FRI0028 Suppression of experimental arthritis by treatment with a novel dmard, smp-114

Abstract

Background A more promising therapeutic approach to rheumatoid arthritis would be to maintain joint function. Our studies have been performed with the above goal in mind and showed that some azole compounds meet these requirements. SMP-114, a novel isoxazole derivative, was selected from them and characterised as a compound with antiarthritic activity and without any cyclooxgenase inhibitory activity. Objectives The objective of these studies was to evaluate the effect of SMP-114 on joint oedema, bone resorption and ankylosis in experimental models of rheumatoid arthritis. Methods Adjuvant arthritis was induced in Lewis rats by a single injection of Mycobacterium butyricum in the plantar surface of right hindpaw on day 0, and animals were treated therapeutically (days 10–24 or days 17–21) with SMP-114. Anti-inflammatory activity was determined by measurements of paw swelling. The protective effect on joint integrity was determined by measuring radiographic and histological changes. Collagen-induced arthritis was induced in DBA/1J mice. Animals were immunised intradermally at the base of the tail with type II collagen (day 0 and day 21). SMP-114 was administered orally (days 0–49). Efficacy was assessed clinically, histologically and radiographically. Results Treatment (days 10–24) of adjuvant arthritis with SMP-114 significantly reduced paw oedema with a minimum effective dose of 10 mg/kg. This was accompanied by a more extensive reduction in bone and cartilage destruction around the metatarsal-phalangeal joint, as assessed by histologic and radiographic examinations. SMP-114 was also able to significantly ameliorate full-blown adjuvant arthritis. When daily administration of SMp-114 began on day 17, well into the chronic destructive phase, the agent produced a dose-response effect on paw oedema, with a minimum effective dose of less than 2.5 mg/kg. The compound (range 20 80 mg/kg) demonstrated a capacity for ameliorating joint inflammation (paw oedema) and protecting joint structure coincident with a decrease in the number of osteoclasts in articular lesions in mice with collagen-induced arthritis. SMP-114 also showed anti-fibroblastic effect and, as a result, reduced a frequency of development of ankylosis in these models. This profile of activity was not shared by nonsteroidal anti-inflammatory drugs such as indomethacin. Conclusion Our studies show that SMP-114 has remarkable protective effects on the joint of adjuvant arthritic rats and collagen-induced arthritic mice. These data suggest that SMP-114 will show greater benefit in slowing joint destruction and disease progression in rheumatoid arthritis in humans.