Allopurinol
Educational program to improve the dosage prescribing of allopurinol.

Peterson GM, Sugden JE.

Tasmanian School of Pharmacy, Faculty of Medicine and Pharmacy, University of Tasmania, Hobart.

OBJECTIVE: To perform and evaluate an educational intervention program aimed at improving the dosage prescribing of allopurinol by general practitioners and based on the application of academic detailing. DESIGN, SETTING AND PARTICIPANTS: General practitioners in southern Tasmania were sent educational material about allopurinol, high-lighting the need to adjust dosages in accordance with the renal function of the patient. Most general practitioners then discussed the rational prescribing of allopurinol directly with a visiting pharmacist. MAIN OUTCOME MEASURES: Pharmacoepidemiological data provided by a statewide database containing dispensing data from community pharmacies throughout Tasmania, and Pharmaceutical Benefits Scheme (PBS) and Repatriation Pharmaceutical Benefits Scheme (RPBS) data. The key variable was the percentage of prescriptions for allopurinol that were for the 100 mg form. RESULTS: The program's success was indicated by a statistically significant increase in the prescribing of 100 mg allopurinol in the intervention region. The database showed an increase from 14.8% to 22.1% of all prescriptions for allopurinol (P < 0.05), while PBS and RPBS data revealed an increase from 12.5% to 22.2% of all prescriptions for allopurinol dispensed under both schemes (P < 0.0001). CONCLUSIONS: A program incorporating academic detailing can modify prescribing practices within the community. A statewide pharmacoepidemiological database provides a valuable means of evaluating interventions designed to improve prescribing.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7838029&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effects of allopurinol on in vivo suppression of arthritis in mice and ex vivo modulation of phagocytic production of oxygen radicals in whole human blood.

Miesel R, Zuber M, Sanocka D, Graetz R, Kroeger H.

Deutsches Rheuma-Forschungszentrum, Berlin, Germany.

Recently, we demonstrated elevated levels of xanthine oxidase in serum of patients with various inflammatory and autoimmune rheumatic diseases. The present study reports the antiarthritic efficacy of the xanthine oxidase inhibitor and immunosuppressant allopurinol in DBA/1xB10A(4r) mice suffering from peroxochromate-induced arthritis. A profound dose-dependent suppression of arthritis was noted (P < 0.001). The ED50 was 80 +/- 14 mumol/kg/day. The arthritis index correlated positively to the phagocytic production of oxygen radicals (r2 > 0.672) and negatively to the concentrations of allopurinol (r2 = 0.915). Ex vivo, allopurinol and various conventional antirheumatic drugs were screened for the inhibition of 12-O-tetradecanoylphorbol-13-acetate-stimulated whole human blood chemiluminescence. The concentrations of antirheumatic drugs required to inhibit the chemiluminescence by 50% were compared to the therapeutic doses administered to rheumatic patients. While D-penicillamine and cis-platinum(II) increased the phagocytic generation of superoxide, nonsteroidal antiinflammatory drugs (NSAIDs), steroids, and slow-acting antirheumatic drugs (SAARDs) inhibited the whole blood chemiluminescence in a dose-dependent manner. Therapeutic doses of NSAIDs, SAARDs, or steroids inhibited the phagocytic generation of reactive oxygen species by 10-50%. In addition to well-known mechanisms of action of NSAIDs and SAARDs, our results support the hypothesis that most common anti-rheumatic drugs act also by modulating the levels of reactive oxygen species, which serve important mediator and signal transduction functions in inflammatory and autoimmune diseases. Pharmacologically safe antioxidants like allopurinol, which simultaneously modify the oxidative burst of phagocytes, inhibit xanthine oxidase, and display immunosuppressive effects may well be suited to control the consequences of chronic phagocytic hyperreactivity in rheumatic patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7843803&dopt=Abstract allopurinol Zyloprim



Allopurinol
Interaction of allopurinol and non-steroidal anti-inflammatory drugs on the carrageenan-induced rat paw edema.

Al-Arfaj AS, Mustafa AA, Alballa SR, Tuwaijri AS, Al-Dalaan AN.

Department of Medicine, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi ARabia. asarfaj ksu.edu.sa

OBJECTIVE: To find out the effect of combining allopurinol with non-steroidal anti-inflammatory drugs on carrageenan-induced rat paw edema. METHODS: The study was carried out at the College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia, over the period 1999 to 2000. Male wistar rats were randomly divided into 12-16 rats in each group. Edema was induced by subplantar injection of 0.1 ml of carrageenan (10 mg/ml) and the resulting edema volume was measured by plethysmograph, 3 hours after the injections. Saline of 0.9% (0.1 ml/100 g) was administered to the first group serving as control. The second and third groups received variable concentration of allopurinol (12.5, 25, 50 mg/kg) and tenoxicam (0.0625, 0.125, 0.25 mg/kg) 30 minutes before carrageenan injection. The fourth group received a combination of tenoxicam and allopurinol. Similar procedures were carried out with respect to diclofenac at 1.25, 2.5, 5.0 mg/kg and indomethacin at 0.25, 0.5, 1.0 mg/kg. The activities of the drugs were expressed as percentage inhibition of edema. RESULTS: Pre-treatment of the rats with the 4 drugs individually resulted in dose-dependent reduction of volume of paw edema. The combination of allopurinol and diclofenac acted synergistically to reduce edema. A similar synergistic action was obtained when allopurinol was combined with indomethacin. By contrast, tenoxicam-allopurinol combination resulted in antagonistic action and produced an effect on edema, which was less than their individual inhibitory action. CONCLUSION: Combining allopurinol with either diclofenac or indomethacin produced synergistic inhibitory action on rat's paw edema. However, tenoxicam, when combined with allopurinol, produced antagonism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12973472&dopt=Abstract allopurinol Zyloprim



Allopurinol
Allopurinol inhibits CXC chemokine expression and leukocyte adhesion in endotoxemic liver injury.

