Effects of a novel azaspirane (SK&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-dipropyl-2-azaspiro[4.5] decane-2-propanamine dihydrochloride) on the arthritic lesions in the tibiotarsal joint of adjuvant arthritic (AA) rats.


METHODS
Inhibition of hindpaw inflammation was measured by water displacement. The protective effects on joint integrity were determined by measuring radiographic and histological changes and by scanning electron microscopy.


RESULTS
Compared to AA control rats, SK&F 105685 suppressed hindpaw edema 64% or 41-54% in AA rats receiving 30 or 20 mg/kg/day, respectively. Radiographic evaluation showed marked decreases in soft tissue swelling and in the severity of skeletal tissue loss 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 tissues, including the content and distribution of proteoglycans of the articular cartilages. Cellular changes included decreases in the inflammatory infiltrate and in the number of osteoclasts and chondroclasts. Whereas AA control rats exhibited marked to severe loss (41-70%) of skeletal tissue mass, the loss in rats given 30 mg/kg SK&F 105685 was mild (< 20%). Scanning electron microscopy of the talus revealed only slight erosion of the articular cartilage and general preservation of the underlying bone. In contrast, in AA controls, there was marked erosion of the talar articular cartilage and severe loss of subchondral bone. Spleen cells from SK&F 105685 treated rats had a reduced capacity to respond to concanavalin A and contained suppressor cell activity as measured in a coculture assay.


CONCLUSIONS
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 retard the degenerative loss of skeletal tissue in rheumatoid arthritis in humans.
High
W B
WB
Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA.
Bugelski
P J
PJ
Nichols
M E
ME
Swift
B A
BA
Solleveld
H A
HA
Badger
A M
AM
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000648:ultrastructure; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D008213:Lymphocyte Activation; D008297:Male; D008855:Microscopy, Electron, Scanning; D010010:Osteoclasts / Q000648:ultrastructure; D051381:Rats; D011917:Rats, Inbred Lew; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D013141:Spiro Compounds; C062162:SK&F 105685