humans; Klinefelter Syndrome; Lupus Erythematosus, Systemic; Male; Uric Acid

Topics: Allopurinol; Drug Hypersensitivity; Gout; Humans; Kidney Failure, Chronic; Kidney Glomerulus; Male; Middle Aged; Vasculitis, Leukocytoclastic, Cutaneous

Topics: Aged; Allopurinol; Desensitization, Immunologic; Drug Hypersensitivity; Female; Humans

Topics: Allopurinol; Desensitization, Immunologic; Drug Hypersensitivity; Female; Humans; Middle Aged

Topics: Aged; Allopurinol; Chronic Disease; Drug Hypersensitivity; Female; Gout; Humans; Oxypurinol; Prognosis

Topics: Adult; Allopurinol; Drug Hypersensitivity; Humans; Male

Topics: Allopurinol; Anti-Bacterial Agents; Body Temperature Regulation; Drug Hypersensitivity; Fever; Humans; Interleukin-1; Isoniazid; Methyldopa; Phenytoin; Procainamide; Quinidine

A case of misdiagnosis and therapeutic misadventure is presented. The misdiagnosis resulted from the coincidental intake of mackerel and poor history taking. The therapeutic misadventure resulted from treatment with allopurinol and thiazide, which may not have been indicated. Dietary regulations for the treatment of certain biochemical abnormalities may be more desirable than therapeutic interventions. Use of allopurinol for hyperuricemia, if indicated, should be reserved for overproducers and not undersecretors.

Topics: Allopurinol; Diagnostic Errors; Drug Hypersensitivity; Female; Food Hypersensitivity; Humans; Medical History Taking; Middle Aged; Uric Acid

Topics: Allopurinol; Drug Hypersensitivity; Female; Humans; Kidney Failure, Chronic; Middle Aged

Hepatic fibrin-ring granulomas were found in a 35-yr-old man who developed fever, myalgias, rash, eosinophilia, and abnormal liver function tests 4 wk after the beginning of allopurinol treatment. All clinical and biochemical abnormalities spontaneously resolved within 6 wk after cessation of therapy. There was no evidence for Q fever or Hodgkin's disease, which are the recognized causes of hepatic fibrin-ring granulomas. It is suggested that allopurinol hypersensitivity might be an additional cause of these peculiar granulomas.

Topics: Adult; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Fibrin; Granuloma; Humans; Liver; Liver Diseases; Male

Patients receiving allopurinol are at risk of developing the allopurinol hypersensitivity syndrome, an immunologic reaction to the drug, characterized by multiple abnormalities such as fever, rash, decreased renal function, hepatocellular injury, leukocytosis, and eosinophilia. The records of 8 patients with the allopurinol hypersensitivity syndrome evaluated at the Downstate Medical Center hospitals and an additional 72 patients described in the literature were reviewed. All were seriously ill. Three of the 8 patients at the Downstate Medical Center hospitals died as a result of allopurinol hypersensitivity; 19 of the 72 previously described patients also died from consequences of taking the drug. Only 1 of our 8 patients with allopurinol hypersensitivity was given allopurinol for an appropriate reason. Eight of the 59 previously described patients on whom there was adequate information had legitimate indications for allopurinol therapy. Severe, often fatal iatrogenic disease occurred unnecessarily in the others.

Topics: Aged; Allopurinol; Drug Hypersensitivity; Drug Prescriptions; Female; Gout; Humans; Male; Medication Errors; Middle Aged

The allopurinol hypersensitivity syndrome is a rare adverse drug reaction. It usually occurs in patients with impaired renal function or when allopurinol is prescribed with a thiazide diuretic. The recognition of the characteristic features of the syndrome is vital since early aggressive therapy is indicated. A case of allopurinol hypersensitivity, possibly the first in a black African, is reported.

Topics: Allopurinol; Dermatitis, Exfoliative; Drug Hypersensitivity; Humans; Male; Middle Aged; Multiple Myeloma

Topics: Allopurinol; Amputation, Surgical; Desensitization, Immunologic; Drug Hypersensitivity; Gout; Humans; Male; Middle Aged

When adverse reactions occur, it is important to identify the etiologic drug. We describe a case of hepatitis associated with allopurinol. A 66-year-old female was admitted for rehabilitation of a cerebral hemorrhage on September 11, 1981. Allopurinol, clofibrate, and baclofen were administered. Severe hepatitis developed on November 13. The clinical laboratory data returned to normal on November 30. Challenge tests were conducted on clofibrate, allopurinol, and baclofen. The challenge test was positive after the administration of allopurinol. Allopurinol hepatitis is most likely a hypersensitivity reaction, as is suggested by the symptoms of eosinophilia and rash. Renal dysfunction may predispose one to develop hepatitis associated with allopurinol.

