Over the past few years, 'NO-releasing' NSAIDs have been developed; in these agents, an NSAID is chemically linked with a NO moiety [99
]. Originally, these were designed to improve the gastrointestinal side-effect profiles of the NSAIDs; in particular, it was hoped that they would reduce ulcer disease and gastrointestinal hemorrhage. However, as more evidence accumulates about the possible adverse cardiovascular effects of many of the NSAIDs, the question of whether the addition of the NO moiety to a NSAID might improve the cardiovascular risk profile of patients taking chronic NSAIDs has arisen. NO is released slowly from the CINOD, and this is thought to take place in vivo
via an enzymatic esterase based reaction [100
]. Various CINODs have been developed, including NO derivatives of aspirin, flurbiprofen, naproxen (naproxcinod), diclofenac, and ibuprofen. Few data are currently available on their effects in humans.
CINODs have extra effects over and above those of their parent NSAID. For example, NO-aspirin, unlike standard aspirin, reduces levels of the proinflammatory cytokine IL-1β by inhibiting gastric caspase-1 activity [101
]. In various animal models of acute and chronic inflammation, CINODs have exhibited similar or even greater effects on inhibition of inflammation to those of their parent NSAIDs [102
]. Also, a NO-releasing aspirin derivative had a sevenfold more potent effect on inhibition of platelet aggregation than aspirin when given to rats [104
Data on the vascular effects of CINODs show that there is some influence on vascular tone. In vitro
, the CINODs NO-flurbiprofen and NO-aspirin, and a NO-steroidal compound, NO-prednisolone, all cause vasorelaxation of rat aortic rings via a NO-dependent mechanism, with a vasodilator potency at least three orders of magnitude less than that of sodium nitroprusside [105
]. However, there were no effects on systemic blood pressure when NO-flurbiprofen or NO-aspirin were given intravenously to anesthetized rats. When naproxen or naproxcinod was administered to rats for 4 weeks, the naproxen treated rats had significantly higher blood pressure than did those treated with naproxcinod or placebo. In a group of rats pretreated with the NOS inhibitor L
-NAME to induce hypertension, naproxcinod reduced the blood pressure significantly whereas naproxen alone increased the blood pressure [106
The effects of naproxcinod on blood pressure in humans have been investigated in clinical studies. A 6-week clinical phase 2 study conducted in osteoarthritis patients comparing naproxcinod versus rofecoxib and naproxen [107
] showed trends toward reductions in mean systolic and diastolic blood pressures with naproxcinod 375 mg and 750 mg twice daily, as compared with trends towards increased blood pressure in the rofecoxib and naproxen 500 mg groups. The first phase 3 study with naproxcinod in patients with osteoarthritis [108
] identified small reductions from baseline in mean office systolic blood pressure with naproxcinod 750 mg twice daily and in mean office diastolic blood pressure with naproxcinod 375 mg twice daily or 750 mg twice daily, as compared with naproxen 500 mg twice daily. In an exploratory 24-hour ambulatory blood pressure monitoring study performed in hypertensive patients [109
], differential effects on blood pressure of naproxcinod compared with naproxen were also observed. Although the primary end-point of least square mean change from baseline in average 24-hour systolic blood pressure (1.9 mmHg) was not statistically significantly different, there was a reduction in the secondary end-point of average 24-hour diastolic blood pressure of 1.9 mmHg (P
= 0.007) in favor of naproxcinod.
Some of the human data presented thus far reveal non-significant trends rather than actual differences in blood pressure. However, even small reductions in blood pressure may have significant effects on cardiovascular outcome within the context of chronic therapy with NSAIDs, because it has been reported that use of many of these agents (including naproxen, meloxicam, diclofenac, and ibuprofen) results in average increases in mean arterial pressure as high as 5.5 mmHg [47
]. Further data are required to evaluate whether there is a true benefit of CINODs on blood pressure in humans, and such studies are currently ongoing. The effects of CINODs on endothelial function are not yet known. Also, it is unclear whether CINODs might be subject to the development of vascular tolerance in a similar way to that seen with organic nitrates.
There is also some evidence that CINODs protect the myocardium from ischemia/reperfusion injury. Using left ventricular end-diastolic pressure as a surrogate marker for myocardial dysfunction in an in vitro
perfused rabbit heart model [113
], pretreatment with aspirin, celecoxib, or meloxicam increased myocardial damage after ischemic insult and reperfusion. However, pretreatment with NCX-4016 (an NO-releasing aspirin derivative) had the opposite effect, reducing myocardial damage and dysfunction caused by the insult. In a similar study [114
], in dose-related manners, naproxen increased ischemia/reperfusion injury compared with vehicle whereas naproxcinod reduced ischemia/reperfusion injury.
It is potentially the case that some of the cardiovascular risk associated with chronic NSAID use may be ameliorated by steady donation of NO in the vasculature. However, further work in humans is necessary to investigate this potential.