Allopurinol
The inhibitory effects of allopurinol on the production and cytotoxicity of tumor necrosis factor.

Olah T, Regely K, Mandi Y.

Department of Clinical Surgery, Albert Szent-Gyorgyi Medical University, Dom ter, Hungary.

Allopurinol, a xanthine oxidase inhibitor, impaired the cytotoxic effect of human recombinant tumor necrosis factor (TNF) against WEHI cells. Actinomycin D abolished the inhibition of cytotoxicity by allopurinol. Allopurinol also exerted an inhibitory effect on the production of TNF by human mononuclear cells stimulated by either heat-killed Staphylococcus aureus or E. coli lipopolysaccharide. It is suggested that allopurinol inhibits TNF cytotoxicity by decreasing the level of oxygen free radicals generated (among other mechanisms) by the action of xanthine oxidase. Whatever the mechanism, the fact that allopurinol counteracts the toxicity of TNF can help towards an understanding of the complex nature of TNF toxicity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7935861&dopt=Abstract allopurinol Zyloprim



Allopurinol
Compatibility of allopurinol sodium with selected drugs during simulated Y-site administration.

Trissel LA, Martinez JF.

Pharmaceutical Analysis Laboratory, University of Texas M.D. Anderson Cancer Center, Houston 77030.

The compatibility of allopurinol sodium with selected drugs during simulated Y-site injection was studied. Five-milliliter samples of allopurinol sodium 3 mg/mL in 0.9% sodium chloride injection were combined with 5-mL samples of solutions of 92 other drugs in 0.9% sodium chloride injection at clinically used concentrations at 22 degrees C (5% dextrose injection was used as the diluent for one drug, amphotericin B). Immediately after and one and four hours after the samples were combined, visual examinations were performed in fluorescent light with the unaided eye and with a high-intensity monodirectional light (Tyndall beam) to enhance the visualization of small particles and low-level turbidity. The turbidity of each drug combination was measured as well. Combinations yielding inconclusive results were subjected to particle sizing and counting. Most of the drugs tested were compatible with allopurinol sodium 3 mg/mL during the observation period. However, 34 drugs showed various incompatibilities with allopurinol sodium, including dense turbidity, particulate formation and precipitation, color change, and effervescence. Allopurinol sodium 3 mg/mL in 0.9% sodium chloride injection was compatible with 58 drugs for up to four hours at 22 degrees C; 34 drugs were not compatible with allopurinol sodium.

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Allopurinol
Xanthine oxidase inhibition reduces reactive nitrogen species production in COPD airways.

Ichinose M, Sugiura H, Yamagata S, Koarai A, Tomaki M, Ogawa H, Komaki Y, Barnes PJ, Shirato K, Hattori T.

Third Dept of Internal Medicine, Wakayama Medical University, Wakayama, Japan. masakazu wakayama-med.ac.jp

Reactive nitrogen species (RNS) have been reported to be involved in the inflammatory process in chronic obstructive pulmonary disease (COPD). However, there are no studies on the modulation of RNS in COPD. It was hypothesised that inhibition of xanthine oxidase (XO) might decrease RNS production in COPD airways through the suppression of superoxide anion production. Ten COPD and six healthy subjects participated in the study. The XO inhibitor allopurinol (300 mg x day(-1) p.o. for 4 weeks) was administered to COPD patients. RNS production in the airway was assessed by 3-nitrotyrosine immunoreactivity and enzymic activity of XO in induced sputum as well as by exhaled nitric oxide (eNO) concentration. XO activity in the airway was significantly elevated in COPD compared with healthy subjects. Allopurinol administration to COPD subjects significantly decreased XO activity and nitrotyrosine formation. In contrast, eNO concentration was significantly increased by allopurinol administration. These results suggest that oral administration of the xanthine oxidase inhibitor allopurinol reduces airway reactive nitrogen species production in chronic obstructive pulmonary disease subjects. This intervention may be useful in the future management of chronic obstructive pulmonary disease.

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Allopurinol
Effect of allopurinol on uric acid levels and brain cell membrane Na+,K(+)-ATPase activity during hypoxia in newborn piglets.

Marro PJ, McGowan JE, Razdan B, Mishra OP, Delivoria-Papadopoulos M.

Department of Pediatrics, Maine Medical Center, Portland 04102.