Topics: Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Female; Humans; Liver Function Tests

Topics: Acute Kidney Injury; Allopurinol; Drug Eruptions; Drug Hypersensitivity; Humans

Topics: Acute Kidney Injury; Adult; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Gout; Humans; Male; Respiratory Distress Syndrome; Stevens-Johnson Syndrome

A 58-year-old Chinese woman was admitted to hospital with a presumed hypersensitivity reaction to allopurinol. Her illness was characterised by high fever, eosinophilia, exfoliative dermatitis and jaundice. She developed fulminant hepatic failure and septicemia with a fatal outcome. Clinical details are presented and the possible relationship of allopurinol hypersensitivity to renal impairment is discussed.

Topics: Allopurinol; Drug Hypersensitivity; Female; Hepatic Encephalopathy; Humans; Liver; Middle Aged

Topics: Aged; Allopurinol; Arthritis; Drug Hypersensitivity; Female; Gout; Humans; Oxypurinol; Pyrimidines; Uric Acid

Topics: Adolescent; Adult; Aged; Allopurinol; Drug Hypersensitivity; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Orchitis; Vasculitis

Topics: Allopurinol; Drug Hypersensitivity; Humans

Topics: Adult; Allopurinol; Autoantibodies; Basement Membrane; Complement C3; Drug Hypersensitivity; Glomerulonephritis; Humans; Immunoglobulin A; Male; Nephritis, Interstitial; Uveitis, Anterior; Vasculitis

Allopurinol hepatotoxicity occurred in two patients. Data from the literature suggest that allopurinol can occasionally cause liver injury, particularly in persons receiving diuretic drugs or with compromised renal function. Clinical and laboratory findings are consistent with hepatocellular injury mediated by a hypersensitivity reaction. Most patients recover when the drug is withdrawn; the possible benefits of corticosteroid treatment remain to be established.

Topics: Adrenal Cortex Hormones; Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Humans; Liver Diseases; Male; Necrosis

An in-vitro lymphocyte transformation test was performed on 252 patients, some of whom were suspected to have hypersensitivities to antibiotics, aspirin, methyldopa, allopurinol, or halothane. Overall, the proportion of patients with clinically documented drug reactions who had positive tests was higher than the corresponding proportion of patients without such reactions. When results from individual drugs were compared, however, significant differences were found only with respect to antibiotics and aspirin. Extent of lymphocytic transformation did not correlate with severity or form of hypersensitivity. A radioallergosorbent test for penicillin-binding IgG and IgE was done on plasmas of 63 patients whose lymphocytes were tested against penicillin in the lymphocytic transformation test. The radioallergosorbent test and the lymphocyte transformation test results did not correlate, but levels of penicillin-binding IgG and IgE showed significant correlation. A greater number of patients with clinical hypersensitivity to penicillin had positive results by both the lymphocyte transformation test and the radioallergosorbent test than by either test alone. The clinical relevances of these tests are discussed.

Topics: Allopurinol; Ampicillin; Anti-Bacterial Agents; Drug Hypersensitivity; Female; Halothane; Humans; Lymphocyte Activation; Male; Methyldopa; Penicillins; Radioallergosorbent Test; Radioimmunoassay

Topics: Aged; Allopurinol; Drug Hypersensitivity; Humans; Male; Middle Aged

The frequency of severe reactions to allopurinol has probably been underestimated. A retrospective study encompassing a five-year period has yielded 20 patients with severe hypersensitivity reactions to allopurinol. Patients with preexisting renal impairment or who were receiving concomitant thiazide diuretics appeared to be especially predisposed. Cutaneous reaction patterns included maculopapular eruptions, exfoliative dermatitis, and toxic epidermal necrolysis. eosinophilia was uncommon. Forty percent of the patients developed hepatic involvement and 45% had renal involvement. Hepatic and renal changes usually were reversible and were not unique to any one cutaneous reaction pattern. Three patients with renal involvement required prolonged administration of systemic steroids. Complications included sepsis, decubitus ulcers, and thromboembolism. Two patients required hyperalimentation. Sequelae included dry eyes, pigmentary disturbances, and keloids. Three patients died as a result of their reaction. It is concluded that allopurinol should be used only in select patients, and the dosage should be modified if renal disease exists.

