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.
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.
Deutsches Rheuma-Forschungszentrum, Berlin, Germany.
R
R
Miesel
M
M
Zuber
D
D
Sanocka
R
R
Graetz
H
H
Kroeger
D000493:Allopurinol / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology; D001168:Arthritis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D002840:Chromates; D006801:Humans; D008163:Luminescent Measurements; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010117:Oxypurinol / Q000097:blood / Q000494:pharmacology; D010545:Peroxides; D010586:Phagocytes / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D002840:Chromates; D010545:Peroxides; D017382:Reactive Oxygen Species; C019537:potassium tetraperoxochromate; D000493:Allopurinol; D014969:Xanthine Oxidase; D010117:Oxypurinol