Allopurinol
Decrease of ischaemia-reperfusion related lung oedema by continuous ventilation and allopurinol in rat perfusion lung model.

Okuda M, Furuhashi K, Nakai Y, Muneyuki M.

Department of Anaesthesiology, Mie University School of Medicine, Japan.

Using isolated perfusion rat lung model, we studied the effect of continuous ventilation without perfusion and allopurinol on the development of ischaemia-reperfusion lung injury. Ischaemia was induced by stopping the perfusion. Normothermic ischaemia for 90 min without ventilation caused significant lung oedema. Continuous ventilation during ischaemia with 21% O2 decreased lung oedema significantly after 60 min of reperfusion. The same protection could be achieved by 100% N2 ventilation during 90 min of ischaemia, suggesting that xanthine oxidase (XO) is unlikely to cause the ischaemia-reperfusion lung injury. On the other hand allopurinol, XO inhibitor, equally inhibited lung oedema after 90 min of ischaemia and 60 min of reperfusion. These results indicate that mechanical movement of alveoli provides successful preservation of ischaemic lung, and allopurinol has some protective effect other than XO inhibition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8266010&dopt=Abstract allopurinol Zyloprim



Allopurinol
Simultaneous determination of allopurinol and oxipurinol in human plasma and urine by high-performance liquid chromatography.

de Vries JX, Voss A, Kutschker C, Reiter S.

Abteilung fur Klinische Pharmakologie, Medizinische Klinik der Universitat, Heidelberg, Fed. Rep. of Germany.

The uricostatic drug allopurinol (CAS 315-30-0) is used for treatment of hyperuricaemia and is mainly bio-transformed to the active metabolite oxipurinol (CAS 2465-59-0) in humans. A new assay was developed for the simultaneous determination of both compounds in plasma and urine using ultrafiltration and ion exchange purification steps for plasma and urine, respectively. Reversed-phase high-performance liquid chromatography with ultraviolet detection was applied for the separation and quantitation of both compounds. The limit of detection was 0.1 microgram/ml for both compounds in plasma and 0.2 and 0.5 microgram/ml for allopurinol and oxipurinol, respectively, in urine. Within-run and day-to-day precision of 3-5% and 5-7% was determined for plasma and 6-8% and 8-10% for urine analysis. The assays were further validated using liquid chromatography with photodiode array detection and by comparison with methods using protein precipitation as the purifying step. The high analytical recoveries, selectivity, sensitivity, accuracy and reproducibility were adequate for the measurement of both compounds in pharmacokinetic studies and for drug monitoring in patients on allopurinol therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8267672&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effect of BOF-4272 on the oxidation of allopurinol and pyrazinamide in vivo. Is xanthine dehydrogenase or aldehyde oxidase more important in oxidizing both allopurinol and pyrazinamide?

Yamamoto T, Moriwaki Y, Suda M, Nasako Y, Takahashi S, Hiroishi K, Nakano T, Hada T, Higashino K.

Third Department of Internal Medicine, Hyogo College of Medicine, Japan.

Allopurinol or pyrazinamide was administered to rats treated with BOF-4272 (a potent xanthine oxidase inhibitor) to investigate to what degree xanthine dehydrogenase participates in the oxidation of these agents. BOF-4272 markedly decreased the plasma concentration and the urinary excretion of both oxypurinol and 5-hydroxypyrazinamide. It also decreased the sum of the urinary excretion of allopurinol and oxypurinol and that of pyrazinamide and its metabolites, although it did not affect the sum of the plasma concentrations of allopurinol and oxypurinol at 105 min after administration of allopurinol or the plasma concentration of pyrazinamide during the period after the administration of pyrazinamide. These results suggested that BOF-4272 almost completely inhibited the oxidation of allopurinol and pyrazinamide and had some effect on the excretion and/or the tissue incorporation of these two compounds. Since the in vitro study demonstrated that BOF-4272 did not inhibit the activity of aldehyde oxidase, which oxidized both allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide, the results suggested that xanthine dehydrogenase was the more important enzyme in converting allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8274161&dopt=Abstract allopurinol Zyloprim



Allopurinol
Decreased 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) in patients with Lesch-Nyhan syndrome.

Imamura A, Yamanouchi H, Arima M.

Division of Child Neurology, National Center Hospital for Mental, Nervous and Muscular Disorders, Tokyo, Japan.

