“Both doses of naproxcinod demonstrated superior efficacy to placebo for all efficacy endpoints. Additionally, compared [with] naproxen, naproxcinod had a favorable effect on blood pressure which was sustained for the entire 13 weeks of [the] pivotal study.”—Thomas Schnitzer, MD, PhD
The COX-inhibiting nitric oxide donators (CINODs, also known as NO-NSAIDs) are generated by fusing an existing NSAID with a nitric oxide (NO)-donating moiety, usually by ester linkage. CINODs are meant to retain the NSAID anti-inflammatory effect with greater gastric and vascular safety due to the vasorelaxation, leukocyte adhesion inhibition, and caspase inhibition caused by NO. Naproxcinod (NicOx SA) is a fusion of naproxen and a NO-donating group.NO plays duel and conflicting roles in inflammation and pain and the redox forms of NO influence its biological activity. “Peroxynitrite exerts pro-inflammatory and pro-apoptotic effects. In general, NO at low concentrations exerts anti-inflammatory or physiological effects,” said Steven Abramson, MD, director of the division of rheumatology at New York University Medical Center in New York City.1
According to Dr. Abramson, the potential benefits of NO in cartilage include protection against vascular injury, inhibition of chondrocyte and osteoclast activation, and activation of COX-1, which is expected to have gastroprotective effects.
NO is produced by nitric oxide synthases. Different isoforms (constituitive NOS or cNOS, or inducible NOS) produce different effects. In general the cNOS pathway produces beneficial effects, but levels of NO from the cNOS pathway may be reduced in joint structures exposed to chronic mechanical or biochemical stressors.
Another interesting effect of NO-donating COX inhibitors is on blood pressure. In a 13-week study comparing efficacy and blood pressure of naproxcinod with placebo and naproxen in 918 patients with knee OA, Thomas Schnitzer, MD, PhD, reported at the 2008 EULAR meeting that CINOD was better than naproxen for all efficacy and had a sustained antihypertensive effect over the course of the study.2
“Both doses of naproxcinod demonstrated superior efficacy to placebo for all efficacy endpoints. Additionally, compared [with] naproxen, naproxcinod had a favorable effect on blood pressure which was sustained for the entire 13 weeks of [the] pivotal study,” said Dr. Schnitzer, professor of medicine at Northwestern University Medical School, Chicago, IL. He noted that naproxcinod inhibits both COX-1 and -2 enzymes and releasing NO.
The trial compared naproxcinod 375 mg bid and 750 mg bid to placebo and naproxen 500 mg bid. Subjects were knee OA patients ≥40 years who demonstrated a flare on washout of current medications. They were randomized at 110 US sites. The primary efficacy endpoints were WOMAC pain and function, and patient's global assessment of disease status. Office blood pressure measurements were taken in a standardized manner between 2 and 4 hours postmorning drug administration. About half of the subjects were hypertensive at baseline.
The researchers reported, “Naproxcinod at both doses was superior to placebo for the three coprimary endpoints (P ≤.0002). At Week 13, the naproxcinod 750 mg bid and 375 mg bid groups showed mean changes from baseline versus naproxen in systolic BP of -2.89 (P = .0154) and -1.82 mm Hg (P = .1207) and in diastolic BP of -1.79 (P = .0193) and -1.55 mm Hg (P = .0386), respectively. By Week 13, more patients on naproxcinod had a decrease in blood pressure compared [with] patients on placebo and naproxen. Overall, 46.7%, 40.8%, 56.4%, and 38.7% of patients receiving naproxcinod 750 mg bid and 375 mg bid, naproxen 500 mg bid and placebo bid experienced at least one adverse event. There were no unexpected safety findings.”
References
1. Abramson SB. Nitric oxide in inflammation and pain. Presented at: EULAR Satellite Symposium; 13 June, 2008; Paris, France.
2. Schnitzer TJ. Comparison of naproxcinod to naproxen and placebo: results of a 13-week phase 3 pivotal trial in patients with osteoarthritis of the knee with particular focus on blood pressure effects. Presented at: EULAR 2008; June 11-14, 2008; Paris, France. Presentation FRI-0350.
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