Allopurinol
Chronic administration of allopurinol fails to exert any cardioprotective effect in rats submitted to permanent coronary artery ligation.

Boucher F, de Leiris J.

Laboratoire de physiologie cellulaire cardiaque, URA CNRS 632, Universite Joseph Fourier, Grenoble, France.

It has been shown that allopurinol, an inhibitor of xanthine oxidase, may limit the extent of myocardial infarction in dogs. In the present work, we studied the effect of a chronic administration of allopurinol on myocardial infarct size measured histochemically 48 h after in situ left coronary artery ligation in the rat. Our results indicate that allopurinol pretreatment does not produce any limitation of the extent of necrosis, but induces a significant increase in the volume of the non-ischemic portion of the myocardium, accompanied by an increase in protein content. This phenomenon, which could be due to the development of an edema in the non-ischemic portion of the myocardium, may well explain some discrepancies reported in previous experimental studies in which the infarct size was conventionally expressed as a percentage of the total volume of ventricular tissue. We have also shown that allopurinol pretreatment failed to improve the residual cardiac function in rats after left coronary artery ligation. We conclude that the enzyme xanthine oxidase is probably not involved in the pathophysiology of myocardial infarction in the rat because of the absence of collateral vasculature in this species which prevents any oxygen supply to the ischemic zone. In most other mammals such as the dog, the existence of a collateral system maintains a residual blood flow and oxygen supply to the ischemic portion of ligated hearts, allowing the xanthine oxidase-induced production of superoxide anions to be activated, thereby initiating peroxidative lesions in membrane lipids.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1772386&dopt=Abstract allopurinol Zyloprim



Allopurinol
Kinetics of allopurinol and its metabolite oxypurinol after oral administration of allopurinol alone or associated with benzbromarone in man. Simultaneous assay of hypoxanthine and xanthine by gas chromatography-mass spectrometry.

Lartigue-Mattei C, Chabard JL, Ristori JM, Bussiere JL, Bargnoux H, Petit J, Berger JA.

Laboratoire de Chimie analytique et de spectrometrie de masse, Faculte de Pharmacie, Clermont-Ferrand, France.

Allopurinol, oxypurinol, hypoxanthine and xanthine were assayed simultaneously using a highly specific method combining gas chromatography and mass spectrometry. Two hypo-uricaemic prescriptions were compared: i) 300 mg of allopurinol (AL); and ii) 100 mg of allopurinol plus 20 mg of benzbromarone (AL + BZB). When administered acutely, their effects on blood uric acid levels were similar. Analysis of the pharmacokinetic parameters of allopurinol and its metabolite after each treatment showed dose-linearity for the metabolite but not for the drug itself. The area under the concentration time curve for allopurinol was 40.3 +/- 9.3 mumol l-1 h after AL, against 8.4 +/- 3.9 mumol-1 h after AL + BZB, while for oxypurinol it was 948.0 +/- 125.4 mumol l-1 h after AL and 285.2 +/- 77.9 mumol l-1 h after AL + BZB. The difference in dosage form may partly account for this difference, but the benzbromarone also seems to be involved. Its role on the blood uric acid lowering action of the drug association is complex. Although benzbromarone appreciably favors the elimination of oxypurinol, which should result in a weakening of its hypo-uricaemic action, this is offset by enhanced elimination of hypoxanthine and xanthine. Renal clearance of xanthine was significantly increased under AL + BZB (173.1 +/- 65.6 ml/min against 112.2 +/- 32.9 ml/min after AL). Similarly, blood xanthine levels were proportionately higher in the presence of benzbromarone. The action of the two agents may thus be synergistic and not antagonistic, a pharmacological justification for the therapeutic use of this drug association.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1778540&dopt=Abstract allopurinol Zyloprim



Allopurinol
Protective effect of allopurinol and superoxide dismutase in renal isografts in cyclosporin A-treated rats.

Heberer M, Jorgensen J, Mihatsch MJ, Marx A, Landmann J.

Department of Surgery, University of Basel, Switzerland.

