THE THERAPEUTIC EFFECTS OF TENIDAP IN CANINE EXPERIMENTAL OSTEOARTHRITIS - RELATIONSHIP WITH BIOCHEMICAL MARKERS

Objective. To define the dose-response relationship of the therapeutic effects of tenidap in experimental osteoarthritis (OA) and relate thi s to the effects on interleukin 1 (IL-1) and metalloprotease activity, Methods. The anterior cruciate ligament of the right knee joints of 2 2 mongrel dogs was sectioned (ACLS) through a stab wound. Seven dogs r eceived no treatment; 5 were treated with oral omeprazole (20 mg/day), another 5 were treated with oral tenidap (1.5 mg/kg bid) plus omepraz ole (20 mg/day), and 5 received tenidap (0.5 mg/kg bid) plus omeprazol e (20 mg/day). The dogs received medication for 8 weeks beginning 4 we eks after surgery, All dogs were killed 12 weeks after surgery, except those In the first group, which were sacrificed at 4 weeks, Lesions w ere evaluated macroscopically for the incidence and size of osteophyte s and the area and grade of cartilage erosions on the condyles and pla teaus, along with histologic evaluation of the severity of tile cartil age lesions and synovial inflammation. Stromelysin, collagenase, and g elatinase activities were measured In cartilage and synovial membrane, Also, the level of IL-1 activity was measured in the synovial fluid. Results. Dogs treated with tenidap at both 1.5 and 0.5 mg/kg bid exhib ited a reduction in the size of osteophytes (2.25 +/- 0.30 mm, 1.70 +/ - 0.65 mm, respectively) compared to the 12 week OA group (3.55 +/- 0. 94 mm). Tenidap also significantly decreased the size and/or grade of cartilage macroscopic lesions on both condyles and plateaus. This redu ction was more pronounced in dogs treated with the higher drug dose, T he histological severity of cartilage lesions on femoral condyles was reduced for both tenidap doses used and significance (p < 0.04) reache d for the 1.5 mg/kg bid tenidap treated dogs, Tenidap markedly and sig nificantly reduced the level of metalloprotease activity for all 3 enz ymes tested in synovial membrane (stromelysin, p < 0.03; collagenase, p < 0.02; gelatinase, p < 0.03) and in cartilage (stromelysin, p < 0.0 2; collagenase, p < 0.02: gelatinase, p < 0.03) with greater reduction , in general, in dogs treated with the higher dose of tenidap. IL-1 ac tivity was significantly reduced (p < 0.02) only in animals treated wi th tenidap at 1.5 mg/kg bid. Conclusion. This study confirms that teni dap is an effective anti-osteoarthritic drug in this ACLS model where therapy was begun 4 weeks after surgery We have defined doses that gav e graded therapeutic effects, and under these conditions the effective ness coincided with the suppression of IL-1 and metalloprotease activi ty, processes known to play a major role in the pathophysiology of OA lesions.