Interaction between inhibitors of inducible nitric oxide synthase and cyclooxygenase in adjuvant-induced arthritis in female albino rats: an isobolographic study

We studied the interaction of S-methylisothiourea (a selective inducible nitric oxide synthase inhibitor) with rofecoxib (a selective cyclooxygenase-2 inhibitor) and mefenamic acid (a non-selective cyclooxygenase inhibitor) in adjuvant-induced arthritis in female albino Wistar rats, applying the isobolographic analysis. Each drug was effective in reducing the progressive increase in paw volume less than 50% except rofecoxib, when used alone. Log dose-response curve was obtained for each drug along with the corresponding ED(25). Following isobolographic analysis, combination of S-methylisothiourea with rofecoxib and mefenamic acid revealed supra-additive or synergistic interaction. Experimental ED(25) of the combinations was significantly lower than the theoretical ED(25) of the corresponding drug combination which substantiated the synergistic type of interaction between inducible nitric oxide synthase and cyclooxygenase in adjuvant-induced arthritis in female albino rats. Results suggest that NO regulates the cyclooxygenase enzyme activity as the activity of cyclooxygenase enzymes in the LPS-stimulated leukocyte lysates was significantly low or hardly detectable in the presence of varying concentrations of S-methylisothiourea. Simultaneous inhibition of inducible nitric oxide synthase and cyclooxygenase appears to offer an alternative approach for ameliorating the progression of arthritis.