Dual inhibition of 5-lipoxygenase and cyclooxygenases 1 and 2 by ML3000 reduces joint destruction in adjuvant arthritis

Objective. To search for potential new therapies to inhibit the progression of joint destruction in patients with rheumatoid arthritis. Methods. We evaluated the dual acting anti inflammatory drug ML3000 (2,2-di methyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl) acetic acid, a dual inhibitor of 5-lipoxygenase (5-LOX) as well as both cyclooxyge nases (COX-1 and COX-2) in the rat model of adjuvant arthritis. On Day 0. f emale Lewis rats (5 per group) were injected intradermally with complete Fr eund's adjuvant at base of the tail. Treatment began on Day 2; the rats rec eived ML3000 (20 or 80 mg/kg/day) twice daily 7 h apart for 28 days and wer e then sacrificed. To reduce pain. the positive control group and 2 treatme nt groups received paracetamol (3 mg/ml water). Joint histology was scored for synovial cell proliferation, fibroproliferative pannus, and cartilage a nd bone erosions, as well as diffuse leukocyte infiltrates. Results. Daily doses of 20 or 80 mg/kg ML3000 significantly reduced the art hritis associated deficiency of body growth, the edema/erythema score. and splenomegaly. In the ankle joint, ML3000 significantly reduced the overall histological score, synovial cell proliferation, and bone/cartilage erosion s, and inhibited the appearance of fibroproliferative pannus. The addition of paracetamol in the drinking water had no influence. No side effects were noted. Conclusion. ML3000 is an antiarthritic drug with a high gastrointestinal to lerability, which can reduce synovial cell proliferation and joint erosion and is capable of markedly suppressing prostaglandin synthesis.