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

Abstract

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.

Tenidap inhibits 5-lipoxygenase product formation in vitro, but this activity is not observed in three animal models

“…Taken together, this data strongly suggests that tenidap indeed can effect 5-LO in human neutrophils. Therefore, the reason for the discrepancy between our results and those reported by Smith et al [53] is uncertain.…”

“…This implies that the inhibition curves for tenidap's two effects on 5-LO overlap to some extent. Two published reports [53,54] state that tenidap's in vitro inhibition of the 5-LO pathway results from an action on AA mobilization. One report by Smith et al [53] bases this conclusion on the similar concentration range (10-100 M) for tenidap's inhibition of calcium ionophore induced arachidonic acid deacylation and LTB 4 synthesis by human neutrophils.…”

“…Two published reports [53,54] state that tenidap's in vitro inhibition of the 5-LO pathway results from an action on AA mobilization. One report by Smith et al [53] bases this conclusion on the similar concentration range (10-100 M) for tenidap's inhibition of calcium ionophore induced arachidonic acid deacylation and LTB 4 synthesis by human neutrophils. As mentioned above, studies by Moilanen [40], also employing human neutrophils, show a dose-related decrease in AA induced LTB 4 production (IC 50 , 13 M) in response to tenidap, suggesting that the drug's action on LTB 4 formation cannot be accounted for by a reduction in mobilization of AA from phospholipid stores in this cell type.…”

Oligonucleotides antisense to the interleukin 1 receptor mRNA block the effects of interleukin 1 in cultured murine and human fibroblasts and in mice.

“…Approaches being explored include drugs that block secretion of IL-I from inflammatory cells (29)(30)(31), use of a soluble, recombinant extracellular binding domain of the IL-l receptor to bind and deplete circulating cytokine (32), and competitive antagonism of the IL-1 receptor (33)(34)(35). Several proteins that compete with IL-I for its receptor have been cloned (34,35); at least one is being investigated as a potential therapeutic agent.…”

The in vitro free radical scavenging activity of tenidap, a new dual cyclo‐oxygenase and 5‐1ipoxygenase inhibitor

“…The role of prostaglandins (PGs), metabolites of arachidonic acid (AA) via the action of cyclo-oxygenase (CO), is well established. Recently, leukotrienes (LTs), 5 13 An ex vivo study of the effects of tenidap on FR activity in patients with RA is currently underway in a double-blind study. The correlation between tenidap's effects on RA activity, and the production and removal of FRs will be assessed.…”