Inhibition of PGE₂ Production by Nimesulide Compared with Diclofenac in the Acutely Inflamed Joint of Patients with Arthritis

Abstract

Objective: Cyclo-oxygenase (COX) exists in two isoforms, COX-1 and COX-2. COX-1 is responsible for homeostatic functions, whereas COX-2 is inducible and responsible for the inflammatory effects of prostaglandins. Nimesulide, a selective inhibitor of COX-2, has been shown to relieve pain rapidly in arthritis. We examined the effect of nimesulide on prostaglandin formation in arthritis, to evaluate if this compound gains access to the site of inflammation and whether this is required for analgesia.

Study Design: This was a single-dose, double-blind, double-dummy, parallel group study of nimesulide 100mg compared with diclofenac 50mg.

Methods: Serial sampling of synovial fluid, whole blood and plasma was performed at baseline and 0.5, 1, 2, 3 and 4 hours after drug administration. Synovial tissue was obtained by needle biopsy at completion of the study period. Synovial fluid prostaglandin E₂ (PGE₂) was measured by enzyme immunoassay. COX-1 and COX-2 activities in whole blood were estimated by serum thromboxane B₂ (TxB₂) and endotoxin-induced PGE₂ concentrations respectively. Synovial tissue COX-1 and COX-2 mRNA and protein expression were studied by reverse transcriptase polymerase chain reaction and immunohistochemistry respectively.

Twenty atients with acute knee inflammation on a background of arthritis of all types completed the study.

Results: Patients were allocated randomly to groups to receive nimesulide (n = 10) or diclofenac (n = 10). The mean (±SEM) plasma concentration of PGE₂ in the nimesulide group decreased from 24.45 ±2.71 ng/mL at baseline to 1.74 ±2.71 ng/ mL at 2 hours. Diclofenac also inhibited PGE₂, but at a later time point (28.15 ±2.86 ng/mL at baseline and 0.85 ±2.86 ng/mL at 4 hours). The mean (±SEM) synovial fluid concentration of PGE₂ was 319 ±89 pg/mL before treatment; it remained unaltered over 4 hours after the administration of nimesulide or diclofenac (235 ±72 pg/mL). In contrast, in six patients receiving long-term treatment with nimesulide or a non-selective NSAID, synovial PGE₂ was 61 ±24 pg/ mL, suggesting that inhibition of synovial prostaglandin formation is delayed compared with that in plasma. Nimesulide caused partial inhibition of serum TxB₂ (a decrease from a mean of 268 ±24 ng/mL to one of 164 ±27 ng/mL at 2 hours), whereas diclofenac had a greater effect (a decrease from 224 ±33 ng/mL, to 76 ±27 ng/mL at 3 hours).

Conclusions: Nimesulide, a COX-2 selective inhibitor, has a rapid onset of action in the blood compartment, with early inhibition of PGE₂ generation, an index of COX-2 activity. In contrast, it exhibits a delay in achieving therapeutic concentrations in the synovial fluid. Thus factors other than local inhibition of prostaglandins may explain the rapid onset of analgesia that is associated with nimesulide, including a possible central mechanism of pain relief.