Suvorova O. Comparative evaluation of the efficacy of non-steroidal anti-inflammatory drugs used in combination with immunosuppressants in experimental rheumatoid arthritis.

This dissertation presents data on the pharmacodynamic interactions of the synthetic and biological immunosuppressants Methotrexate, Leflunomide, and Enbrel with nonsteroidal anti-inflammatory drugs (NSAIDs) that differ in their selectivity for cyclooxygenase (COX) isoforms. The study examined the effects of Diclofenac on arthritis induced by complete Freund's adjuvant. The study found that, unlike all other drugs, Diclofenac caused mortality in 31% of rats treated with adjuvant arthritis when administered alone. The combined use of Diclofenac with Methotrexate and Diclofenac with Enbrel resulted in mortality in 33% and 13% of rats, respectively, whereas no mortality was observed with Diclofenac and Leflunomide. The immunosuppressant Enbrel reduced the mortality rate, while Leflunomide completely eliminated the negative effects of Diclofenac. Diclofenac exhibits significant analgesic activity. Its analgesic potency ranged from 30% to 63% during different phases of adjuvant arthritis development. Celecoxib exhibited analgesic activity only during the acute period and early manifestation of adjuvant arthritis. Leflunomide exerted analgesic activity, as evidenced by a significant increase in the pain threshold and its analgesic potency – (34.4-102)% – in white rats during different phases of adjuvant arthritis development. The analgesic potency of Enbrel and Methotrexate was recorded only during the acute period of adjuvant arthritis and amounted to (102-192)% and (35-60)%, respectively. Diclofenac and celecoxib potentiated the analgesic effects of leflunomide and methotrexate. Antagonism of analgesia was observed with each NSAID and Enbrel, making it impossible to recommend its combined use with any NSAID for pain management in adjuvant arthritis. Diclofenac exhibited significant anti-edema activity during all phases of adjuvant arthritis development. Celecoxib's anti-edema activity was significantly lower than Diclofenac's during the acute phase and similar to Diclofenac's activity during other phases of adjuvant arthritis development. Leflunomide, unlike methotrexate, exhibits high anti-edema activity during the acute phase and the manifestation phase of the inflammatory process. Enbrel has the ability to increase extremity edema during the acute phase and the generalization phase of adjuvant arthritis. Methotrexate did not affect the anti-exudative effect of Celecoxib and reduced the anti-inflammatory effect of Diclofenac, indicating their antagonistic relationship. Diclofenac exhibited hypotensive activity during the generalization and remission periods of adjuvant arthritis. Leflunomide and Enbrel, when used alone, resulted in a significant, similar reduction in blood pressure during the generalization period. Methotrexate led to the development of hypertension during the manifestation and remission periods of adjuvant arthritis. Diclofenac reversed the prohypertensive effect of methotrexate, had no effect on blood pressure when combined with leflunomide, and led to a significant increase in blood pressure when combined with Enbrel. The interaction of celecoxib with methotrexate resulted in a significant synergistic increase in hypertensive activity. The combined use of celecoxib with Enbrel did not result in significant changes in blood pressure. Diclofenac and Celecoxib reduced the positive chronotropic effect of synthetic immunosuppressants and significantly reduced the negative chronotropic effect of Enbrel, preventing the development of bradycardia. NSAIDs with different COX selectivity and immunosuppressants of various origins did not fully eliminate the symptoms of gastric mucosal damage. Diclofenac, Celecoxib, and Methotrexate were the most vulnerable agents to gastric mucosal damage in adjuvant arthritis, both when used alone and in combination with each NSAID. The safest combination for gastric mucosal damage was the use of each NSAID with Leflunomide during all phases of adjuvant arthritis and with Enbrel during the generalization and resolution of inflammation. The efficacy/ineffectiveness of analgesic and anti-edema drugs in combination with each of the studied NSAIDs and each immunosuppressant was experimentally demonstrated. A comparative analysis of the adverse effects of Diclofenac, Celecoxib, Leflunomide, Methotrexate, and Enbrel when used alone over a long period was presented, and the cardio- and gastrointestinal toxicity associated with the combined use of NSAIDs and immunosuppressants in patients with adjuvant arthritis was determined.