Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study.
OBJECTIVE
NCX-4016 is a nitric oxide-releasing derivative of aspirin with antiplatelet activity. The aim of this study was to investigate the effect of NCX-4016 on gastrointestinal mucosa and platelet functions in healthy human volunteers.


METHODS
This was a parallel-group, double-blind, placebo-controlled study. Forty healthy subjects were randomly allocated to receive 7 days of treatment with NCX-4016 (400 and 800 mg twice daily), equimolar doses of aspirin (200 and 420 mg twice daily), or placebo. Upper endoscopies were performed before and at the end of the treatment period, and gastroduodenal lesions were graded using a predefined scoring system. Basal and posttreatment platelet aggregation in response to arachidonic acid (AA) and serum thromboxane (TX) B(2) and AA-stimulated platelet TXB(2) production were investigated.


RESULTS
Mucosal endoscopic injury score on day 7 was 0.63 +/- 0.16 in the placebo group and 11.0 +/- 3.0 and 16.1 +/- 1.6 in healthy volunteers treated with 200 and 420 mg aspirin twice daily (P < 0.0001 vs. placebo). NCX-4016 was virtually devoid of gastric and duodenal toxicity, resulting in a total gastric and duodenal endoscopic score of 1.38 +/- 0.3 and 1.25 +/- 0.5 (P < 0.0001 vs. aspirin, not significant vs. placebo). NCX-4016 inhibited AA-induced platelet aggregation as well as serum TXB(2) and platelet TXB(2) generation induced by AA to the same extent as aspirin (not significant vs. aspirin).


CONCLUSIONS
In this study, we have proven the concept that addition of an NO-donating moiety to aspirin results in a new chemical entity that maintains cyclooxygenase-1 and platelet inhibitory activity while nearly avoiding gastrointestinal damage.
Fiorucci
Stefano
S
Clinica di Gastroenterologia ed Epatologia, Dipartimento di Medicina Clinica e Sperimentale, Università di Perugia, Perugia, Italy. fiorucci@unipg.it
Santucci
Luca
L
Gresele
Paolo
P
Faccino
Roberto Maffei
RM
Del Soldato
Piero
P
Morelli
Antonio
A
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology*; D001241:Aspirin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000494:pharmacology*; D004064:Digestive System / Q000187:drug effects* / Q000473:pathology; D004311:Double-Blind Method; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D010865:Pilot Projects; D010919:Placebos / Q000009:adverse effects / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D013929:Thromboxane B2 / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002316:Cardiotonic Agents; D010919:Placebos; D013929:Thromboxane B2; C102148:nitroaspirin; D001241:Aspirin