Traditional nonsteroidal anti-inflammatory drugs, tNSAIDs, are effective medication for prevention of ischemic events and treatment of
pain,
fever and
inflammation. However their use associates with a significant risk to develop gastrointestinal and cardiovascular complications. Low doses of acetyl
salicylic acid (ASA) and effective doses of tNSAIDs associate with a 2-6 fold increase in the risk of gastrointestinal
bleeding. ASA and tNSAIDs inhibit
cyclooxygenases (COXs). The COX exists at least in two
isoforms, COX-1 and COX-2. Selective inhibitors of COX-2, the
coxibs, spares the gastrointestinal tract while exert anti-inflammatory and
analgesic effects. However,
coxibs increase the risk of thrombo-embolic events.
Nitric oxide (NO) and
hydrogen sulfide (H₂S), are potent vasodilatory agents that maintain mucosal integrity in the gastrointestinal tract. Hybrid molecules generated by coupling a NO or H₂S releasing moiety to ASA or tNSAIDs has resulted into new classes of
NSAIDs. These agents, the NO-releasing
NSAIDs, or CINOD, and the H₂S releasing
NSAIDs are currently investigated as a potential alternative to tNSAIDs and
coxibs.
Naproxcinod has been the first, and so far the only, CINOD investigated in clinical trials. These studies have shown a slightly improvement in gastrointestinal tolerability in comparison to
naproxen in
surrogate endpoints (number of gastric and
duodenal ulcers) and a significant reduction in the risk of destabilization of blood pressure control in patients with osteoarthosis taking
anti-hypertensive medications in comparison to either
naproxen and
rofecoxib. The lack of outcome studies, however, has precluded the approval of
naproxcinod by the Food and Drug Administration leading to a voluntary withdrawn of an application to the EMEA in May 2011.
NSAIDs that releases H₂S as a mechanism supporting an intrinsic gastrointestinal and cardiovascular safety are being investigated in preclinical models. Either
naproxen and
diclofenac hybrids have been reported to cause less gastrointestinal injury than parent
NSAIDs. These novel chemical entities exert a variety of beneficial effects in rodent models of cardiovascular and metabolic disorders through a mechanism that might involve the release of H₂S and/or by exerting
anti-oxidant effects. The beneficial role these mechanisms in clinical settings await a proof-of-concept study.