Allopurinol dosing,combined with

The daily dose of allopurinol is 300-600 mg. In combination with benzbromarone, the daily allopurinol dose is reduced to 100 mg. In general, allopurinol is well tolerated. The incidence of side effects is 2-3%. Exanthems, pruritus, gastrointestinal problems, and dty mouth have been observed. In rare cases, hair loss, fever, leukopenia, toxic epidermolysis (Lyell syndrome), and hqDatic dysfunction have been reported. Allopurinol inhibits the metabolic inactivation of the cytostatic dtugs azathioprine and 6-mercaptopurine. Accordingly, the administered doses of azathioprine and 6-mercaptopurine must be reduced if allopurinol is given simultaneously. 

The daily dose of benzbromarone is 50-200 mg. In combination with allopurinol, the benzbromarone dose is reduced to 20 mg. Benzbromarone is well tolerated. Rare side effects are headaches, gastrointestinal problems, and exanthems. 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

Azathioprine can be administered both orally and intravenously. It is well absorbed orally and after its rapid conversion to 6-mercaptopurine it is inactivated by xanthine oxidase which converts 6-mercaptopurine to 6-thiouric acid. This final metabolite is then excreted in the urine. In combination with the xanthine oxidase inhibitor allopurinol dose adjustments of azathioprine are needed. Renal disease also raises 6-mercaptopurine concentrations and can make dose adjustments necessary. Azathioprine is still used in organ transplantation programs and for the management of several autoimmune diseases. Its adverse effects include nausea, vomiting, diarrhea and, more seriously, bone marrow suppression and hepatotoxicity. Azathioprine is not thought to cause fetal malformation. 

Allopurinol is indicated in recurrent gout, when at least three attacks occur per year, in blood diseases where there is spontaneous hyperuiicaemia, and during treatment of myeloproliferative disorders where cell destruction creates a high urate load. Allopurinol prevents the hyperuricaemia due to diuretics and may be combined with a uricosuric agent. The dose is usually 300 mg/d by mouth but some patients may need as much as 600 mg daily. 

It may be prepared by the interaction of hypoxanthine with phosphorus pentasulphide. Mercaptopurine is found to inhibit experimental orthoimmune encephalomyletis and thyroiditis and hence used in combination with vincristine, methortrexate and prednisone in the treatment of childhood leukemia. As such 6-MP may cause hyperuricamia but it is usually administered with allopurinol—an analogue of hypoxanthine which blocks the conversion of 6-MP to uric acid and hence the dose of 6-MP is reduced and still the desired response is obtained. 

Ansari A, Patel N, Sanderson J, O Donohue J, Duley JA, Florin TH. Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2010 31(6) 640-7. 

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... 

Combined administration of azathioprine and allopurinol may result in severe pancytopenia. The dose of Azathioprine should be reduced by two-thirds when given with allopurinol. Azathioprine rarely causes liver dysfunction, frequently manifested by an isolated rise in ALT and bilirubin. With the introduction of mycophenolate mofetil, azathioprine may be relegated to a second-line anti metabolite for the prevention of graft rejection. 

Allopurinol increases didanosine plasma concentrations and their coadministration is not recommended. Ganciclovir, tenofovir and disoproxil also increase didanosine plasma concentrations, and dose reduction is recommended. Conversely, methadone decreases didanosine plasma concentrations, and appropriate doses for the combination have not been established. Didanosine should not be administered with drugs that cause pancreatic or neurotoxicity. Ribavirin increases its risk of toxicity and should not be coadministered. 

Momeni AZ, Reiszadae MR, Aminjavaheri M. Treatment of cutaneous leishmaniasis with a combination of allopurinol and low-dose meglumine antimoniate. Int J Dermatol 2002 41(7) 441-3. 

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. 

This potent uricosuric agent is used in Europe. It is a potent and reversible inhibitor of the urate-anion exchcmger in the proximal tubule. As the micronized powder, it is effective in a single daily dose of 40-80 mg. It is effective in patients with renal insufficiency and may be useful clinically in patients who are either allergic or refractory to other drugs used for the treatment of gout. Preparations that combine allopurinol and benzbromarone lower serum uric acid levels more effectively than either drug alone, despite the fact that benzbromarone lowers plasma levels of oxypurinol, the active metabolite of allopurinol. 

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. 

The median dose of mercaptopurine in adults fell four- to fivefold after the addition of allopurinol lOOmg/day in 20 adults and children, with preferential metabolism of 6-mercaptopurine to 6-methylmercaptopurine [174 ]. Before the addition of allopurinol, six patients had mild rises in aminotransferase activities associated with high concentrations of methylmercaptopurine all subsequently had normalization with mercaptopurine dosage reduction. There were no adverse reactions, such as rash, renal failure, or pancreatitis, attributable to the combination of allopurinol and mercaptopurine. Three patients developed mild leukopenia after starting allopurinol. 

Patients with chronic gouty arthritis unresponsive to allopurinol are generally dismissed as poor compliers. This paper presents studies in a middle-aged male with a 20-year history of gout in whom allopurinol in varying doses and combinations had proved ineffective in controlling either plasma uric acid levels or the gouty arthritis. The patient was studied on two separate occasions under Metabolic Ward conditions because the initial study on low dose allopurinol had failed to reduce plasma uric acid levels -they had in fact increased. 

---