EDITORIAL COMMENT
Theriac found? Nitric oxide-aspirin and the search for the universal cure*
Richard I. Levin, MD, FACC, FACP, FAHA ,*
Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, New York, USA
* Reprint requests and correspondence: Dr. Richard I. Levin, NYU School of Medicine, MSB-153, 550 First Avenue, New York, New York 10016, USA.
richard.levin{at}med.nyu.edu
In the second century of this era, a consul of Rome introduced his doctor, Claudius Galenus of Pergamum, to emperor Marcus Aurelius. They got along famously, and Galen became the court physician. Renowned for his public vivisections, which allowed startling advances in the fields of anatomy and physiology, Galen joined a band of both notable and notorious doctors on a 4,000-year-old quest for the universal cure. Galen's theriac (loosely from the Greek for animal flesh), or antidote, was a grand version of the compounded drug of the day. It was the antidote to nothing, but presaging Jenner's invention of immunotherapy by prior exposure to a related antigen, and among its 70 or more ingredients, it contained snake meat for protection against snakebite. Its active ingredients were opium and the finest of white Falernian wines from the central slopes north of Naples (1). No cure-all, but after brewing for 40 days, it was imbibed with gusto.
In this issue of the Journal, Fiorucci et al. (2) embellish their interesting story and tell us of the clinical relevance of a modern, actual theriac called nitric oxide (NO)-aspirin (NCX-4016). Like Galen's, it is a designer drug whose two active ingredients, the molecules of the year of 1897 and 1992 (3), dissociate from the parent molecule to exert their effects (Fig. 1). Acetylsalicylic acid, or aspirin, was probably first synthesized by Gerhardt in 1853, resynthesized in a purer form by Kraut in 1869, and then "discovered" by Hoffmann of Friedrich Bayer & Co. in 1897 (4). Mimicking other legends of rational drug design, what it does is not nearly what it was supposed to do. Salicylic acid, an anti-inflammatory in its own right (5), is highly toxic to the gastrointestinal tract, and those European chemists of the late 19th century used acetylation as a means to buffer the parent compound. However, the remarkable activity of aspirin against the leading causes of death in the West, in both the prevention of thrombotic vascular events (6) and the chemoprevention of cancer (7), resides not in the salicylate, but in the acetyl group. Acetylation of the catalytic sites of the first enzyme in the prostaglandin cascade, either cyclooxygenase (prostaglandin H synthase)-1 at Ser529 or its isozyme cyclooxygenase-2 at Ser516, shuts down the prostanoid synthesis in platelets for their lifetimes and in nucleated cells until more synthase can be made (8,9). Donating its acetyl group allows aspirin to reduce thrombotic vascular events by 30%, deaths by 15% to 20% (10), and gastrointestinal neoplasia by 40% to 50% (11).
View larger version (165K):
[in this window]
[in a new window]
|
Figure 1 On the left is a three-dimensional rendering of aspirin or acetylsalicylic acid. On the right is nitric oxide (NO)-aspirin (NCX-4016) showing, from the left and moving clockwise, the aspirin group, a spacer joined by an ester linkage, and the NO-releasing group. In vivo, esterases separate the aspirin moiety from the substituted benzene spacer-NO complex, and then NO is released slowly from the NO-releasing group (16). Images generated by T. Cardozo using ICM software (Molsoft LLC, La Jolla, California).
|
|
Given the expectations at its synthesis, the astonishing benefits of aspirin come at the ironical price of gastritis, hemorrhage, and a host of less common side effects—which brings us to NO and an intriguing question. If adding an acetyl residue made salicylate better, does adding a NO-generating residue make aspirin better? As though an immortal hand had framed this symmetry, the answer is "yes" (2). Nitric oxide is one of the great contributions of 20th-century vascular biology (3,12). It was discovered because endothelium-derived relaxing factor (13) was not prostacyclin (14,15). It is a ubiquitous signaler in both the plant and animal kingdoms, and its biological activity is remarkable, expansive, and complex (12). Nitric oxide protects the gastric mucosa, induces vasodilation, and inhibits platelet aggregation, inflammation, cellular proliferation, and apoptosis through both cyclic guanosine monophosphate-dependent and -independent mechanisms (16).
There are tantalizing suggestions in experimental animals, in well-conducted studies with NO-aspirin, about the control of hypertension (17,18), the reduction of brain damage after stroke (19), and the inhibition of restenosis after percutaneous intervention (20). It also may be better than aspirin alone in preventing or controlling colonic adenocarcinoma (21). Thus, it appears to have broad, protective properties against both cancer and atherosclerotic vascular diseases and their complications.
Fiorucci and colleagues on both sides of the Atlantic have described much of the basic and clinical pharmacology of NO-aspirin. In their current work (2), they extend previous observations to a 21-day trial of NCX-4016 in comparison with aspirin in healthy subjects. Aspirin had been synthesized to avoid the gastric irritation of salicylic acid alone but was entirely unsuccessful. Nitric oxide-aspirin, at least during a period of three weeks, fixed what inhibition of cyclooxygenase synthase made worse. The authors show convincingly that NO-aspirin alone causes no gastroduodenal damage and that it significantly attenuates the damage done by co-administered aspirin at a daily dose of 325 mg. At the same time, alone or in combination with aspirin, it inhibits platelet thromboxane synthesis and aggregation. It does something, however, that aspirin does not do. In human monocytes, it down-regulated tissue factor and markedly inhibited interleukin-6 and monocyte chemoattractant protein-1 expression. Because atherogenesis and plaque rupture are points on the continuum of vascular inflammation, it is reasonable to speculate that long-term trials of NO-aspirin would best the parent compound in the primary and secondary prevention of vascular events.
