P9 Gastrointestinal-sparing effects of a hydrogen sulfide-releasing naproxen derivative in rats with compromised mucosal defence

Abstract

The gastrointestinal (GI) ulceration and bleeding caused by non-steroidal anti-inflammatory drugs (NSAIDs) is particularly prevalent in older patients with various co-morbidities. Hydrogen sulfide (H 2 S) has been shown to increase mucosal resistance to damage and accelerate ulcer healing. We evaluated the GI safety of a H 2 S-releasing naproxen derivative (ATB-346) versus naproxen in rat models of the co-morbidities in humans that increase susceptibility to GI damage and bleeding: obesity, arthritis, hypertension, elderly, and polypharmacy (concomitant use off low-dose aspirin and/or omeprazole). Co-morbid rats (Zucker obese, Freund’s adjuvant arthritis, spontaneously hypertensive or aged (19 months); n ⩾ 5 per group) and healthy controls were treated orally twice-daily for 4 days with vehicle, an anti-inflammatory dose of naproxen (10 mg/kg), equimolar (and equi-effective) dose of ATB-346 (14.5 mg/kg), or celecoxib (10 mg/kg) for 4 days. For polypharmacy, rats received the test drug plus omeprazole (10 mg/kg bid) and low-dose aspirin (10 mg/kg od). Hemorrhagic GI damage was blindly scored 3 h after the final dose of NSAID. ATB-346 suppressed gastric prostaglandin (>85%) and whole blood thromboxane (>95%) synthesis as effectively as naproxen. In healthy rats, test drugs induced very little or no GI damage at the doses tested. In arthritic rats, naproxen caused 10-times as much GI damage as in healthy controls, while ATB-346 did not elicit detectable GI damage. Obese rats given naproxen had a 9-fold increase in intestinal damage versus lean rats (47 ± 11 vs. 5 ± 2, respectively; p < 0.01), whereas ATB-346 did not elicit GI damage in either group. In aged rats, naproxen caused extensive gastric damage (score of 19 ± 4; p < 0.01), whereas those with ATB-346 (2 ± 1) were not different from vehicle-treated rats. Hypertensive rats exhibited similar susceptibility to naproxen-induced damage as healthy controls, while ATB-346 displayed no damage in normotensive or hypertensive rats. Co-administration of naproxen or celecoxib with low-dose aspirin and omeprazole resulted in extensive intestinal damage (scores of 23 ± 6 and 49 ± 6, respectively), whereas no damage was observed when ATB-346 was combined with low-dose aspirin and omeprazole. Rats with clinically relevant co-morbidities, excluding hypertension, exhibit a substantial increase in susceptibility to NSAID-induced GI injury. In contrast, the H 2 S-releasing naproxen derivative (ATB-346) spared the stomach and small intestine of damage, regardless of the model in which it was tested, and despite still inhibiting the key target enzymes for its anti-inflammatory and GI-damaging effects (COX-1 and COX-2). This novel NSAID also exhibited comparable anti-inflammatory activity to naproxen and celecoxib in arthritic rats and was significantly better tolerated when co-administered with low-dose aspirin and omeprazole. ATB-346 has superior GI safety to existing NSAIDs in models that mimic the clinical scenarios of polypharmacy and impaired GI mucosal defence. This is likely related to its ability to release the cytoprotective mediator hydrogen sulfide.