Beneficial effects of SK&F 105685 in rat adjuvant arthritis: prophylactic and therapeutic effects on disease parameter progression.
Prophylactic administration of SK&F 105685 (N, N-dimethyl-8,8,-dipropyl-2-azaspiro[4.5]decane-2-propanamine dihydrochloride) at 30 mg/kg/day inhibited hindpaw lesions in adjuvant arthritic (AA) rats following 16 (84% inhibition) and 24 (70% inhibition) days of treatment. In a therapeutic protocol, where dosing was initiated on day 10 after disease induction, SK&F 105685 (20 mg/kg/day) effectively halted disease progression, and the inflammatory lesion was suppressed by 70% following treatment for 20 days. Histological evaluation of the joint periarticular soft tissue, bone and articulation (joint space and joint surface) from therapeutically treated rats showed a clear beneficial effect. Most rats presented moderate lesions rather than the severe lesions seen in the AA animals. AA control rats and AA rats treated prophylactically or therapeutically with SK&F 105685 had significant and similar increases in their total white blood cell (WBC), neutrophil, monocyte and platelet counts. Although increases were seen in the absolute number of neutrophils and platelets, there were no differences in the levels of leukotriene B4 (LTB4) and hydroxyheptadecatrienoic acid (HHT), per cell when these cells were stimulated with the calcium ionophore A23187. These results, describing the beneficial effects of SK&F 105685 administered therapeutically to the AA rat, indicate that this compound possesses properties desirable of an anti-arthritic agent and may potentially modify the disease outcome.
Badger
A M
AM
SmithKline Beecham Pharmaceuticals, Departments of Cellular Biochemistry, Pharmacology and Toxicology, King of Prussia, PA 19406-0939.
Swift
B A
BA
Webb
E F
EF
Clark
R K
RK
Bugelski
P J
PJ
Griswold
D E
DE
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D001772:Blood Cell Count; D004487:Edema / Q000188:drug therapy / Q000517:prevention & control; D015777:Eicosanoids / Q000096:biosynthesis; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013141:Spiro Compounds / Q000627:therapeutic use*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D013141:Spiro Compounds; C062162:SK&F 105685