Effect of a nitric oxide-releasing naproxen derivative on hypertension and gastric damage induced by chronic nitric oxide inhibition in the rat.
Muscara MN, McKnight W, Del Soldato P, Wallace JL. Department of Pharmacology and Therapeutics, University of Calgary, Alberta, Canada.
NSAIDs can elevate blood pressure through mechanisms such as renal vasoconstriction and sodium retention. These effects are particularly evident in hypertensive individuals. Nitric oxide-releasing NSAID derivatives have been shown to have greatly reduced toxicity in the gastrointestinal tract and kidney. We therefore evaluated the effects of a 4 week treatment with either naproxen or its nitric oxide-releasing derivative (NO-naproxen) on systemic arterial blood pressure and gastric damage in rats in which hypertension was induced by L-NAME. Rats received either L-NAME dissolved in the drinking water (400 mg/L) or tap water (control). Vehicle, naproxen (10 mg/kg) or an equimolar dose of NO-naproxen (14.5 mg/kg) were administered orally each day. After 4 weeks, blood pressure was measured, blood samples were taken for measurement of thromboxane synthesis, and gastric damage was evaluated by blind, macroscopic scoring. Both naproxen and NO-naproxen inhibited systemic cyclooxygenase activity by >90%. NO-naproxen-treated rats exhibited no significant gastric damage. The gastric damage produced by L-NAME alone was potentiated by naproxen but prevented by NO-naproxen. L-NAME treatment significantly increased blood pressure. In the absence of L-NAME, the naproxen group had significantly higher blood pressure than both the control and NO-naproxen groups. In rats receiving L-NAME, the same conclusions apply, but the concomitant administration of NO-naproxen was able to significantly reduce the blood pressure compared to L-NAME alone. Based on these results, we conclude that NO-naproxen may represent a safer alternative to standard NSAIDs in the treatment of inflammatory conditions in hypertensive patients.
IDrugs. 1998 Nov;1(7):807-12.
Nitroflurbiprofen (NicOx SA)
Wang X. Cornell University Medical College, 450 East 63rd Street, Rm 7G, New York, NY10021, USA.
NicOx is developing nitroflurbiprofen (HCT-1026) as a non-steroidal anti-inflammatory drug (NSAID) which has the ability to release nitric oxide. It has completed phase I clinical trials as a potential treatment for inflammation and rheumatoid arthritis [198694]. In the trial, which took place at Queens Medical Center, Nottingham, UK, the drug showed excellent tolerability, as well as potent and long lasting serum thromboxane inhibition in healthy volunteers after single oral doses of 50 and 100 mg [243679]. A repeated dose endoscopic study showed that nitroflurbiprofen causes less gastrointestinal damage in healthy volunteers than flurbiprofen [265025,295029]. Although phase II studies in patients with musculoskeletal disorders were scheduled for 1997 [243679], it seems they have not yet commenced.
