RT Journal Article
SR Electronic
T1 Dual inhibition of 5-lipoxygenase and cyclooxygenases 1 and 2 by ML3000 reduces joint destruction in adjuvant arthritis.
JF The Journal of Rheumatology
JO J Rheumatol
FD The Journal of Rheumatology
SP 2060
OP 2065
VO 28
IS 9
A1 R E Gay
A1 M Neidhart
A1 F Pataky
A1 S Tries
A1 S Laufer
A1 S Gay
YR 2001
UL http://www.jrheum.org/content/28/9/2060.abstract
AB 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 antiinflammatory drug ML3000 (2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro- H-pyrrolizine-5-yl) acetic acid, a dual inhibitor of 5-lipoxygenase (5-LOX) as well as both cyclooxygenases (COX-1 and COX-2) in the rat model of adjuvant arthritis. On Day 0, female Lewis rats (5 per group) were injected intradermally with complete Freund's adjuvant at base of the tail. Treatment began on Day 2; the rats received ML3000 (20 or 80 mg/kg/day) twice daily 7 h apart for 28 days and were then sacrificed. To reduce pain, the positive control group and 2 treatment groups received paracetamol (3 mg/ml water). Joint histology was scored for synovial cell proliferation, fibroproliferative pannus, and cartilage and bone erosions, as well as diffuse leukocyte infiltrates. RESULTS: Daily doses of 20 or 80 mg/kg ML3000 significantly reduced the arthritis 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 erosions, 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 tolerability, which can reduce synovial cell proliferation and joint erosion and is capable of markedly suppressing prostaglandin synthesis.