Disease-modifying activity of SK&F 106615 in rat adjuvant-induced arthritis. Multiparameter analysis of disease magnetic resonance imaging and bone mineral density measurements.
OBJECTIVE
To evaluate the effect of SK&F 106615 on joint integrity in rats with adjuvant-induced arthritis (AIA).


METHODS
AIA was induced in Lewis rats on day 0, and the animals were treated either prophylactically (days 0-16 or days 0-23) or therapeutically (days 10-23) with SK&F 106615. Efficacy was determined by measurements of paw inflammation, bone mineral density (BMD) using dual x-ray absorptiometry, and magnetic resonance imaging (MRI). Joint integrity was also determined histologically, and serum interleukin-6 (IL-6) levels were measured as a marker of the antiinflammatory effects of the compound.


RESULTS
Prophylactic treatment (days 0-16) of AIA rats with SK&F 106615 significantly inhibited paw volume at doses of 545 mg/kg/day given orally on 5 days each week. Extensive evaluation of joint integrity in rats treated with SK&F 106615 20 mg/kg/day orally for 23 days showed inhibition of paw volume, normalization of BMD, and significant improvement in disease by MRI and histologic assessment compared with the AIA controls. Elevated levels of serum IL-6 in AIA rats were reduced dramatically by SK&F 106615. Therapeutic treatment (days 10-23) resulted in similar protective effects measured by paw inflammation, BMD, and MRI. In the therapeutic protocol, serum IL-6 appeared to be a more sensitive marker of antiinflammatory activity than paw edema.


CONCLUSIONS
Symptoms of AIA in rats are significantly reduced by prophylactic and therapeutic treatment with SK&F 106615. Of particular note, this compound appears to exert a protective effect on joint integrity and to have disease-modifying properties.
Bradbeer
J N
JN
SmithKline Beecham, King of Prussia, PA 19406, USA.
Kapadia
R D
RD
Sarkar
S K
SK
Zhao
H
H
Stroup
G B
GB
Swift
B A
BA
Rieman
D J
DJ
Badger
A M
AM
D015502:Absorptiometry, Photon; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy*; D015519:Bone Density / Q000187:drug effects; D015850:Interleukin-6 / Q000097:blood; D007596:Joints / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013141:Spiro Compounds / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D013141:Spiro Compounds; C099015:azaspirane