In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis - Suppression of collagenase 1 and interleukin-1 beta synthesis

Objective. To study the therapeutic effectiveness of ML-3000, a new antiinf lammatory drug that has balanced dual inhibitory activity against 5-lipoxyg enase and cyclooxygenase, on the development of lesions in the experimental osteoarthritis (OA) dog model, and to determine the action of ML-3000 on t he synthesis of collagenase 1 in cartilage and interleukin- 1 beta (IL-1 be ta) in synovial membrane. Methods. The anterior cruciate ligament of the right stifle joint of 21 mon grel dogs was sectioned with a stab wound. Dogs were divided into 3 groups: group 1 (n = 7) received placebo; groups 2 (n = 7) and 3 (n = 7) were trea ted with therapeutic dosages of oral ML-3000 at 2.5 mg/kg/day and 5 mg/kg/d ay, respectively. The dogs began receiving medication the day after surgery and were killed 8 weeks later. The size and grade of cartilage erosions on both the condyles and plateaus were evaluated, and the severity of the car tilage lesions and synovial inflammation was examined histologically. Level s of collagenase 1 in cartilage and IL-1 beta in the synovial membrane were measured by immunohistochemistry. In addition, levels of prostaglandin E-2 (PGE(2)) in the synovial fluid and leukotriene B-4 (LTB4) in cultured syno vial membrane explants were determined using specific enzyme immunoassays. Results. Serum levels of ML-3000 in treated dogs were within the therapeuti c range. ML-3000 significantly decreased the size and grade of the cartilag e lesions in tibials and plateaus, compared with placebo. At the histologic level, the severity of cartilage lesions was also decreased in the ML-3000 -treated dogs versus the placebo-treated dogs in both the condyles and the plateaus. All 3 OA groups exhibited a notable and similar level of synovial inflammation. ML-3000 significantly decreased the level of PGE(2) in synov ial fluid and LTB4 production by synovium. It also markedly reduced the lev els of collagenase 1 in cartilage and IL-1 beta in synovial membrane. Conclusion. ML-3000 significantly reduced the development of lesions in exp erimental dog OA. The drug acts by reducing the synthesis of the inflammati on mediators PGE(2) and LTB4 and catabolic factors such as collagenase 1 an d IL-1 beta, which are known to play an important role in the pathophysiolo gy of OA lesions. The effect of the drug on catabolic factors could possibl y be related to its inhibitory action on LTB4 synthesis.