Topics: Adult; Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Dermatitis, Exfoliative; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Kidney Diseases; Male; Middle Aged; Prednisone; Retrospective Studies; Stevens-Johnson Syndrome

Topics: Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Hypersensitivity; Humans; Kidney Diseases; Male; Middle Aged; Prednisone; Stevens-Johnson Syndrome

Hypersensitivity reactions to allopurinol, a drug commonly used in the treatment of hyperuricemia, are being reported with increasing frequency. Of thirty-eight patients reviewed herein (including seven from our hospital and thirty-one from a review of the literature), ten deaths (26%) were related to complications of allopurinol hypersensitivity. Preexisting renal disease was present in 97% of patients, and, in the majority of these, the dosage of allopurinol was not reduced despite instructions contained in the package insert for this drug. At least 78% of patients were taking a thiazide diuretic prior to starting allopurinol therapy. Over 60% of patients had received allopurinol for asymptomatic hyperuricemia. Hallmarks of this hypersensitivity syndrome include a prolonged illness initially manifested by fever, a prominent cutaneous reaction, eosinophilia, hepatic abnormalities, and acute renal failure. Other involvement such as gastrointestinal bleeding is common. The mechanism of the hypersensitivity reaction is not clear, but it may represent an immune complex disease prolonged by the persistence of a currently undefined antigen. Treatment with systemic corticosteroids, often for several months, is usually necessary for the gradual resolution of this potentially fatal syndrome.

Topics: Adult; Allopurinol; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Middle Aged; Skin

Topics: Adult; Allopurinol; Drug Hypersensitivity; Gout; Humans; Male

Topics: Acute Disease; Allopurinol; Cholangitis; Drug Hypersensitivity; Humans; Male; Middle Aged

There have been recent reports of a characteristic hypersensitivity syndrome associated with the use of allopurinol. The authors describe this syndrome, emphasizing predisposing factors and clinical features.

Topics: Adult; Aged; Allopurinol; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Syndrome; Uric Acid

Major hypersensitivity reactions to allopurinol are rare. They are characterized by systemic vasculitis associated with a grave clinical picture. 20 days after beginning treatment with allopurinol, a 70-year-old patient presented with a maculo-papular, erythemato-squamous eruption which developed into erythroderma with fever, edema, polyadenopathy, marked eosinophilia, cholostatic jaudice, and aggravation of preexisting renal insufficiency. Skin biopsy showed vasculitis with fibrinoid necrosis and a chiefly lymphocytic infiltrate suggestive of a malignant lymphoma-type process. As soon as allopurinol was discontinued, and without steroid treatment, the patient spontaneously recovered. A lymphocyte transformation test was positive for this drug. The poorly know mechanism is immunological, with formation of immune complex deposits on the endothelial cells and at the dermo-epidermal junction, fibrinoid necrosis of small vessels and cellular reaction which is lymphocytic. It is not a toxic reaction related to the dose administered, though most authors have emphasized that preexisting renal insufficiency could favor hypersensitivity to allopurinol.

Topics: Aged; Allopurinol; Drug Hypersensitivity; Humans; Lymphocyte Activation; Male; Vasculitis, Leukocytoclastic, Cutaneous

A 17-year-old boy with partial hypoxanthine-guanine phosphoribosyl transferase deficiency developed a hypersensitivity reaction to allopurinol. The reaction was manifested by the development of bizarre, atypical seizures. The patient had been neurologically normal prior to the reaction. Seizures disappeared following discontinuation of allopurinol therapy. Allopurinol apparently can cause a diffuse vasculitis involving cerebral vessels after many year of therapy, resulting in atypical seizures.

Topics: Adolescent; Allopurinol; Arteritis; Cerebral Arterial Diseases; Drug Hypersensitivity; Humans; Hypoxanthine Phosphoribosyltransferase; Male; Seizures

Topics: Adult; Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Hypersensitivity; Humans; Inflammation; Kidney Diseases; Male; Middle Aged; Vascular Diseases

Five patients developed fever, "toxaemia", severe skin reactions and eosinophilia, three to six weeks after commencing allopurinol therapy. The presenting feature in these patients was an extensive erythema, progressing to an exfoliative dermatitis, sometimes with oral mucous membrane involvement. One patient developed toxic epidermal necrolysis. The clinical course in two patients was complicated by acute renal failure which necessitated dialysis. The clinical and laboratory features support an acute hypersensitivity mechanism in these allopurinol associated reactions, in agreement with previous studies. Patients with chronic renal failure appear particularly prone to severe, potentially fatal reactions. If these patients need allopurinol, a lower dose than would be normally required should be given.

