EFFECTS OF A NOVEL AZASPIRANE (SK-AND-F-105685) ON ARTHRITIC LESIONS IN THE ADJUVANT LEWIS RAT - ATTENUATION OF THE INFLAMMATORY PROCESS AND PRESERVATION OF SKELETAL INTEGRITY

Objective. To determine the effects of SK&F 105685 (N,N-dimethyl-8,8-d ipropyl-2-azaspiro[4.5] decane-2-propanamine dihydrochloride) on the a rthritic lesions in the tibiotarsal joint of adjuvant arthritic (AA) r ats. Methods. Inhibition of hindpaw inflammation was measured by water displacement. The protective effects on joint integrity were determin ed by measuring radiographic and histological changes and by scanning electron microscopy. Results. Compared to AA control rats, SK&F 105685 suppressed hindpaw edema 63-64% or 41-54% in AA rats receiving 30 or 20 mg/kg/day, respectively. Radiographic evaluation showed marked decr eases in soft tissue swelling and in the severity of skeletal tissue l oss at the tibiotarsal joint in both dose groups. Histologically SK&F 105685 markedly attenuated the extent and severity of the inflammatory lesion and preserved the basic integrity of bone and cartilaginous ti ssues, including the content and distribution of proteoglycans of the articular cartilages. Cellular changes included decreases in the infla mmatory infiltrate and in the number of osteoclasts and chondroclasts. Whereas AA control rats exhibited marked to severe loss (41-70%) of s keletal tissue mass, the loss in rats given 30 mg/kg SK&F 105685 was m ild (<20%). Scanning electron microscopy of the talus revealed only sl ight erosion of the articular cartilage and general preservation of th e underlying bone. In contrast, in AA controls, there was marked erosi on of the talar articular cartilage and severe loss of subchondral bon e. Spleen cells from SK&F 105685 treated rats had a reduced capacity t o respond to concanavalin A and contained suppressor cell activity as measured in a coculture assay. Conclusion. Our studies show that SK&F 105685 has remarkable protective effects on the joints of AA rats and suggests that it may attenuate the overall inflammatory process and re tard the degenerative loss of skeletal tissue in rheumatoid arthritis in humans.