NO-aspirin: mechanism of action and gastrointestinal safety
Section snippets
Aspirin: the same mechanism for activity and toxicity
Aspirin exerts its effect primarily by interfering with the biosynthesis of cyclic prostanoids, i.e., thromboxane A2 (TXA2), prostacyclin, and other prostaglandins [1]. These prostanoids are generated by the enzymatically catalyzed oxidation of arachidonic acid, which is itself derived from membrane phospholipids (Fig. 1). Arachidonic acid is metabolized by the enzyme prostaglandin (PG) H-synthase, which, through its cyclooxygenase (COX) and peroxidase activities, results in the production of
NO-aspirins
An approach that has been taken to develop a drug that inhibits COX-1 activity that spares the gastrointestinal tract is the coupling of aspirin to a nitric oxide (NO)-releasing moiety (Fig. 2). NO exerts protective effects on the stomach [14] and mediates many components of gastrointestinal mucosal defence (Table 1), thus the addition of the NO-releasing moiety to aspirin will results in a new chemical entity that maintains and possibly expands the pharmacological properties of parent drug,
NCX-4016
NCX-4016 is the prototype of NO-aspirins. The structure of NCX-4016, shown in Fig. 2, consists of the parent molecule (aspirin) linked to a ‘spacer’ via an ester linkage, which is in turn connected to an NO-releasing moiety [22], [23], [24]. Both the aspirin and the NO moieties of NCX-4016 contribute to its effectiveness, the latter occurring via both cyclic guanosyl monophosphate (cGMP)-dependent and -independent mechanisms (Table 2). In contrast to conventional NO donors, NO-aspirin is stable
Gastrointestinal safety and anti-platelet activity of NCX-4016 in humans: the proof of concept
In terms of gastrointestinal safety, NCX-4016 can be clearly distinguished from aspirin. This compound does not produce gastric or intestinal damage in laboratory animals as is seen with aspirin [21], [22], [23]. Preclinical studies have extensively demonstrated that NCX-4016 is considerably well tolerated, even at the dose of 250 mg/kg, despite it completely suppress COX-1 activity in the gastric mucosa [24]. Although several mechanisms have been postulated to explain the gastro-sparing
Conclusion
Human studies have confirmed that NCX-4016 imparts its activity by inhibiting COX-dependent and COX-independent, NO-sensitive, targets. These studies have proven that addition of a NO-releasing moiety to aspirin results in a new chemical entity that exerts a multilevel regulation of the coagulation network. Despite its potent anti-thrombotic activity NO-aspirin spares the gastric mucosa, and is significantly better tolerated than aspirin. Further studies are ongoing to define whether this
Conflict of interest statement
Research described in this paper was partially supported by a grant from Nicox to S. Fiorucci. P. Del Soldato is Scientific Director of Nicox.
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