Allopurinol
Remark on utility and error rates of the allopurinol test in detecting mild ornithine transcarbamylase deficiency.

Oexle K, Bonafe L, Steinmann B.

Division of Metabolism and Molecular Pediatrics, University Children's Hospital, Zurich, Switzerland. konrad.oexle kispi.unizh.ch

Carriers of X-linked ornithine transcarbamylase deficiency (OTCD) are themselves mildly affected. The allopurinol test is quite sensitive (92.7%) and very specific in detecting these carriers. Consequently, it has also been recommended for the diagnosis of mild OTCD in the general population. However, there is a controversy on its utility since OTCD could not be demonstrated in several patients with positive test results but negative family histories. We show that this controversy is due to an improper use of statistical concepts, i.e., to the postulate of a specificity of "100%," and to the confusion of specificity with type I error rate. Spontaneous orotic aciduria implies a positive allopurinol test and limits the specificity of the test to a maximum of 99.7%. Therefore, according to Bayes' theorem, almost all positive test results in the general population must turn out to be type I errors, due to the minute prevalence (1/32,000) of mild OTCD (i.e., asymptomatic carriers and male patients with inapparent disease). Family history seems to be the only preselective parameter that can sufficiently raise the prevalence in the group to be tested. Bayesian analysis also yields the rate of type II errors (OTCD inspite of a negative test) which is high in closely related at-risk females (22.6% in mothers of male patients) but minimal in the general population. Conclusion. The allopurinol test is useful for the exclusion but not for the diagnosis of inapparent OTCD in sporadic individuals. Test results in possible carriers should be interpreted with caution.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12175784&dopt=Abstract allopurinol Zyloprim



Allopurinol
Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase 2 and CYP1A2 activities.

Fuchs P, Haefeli WE, Ledermann HR, Wenk M.

University of Basel, Switzerland.

OBJECTIVES: To evaluate the in vivo effect of xanthine oxidase (XO) inhibition by allopurinol on the determination of polymorphic N-acetyltransferase 2 (NAT2) and cytochrome P450 1A2 (CYP1A2) with urinary caffeine metabolic ratios. METHODS: In an open, prospective study involving 21 healthy subjects (eight fast, 13 slow NAT2 acetylators) allopurinol (300 mg perday) was administered orally on trial days 1-8, followed by a wash-out period of 8 days. Urinary caffeine tests (200 mg caffeine p.o.) were performed repetitively. Urine was collected for 8 h and venous blood samples for the determination of allopurinol, oxypurinol and uric acid were drawn. The urinary caffeine metabolites 1-methyluric acid (1MU), 1-methylxanthine (1MX), 1,7-dimethyluric acid (17MU), 1,7-dimethylxanthine (17MX), 5-acetylamino-6-formylamino-3-methyluracil (AFMU), plasma allopurinol and oxypurinol were analysed using high-performance liquid chromatography (HPLC). RESULTS: During XO inhibition by allopurinol, the formation of 1MU from 1MX and therefore the XO ratio 1MU/1MX decreased to 15.9 (1.2)% [mean with (SEM)] of baseline values (P < 0.005). The NAT2 ratio AFMU/1MX decreased likewise to 56.7 (6.3)% (P < 0.005). AFMU/(AFMU + 1MX + 1MU), an alternative NAT2 ratio, remained constant, but the CYP1A2 ratio (AFMU + 1MX + 1MU)/17MU, used to express CYP1A2 activity, transiently increased to 167 (13)% (P < 0.005). The NAT2 phenotype did not influence CYP1A2 and XO ratios or plasma oxypurinol pharmacokinetics. CONCLUSIONS: Several caffeine metabolic ratios are commonly used to express the activities of NAT2, CYP1A2 and XO both in healthy volunteers and in polymedicated patients, although their reliability has not been evaluated thoroughly during concurrent drug administration. The findings of this study suggest that NAT2 phenotyping should be performed using the ratio AFMU/(AFMU + 1MX + 1MU) if an XO inhibitor may be present. It also shows that the determination of CYP1A2 activity with caffeine as a metabolic probe is considerably altered under these conditions. Thus, concomitant drug administration may impair the robustness of multiple pathways of the complex caffeine test. This points to the need for alternative probes, designed to assess only the activity of a single enzyme because, in contrast to healthy volunteers, in patients known or unknown drug interactions may often be present.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10027663&dopt=Abstract allopurinol Zyloprim



Allopurinol
[Suppression of experimental autoimmune uveoretinitis with a combination of cyclosporin and allopurinol]

[Article in Japanese]

Matuura G, Goto H, Kezuka T, Yamakawa N, Usui M.

Department of Ophthalmology, Tokyo Medical College, Japan.

PURPOSE: We assessed the suppressive effect of a combination of cyclosporin (an immunosuppressive agent) and allopurinol (a xanthine oxidase inhibitor and radical scavenger) on experimental autoimmune uveoretinitis (EAU) in Lewis rats, induced by interphotoreceptor retinoid-binding protein (IRBP). METHODS: After the immunization of Lewis rats with 30 micrograms of IRBP. We administrated cyclosporin and/or allopurinol to the IRBP-immunized Lewis rats. We observed the incidence and the severity of EAU. Histological, immunological, and biochemical examinations were performal 13 days after the immunization. The suppressive effect of these drugs in vitro on the production of free radicals derived from polymorphonuclear leukocytes. RESULTS: The incidence of EAU was suppressed by 50% at 13 days after immunization, and in terms of clinical and histological findings, inflammatory reaction was more inhibited by the combination of these drugs than by either cyclosporin or allopurinol alone. Lymphocyte proliferation assay against IRBP was significantly inhibited by the combination of drugs. No adverse systemic effects were identified. Cyclosporin and allopurinol inhibited radical production both separately and in combination. CONCLUSION: This suggests that suppression of EAU is based not only on inhibited cell-mediated immunity but also on inhibited production of free radicals derived from polymorphonuclear leukocytes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10036921&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effect of allopurinol in the course of adriamycin induced nephropathy.

