ACUTE AND CHRONIC ANTIINFLAMMATORY PROPERTIES OF [2,2-DIMETHYL-6-(4-CHLOROPHENYL)-7-PHENYL-2,3-DIHYDRO-1H-PYRROLIZINE-5-YL]-ACETIC ACID

The carrageenan-induced paw oedema in the rat was chosen as the experimental model for acute antiphlogistic activity. ED(50) values of 3 mg/kg p.o. for indometacin and of 17 mg/kg/p.o. for [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H- pyrrolizine-5-yl]-acetic acid (ML 3000) at calculated plasma levels (mu/ml) of approximately 5.0 and 20.0 were recorded for indometacin and ML 3000, respectively. The activity ratio of indometacin: ML 3000 is therefore about 1:6 with regard to the oral dose and about 1:4 with regard to the calculated plasma level. Indometacin is more potent than ML 3000 on the one hand, but on the other hand ML 3000 is better tolerated by the stomach in this experimental study: the ulcerogenic dose UD50 (indometacin) is 7 mg/kg p.o., whereas ML 3000 is tolerated well up to the highest tested dose of 100 mg/kg p.o. The adjuvant arthritis in the rat served as the model for chronic antiphlogistic activity. ML 3000 at doses of 20 mg/kg/d p.o and higher, and indometacin at a dosage of 2 mg/kg/d p.o. produced a similar rate of reduction of the adjuvant-induced secondary lesions and paw swelling of the injected and uninjected paws, following prophylactic as well as therapeutic treatment with the compounds.