Xanthine oxidase allopurinol therapy

MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important issue because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50-75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol. 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Allopurinol and its major metabolite, oxypurinol, are xanthine oxidase inhibitors and impair the conversion of hypoxanthine to xanthine and xanthine to uric acid. Allopurinol also lowers the intracellular concentration of PRPP. Because of the long half-life of its metabolite, allopurinol can be given once daily orally. It is typically initiated at a dose of 100 mg/day and increased by 100 mg/day at 1-week intervals to achieve a serum uric acid level of 6 mg/dL or less. Serum levels can be checked about 1 week after starting therapy or modifying the dose. Although typical doses are 100 to 300 mg daily, occasionally doses of 600 to 800 mg/day are necessary. The dose should be reduced in patients with renal insufficiency (200 mg/day for CLcr 60 mL/min or less, and 100 mg/day for CLcr 30 mL/min or less). 

Allopurinol is the antihyperuricemic drug of choice in patients with a history of urinary stones or impaired renal function, in patients who have lymphoproliferative or myeloproliferative disorders and need pretreatment with a xanthine oxidase inhibitor before initiation of cytotoxic therapy to protect against acute uric acid nephropathy, and in patients with gout who are overproducers of uric acid. 

Allopurinol, a xanthine-oxidase inhibitor, may decrease tissue urate deposits in patients who are overproducers of uric acid, i.e. patients with primary hypemricaemia, in myeloproliferative neoplastic diseases and in hyperuricaemia resulting from tissue breakdown after cancer chemotherapy or radiation therapy. Allopurinol may also be recommended, in certain circumstances, in undersecre-tors of uric acid. 

Allopurinol is an xanthine oxidase inhibitor. It reduces urate production and is used in primary and secondary urate overproduction. Therapy of hyperuricemia prevents recurring attacks of acute gouty arthritis. Allopurinol dosages are 300 mg/day for serum creatinine < 1.5 mg/dl and 100 mg/day for serum creatinine between 1.6-2.0 mg/dl. Reduction of tophi is slow with allopurinol, particularly in patients with giant tophi and renal insufficiency where drug dosage is limited. 

The preferred and standard-of-care therapy for gout in the intercritical period (the period between acute episodes) is allopurinol, which reduces total uric acid body burden by inhibiting xanthine oxidase. 

Mercaptopurine is used in the treatment of acute lymphoid leukemia. Maintenance therapy makes use of both methotrexate and 6-mercaptopurine. Mercaptopurine is absorbed well from the gastrointestinal tract. It is metabolized through (1) methylation of the sulfhydryl group and subsequent oxidation, and (2) conversion to 6-thiouric acid with the aid of xanthine oxidase, which is inhibited by allopurinol. Mercaptopurine may cause hyperuricemia. Its chief toxicities are hepatic damage and bone marrow depression. 

Treatment the drug that most effectively inhibits the formation of uric acid is allopurinol, a competitive inhibitor of xanthine oxidase. Hypoxanthine and xanthine are excreted during allopurinol therapy. Allopurinol, as with guanine and hypoxanthine, can be converted to its ribonucleotide form by HGPRT. Reducing the formation of uric acid with allopurinol relieves the symptoms of gout and decreases the possibility that uric acid kidney stones will form. 

Allopurinol (4-hydroxypyrazolo [3, 4-d] pyrimidine) is an inhibitor of xanthine oxidase that was successfully introduced in the treatment of primary gout about 45 years ago [171]. Allopurinol continues to be accepted as standard therapy in the treatment of primary and secondary hyperuricemia. Adverse reactions occur in about 10% of patients treated with allopurinol and are relatively mild and self-limited [171,172]. A mild maculopapular eruption or gastrointestinal disorders are usually noted, which promptly regress with cessation of therapy. Isolated instances of allopecia [173], bone marrow depression [174], ocular lesions [175], acute cholangitis [176], various types of hepatic injuries [177,178] temporal arthritis [179], and xanthine stones [180] have been reported. Recently, LaRosa et al [180a] have reported a case of xanthine nephropathy during treatment of childhood T-cell ALL. 

Recurrences of acute gouty arthritis may be prevented with continuous low-dose daily oral colchicine or by uric acid-lowering therapy with either uricosuric agents or inhibition of xanthine oxidase with allopurinol. Combination therapy consisting of colchicine plus a uricosuric agent or allopurinol may be employed in resistant cases. The choice of treatment depends on the serum urate concentration, the amount of uric acid excreted in a 24-hour period, and the renal function stams of the patient. 

Allopurinol is the antihyperuricemic drug of choice in patients with a history of urinary stones or impaired renal function, in patients who have lymphoproliferative or myeloproliferative disorders and need pretreatment with a xanthine oxidase inhibitor before initiation of cytotoxic therapy to protect against acute uric acid nephropathy, and in patients with gout who are overproducers of uric acid. The major side effects of allopurinol are skin rash, leukopenia, occasional gastrointestinal toxicity, and increased frequency of acute gouty attacks with the initiation of therapy. An allopurinol hypersensitivity syndrome characterized by fever, eosinophilia, dermatitis, vasculitis, and renal and hepatic dysfunction is a rare side effect, but is associated with a 20% mortality rate. ... 

AUopurinol inhibits xanthine oxidase and prevents the synthesis of urate from hypoxanthine and xanthine. It is used to treat hyperuricemia in patients with gout and to prevent it in those with hematological malignancies about to undergo chemotherapy (acute tumor lysis syndrome). Even though underexcretion rather than overproduction is the underlying defect in most gout patients, allopurinol remains effective therapy. 

Allopurinol. a xanthine oxidase inhibitor, is given to control the hyperuricemia that occurs as a result of large cell kills in the successful drug therapy of malignant diseases. The antimetabolite mercaptopurine is metabolized by xanthine oxidase and, in the presence of an inhibitor of this enzyme (eg, allopurinol), toxic levels of the drug may be reached rapidly. The answer is (J). 

Drug-drug iuteractious Allopurinol Treatment with allopurinol, a xanthine oxidase inhibitor, shifts metabolism towards higher thioguanine concentrations, reduces aminotransferase activities, and improves disease activity scores. In 41 patients with adverse reactions to full-dose thiopurines (25 with non-hepatic reactions and 16 with hepatic reactions), a combination of allopurinol with reduced-dose thiopurine bypassed many adverse drug reactions [173 ]. Remissions were achieved in 32 patients with a median follow-up of 41 (range 0.5-400) weeks. Patients who did not respond to combination therapy tended to fail early with the same adverse reaction. 

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