Hydrogen sulfide-based therapies: focus on H2S releasing NSAIDs

Nonsteroidal anti-inflammatory pain medications, commonly referred to as NSAIDs, are effective treatment for pain, fever and inflammation. However their use associates with a 4-6 fold increase in the risk of gastrointestinal bleeding. The basic mode of action of NSAIDs lies in the inhibition of cyclooxygenases (COXs), a family of enzymes involved in the generation of prostaglandins (PGs). The COX exists at least in two isoforms, COX-1 and COX-2, with PGs mediating inflammation at site of injury generated by the COX-2, while COX-1 produces PGs that are essential in maintaining integrity in the gastrointestinal tract. Selective inhibitors of COX-2, the coxibs, spare the gastrointestinal tract while exerting anti-inflammatory and analgesic effects. However, their use has been linked to an increased risk of thrombo-embolic events. Nitric oxide (NO) and hydrogen sulfide (H(2)S), are potent vasodilatory agents that maintain mucosal integrity in the gastrointestinal tract. In the last decade hybrid molecules that release NO or H(2)S have been coupled with non-selective NSAIDs to generate new classes of anti-inflammatory and analgesic agents with the potential to spare the gastrointestinal and cardiovascular system. These agents, the NO-releasing NSAIDs, or CINOD, and the H(2)S-releasing NSAIDs are currently investigated as a potential alternative to NSAIDs and coxibs. Naproxcinod has been the first, and so far the only, CINOD extensively investigated in clinical trials. Despite its promising profile, the approval of this drug was recently rejected by the Food and Drug Administration because the lack of long-term controlled studies. NSAIDs that release H(2)S as a mechanism to support an enhanced gastrointestinal and cardiovascular safety are being investigated in preclinical studies. Either naproxen or diclofenac coupled to an H(2)S releasing moiety has been reported to cause less gastrointestinal and cardiovascular injury than parent NSAIDs in preclinical models.