To define the dose-response relationship of the therapeutic effects of tenidap in experimental osteoarthritis (OA) and relate this to the effects on interleukin 1 (IL-1) and metalloprotease activity.
The anterior cruciate ligament of the right knee joints of 22 mongrel dogs were sectioned (ACLS) through a stab wound. Seven dogs received no treatment, 5 were treated with oral omeprazole (20 mg/day), another 5 were treated with oral tenidap (1.5 mg/kg bid) plus omeprazole (20 mg/day), and 5 received tenidap (0.5 mg/kg bid) plus omeprazole (20 mg/day). The dogs received medication for 8 weeks beginning 4 weeks after surgery. All dogs were killed 12 weeks after surgery, except for those in the first group, which were sacrificed at 4 weeks. Lesions were evaluated macroscopically for the incidence and size of osteophytes and the area and grade of cartilage erosions on the condyles and plateaus, along with histologic evaluation of the severity of the cartilage lesions and synovial inflammation. Stromelysin, collagenase, and gelatinase activities were measured in cartilage and synovial membrane. Also, the level of IL-1 activity was measured in the synovial fluid.
Dogs treated with tenidap at both 1.5 and 0.5 mg/kg bid exhibited a reduction in the size of osteophytes (2.25 +/- 0.30 mm, 1.70 +/- 0.65 mm, respectively) compared to the 12 weeks OA group (3.55 +/- 0.94 mm). Tenidap also significantly decreased the size and/or grade or cartilage macroscopic lesions on both condyles and plateaus. This reduction was more pronounced in dogs treated with the higher drug dose. The histological severity of cartilage lesions on femoral condyles was reduced for both tenidap doses used and significance (p < 0.04) reached for the 1.5 mg/kg bid tenidap treated dogs. Tenidap markedly and significantly reduced the level of metalloprotease activity for all 3 enzymes tested in synovial membrane (stromelysin, p < 0.03; collagenase, p < 0.02; gelatinase, p < 0.03) and in cartilage (stromelysin, p < 0.02; collagenase, p < 0.02; gelatinase, p < 0.03) with greater reduction, in general, in dogs treated with the higher dose of tenidap. IL-1 activity was significantly reduced (p < 0.02) only in animals treated with tenidap at 1.5 mg/kg bid.
This study confirms that tenidap is an effective anti-osteoarthritic drug in this ACLS model where therapy was begun 4 weeks after surgery. We have defined doses that gave graded therapeutic effects, and under these conditions the effectiveness coincided with the suppression of IL-1 and metalloprotease activity, processes known to play a major role in the pathophysiology of OA lesions.