Pharmacological profile of a novel H2S-releasing aspirin

Prevention of aspirin toxicity represents still an unmet medical need. Already several years ago, nitric oxide was utilized as a tool to reduce gastric toxicity [1], by preparing NOreleasing aspirin (NO-aspirin) and many other NO-donating agents. NO-aspirin appears unequivocally to be better tolerated in animals and humans, although consistently higher doses were needed to obtain comparable prostaglandin suppression to aspirin in humans. It remains to be understood if this could be at least partially dependent on the tachyphylaxis responses observed for NO-aspirin. With this general approach in mind, we were intrigued to determine whether a chemically modified aspirin with the ability to release hydrogen sulfide (H2S) might prove of value as a novel stomach-sparing aspirin. The idea came from the evidence that this gaseous mediator possesses all of the positive effects of NO without the capacity to form peroxynitrite, the toxic metabolite, which has been thought to be involved in tachyphylaxis and related to redox imbalance disorders. The pharmacological profile of a new safe and effective hydrogen sulfide-releasing aspirin (ACS 14) will be described. We report the synthesis of this compound and of its metabolite(ACS21) and the preliminary pharmacokinetics and in vivo metabolism with the determination of the hydrogen sulphide (H2S) plasma levels after intravenous rat administration, using an improved validated HPLC analytical method. While it maintains the thromboxane suppressing activity owned by the parent compound, ACS14 appears to spare the gastric mucosa, by affecting redox imbalance processes via H2S/GSH increased formation and isoprostane suppression. In conclusion, the new H2S-donating aspirin appears to be an effective and safe compound, with significant advantages over the native aspirin