Deciphering the pathogenesis of NSAID enteropathy using proton pump inhibitors and a hydrogen sulfide-releasing NSAID

The small intestine is a significant site of ulceration and bleeding induced by nonsteroidal anti-inflammatory drugs (NSAIDs). The pathogenesis is poorly understood. The present study explored the roles of bile, bacteria, and enterohepatic circulation to NSAID enteropathy, using both a conventional NSAID (naproxen) and a gastrointestinal-safe naproxen derivative (ATB-346), as well as proton pump inhibitors (PPIs). Rats were treated orally with naproxen or equimolar doses of ATB-346 over a 5-day period, with or without PPI administration, and intestinal damage was quantified. The cytotoxicity of bile from the rats was evaluated in vitro. Biliary excretion of naproxen and ATB-346 was determined. The impact of the NSAIDs and of PPIs on the composition of the intestinal microbiota was examined by deep sequencing of 16s rRNA. Naproxen caused significant intestinal damage and inflammation, whereas ATB-346 did not. Naproxen, but not ATB-346, dose dependently increased the cytotoxicity of bile, and it was further increased by PPI coadministration. Whereas biliary excretion of naproxen was significant in naproxen-treated rats, it was greatly reduced in rats treated with ATB-346. The enteric microbiota of naproxen-treated rats was distinct from that in vehicle- or ATB-346-treated rats, and PPI administration caused significant intestinal dysbiosis. The increase in cytotoxicity of bile induced by naproxen and PPIs may contribute significantly to intestinal ulceration and bleeding. Some of these effects may occur secondary to significant changes in the jejunal microbiota induced by both naproxen and PPIs.

Recommendations for the Appropriate Use of Anti-Inflammatory Drugs in the Era of the Coxibs: Defining the Role of Gastroprotective Agents

Treatment with anti-inflammatory drugs and the analgesic efficacy of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are compromised by a two- to fourfold increased risk of gastrointestinal complications. This increased risk has resulted in an increasing use of the new selective cyclooxygenase-2 inhibitors or coxibs, which, in clinical trials and outcomes studies, reduced gastrointestinal adverse events by 50% to 65% compared with conventional NSAIDs. However, the coxibs are not available to all patients who need them, and NSAIDs are still widely used. Moreover, treatment with a coxib cannot heal pre-existing gastrointestinal lesions, and cotherapy with an anti-secretory drug or mucosal protective agent may be required.This paper addresses the management of patients with risk factors for gastrointestinal complications who are taking NSAIDs and makes recommendations for the appropriate use of ‘gastroprotective’ agents (GPAs) in patients who need to take an NSAID or a coxib. When economically possible, a coxib alone is preferable to a conventional NSAID plus a GPA to minimize exposure to potential gastrointestinal damage and avoid unnecessary dual therapy. Patients at high risk require a GPA in addition to a coxib.