Allopurinol
HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol.

Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, Lin YL, Lan JL, Yang LC, Hong HS, Chen MJ, Lai PC, Wu MS, Chu CY, Wang KH, Chen CH, Fann CS, Wu JY, Chen YT.

Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15743917&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol: intravenous use for prevention and treatment of hyperuricemia.

Smalley RV, Guaspari A, Haase-Statz S, Anderson SA, Cederberg D, Hohneker JA.

Synertron, Inc, Madison, WI 53705-0630, USA. rvsmalley aol.com

PURPOSE: To tabulate data obtained over a 21-year period to determine the efficacy and safety of an intravenous (IV) allopurinol preparation. PATIENTS AND METHODS: IV allopurinol was provided on a compassionate plea basis to patients of any age in whom xanthine oxidase inhibitor therapy was indicated as an adjunct to chemotherapy and for whom oral intake was restricted. Three hundred twenty-seven investigators at multiple hospitals in the United States treated 1,172 patients with IV allopurinol. The vast majority of these patients had a malignancy and were in danger of developing tumor lysis syndrome (TLS) and subsequent acute uric acid nephropathy (AUAN) and were unable to take oral allopurinol. Data referable to the time period of IV allopurinol administration were collected, collated, and analyzed retrospectively. There was no randomization. RESULTS: In patients initiating treatment for an elevated serum uric acid (SUA), the SUA normalized or improved in 87% of adult patients and normalized or improved in 95% of pediatric patients. IV allopurinol, administered prophylactically to patients at high risk of developing hyperuricemia and TLS, prevented an increase in SUA levels in 93% of adults and 92% of children. Toxicities caused by IV allopurinol were minimal and consisted of 10 instances of mild to moderate skin or allergic reactions. CONCLUSION: IV allopurinol is as efficacious and safe as oral allopurinol and will be of significant benefit to patients at risk of TLS and AUAN and unable to take oral medication.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10764437&dopt=Abstract allopurinol Zyloprim



Allopurinol
[Immunological effect of systemically administered allopurinol in experimental autoimmune uveitis]

[Article in German]

Grus FH, Augustin AJ, Sekundo W, Loeffler K.

Universitats-Augenklinik Mainz. Fgrus CSI.COM

PURPOSE: Allopurinol shows beneficial effects in the systemic treatment of lens-induced uveitis. This is believed to be due to the reduction of oxidative tissue damage via a dose-dependent free radical scavenging ability and an immunomodulating effect. The purpose of this study was to investigate the immunological effects in experimental autoimmune uveitis after systemic treatment with allopurinol (AL) and steroids (STER). METHODS: 31 male Lewis rats were immunized with crude retinal extract, Freund's Adjuvans and pertussis toxin. The rats were divided into four groups: healthy rats (BASIS, n = 3), experimental autoimmune-uveitis without therapy (EAU, n = 9), 50 mg/kg bw. allopurinol i.v. (ALSYS, n = 9), and 7.5 mg/kg bw. methylprednisolone i.v. (STSYS, n = 10). ALSYS and STSYS received five intravenous injections during the 2 weeks immunization period. The rats' sera were tested against Western Blots (WB) of electrophoretic separations of retinal proteins. Based on digital image analysis, an analysis of discriminance was performed. RESULTS: The multivariate analysis of discriminance revealed a significance difference between the WBs of ALSYS and STSYS (p < 0.01) compared to EAU without therapy. The number and intensity of peaks in WBs were strongly reduced in the ALSYS group compared to EAU. CONCLUSION: AL revealed a strong immunomodulating effect in the treatment of experimental autoimmune uveitis that is markedly stronger than that of steroids. Together with the antioxidative effect of allopurinol known from previous studies, this drug could be a new promising therapeutic approach in the treatment of uveitis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10773981&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol induces renal toxicity by impairing pyrimidine metabolism in mice.

Horiuchi H, Ota M, Nishimura S, Kaneko H, Kasahara Y, Ohta T, Komoriya K.

Pharmaceuticals Development Research Laboratories, Teijin Institute for Bio-Medical Research, Hino, Tokyo, Japan. h.horiuchi teijin.co.jp

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10823345&dopt=Abstract allopurinol Zyloprim



Allopurinol
Topical allopurinol or corticosteroids and acetylcysteine in the early treatment of experimental corneal alkali burns: a pilot study.

Sekundo W, Augustin AJ, Strempel I.

Department of Ophthalmology, Philipps University Marburg, Germany. sekundo mailer.uni-marburg.de

PURPOSE: To investigate the effect of topical allopurinol on experimental corneal burns and to compare this to established treatment modalities such as topical prednisolone and acetylcysteine. METHODS: Twenty Wistar rats were randomly assigned to four groups (n=5 each). The groups were controls (normal saline), allopurinol 0.4% eye drops, prednisolone acetate 1% eye drops and acetylcysteine 8% eyedrops. Corneal burn was induced using a 3 mm paper disc soaked in 1N NaOH for 60 seconds. Drops were instilled 6 times per day. In addition, one drop/day ofloxacine was given to prevent secondary infections. Eyes were enucleated 50 hours later and fixed in 4.5% formaldehyde. Three histological levels of each globe were stained with hematoxylin-eosin and examined by two independent masked investigators using a 0 to 4+ inflammatory score. All pair-wise multiple comparison procedures (Student-Newman-Keuls method) were applied for statistical work-up. RESULTS: All three substances significantly reduced the number of histologically visible inflammatory cells compared to the control group (p<0.05). CONCLUSIONS: In the present study, topical allopurinol was as effective as established drugs, namely steroids and acetylcysteine, in the early treatment of experimental alkali corneal burns.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12474917&dopt=Abstract allopurinol Zyloprim



Allopurinol
Flow cytometric assessment of allopurinol susceptibility in Leishmania infantum promastigote.

Kamau SW, Hurtado M, Muller-Doblies UU, Grimm F, Nunez R.

Institute of Parasitology, University of Zurich, Switzerland.

BACKGROUND: Leishmaniasis is a major tropical and subtropical parasitic disease. Sodium stibogluconate, N-methyl -D-glucamine antimoniate, amphotericin B, pentamidine, and ketoconazole are drugs used to treat this disease. Some of these drugs cause severe adverse side effects and treatment failures are common. Allopurinol, a purine analog, has been used to treat leishmaniasis, alone or combined with the previously mentioned drugs. Low cost, ease of administration (oral), and lack of toxicity make allopurinol a particularly appealing candidate. METHODS: The effect of allopurinol on Leishmania infantum (MCAN/ES/89/IPZ229/1/89, zymodeme MON1) wild-type promastigotes (wt-p229), and an altered form of these promastigotes (allo-p229) resulting from long term in vitro exposure to allopurinol, was determined by [(3)H]-thymidine incorporation assays and by diverse flow cytometric approaches. RESULTS: Allopurinol arrested the proliferative capacity of wt-p229 promastigotes, reduced the proportion of viable cells, and decreased their total protein content. In contrast, allo-p229 promastigote proliferation was only slightly decelerated and the proportion of viable cells and the protein content were not affected by the allopurinol treatment. CONCLUSIONS: The flow cytometry approach allowed us to demonstrate differences in allopurinol susceptibility of the two promastigote forms, expanding the spectrum of flow cytometry applications in studies of parasite resistance. Copyright 2000 Wiley-Liss, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10918286&dopt=Abstract allopurinol Zyloprim