Novel Pro-Drugs "Superaspirins": More Effective, Less GI Toxicity Than Conventional Aspirin

NEW ORLEANS, LA—Synthesis and characterization of two of novel aspirin pro-drugs—or “superaspirins”—suggest not only can efficacy and safety of conventional aspirin be improved, but therapy failure with aspirin due to gastrointestinal (GI) side effects may be reduced. This raises the possibility of new applications of aspirin beyond secondary prevention of CV disease.

While treatment with conventional aspirin can significantly reduce incidence of CV events, MI, or stroke in patients with previous CV events, treatment failure is common, noted Mark T. Ledwidge, MD and colleagues from Trinity College and St. Vincents University Hospital, Dublin, Ireland. Novel pro-drug approaches may solve the dual challenge of efficacy and tolerability.

Using in vitro and in vivo models of platelet aggregation, the investigators evaluated comparative efficacy of three novel aspirin pro-drugs (ST0701, ST0702, ST0703) vs. conventional aspirin at equimolar doses. The comparative topical effects of high doses of the pro-drugs and conventional aspirin were also examined over 3 days in rat and rabbit models of GI injury.

Compared with conventional aspirin, two of the prodrugs were significantly more effective in attenuating platelet aggregation in human platelet rich plasma in response to adenosine diphosphate, collagen, and arachidonic acid, Dr. Ledwidge noted during ACC.11, the American College of Cardiology's 60th Annual Scientific Session. Additionally, ST0702 was more effective (P<0.05) at inhibiting lipoprotein(a) than either niacin or aspirin. It also attenuated low-density lipoproteins (LDL) and triglycerides. However, unlike niacin, ST0702 did not raise plasma PgD2, the arachidonic acid metabolite that is believed to cause flushing. This may be due to aspirin release from ST0702 or its pharmacokinetic-pharmacodynamic profile.

In vivo preclinical studies demonstrated that at equimolar doses, one of the agents was more effective than aspirin in inhibiting thromboxane B2 production. At high doses (30mg/kg/day for 3 days), conventional aspirin produced significant ulceration in in-vivo models of GI injury; in contrast, the pro-drugs caused no damage at equimolar doses.