Thrombosis Research 93 (1999) 43–50 BRIEF COMMUNICATION In Vivo Antithrombotic Effects of a Nitric Oxide-Releasing Aspirin Derivative, NCX-4016 John L. Wallace 1 , Marcelo N. Muscara 1 , Webb McKnight 1 , Michael Dicay 1 , Piero Del Soldato 2 and Giuseppe Cirino 3 1 Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada; 2 NicOx S.A., Paris, France; 3 Department of Experimental Pharmacology, University of Naples, Naples, Italy. (Received 10 February 1998 by Editor C. Cerletti; revised/accepted 29 June 1998) Key Words: Nitric oxide; Platelet; Ulcer; Thrombosis; antiplatelet effects of NCX-4215 appeared to be Thromboxane entirely attributable to the nitric oxide released from the compound, as it was found to be com- pletely devoid of any inhibitory activity on throm- T here is convincing evidence for the efficacy boxane synthesis. Indeed, even after repeated ad- of aspirin (ASA) in long-term prophylaxis ministration of a high dose of the compound for 5 of myocardial infarction and stroke [1–5]. days, NCX-4215 did not significantly affect platelet The mechanism through which ASA produces thromboxane synthesis. Given that agents such as these beneficial effects is related to its ability to NSAIDs and nitric oxide inhibit platelet aggrega- irreversibly inhibit thromboxane production by tion through distinct mechanisms and that the de- platelets [6]. Low doses of ASA used over many gree of inhibition of aggregation depends to some days can produce a very effective blockade of extent on the agonist that is used, it is possible that thromboxane synthesis, with little effect on prosta- a compound with the combined ability to inhibit glandin synthesis by most tissues [7,8]. However, thromboxane synthesis and release nitric oxide even with these low doses of ASA (10–100 mg), would exhibit enhanced anti-aggregatory activity there remains a significant risk of bleeding, particu- in vivo. In an attempt to test this hypothesis, we larly in the gastrointestinal tract [4,9–11]. Indeed, have evaluated the antithrombotic properties of a in one study, daily administration of ASA at a dose nitric oxide-releasing ASA derivative (NCX-4016) of only 10 mg resulted in a significant increase in (Fig. 1), which, unlike NCX-4215, exerts weak in- the incidence of endoscopically detected gastrodu- hibitory activity on thromboxane synthesis [17,18]. odenal lesions [10]. The effects of this compound have been compared We recently described a series of nitric oxide- with ASA and sodium nitroprusside in an in vivo releasing derivatives of nonsteroidal anti-inflam- thrombosis model in the rat. This model was se- matory drugs (NSAIDs) which have greatly re- lected because it has been reported to be aspirin duced damaging effects in the gastrointestinal tract sensitive [19]. Ulcerogenic effects of the two drugs [12–15]. Moreover, we have described a nitroxybu- on the stomach were also evaluated. tylated derivative of ASA (NCX-4215), which was found to be a potent inhibitor of platelet aggrega- tion but did not cause gastric damage [16]. The 1. Materials and Methods 1.1. Animals Abbreviations: ASA, acetylsalicylic acid; NSAID, nonsteroidal anti-inflammatory drug. Corresponding author: John L. Wallace. Department of Pharma- Male, Wistar rats (175–200 g) were obtained from cology and Therapeutics, University of Calgary, 3330 Hospital Charles River Breeding Farms (Montreal, Quebec) Drive NW, Calgary, Alberta, T2N 4N1, Canada. Tel: +1 (403) 220 4539; Fax: +1 (403) 270 3353; E-mail: wallacej@ucalgary.ca. and were housed in polypropylene cages and fed 0049-3848/99 $–see front matter  1998 Elsevier Science Ltd. Printed in the USA. All rights reserved. PII S0049-3848(98)00134-0