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 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.


CONCLUSIONS
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.
Gay
R E
RE
Center for Experimental Rheumatology, University Hospital, Zürich, Switzerland.
Neidhart
M
M
Pataky
F
F
Tries
S
S
Laufer
S
S
Gay
S
S
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000187:drug effects*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D011336:Probability; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology*; D016059:Range of Motion, Articular; D051381:Rats; D011917:Rats, Inbred Lew; D012016:Reference Values; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
D000085:Acetates; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; C088092:licofelone