NO-aspirins: Antithrombotic activity of derivatives of acetyl salicylic acid releasing nitric oxide

Nitroderivatives of acetylsalicylic acid have recently been synthesized (NO-aspirins; NicOx, S.A., Paris, France). Two of these compounds, NCX 4215 and NCX 4016, have been tested for their effects on platelet function and their gastrointestinal tolerability. These compounds appear to have a dual pharmacological activity: they inhibit COX activity (ASA-like activity) and activate intracellular soluble guanylyl cyclase (NO-like activity). Both NO-aspirins inhibit agonist-induced platelet aggregation in vitro, and are more effective than ASA as inhibitors of thrombin-induced platelet aggregation. This effect appears to be mediated by the release of NO, since scavengers of NO were shown to prevent it. NCX 4016 inhibits both platelet adhesion and the expression of adhesion molecules. NCX 4016 is more potent than NCX 4215 as an inhibitor of arachidonic acid-induced aggregation and, likewise, of platelet COX. In vivo, both NCX 4215 and NCX 4016 inhibited thrombin-induced platelet aggregation. Like aspirin, cumulative doses of NCX 4016 inhibited the production of platelet TXB2. The release of NO by NCX 4215 and NCX 4016 was demonstrated in vivo as well as in vitro. Similarly, NO-like biological activities were displayed by both compounds. The gastrointestinal tolerability of NCX 4215 or NCX 4016 is superior to that of ASA. This superiority can be attributed to the gastroprotective activity of NO released from these drugs as well as by only slight inhibition of COX in the gastric mucosa.