Xiang L, Klintman D, Thorlacius H.

Department of Surgery, Malmo University Hospital, Lund University, 205 02 Malmo, Sweden.

OBJECTIVE: Leukocyte activation and recruitment are rate limiting steps in endotoxemic liver injury. We investigated the effect of allopurinol on the expression of CXC chemokines and leukocyte-endothelium interactions, microvascular perfusion failure, and cellular injury and apoptosis in endotoxemic liver injury. MATERIALS AND METHODS: Mice were treated with allopurinol prior to challenge with lipopolysaccharide (LPS) + D-Galactosamine (Gal). Intravital microscopy of the liver microcirculation and analysis of liver enzymes were conducted 6 h later. RESULTS: We observed that allopurinol pre-treatment reduced the number of firmly adherent leukocytes by more than 57% in postsinusoidal venules of endotoxemic mice. Indeed, endotoxin-induced liver injury enzymes were decreased by 76% and sinusoidal perfusion failure was reversed in mice pre-treated with allopurinol. Moreover, administration of allopurinol reduced LPS-induced hepatocyte apoptosis by 56%. Notably, it was found that allopurinol significantly decreased the levels of CXC chemokines (more than 83% reduction) in livers of endotoxemic mice. CONCLUSIONS: This study shows that allopurinol markedly protects against endotoxemic liver injury and indicates that reactive oxygen species (ROS) mediate synthesis of CXC chemokines and leukocyte adhesion in the liver in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14504661&dopt=Abstract allopurinol Zyloprim



Allopurinol
Free radical scavenging and antioxidant activity of allopurinol and oxypurinol in experimental lens-induced uveitis.

Augustin AJ, Boker T, Blumenroder SH, Lutz J, Spitznas M.

University Eye Hospital, University of Bonn, Germany.

PURPOSE. In addition to the inhibition of xanthine oxidase, allopurinol is known to act, dependent on the dose, as a free radical scavenger, an antioxidant, and a "scavenger" of hypochlorous acid. This activity was investigated using a model of lens-induced uveitis. METHODS. Lipid peroxides (LPO) were determined in aqueous humor and in retinal tissue. Reduced and oxidized glutathione (GSH and GSSG) of the aqueous humor and myeloperoxidase (MPO) activity in the iris-ciliary body complex were analyzed. Allopurinol and oxypurinol concentrations were determined by high-performance liquid chromatography in aqueous humor and retinal tissue of both control eyes and eyes with uveitis. These measurements were performed 6 hours after intravenous application of allopurinol. RESULTS. In lens-induced uveitis, LPO are significantly elevated, GSH is reduced, and GSSG and MPO are increased. A xanthine oxidase inhibition dose (< 10 mg/kg body weight) of allopurinol showed no effects on oxidative tissue damage in the model used in this study. Higher doses, however, were able to reduce the oxidative damage. Allopurinol (20 mg/kg body weight) had slight effects on GSH and GSSG. All parameters improved using a dose of 50 mg/kg body weight; a dose of 100 mg/kg body weight only showed additional improvement in GSH and GSSG. There was no further change in the other parameters. Allopurinol and oxypurinol concentrations in aqueous humor and retinal tissue showed a dose dependency reaching scavenger concentrations after application of 50 mg/kg body weight of allopurinol. CONCLUSIONS. These results suggest that the xanthine oxidase mechanism plays a minor role in the oxidative tissue damage due to lens-induced uveitis. Free radicals and oxidants are generated by activated leukocytes; therefore, the effect of higher doses of allopurinol is due to its free radical scavenging and antioxidative activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7928187&dopt=Abstract allopurinol Zyloprim



Allopurinol
Moment analysis of hepatic local disposition of allopurinol and oxipurinol: metabolism kinetics from allopurinol to oxipurinol in the rat isolated perfused liver.

Yasui H, Yamaoka K, Nishimura M, Naito S, Nakagawa T.

Faculty of Pharmaceutical Sciences, Kyoto University, Japan.

Drug metabolism in the liver was examined by the rat isolated perfused liver using the single-pass bolus-input technique. The test compounds, allopurinol and its metabolite oxipurinol, were independently introduced into the liver from the portal vein, and the concentration profiles in the venous outflow were monitored and kinetically analysed by moment theory. The recovery ratios of allopurinol and oxipurinol after the individual administration of each drug were estimated to be 0.17 (+/- 0.08 s.d.) and 1.03 (+/- 0.02 s.d.), respectively. The outflow recovery ratio of oxipurinol as the metabolite after allopurinol administration was estimated to be 0.80 (+/- 0.07 s.d.). These results indicate that the combined outflow recovery of the precursor and the metabolite after allopurinol administration is almost 100% in the rat liver.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7932056&dopt=Abstract allopurinol Zyloprim