naproxen-n-butyl-nitrate and Hypertension

The blood pressure (BP) effects of naproxcinod and naproxen were assessed in an 8-week, double-blind, crossover study in 131 hypertensive patients aged 50 to 74 years. Patients received naproxcinod 750 mg twice daily or naproxen 500 mg twice daily, then the alternate treatment, each for 14 days, with placebo run-in/washout before each active treatment period and 24-hour ambulatory BP monitoring conducted before and after each active treatment period. Mean change from baseline in average 24-hour systolic BP (SBP) after 2 weeks of treatment numerically favored naproxcinod 750 mg twice daily (least-squares [LS] mean for naproxcinod minus naproxen: -1.6 mm Hg; P=.12). Post hoc analyses showed statistically significant SBP differences favoring naproxcinod for the 8 elapsed hours (LS mean: -4.4 mm Hg; P<.0001) and the 24 hours following morning dosing (LS mean: -2.4 mm Hg; P=.006). Naproxcinod may be a beneficial alternative for patients with osteoarthritis requiring nonsteroidal anti-inflammatory drugs.

Topics: Aged; Blood Pressure; Cross-Over Studies; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Naproxen; Nitric Oxide Donors; Treatment Outcome

Traditional nonsteroidal anti-inflammatory drugs are associated with the destabilization of blood pressure (BP) control, particularly in hypertensive patients treated with blockers of the renin-angiotensin system. To assess the potential impact of nitric oxide donation, the effects of naproxcinod with naproxen and placebo on changes in BP were compared in a randomized clinical trial of 916 patients with osteoarthritis after 13 weeks of therapy. In addition, the effects of naproxcinod versus naproxen and placebo on systolic BP in patients with hypertension treated with renin-angiotensin system blockers were evaluated. Naproxcinod 750 mg twice daily reduced systolic BP compared to naproxen 500 mg twice daily (p <0.02). The 2 doses of naproxcinod showed reductions from baseline in diastolic BP relative to naproxen (p <0.04) and similar changes compared to placebo. In 207 patients with hypertension treated with renin-angiotensin-blocking agents alone or with diuretics, the difference in mean change from baseline in systolic BP between naproxen 500 mg and naproxcinod 750 mg was 6.5 mm Hg in favor of naproxcinod (p <0.02). The proportion of patients in the overall population with systolic BP increases > or =10 mm Hg was greater with naproxen 500 mg (22%) compared to naproxcinod 750 mg (14%, p = 0.04), naproxcinod 375 mg (14%, p = 0.055), and placebo (15.6%, p = 0.155). In conclusion, naproxcinod did not induce elevations of BP seen with naproxen, and it had similar effects on BP to that of placebo in patients with osteoarthritis.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Comorbidity; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Naproxen; Nitric Oxide Donors; Osteoarthritis

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.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Gastric Mucosa; Hypertension; Male; Naproxen; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Stomach Ulcer; Thromboxane B2