Acute tubular necrosis (ATN) after renal transplantation is related to the duration of warm and cold ischemia and leads to temporary or permanent impairment of graft function. An increased incidence of ATN has been reported since the introduction of cyclosporin A. Kidney damage resulting from hypothermic storage is generated in part during reperfusion rather than during ischemia itself. Potential mediators of the reperfusion injury are oxygen-derived free radicals. Therefore, the influence of two oxygen radical antagonists, allopurinol and superoxide dismutase, was evaluated in syngeneic rat kidney transplantation with and without concurrent administration of cyclosporin A. At 15 h cold ischemia, 28-day survival increased from 8% (no treatment) to 22% (superoxide dismutase), 33% (superoxide dismutase and allopurinol), and 73% (allopurinol). Cyclosporin A cotreatment (10 mg/kg over 14 days) resulted in survival rates of 0%, 25%, 17%, and 50% for the respective treatment groups. The results of serum creatinine values and morphological evaluation of biopsies paralleled the survival rates. Cyclosporin A nephrotoxicity was evidenced by significant serum creatinine elevations throughout the 28-day period of observation. In conclusion, allopurinol significantly protects syngeneic rat kidney transplants against a critical duration of cold ischemia. Under the conditions of this experiment, allopurinol was clearly superior to superoxide dismutase treatment. Cyclosporin A nephrotoxicity was, however, not ablated by the oxygen radical antagonists employed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1780491&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol does not affect the anticonvulsant activity of carbamazepine and valproate in maximal electroshock-induced convulsions in mice.

Parada-Turska J, Czuczwar M, Kis J, Czuczwar P, Cioczek A, Luszczki J, Czuczwar SJ.

Department of Rheumatology, Medical University, Jaczewskiego 8, PL 20-090 Lublin, Poland. jturska asklepios.am.lublin.pl

Allopurinol, an inhibitor of xanthine oxidase, is indicated in the management of patients with elevated serum and urinary uric acid levels. It was also reported to be beneficial in patients with epilepsy when added to traditional antiepileptic drug. Here, we investigated the effect of allopurinol upon the electrical seizure threshold and its effect on the protective efficacy of common antiepileptic drugs, carbamazepine (CBZ) and valproate (VPA) against maximal electroshock (MES)-induced convulsions in mice. We found that allopurinol administered at doses of 5, 15 or 45 mg/kg, did not affect electrical seizure threshold. When administered acutely or for a prolonged period of time (5 times every 24 h), it did not affect anticonvulsant activity of CBZ and VPAin MES. Free plasma concentration of both anticonvulsants was not affected by allopurinol given at a dose of 45 mg/kg for 5 days. Thus, our results did not support suggestions that allopurinol can be beneficial as add-on drug in the management of epilepsy at least in patients treated with CBZ or VPA.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15047979&dopt=Abstract allopurinol Zyloprim



Allopurinol
Orotidine accumulation in human erythrocytes during allopurinol therapy: association with high urinary oxypurinol-7-riboside concentrations in renal failure and in the Lesch-Nyhan syndrome.

Simmonds HA, Reiter S, Davies PM, Cameron JS.

Purine Research Laboratory, Clinical Science Laboratories, UMDS, Guy's Hospital Medical School, London.

1. A compound identified as orotidine has been found in the erythrocytes of all subjects on allopurinol. 2. The erythrocyte orotidine concentrations were much higher in patients with renal failure or with the Lesch-Nyhan syndrome. 3. In addition, increased amounts of oxypurinol-7-riboside were excreted in the urine by both of these groups compared with control subjects or with patients with normal renal function on allopurinol. 4. A good correlation was found between urinary oxypurinol-7-riboside excretion and erythrocyte orotidine concentrations. 5. Increased erythrocyte levels of the pyrimidine-sugar UDP-glucose were also found in patients with the highest orotidine levels. 6. The combined results suggest a derangement of pyrimidine nucleotide metabolism during allopurinol therapy. We propose that erythrocyte orotidine formation results primarily from inhibition of orotidine-5'-monophosphate decarboxylase by oxypurinol-7-ribotide.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1850677&dopt=Abstract allopurinol Zyloprim



Allopurinol
Intravenous desensitization to allopurinol in a heart transplant patient with gout.

Schumacher MJ, Copeland JG.

Department of Pediatrics, University of Arizona Health Sciences Center, Tucson, Arizona 85724, USA. schumach u.arizona.edu

BACKGROUND: Oral desensitization with allopurinol presents a problem for patients with allopurinol hypersensitivity and gout that needs to be controlled rapidly. To our knowledge, only 1 case report of intravenous (i.v.) desensitization has been previously published. OBJECTIVE: To present a case report of a patient with cutaneous reactions to allopurinol who underwent i.v. allopurinol desensitization. METHODS: Intravenous infusion of allopurinol was performed using an escalating, 19-dose protocol. RESULTS: No adverse reactions were precipitated by 2 i.v., escalating dose procedures, allowing continuation of effective treatment of the patient's hyperuricemia. CONCLUSIONS: This case of safe and effective desensitization with allopurinol by the i.v. route should emphasize the need for a trial of this protocol in additional patients in whom rapid desensitization would be advantageous.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15049403&dopt=Abstract allopurinol Zyloprim