ABSTRACT
A large series of N-arylanthranilic acids has been prepared. Many of these compounds show high anti-inflammatory activity as measured by the anti-UV-erythema test. From this series have come the clinically useful non-steroidal anti-inflammatory agents, flufenamic acid (Arlef), mefenamic acid (Ponstel), and the latest and most potent agent, N-(2,6-dichloro-m-tolyl)anthranilic acid (meclofenamic acid, Meclomen = the sodium salt). The structure-activity relationships of this series is discussed and a graphical representation is presented which allows the prediction of activity of new agents.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , ortho-Aminobenzoates/pharmacology , Animals , Chemical Phenomena , Chemistry , Erythema/drug therapy , Guinea Pigs , Structure-Activity Relationship , ortho-Aminobenzoates/chemical synthesisABSTRACT
A method for the comparative bioassay of nonsteroidal anti-inflammatory agents is presented which exploits the early inflammation induced by injection of adjuvant into the plantar surface of a hind paw of the rat. The inflammation reaches a peak on the 4th postinjection day. Daily treatment with nonsteroidal anti-inflammatory agents reduces paw volumes and the associated impairment of body growth with optimal improvement on the 4th postinjection day. In this model, phenylbutazone has shown significant activity at doses as low at 1.33 mg/kg/day. Statistically valid comparative assays conducted at dose levels equivalent to or below those used in human therapy yield potency ratios with relatively narrow confidence limits. Potencies relative to phenylbutazone for inhibiting primary adjuvant-induced inflammation are: aminopyrine, 0.066 (0.36-0.11)95%; aspirin, 0.087 (0.039-0.19)95%; mefenamic acid, 0.98 (0.64-1.6)95%; flufenamic acid, 13 (7.4-26)95%; meclofenamic acid, 23(16-33)95%; and indomethacin, 53 (35-82) 95%. Ancillary and sometimes quantitative information is also provided by the improvement in well being of the animals as reflected in body weight changes with treatment.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Arthritis, Rheumatoid/immunology , Biological Assay/methods , Freund's Adjuvant , Aminopyrine/therapeutic use , Analysis of Variance , Animals , Arthritis, Rheumatoid/drug therapy , Aspirin/therapeutic use , Disease Models, Animal , Dose-Response Relationship, Drug , Flufenamic Acid/therapeutic use , Indomethacin/therapeutic use , Male , Mefenamic Acid/therapeutic use , Phenylbutazone/therapeutic use , Rats , Time FactorsABSTRACT
Relative anti-inflammatory potencies of aspirin, phenylbutazone, indomethacin, three fenamates and several other nonsteroidal anti-inflammatory agents were obtained in several laboratory models of acute and chronic inflammation. Relative toxicities and ulcerogenicities were determined in rats of the same source, strain and sex. The acute ulcerogenic assay measures the minimal irritation potential of these agents and leads to a sensitive index of the safety of such compounds when compared with their therapeutic potencies. By these criteria, meclofenamic acid is a highly potent, acceptably safe and exceptionally well tolerated anti-inflammatory-antipyretic agent in rats when compared with other such drugs.
