A comparative study on the anti-inflammatory effects of single oral doses of naproxen and its hydrogen sulfide (H2S)-releasing derivative ATB-346 in rats with carrageenan-induced synovitis

摘要

Background Non-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, although gastric effects limit their long-term use. Considering the reported gastric safety of hydrogen sulfide (H₂S)-releasing NSAIDs, in addition to the anti-inflammatory effects of H₂S administration to rats with synovitis, we decided to evaluate the effects of the H₂S-releasing naproxen derivative ATB-346 in this animal model. Methods Male Wistar rats were anesthetized with inhalatory halothane and pre-treated with equimolar oral doses of either naproxen (0.3, 1, 3 or 10?mg/kg) or ATB-346 (0.48, 1.6, 4.8, or 16?mg/kg) 30?min before the i.art. injection of 7.5?mg of carrageenan (CGN) into the right knee joint cavity. Joint swelling and pain score were assessed after 1, 3 and 5?h, and tactile allodynia after 2 and 4?h. After the last measurement, the joint cavity lavages were performed for counting of the recruited leukocytes. The drugs (at the highest doses) were also tested for their gastric effects by evaluating macroscopical damage score and neutrophil recruitment (measured as myeloperoxidase – MPO activity) in the stomachs 5?h after administration of the drugs. In addition, the serum naproxen pharmacokinetic profiles of both compounds, administered at the highest equimolar doses, were obtained during the first 6?h after dosing. Results At the two highest tested doses, both naproxen and ATB-346 reduced edema and pain score (measured 3 and 5?h after CGN; P? Conclusion The presence of a H₂S-releasing moiety in the ATB-346 structure does not impair the antiinflammatory activity of the parent compound in rats with CGN-induced synovitis. In addition, released H₂S may account for the absence of deleterious gastric effects, thus making of ATB-346 a potentially useful therapeutic alternative to traditional naproxen for treatment of patients with arthritis.