New research using murine models helps to clarify the mechanism by which cyclooxygenase-2 (COX-2) inhibitors increase the incidence of myocardial infarction and stroke, potentially paving the way for a new generation of drugs that will avoid this effect. The new study, published in the May issue of the Journal of Clinical Investigation,¹ suggests that blocking the microsomal prostaglandin E synthase (mPGES-1) enzyme may be as effective at treating pain and inflammation as nonsteroidal anti-inflammatory drugs (NSAIDs)—without the cardiovascular side effects.

The researchers used animal models that mimicked the effect of either COX-2 inhibitors or low-dose aspirin and compared them with healthy mice treated with COX-2 inhibitors. They found that genetic disruption of COX-2, inhibition of the COX-2 enzyme by specific inhibitors, and disruption of the effects of prostacyclin through the removal of its receptor all predisposed the mice to thrombogenesis and elevated blood pressure. Furthermore, the thrombogenetic and hypertensive responses were attenuated by decreasing the levels of COX-1 enzyme, which mimics the beneficial effects of low-dose aspirin.

The new results "align mechanism with drug effect in a manner that is compelling, [and] are consistent with the effect of the drugs as observed in studies of their action in humans and in clinical trials," says Garret FitzGerald, MD, senior study author and director of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania in Philadelphia. According to Dr. FitzGerald, it is important to remember that "manifestations of this mechanism—a heart attack or stroke—would be conditioned by issues like dosage, kinetics, and duration of drug treatment, other treatments (eg, aspirin), and the underlying cardiovascular risk of the patients involved." He adds that "we studied in detail the elements of variability of response to Celebrex and Vioxx and concluded that up to 30% [of the response] was attributable to genetic variants."

The findings also bring researchers closer to validating the "FitzGerald Hypothesis," which suggests that, unlike aspirin and nonselective NSAIDs, COX-2 inhibitors depress systemic prostacyclin without concomitant inhibition of platelet-derived thromboxane (TxA2), resulting in an augmented response to thrombotic and hypertensive stimuli. This could explain the acceleration of atherogenesis that was observed.

Although the role of aspirin in potentially mediating cardiovascular risk among patients taking COX-2 inhibitors is unclear, Dr. Fitzgerald indicates that "these experimental data suggest that aspirin would attenuate the [cardiovascular] risk," adding that since aspirin will also attenuate hypertension, not just clotting, a human study to determine whether aspirin will decrease the cardiovascular risk might be worth performing. "On the other hand, we know from human studies that aspirin will undermine the gastrointestinal advantage of COX-2 inhibitors," he says.

The study also demonstrated that deleting the mPGES-1 gene decreased PGE2 expression, increased prostacyclin expression, and had no effect on thromboxane biosynthesis in vivo. More importantly, mPGES-1 deletion did not affect thrombogenesis or blood pressure. Other investigators have shown that deletion of the mPGES-1 gene may be as effective as NSAIDs in reducing pain and inflammation.² The data from this research suggest that inhibitors of mPGES-1 may retain their anti-inflammatory efficacy by depressing PGE2 while avoiding the adverse cardiovascular consequences associated with COX-2-mediated prostacyclin suppression. "The drugs are just about to go into human [trials], so we don't know [what their potential is]," Dr. FitzGerald tells CIAOMed. "We only know that knocking out the enzyme in mice looks very effective, so we have everything to play for at this early stage."

References

1. Cheng Y, Wang M, Yu Y, et al. Cycclooxygenase, microsomal prostaglandin E-synthase-1 and cardiovascular function. J Clin Invest. [serial online] April 13, 2006;doi:10.1172/JCI27540.
2. Trebino CE, Stock JL, Gibbons CP, et al. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc Natl Acad Sci USA. 2003;100:9044-9049.