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.