The coagulation abnormality in patients with Lesch-Nyhan syndrome (LNS) prompted us to examine 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), a stable metabolite of prostacyclin (PGI2). Plasma levels of 6-keto PGF1 alpha were significantly low in 4 patients with LNS, but they were elevated after discontinuation of allopurinol. Other indicators of coagulation and fibrinolysis systems did not change after the discontinuation of allopurinol. PGI2 prevents the production of superoxide which is formed after cerebral ischemia. The potential source of superoxide is xanthine oxidase which is inhibited by allopurinol. It is assumed that plasma PGI2 increased in response to formed superoxide because xanthine oxidase inhibition was abolished after discontinuation of allopurinol.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8279655&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effect of allopurinol and superoxide dismutase on indomethacin-induced gastric lesions in the rat.

Kohut A, Mojzis J.

Department of Pharmacology, Faculty of Medicine, Safarik University, Kosice, Slovak Republic.

Gastric lesions induced by indomethacin (20 mg.kg-1 i.p.) were studied in rats after a 24 hour fast. The size of the lesions was correlated with gastric vascular permeability (determined from the Evans blue concentration in the stomach tissue after its i.v administration) and with the rate of gastric emptying (determined from the phenol red concentration after its intragastric application). These changes were correlated with the prevention of gastric lesions by allopurinol (50 mg.kg-1) after a single dose or once daily for 3 days before indomethacin and by a single dose (15,000 U.kg-1) of superoxide dismutase (SOD). Indomethacin significantly increases the rate of gastric emptying concomitantly with gastric vascular permeability. The pretreatment of animals with allopurinol and SOD inhibits gastric lesions as well as gastric vascular permeability without changing gastric emptying which was increased after indomethacin administration. The inhibition of gastric lesion formation and gastric vascular permeability was more marked in rats pretreated with allopurinol for 3 days when compared with rats treated with a single dose of allopurinol only. These results support the suggestion that oxygen-derived free radicals contribute to the pathogenesis of indomethacin-induced gastric lesions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8280727&dopt=Abstract allopurinol Zyloprim



Allopurinol
Experimental visceral leishmaniasis: role of trans-aconitic acid in combined chemotherapy.

Kar S, Kar K, Bhattacharya PK, Ghosh DK.

Leishmania Group, Indian Institute of Chemical Biology, Calcutta.

We previously reported the effectiveness of trans-aconitic acid (TAA) as an antileishmanial compound. Inhibitory effects of TAA along with other antileishmanial compounds on transformation and in vitro multiplication in macrophage cultures of Leishmania donovani have been assessed. The efficacy of TAA in combined chemotherapy of experimental visceral leishmaniasis has also been evaluated along with those of commonly used antileishmanial compounds such as sodium stibogluconate, pentamidine, and allopurinol. TAA (2 mM) inhibited transformation of L. donovani amastigotes to promastigotes by 95.2%, whereas in combination with pentamidine (5 micrograms/ml), allopurinol (10 micrograms/ml), and sodium stibogluconate (50 micrograms of Sb per ml), it inhibited transformation by about 100, 99, and 98.5%, respectively. Sodium stibogluconate (20 micrograms of Sb per ml), pentamidine (2 micrograms/ml), and allopurinol (5 micrograms/ml) suppressed the amastigote burden in peritoneal macrophage cultures from BALB/c mice by 32.6, 56.1, and 46.3%, respectively. When these three drugs were used along with TAA (5 mM), the parasite loads were reduced by 100, 100, and 88.1%, respectively. TAA (5 mM) alone suppressed the amastigote burden by 59.5%. In experimental visceral leishmaniasis in hamsters (1-month model), TAA at a dose of 200 mg/kg of body weight per day suppressed the spleen parasite load by 73.5%, and TAA in combination with sodium stibogluconate (50 mg of Sb per kg per day), pentamidine (8 mg/kg/day), and allopurinol (15 mg/kg/day) inhibited the spleen parasite load by 98, 98.9, and 97%, respectively. Individually, these three drugs inhibited the parasite load by 35, 20, and 22%, respectively. TAA (400 mg/kg/day) inhibited the spleen parasite load by 99.8%, but an inhibitory effect of approximately 100% was noted when TAA was supplemented with an antileishmanial drug. TAA was administered in experimental animals through oral, intraperitoneal, and intramuscular routes; the intramuscular route was most effective.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8285634&dopt=Abstract allopurinol Zyloprim