The study leaves us with many questions, such as whether an agent with such broad biologic properties, taken daily for life after the age of 45, might not have unexpected and undesirable effects. An equally important question relates to the ideal dose of aspirin against which to compare this theriac of nitrate. We still do not know (6,22). When the anti-platelet trialists published their first article in 1988 (10), they made it clear that nothing was to be gained from high doses of aspirin. Indeed, a dose of approximately 25 mg, perhaps even lower, may be sufficient for prevention of vascular events, and such a dose might lower gastrointestinal and hemorrhagic complications (6,10,22,23). We still do not know. However, most of the large, modern, multicenter cardiovascular trials have used doses of 325 to 650 mg; so the evidence favors standard doses, and before we rush to reduce the dose to nanograms as the homeopaths would have recommended, there also is the unexplored issue of aspirin resistance to resolve (24).
After six millennia of brewing and searching for a universal cure, the compounded pharmaceutical described as NO-aspirin may be nearly a theriac. But we must wait; the drug is in Phase II clinical trials, and we will not know for some time whether it is an antidote to that which kills us. And who can say that the next versions, with a pinch of statin and eye of newt, will not be even better?
 |
Footnotes
|
|---|
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
|
References
|
|---|
1. The history of drinking. Uncorking the past. The Economist [print edition], December 22, 2001. Available at: http://www.economist.com/diversions/displayStory.cfm?story_id=883706. Accessed March 22, 2004
2. Fiorucci S, Mencarelli A, Meneguzzi A, et al. Co-administration of nitric oxide-aspirin (NCX-4016) and aspirin prevents platelet and monocyte activation and protects against gastric damage induced by aspirin in humans. J Am Coll Cardiol 2004;44:635–41.
3. Koshland DE. The molecule of the year. Science. 1992;258:1861[Free Full Text]
4. Andermann AAJ. McGill Journal of Medicine 1996;2:115–20. Available at: http://www.med.mcgill.ca/mjm/issues/v02n02/aspirin.html. Accessed March 17, 2004
5. Abramson S, Korchak H, Ludewig R, et al. Modes of action of aspirin-like drugs. Proc Natl Acad Sci USA 1985:7227–31.
6. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: The relationships among dose, effectiveness, and side effects. Chest. 2001;119(Suppl 1):39S–63S[CrossRef][Medline]
7. Janne PA, Mayer RJ. Chemoprevention of colorectal cancer. N Engl J Med. 2004;342:1960–1968
8. Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci USA. 1975;72:3073–3077[Abstract/Free Full Text]
9. Loll PJ, Picot D, Garavito RM. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nat Struct Biol. 1995;2:637–643[CrossRef][Medline]
10. Antiplatelet Trialists' Collaboration. Collaborative overview of randomized trials of antiplatelet therapy: I. prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81–106[Abstract/Free Full Text]
11. Imperiale TF. Aspirin and the prevention of colorectal cancer. N Engl J Med. 2003;348:879–880[Free Full Text]
12. Stuart-Smith K. Demystified. Nitric oxide. Mol Pathol. 2002;55:360–366[Abstract/Free Full Text]
13. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–376[CrossRef][Medline]
14. Ignarro LJ, Byrns RE, Buga GM, et al. Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacological and chemical properties that are identical to those of nitric oxide radical. Circ Res. 1987;61:866–879[Abstract/Free Full Text]
15. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524–526[CrossRef][Medline]
16. Wallace JL, Ignarro LJ, Fiorucci S. Potential cardioprotective actions of NO-releasing aspirin. Nat Rev Drug Discov. 2002;1:375–382[CrossRef][Medline]
17. Muscara MN, Lovren F, McKnight W, et al. Vasorelaxant effects of a nitric oxide-releasing aspirin derivative in normotensive and hypertensive rats. Br J Pharmacol. 2001;133:1314–1322[CrossRef][Medline]
18. Rossoni G, Manfredi B, Del Soldato P, Berti F. NCX 4016, a nitric oxide-releasing aspirin, modulates adrenergic vasoconstriction in the perfused rat tail artery. Br J Pharmacol. 2002;137:229–236[CrossRef][Medline]
19. Fredduzzi S, Mariucci G, Tantucci M, Del Soldato P, Ambrosini MV. Nitro-aspirin (NCX4016) reduces brain damage induced by focal cerebral ischemia in the rat. Neurosci Lett. 2001;302:121–124[CrossRef][Medline]
20. Napoli C, Aldini G, Wallace JL, et al. Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis. Proc Natl Acad Sci USA. 2002;99:1689–1694[Abstract/Free Full Text]
21. Nath N, Kashfi K, Chen J, Rigas B. Nitric oxide-donating aspirin inhibits ß-catenin/T cell factor (TCF) signaling in SW480 colon cancer cells by disrupting the nuclear ß-catenin-TCF association. Proc Natl Acad Sci USA. 2003;100:12584–12589[Abstract/Free Full Text]
22. Kong DF, Hasselblad V, Kandzari DE, Newby LK, Califf RM. Seeking the optimal aspirin dose in acute coronary syndromes. Am J Cardiol. 2002;90:622–625[CrossRef][Medline]
23. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long-term use of aspirin: Meta-analysis. BMJ. 2000;321:1183–1187[Abstract/Free Full Text]
24. Chen W-H, Lee P-Y, Ng W, Tse H-F, Lau C-P. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol. 2004;43:1122–1126[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
E. Fosslien
Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs
Ann. Clin. Lab. Sci.,
October 1, 2005;
35(4):
347 - 385.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. I. Levin
The Puzzle of Aspirin and Sex
N. Engl. J. Med.,
March 31, 2005;
352(13):
1366 - 1368.
[Full Text]
[PDF]
|
|
|
|
Top
References