Topics: Acute Kidney Injury; Adult; Allopurinol; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Stevens-Johnson Syndrome

Topics: Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Female; Humans; Middle Aged; Necrosis; Pruritus; Uric Acid; Urticaria

Topics: Allopurinol; Drug Hypersensitivity; Female; Humans; Vasculitis, Leukocytoclastic, Cutaneous

A 25-year-old white man with gout and nephropathy and with a previous reaction to allopurinol was given a trial dose of oxypurinol. He developed malaise, a generalized erythematous reaction with edema, pruritus, and emesis; this was clinically identical to the reaction he experienced with allopurinol. When the patient's lymphocytes were exposed in vitro to oxypurinol and allopurinol, increased DNA synthesis was observed, suggesting an immunologic basis for the reaction. This patient indicates that clinical cross reactivity to allopurinol and oxypurinol does occur and may be of an immunologic basis. There is a need for additional xanthine oxidase inhibitors for such patients.

Topics: Adult; Allopurinol; Cross Reactions; Drug Eruptions; Drug Hypersensitivity; Gout; Humans; Lymphocyte Activation; Male; Oxypurinol; Pyrimidines; Skin Tests

A patient with allopurinol hypersensitivity, manifested by fever, lymphadenopathy and a severe erythematous, morbilliform, maculopapular rash was studied. On immunofluorescent staining of the patient's skin, heavy granular deposits of immunoglobulin M (IgM) were found at the dermal-epidermal junction. Transformation of the patient's lymphocytes could not be effected by a variety of combinations of allopurinol, allopurinol metabolites and serum. These data suggested that the hypersensitivity reaction caused by allopurinol had immune complex deposition as the central feature in pathogenesis. The predominance of IgM may provide a distinctive feature from the deposits generally seen in systemic and discoid lupus erythematosus.

Topics: Allopurinol; Antibodies; Basement Membrane; Diagnosis, Differential; Drug Hypersensitivity; Female; Humans; Immunoglobulin G; Immunoglobulin M; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Lymphocyte Activation; Middle Aged; Skin

Topics: Allopurinol; Desensitization, Immunologic; Drug Hypersensitivity; Gout; Humans; Kidney Failure, Chronic; Male; Middle Aged

Topics: Adult; Aged; Albuminuria; Allopurinol; Benzothiadiazines; Diuretics; Drug Hypersensitivity; Drug Interactions; Fever; Gastritis; Gastrointestinal Hemorrhage; Glomerulonephritis; Gout; Hematuria; Humans; Kidney; Male; Sodium Chloride Symporter Inhibitors

Topics: Aged; Allopurinol; Ampicillin; Anemia; Bone Marrow Cells; Bone Marrow Diseases; Bone Marrow Examination; Drug Hypersensitivity; Eosinophils; Female; Fibroblasts; Histiocytes; Humans; Lymphoid Tissue; Male; Mast Cells; Middle Aged; Plasma Cells; Procainamide

Topics: Acute Disease; Allopurinol; Arthritis; Biopsy; Dermatitis, Exfoliative; Drug Hypersensitivity; Eosinophilia; Eosinophils; Female; Gout; Humans; Liver; Male; Middle Aged; Prednisone; Pruritus; Skin; Time Factors

Topics: Adolescent; Adult; Aged; Allopurinol; Anaphylaxis; Asparaginase; Blood Coagulation Disorders; Cytarabine; Daunorubicin; Drug Hypersensitivity; Female; Fever; Gastrointestinal Hemorrhage; Hallucinations; Humans; Hyperglycemia; Injections, Intravenous; Jaundice; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Liver; Male; Mercaptopurine; Methotrexate; Middle Aged; Oral Hemorrhage; Prednisone; Thioguanine; Uremia; Vincristine; Vomiting

Topics: Allopurinol; Drug Hypersensitivity; Female; Humans; Male; Middle Aged

Topics: Aged; Allopurinol; Drug Hypersensitivity; Gout; Humans; Inflammation; Male; Pulmonary Artery; Renal Artery; Spleen; Vascular Diseases