allopurinol and Hypersensitivity

Nitrogen dioxide (NO2) is an environmental air pollutant and endogenously generated oxidant that contributes to the exacerbation of respiratory disease and can function as an adjuvant to allergically sensitize to an innocuous inhaled Ag. Because uric acid has been implicated as a mediator of adjuvant activity, we sought to determine whether uric acid was elevated and participated in a mouse model of NO2-promoted allergic sensitization. We found that uric acid was increased in the airways of mice exposed to NO2 and that administration of uricase inhibited the development of OVA-driven allergic airway disease subsequent to OVA challenge, as well as the generation of OVA-specific Abs. However, uricase was itself immunogenic, inducing a uricase-specific adaptive immune response that occurred even when the enzymatic activity of uricase had been inactivated. Inhibition of the OVA-specific response was not due to the capacity of uricase to inhibit the early steps of OVA uptake or processing and presentation by dendritic cells, but occurred at a later step that blocked OVA-specific CD4(+) T cell proliferation and cytokine production. Although blocking uric acid formation by allopurinol did not affect outcomes, administration of ultra-clean human serum albumin at protein concentrations equivalent to that of uricase inhibited NO2-promoted allergic airway disease. These results indicate that, although uric acid levels are elevated in the airways of NO2-exposed mice, the powerful inhibitory effect of uricase administration on allergic sensitization is mediated more through Ag-specific immune deviation than via suppression of allergic sensitization, a mechanism to be considered in the interpretation of results from other experimental systems.

Topics: Adaptive Immunity; Allergens; Allopurinol; Animals; Antigen Presentation; Asthma; Cytokines; Disease Models, Animal; Humans; Hypersensitivity; Lung; Mice; Mice, Inbred BALB C; Nitrogen Dioxide; Ovalbumin; Serum Albumin; Th2 Cells; Urate Oxidase; Uric Acid

Allopurinol, a widely used urate-lowering agent, is a leading cause of severe cutaneous adverse reactions (SCARs), especially in patients with HLA-B*58:01. Despite its routine use for the prevention of tumor lysis-related hyperuricemia prior to chemotherapy, the risk of allopurinol-induced hypersensitivity has not been investigated in patients with hematologic malignancies. This retrospective cohort study was conducted to investigate the incidence and risk factors of allopurinol-induced hypersensitivity in patients at least 18 years of age with hematologic malignancies. We reviewed 463 patients who had ever taken allopurinol for the prevention of hyperuricemia prior to chemotherapy and had undergone serologic HLA typing as a pre-transplant evaluation from January 2000 to May 2010. Thirteen (2.8%) patients experienced maculopapular eruptions (MPE) and none experienced SCARs. Among subtypes of underlying hematologic malignancies, percentage of chronic myeloid leukemia was significantly higher in the allopurinol hypersensitivity group compared with the tolerant group (23.1% (3/13) vs. 5.9% (26/440), P = 0.044). According to HLA subtypes, the incidence of allopurinol-induced MPE was 4.0% in HLA-B58 (+) patients (2/50) and 2.7% in HLA-B58 (-) patients (11/403) but this difference was statistically insignificant. In contrast to HLA-B58, the frequencies of DR9 and DR14 were significantly higher in the allopurinol-induced MPE group compared with the allopurinol tolerant group (38.5% (5/13) vs. 13.6% (53/443), P = 0.019, and 38.5% (5/13) vs. 15.6% (41/440), P = 0.038, respectively). In conclusion, HLA-DR9 and DR14, but not HLA-B58, are associated with hypersensitivity reaction by allopurinol when administered in patients with hematologic malignancy prior to chemotherapy.

Topics: Adult; Alleles; Allopurinol; Asian People; Female; Gene Frequency; Hematologic Neoplasms; HLA-DR Serological Subtypes; Humans; Hypersensitivity; Male; Phenotype; Republic of Korea

A 56-year-old white woman was referred to our institution with a 16-month history of severe, gouty, recurrent, acute polyarthritis involving the finger joints. She also had numerous small subcutaneous tophi in her hands. The patient was intolerant to allopurinol and had mild renal insufficiency attributed to uric-acid nephrolithiasis and interstitial nephropathy.. Physical examination, laboratory testing, X-rays of the hands, feet and pelvis, CT of the pelvis, microscopic analysis of an aspirate from a finger tophus.. Tophaceous gout associated with urate nephropathy in a patient intolerant to allopurinol.. Acute polyarthritis was successfully managed by intravenous bolus methylprednisolone combined with codeine, diclofenac and low-dose colchicine. Rasburicase infusions combined with fenofibrate and sodium bicarbonate achieved to maintain serum acid uric below 360 micromol/l.

Topics: Allopurinol; Arthritis, Gouty; Diagnosis, Differential; Female; Finger Joint; Gout Suppressants; Humans; Hypersensitivity; Middle Aged; Recombinant Proteins; Severity of Illness Index; Urate Oxidase

Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol-SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol-SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol-SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) (P < 10(-7)). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-SCAR, but only in 20 (15%) of 135 tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4-9780.9); corrected P value = 4.7 x 10(-24)] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23-6665.26); corrected P value = 8.1 x 10(-18)]. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.

Topics: Aged; Aged, 80 and over; Allopurinol; Female; Gene Frequency; Genetic Predisposition to Disease; Gout Suppressants; Haplotypes; HLA-B Antigens; Humans; Hypersensitivity; Male; Middle Aged; Polymorphism, Single Nucleotide; Skin Diseases

Lodoxamide tromethamine and several other anti-allergy drugs, i.e. inhibitors of rat passive cutaneous anaphylaxis, are inhibitors of purified xanthine oxidase. Inhibition is noncompetitive with Ki's in the 1-13 micromolar range. Lodoxamide tromethamine had no effect on another flavoprotein, glucose oxidase. Other studies have shown several of these drugs are inhibitors of aldose reductase. It is speculated that the anti-allergy drugs inhibit mediator release from mast cells by blocking univalent electron transfers which are essential for release.

Topics: Aldehyde Reductase; Amino Acids; Drug Evaluation, Preclinical; Histamine H1 Antagonists; Hypersensitivity; Kinetics; Mast Cells; Nitriles; Oxamic Acid; Tromethamine; Xanthine Oxidase

Topics: Aged; Allopurinol; Antineoplastic Agents; Autoantibodies; Child; Female; Glomerulonephritis; Humans; Hypersensitivity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Kidney; Male; Nephrotic Syndrome; Purpura; Skin

Topics: Allopurinol; Animals; Biological Clocks; Cell Division; Erythrocytes; Hypersensitivity; Mice; Mononuclear Phagocyte System; Periodicity; Plasmodium; Rats