NicOx’s nitro-derivative of naproxen, HCT 3012, shown to be effective in a model of myocardial infarction

DailyUpdates 11th May: A number of clinical studies including the VIGOR trial have suggested that the NSAID naproxen may reduce the incidence of myocardial infarction.  However the gastrointestinal side-effects of naproxen and its ability to exacerbate hypertension preclude its use in at-risk individuals.  Upcoming data about to be published in the journal JPET demonstrate the efficacy of the safer and anti-hypertensive nitro-derivative of naproxen, HCT 3012, in a model of myocardial infarction.

Representing the most common cause of death in the US and driving a therapeutic market valued at an estimated $73.7bn in 2002, cardiovascular diseases occupy a central place in the pharmaceutical arena (for a detailed analysis of this arena access "The Cardiovascular Market Outlook to 2008" [more]). Coronary heart disease, one of the most prevalent cardiovascular diseases affects 12 million Americans and causes the death of 1 million of these individuals each year.

Aspirin prevents thromboxane A2 formation and consequent platelet aggregation and mediator release and these anti-thrombotic properties of make it a commonly employed preventative treatment in patients at risk of myocardial infarction.  Indeed aspirin can reduce the incidence of myocardial infarction in unstable angina patients by 50% and it is recommended for these patients.  Likewise nitroglycerin, which acts to vasodilate coronary vessels through the increased formation of nitric oxide (NO), is also commonly used in patients with angina.

Although NSAIDs have anti-inflammatory and antiplatelet effects similar to those of aspirin, these drugs have not been found to confer a protective effect against acute myocardial infarction. With the exception that one particular NSAID, naproxen has been shown to significantly reduce the incidence of acute myocardial infarction.

Although naproxen represents a potentially useful tool for the prevention of myocardial infarction gastro-intestinal side effects of the NSAIDs preclude their use in at risk individuals. Furthermore, NSAIDs have been shown to exacerbate hypertension presenting a further risk to patients with cardiovascular disease.

NO facilitates the repair of injury to the gastrointestinal tract by stimulating mucus secretion and by regulating the blood flow in the capillaries of the gastrointestinal tract and the mucus membrane. The multiple indications of NO therapeutics including gastroprotective activity has led to a surge in pharmaceutical activity (click here for an evaluation of NO therapeutics) and the French company NicOx has become one of the leaders in developing NO derivatives of established therapeutic entities in order to improve their safety profiles.

NicOx’s nitro derivative of naproxen, HCT 3012 is in development for the treatment of osteoarthritis and in January, an independent US Clinical Consultant Advisory Board (CAB), after reviewing the results from the full phase II clinical program with HCT 3012, recommended the further development of this therapeutic for the treatment of osteoarthritis. HCT 3012 is the first of a new class of analgesic and anti-inflammatory drugs known as COX-inhibiting nitric oxide donators (CINODs) designed for the treatment of acute and chronic pain. AstraZeneca has completed a Phase II clinical program involving more than 3000 subjects in September 2003. In this program, HCT 3012 has demonstrated efficacy and gastric tolerability

Grafting NO to naproxen has been proposed to combine its anti-thrombotic effects with enhanced gastro-intestinal safety making it a potential candidate treatment of coronary heart disease.  This concept was strengthened in 2000 when Muscara et al reported that HCT 3012 can reverse experimental hypertension.  In their upcoming Journal of Pharmacology & Experimental Therapeutics Rossoni et al evaluate the anti-ischemic activity of HCT 3012 in a model of acute ischemia and reperfusion of the rabbit heart.

In this study, HTC-3012 brought about a dose-dependent normalisation of coronary perfusion pressure and a reduction of ventricular contracture during ischemia with remarkable improvement of left ventricular developed pressure at reperfusion. These beneficial effects were accompanied by a substantial release of nitrite/nitrate in the heart perfusates, indicating that NO has been released by HCT-3012 and donated to the cardiac tissue. NO has been shown to reduce damage during ischemia/reperfusion both by causing vasodilation and by mopping up free radicals.  In the present study the ability of NO release to prevent cardiac damage was illustrated by a significant reduction of creatine kinase activity in heart perfusates during reperfusion.

The results of this study indicate that HCT-3012 by donating NO displays a noticeable anti-ischemic effect in reperfused ischemic rabbit hearts. This effect as well as the safer gastrointestinal profile of HCT-3012 and its ability to control experimental hypertension suggest that HCT-3012 may have therapeutic potential in the prevention of myocardial ischemic events and could represent a better alternative to conventional non-steroidal anti-inflammatory drugs.

Source DailyUpdates 11th May; for a full abstract of the original papers see J Pharmacol Exp Ther. 2004 Apr 13 [Epub ahead of print]

Recommended further reading:

• Nitric Oxide - Therapeutics, Markets and Companies
• The Cardiovascular Market Outlook to 2008 2003 Cardiovascular Market Update: Part 1 - Anti-hypertensives, Anti-dyslipidemics and Cardiac Therapy
• 2003 Cardiovascular Market Update: Part 2 - Antithrombotics

In this edition of DailyUpdates, LeadDiscovery also highlights DNA vaccination with CD25 as a possible treatment of rheumatoid arthritis...a series of novel MMP-2 inhibitors...oral N-acetylcysteine as a possible treatment of pulmonary emphysema...and much more.