Dexamethasone (DEX), a widely prescribed corticosteroid (CS), has long been the cornerstone for the treatment of inflammation and immunological dysfunctions in Rheumatoid Arthritis (RA). The CS are frequently used in combination with other anti-rheumatic agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs) to mitigate disease symptoms and minimize unwanted effects. The steroid dose-sparing potential of the NSAID naproxen (NPX) was explored with in vitro and in vivo studies. We investigated the single and joint suppressive effects of DEX and NPX on the in vitro mitogen-induced proliferation of T lymphocytes in blood and their anti-inflammatory actions on paw edema in female and male Lewis rats with collagen-induced arthritis (CIA). DEX was far more potent than NPX in these systems as expected. Mathematical models incorporating an interaction term ψ were applied to quantitatively assess the nature and intensity of pharmacodynamic (PD) interactions between DEX and NPX. Modest synergistic effects of the two drugs was found in suppressing the mitogenic response of T lymphocytes. A pharmacokinetic (PK)/PD/disease (DIS) progression model integrating dual drug inhibition quantitatively described the PK, time-course of single and joint anti-inflammatory effects (paw edema), and sex differences in CIA rats, and indicated additive effects of DEX and NPX. Further model simulations demonstrated the promising steroid-sparing potential of NPX in CIA rats, with beneficial effects of the combination therapy more likely in males than females.
- The American Society for Pharmacology and Experimental Therapeutics