Evaluation of Tenidap (CP-66,248) on human neutrophil arachidonic acid metabolism, chemotactic potential and clinical efficacy in the treatment of rheumatoid arthritis

Ten patients with rheumatoid arthritis (RA) were evaluated in a placebo-controlled, double-blind study examining the clinical efficacy of a novel nonsteroidal anti-inflammatory agent: Tenidap (CP-66,248). RA patients receiving active drug therapy (n = 6) demonstrated clinically significant improvements in observer assessment of pain (p less than 0.025), painful joint count (p less than 0.010), and overall clinical assessment as based on a modified rheumatoid activity index, MRAI (p less than 0.025). In parallel laboratory assays, Tenidap was found to exhibit a significant in vitro dose-dependent inhibition of ionophore-stimulated neutrophil production of the 5-lipoxygenase product: 3H]leukotriene B4 (LTB4). Although more importantly, Tenidap was also found to exhibit an in vitro dose-dependent inhibition (IC50 20 microM) of the ionophore-stimulated release (deacylation) of the precursor 3H]arachidonic acid (AA) from membrane phospholipids. In further studies, Tenidap did not have any effect on fMLP-induced neutrophil chemotactic response. These results suggest that one of the possible mechanisms for the clinical effectiveness of this agent, may be through its effect at inhibiting the release of free AA from membrane phospholipids and therefore limiting its further metabolism into certain biologically-active inflammatory lipids.