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EVALUATION OF NOVEL GI-SPARING NSAIDS IN MODELS OF COMPROMISED MUCOSAL DEFENCE
R Blackler1, G McKnight1, M Bolla2, E Ongini2, J Wallace11Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON; 2NicOx Ltd, Nice, France
Aims: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs, due to their ability to alleviate pain and inflammation. As the populations of developed countries age, the prevalence of age-related diseases, such as osteoarthritis, will increase substantially, likely increasing the use of NSAIDs. However, NSAID use is considerably hindered by their ability to cause clinically significant gastrointestinal (GI) damage and bleeding. Moreover, the risk of adverse GI events from chronic NSAID use is significantly increased in patients with co-morbidities (Laine, 2006). These facts emphasize the need for novel drug evaluation in models of compromised mucosal defence. Two novel NSAIDs, ATB-346 and NCX-429 (hydrogen sulfide- and nitric oxide-releasing naproxen derivatives, respectively) were evaluated for their ability to induce GI damage in rat models of obesity, arthritis and advanced age.
Methods: Co-morbid rats (Zucker obese, Freund's adjuvant arthritis, or aged (19 months)) and healthy controls were treated orally twice-daily with vehicle, an anti-inflammatory dose of naproxen (10 mg/kg), or equimolar (and equi-effective) doses of ATB-346 (14.5 mg/kg) or NCX-429 (14.88 mg/kg) for 4 days. Three hours after the final administration, the stomach and small intestine were blindly evaluated for hemorrhagic damage. Samples of gastric tissue were collected for prostaglandin E2 measurement. Whole blood thromboxane B2 synthesis was measured as an index of systemic COX-1 activity.
Results: ATB-346 and NCX-429 were as effective at suppressing prostaglandin (>85%) and thromboxane (>95%) synthesis, as the equimolar dose of naproxen. In healthy rats, none of the test drugs induced significant GI damage at the doses tested. In obese rats, naproxen caused a 40-fold increase in intestinal damage over healthy controls, whereas ATB-346 did not elicit any intestinal damage. In arthritic rats, naproxen caused ~10-times as much gastric and intestinal damage as in healthy controls. ATB-346 did not elicit detectable damage in the stomach or intestine of arthritic rats. In aged rats, naproxen caused extensive gastric damage (damage score of 19±4.2), whereas ATB-346 (1.7±0.7) and NCX-429 (2.0±1.1) caused no significant damage. None of the drugs elicited intestinal damage in aged rats.
Conclusions: Rats with clinically relevant co-morbidities exhibit a substantial increase in susceptibility to naproxen-induced GI injury. Despite this, both naproxen derivatives (ATB-346 and NCX-429) were well tolerated in the GI tract, producing negligible damage despite comparable anti-inflammatory effects to naproxen. This may be related to their ability to release gastro-protective mediators (hydrogen sulfide and nitric oxide, respectively).