Oxygen-free radicals generated by xanthine oxidase during hypoxia-ischemia may result in cellular injury through harmful effects on membrane phospholipids. The present study investigated the effect of administration of allopurinol, an inhibitor of xanthine oxidase, on free-radical generation and brain cell membrane injury during hypoxia by inhibiting the breakdown of hypoxanthine to uric acid. Brain cell membrane Na+,K(+)-ATPase activity and lipid peroxidation products (conjugated dienes and fluorescent compounds) were determined as indices of brain membrane function and structure. Cerebral oxygenation was continuously monitored during hypoxia by 31P-NMR spectroscopy. Plasma and brain tissue levels of uric acid were measured to evaluate xanthine oxidase activity and purine degradation. Na+,K(+)-ATPase activity decreased significantly in both hypoxic groups; however, the allopurinol-treated hypoxic group showed a smaller decrease than the untreated hypoxic group (47.3 +/- 4.9 vs. 42.0 +/- 2.7 mumol Pi/mg protein/h, P < 0.05), respectively. Conjugated dienes increased significantly in the untreated hypoxic compared to control animals (0.070 +/- 0.045 vs. 0.004 +/- 0.006 mumol/g brain, P < 0.05), with the allopurinol-treated animals having intermediate values (0.053 +/- 0.039 mumol/g brain). Fluorescent compounds were lower in the allopurinol-treated hypoxic group compared to the untreated hypoxic group (0.79 +/- 0.19 vs. 1.06 +/- 0.60 micrograms/quinine sulfate/g brain, P < 0.05). Measurements of serum and brain tissue uric acid were significantly lower during hypoxia in the allopurinol-treated compared to the untreated group (30.3 +/- 15.6 vs. 45.7 +/- 10.6 microM (P < 0.05) and 1.69 +/- 0.97 vs. 4.27 +/- 2.37 nmol/g (P < 0.05), respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

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Allopurinol
The effect of allopurinol on the liver ultrastructure, reduced glutathione and lipid peroxide levels during liver ischemia in guinea pigs.

Durmus O, Aricioglu A, Guven T, Oguz M, Yel M, Turkozkan N.

Department of General Surgery, Faculty of Medicine, University of Gazi, Ankara, Turkiye.

1. The preventive effect of allopurinol on reduced glutathione and lipid peroxide levels of the liver and the accompanying ultrastructural changes during liver ischemia was investigated in guinea pigs. 2. Liver glutathione levels decreased significantly while lipid peroxide levels increased slightly in the ischemic group. 3. Allopurinol administered before ischemia resulted in a reverse significant increase in liver glutathione levels and a significant decrease in lipid peroxide levels indicating a protective effect upon cell membrane during ischemia. 4. On the other hand, electron microscopic changes in the liver associated with ischemia could not be altered by allopurinol.

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Allopurinol
The pharmacokinetics of injectable allopurinol in newborns with the hypoplastic left heart syndrome.

McGaurn SP, Davis LE, Krawczeniuk MM, Murphy JD, Jacobs ML, Norwood WI, Clancy RR.

Division of Neurology, Children's Hospital of Philadelphia.

OBJECTIVE. The purpose of this investigation was to determine the pharmacokinetic disposition of intravenous allopurinol and its metabolite oxypurinol in neonates with the hypoplastic left heart syndrome (HLHS) and to evaluate the subsequent degree of xanthine oxidase inhibition using serum uric acid as a marker. METHODS. Pharmacokinetic data were evaluated in 12 stable preoperative neonates with HLHS after a single intravenous allopurinol administration of 5 mg/kg or 10 mg/kg. Pharmacokinetic parameters were determined for elimination half-life, clearance, volume of distribution, and mean residence time. Xanthine oxidase inhibition, measured by serum uric acid reduction, was also measured. RESULTS. Pharmacokinetic parameters revealed no statistically significant differences between a 5-mg/kg and 10-mg/kg dose of intravenous allopurinol on elimination half-life, clearance, volume of distribution, and mean residence time. Mean serum uric acid levels were significantly reduced from baseline by 39.99 and 42.94%, respectively, in the 5- and 10-mg/kg treatment groups. DISCUSSION. The enzyme xanthine oxidase plays a key biochemical role in the generation of toxic oxygen-derived free radicals during ischemia-reperfusion conditions. Allopurinol and its active metabolite oxypurinol inhibit xanthine oxidase, and significantly reduce the conversion of hypoxanthine to xanthine and xanthine to uric acid. Cell injury may be caused by toxic oxygen free radicals produced by ischemia-reperfusion injury such as could occur during the repair of HLHS under hypothermic total circulatory arrest. We hypothesize that allopurinol may provide protection from cellular injury in this clinical context.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7970996&dopt=Abstract allopurinol Zyloprim