Determination of the Therapeutic Mean Effective Doses of Several Anti-inflammatory Agents in Adjuvant Arthritic Rats

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Abstract
The large variation in the severity of the arthritic response of the adjuvant-injected rat often makes it impossible to obtain statistically manageable dose–response curves with anti-inflammatory drugs. Consequently, the relative potency of anti-inflammatory drugs generally was not established. In the present study, with a modification of the therapeutic test, reliable dose–response curves were obtained with seven anti-inflammatory drugs. With this method the "therapeutic" mean effective dose (ED50) and relative potency were calculated by probit analysis. Charles River rats were injected in the left hind paw with adjuvant. On day 14, rats with an injected paw volume of 4–6 ml that increased by at least 0.5 ml between days 10 and 14 were selected for drug treatment. Groups of 6–12 rats with a mean injected paw volume of 5–5.5 ml were formed. Dosing with compounds was started on day 14 and continued daily until day 22 (nine injections). Ninety-four percent of the arthritic control rats showed a further increase in injected paw size between days 14 and 22 (mean, 1.06 ± 0.12 ml) whereas rats dosed with anti-inflammatory compounds showed a dose-related decrease in paw size during the same period. A decrease of 0.5 ml or more between days 14 and 22 was considered to be a therapeutic effect, smaller decreases were taken as no effect. The oral ED50's in milligrams per kilogram were indomethacin, 0.22 ± 0.05; prednisolone, 3.49 ± 1.0; hydrocortisone, 12.4 ± 3.0; phenylbutazone, 13.27 ± 2.7; mefenamic acid 20.10 ± 5.8; aminopyrine, 129.95 ± 25.3; and aspirin, 279.0 ± 24.6. Except for aspirin, the relative potency of the compounds studied by this therapeutic test (chronic) was comparable to that reported for the acute carrageenin assay. Aspirin appears to be markedly less active in chronic inflammation than in acute. This finding is consistent with both experimental and clinical observations.

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