Bioavailability of superoxide dismutase: implications for the anti-inflammatory action mechanism of orgotein
Huber, W.; Menander-Huber, K.B.; Saifer, M.G.; Williams, L.D.
Agents and Actions. Supplements 7: 185-195
1980
ISSN/ISBN: 0379-0363 PMID: 6454334 Document Number: 5037
Oxygen-derived radicals can act as potent promoters of inflammation. Phagocytosing cells produce copious amounts of superoxide anion (Oi) at inflammatory sites, which when unchecked by superoxide dismutase (SOD), can damage adjacent tissues or cells. Lysis in situ releases lysosomal inflammants adding to the inflammatory stimulus of the oxygen-derived radicals. We have shown previously that orgotein, the drug version of bovine Cu- Zn SOD, when administered systemically (s.c., i.m., i.v., i.p.), is an effective, slowacting, non-analgesic, pure anti-inflammatory drug. Pharmacokinetic and bioavailability studies in animals and man show that after systemic administration, SOD concentrations in serum were dose but not species-related with mean peak levels of 1.0 mcg/ml/mg/kg, seen between 3-6 h. The anti-inflammatory effect of orgotein in animal models as well as in man was found in blind tests to last much longer than the dwell time of native SOD activity as derived from the bioavailability data. For example, orgotein administered systemically at 0.6 mg/kg, 17-20 h before inflammant administration gave>45% and>40% inhibition (2p<.01) in the reverse Arthus skin edema and the Carrageenan foot paw edema models respectively. As orgotein efficacy in these animal models clearly remains long after demonstrable enzyme activity has disappeared from plasma and tissues, it appears that action mechanisms other than, or in addition to, circulating, intact SOD activity appear to be responsible for the prolonged efficacy. Membrane stabilization of phagocytosing and/or tissue cells either by interaction with receptors or inhibition of lipid peroxidation, or both, are possible candidates. In patients with active rheumatoid arthritis, when used therapeutically, orgotein injections three times per week at 0.13 mg/kg gave significant improvement at the end of 3 months. In osteoarthritis statistically and clinically significant improvements were obtained with one 4 mg intra-articular (knee) injection per week for eight times. In both diseases the beneficial effects lasted for many weeks beyond the cessation of orgotein therapy. These response patterns indicate that attainment and maintenance of efficacy in orgotein therapy does not require the uninterrupted presence of intact SOD activity.
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