Carvalho MF, Viero RM, Soares VA.

Department of Internal Medicine, Botucatu Medical School-UNESP, SP, Brazil.

The role of superoxide in adriamycin-induced nephropathy (single dose; i.v. 3 mg/kg) has been studied by blocking superoxide synthesis through the administration of allopurinol (500 mg/L in drinking water). In Experiment I (EI), allopurinol administration was started 3 days prior to nephropathy induction and continued until day 14. In Experiment II (EII) allopurinol administration was started 2 weeks after nephropathy induction and was maintained until the end of the experiment (26 weeks). Affected glomeruli frequency and tubulointerstitial lesion index (TILI) were determined at Weeks 2 and 4 (EI) and Week 26 (EII). In EI, the 24 h mean proteinuria in the nephrotic control group (NCG-I) differed from that of the treated nephrotic group (TNG-I) at Week 1 (TNG = 33.3 +/- 6.39 mg/24 h; NCG = 59.8 +/- 6.3 mg/24 h; p < 0.05) and 2 (NCG-I = 80.0 +/- 17.5 mg/24 h; TNG-I = 49.1 +/- 8.4 mg/24 h; p < 0.05). No glomerular alterations were observed and TILI medians were not different in both nephrotic groups at week 2 (NCG-I = 1+: TNG = 1+) and 4 (NCG = 4+; TNG = 4+). In EII, NCG-II and TNG-II presented different 24 h proteinuria values only at Week 6, (136.91 +/- 22.23 mg/24 h and 72.66 +/- 10.72 mg/24 h, respectively; p < 0.05). Between nephrotic groups, there was no statistical difference in the median of affected glomeruli (CNG-II = 56%; TNG-II = 48%) and TILI (NCG-II = 8+; TNG-II = 9+). Thus, allopurinol was associated with a transient reduction in proteinuria and it did not alter the progression of the nephropathy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10088175&dopt=Abstract allopurinol Zyloprim



Allopurinol
Observations and effects of educational consults on allopurinol prescribing.

Devlin JW, Bellamy N, Bayliff CD.

Victoria Hospital, London, Ontario.

Allopurinol has been used in the management of hyperuricemic states for several years. Despite its efficacy for these indications, recent concerns have been raised regarding the unnecessary morbidity and mortality occasionally associated with its inappropriate use. In an effort to assess the utilization of allopurinol, a concurrent drug utilization review was undertaken. Fifty patients who were prescribed allopurinol were entered into the study and underwent health record review and patient interview, to determine appropriateness of therapy and the need for educational intervention. A number of inconsistencies with regard to established guidelines were identified. As well, 11 of 50 patients (22%) required intervention because of either lack of indication or excessive dose. Fifty-five percent of the educational interventions, performed by the pharmacist, were accepted as written. The current utilization of allopurinol at our facility differs substantially from guidelines developed for optimal utilization of allopurinol. Further, a pharmacy based intervention program can improve prescribing practices of allopurinol.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10117359&dopt=Abstract allopurinol Zyloprim



Allopurinol
Determination of 6-thioguanine and 6-methylmercaptopurine metabolites in renal transplantation recipients and patients with glomerulonephritis treated with azathioprine.

Chrzanowska M, Krzymanski M.

Department of Physical Chemistry, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.

The metabolism of azathioprine (AZA) was studied by monitoring the concentrations of red blood cell (RBC) 6-thioguanine nucleotides (6-TGN) and of 6-methylmercaptopurine metabolites (6-mMP) in 27 renal transplantation recipients and in 10 patient subjects with glomerulonephritis (GN). Concentrations of 6-TGNs and 6-mMP metabolites were measured using high-performance liquid chromatography (HPLC). Six patients from the group of renal transplantation recipients were also administered allopurinol. Median values of RBC 6-TGN and of 6-mMP metabolites concentrations in 21 renal transplantation recipients (without allopurinol) were 122 pmol/8x10(8) RBCs (range, <60-298) and 280 pmol/8x10(8) RBC (range, <150-1330), respectively; there was no correlation between concentrations of 6-TGN and of 6-mMP metabolites. The group of 21 renal transplantation recipients received different AZA doses (100 or 50 mg/d) related to clinical symptoms of AZA intolerance. The median values of 6-TGN concentrations in these subgroups were 131 and 122 pmol/8x10(8) RBCs and were not significantly different. Median values of 6-TGN concentrations in patients given allopurinol were significantly higher, despite AZA dose reduction, compared with the group without allopurinol and were equal to 363 and 122 pmol/8x10(8) RBC, p < 0.004, respectively. No significant differences were found between the concentrations of 6-mMP metabolites in either group. In the group of renal transplantation recipients, a significant correlation between white blood cell (WBC) count and 6-TGN concentration was established (r(s) = -0.59, p < 0.005). In the group of GN patients, the median values of 6-TGN and of 6-mMP metabolites concentrations were 108 pmol/8x10(8) RBCs (range, 0-297) and 420 pmol/8x10(8) RBC (range, 0-1440), respectively. There were no significant correlations between either the WBC count and 6-TGN concentrations or between 6-TGN concentrations and 6-mMP metabolites. We expect the results of our study to provide indications for better individualization of AZA therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10217345&dopt=Abstract allopurinol Zyloprim