DISEASE-MODIFYING ACTIVITY OF SK-AND-F-106615 IN RAT ADJUVANT-INDUCEDARTHRITIS - MULTIPARAMETER ANALYSIS OF DISEASE INCLUDING 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 prophylact ically (days 0-16 or days 0-23) or therapeutically (days 10-23) with S K&F 106615. Efficacy was determined by measurements of paw inflammatio n, bone mineral density (BMD) using dual x-ray absorptiometry, and mag netic resonance imaging (MRI). Joint integrity was also determined his tologically, and serum interleukin-6 (IL-6) levels were measured as a marker of the antiinflammatory effects of the compound. Results. Proph ylactic treatment (days 0-16) of AIA rats with SK&F 106615 significant ly inhibited paw volume at doses of 5-45 mg/kg/day given orally on 5 d ays 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 dise ase by MRI and histologic assessment compared with the AIA controls. E levated levels of serum IL-6 in AIA rats were reduced dramatically by SK&F 106615. Therapeutic treatment (days 10-23) resulted in similar pr otective effects measured by paw inflammation, BMD, and MRI. In the th erapeutic protocol, serum IL-6 appeared to be a more sensitive marker of antiinflammatory activity than paw edema. Conclusion, Symptoms of A IA in rats are significantly reduced by prophylactic and therapeutic t reatment with SK&F 106615. Of particular note, this compound appears t o exert a protective effect on joint integrity and to have disease-mod ifying properties.