Naproxcinod (
nitronaproxen) is a
non-steroidal antiinflammatory drug (NSAID) developed by the French pharmaceutical company
NicOx. It is derived from
naproxen but substituted with a nitroxybutyl ester to allow it to also act as a
nitric oxide (NO) donor. This second mechanism of action makes naproxcinod the first of a new class of drugs, the
cyclooxygenase inhibiting nitric oxide donators (CINODs), that are hoped to produce similar
analgesic efficacy to traditional NSAIDs, but with less gastrointestinal and cardiovascular side effects.
[1][2]
On December 2006,
Scientific American distinguished naproxcinod as one of the ten most promising treatments for the world's biggest health threats.
[3]
Contents
[hide]
[edit] Current situation in pain treatment
Many people are currently relying on traditional non-steroidal antiinflammatory drugs and
COX-2 inhibitors (for example
celecoxib) to treat
chronic pain and
inflammation. COX-2 inhibitors have been associated with an increased risk of serious cardiovascular events such as
strokes or
heart attacks.
[4] Therefore, there is an unmet need for safer medications. This need is particularly acute among patients with high cardiovascular risk like hypertension which represents 50% of osteoarthritis sufferers.[
citation needed]
[edit] Indications
Three phase III
clinical trials led by NicOx have shown that naproxcinod was effective to treat pain against knee
osteoarthritis[5][6][7] and hip osteoarthrtis
[8]. A phase II study showed no significant differences in
efficacy between naproxcinod and the COX-2 inhibitor
rofecoxib in the treatment of pain.
[9]
In osteoarthritis, a 750 mg dose is equipotent to 500 mg of naproxen for the treatment of inflammation but with the added benefit of attenuating the cardiovascular effects traditionally associated with NSAIDs.
[10]
[edit] Mechanism of action
Naproxcinoid is metabolized to naproxen and a nitric oxide donating
moiety. NO has various cardiovascular effects, including
vasodilatory and
platelet-inhibitory actions as well as the inhibition of
vascular smooth muscle proliferation that serves to maintain normal vascular tone.
[10]
[edit] Safety profile
[edit] Blood pressure profile
According to some experts[
who?], cardiovascular risks induced by COX-2 inhibitors are caused by increases in blood pressure. Naproxcinod demonstrated in a clinical trial with 916 patients to have a blood pressure profile similar to
placebo.
[10] Two phase II randomized controlled trials have shown a decreased systolic blood pressure by 2.1
mmHg after patients took naproxcinod (375 mg or 750 mg twice daily) for six weeks. These effects were especially pronounced in hypertensive populations.
[9][11]
[edit] Clinical relevance of small increase in blood pressure
During an
U.S. Food and Drug Administration (FDA) COX-2 advisory committee meeting, doctors have underlined the important role of small increase in blood pressure.
[12] They cited the
CAMELOT trial which has concluded that even a small decrease in systolic blood pressure of 5 mmHg could lead to a reduction of 31% in cardiovascular events.
[13] Clinical studies about rofecoxib have shown that this drug increases the systolic blood pressure.
[14]
A 2005 analysis shows that a blood pressure decrease of 3.1 mmHG could avoid over 30,000 deaths from stroke and 2,000 deaths from
coronary disease, resulting in more than 449,000
person years of life saved and 1.4 billion
US$ in direct health care cost savings.
[15]
[edit] Gastrointestinal safety
Non-steroidal antiinflammatory drugs have also been associated with
gastrointestinal risks such as bleedings. Early studies demonstrated that naproxcinod had a better gastrointestinal profile than naproxen, especially for the
gastroduodenal mucosa,
[16][17] but a 2009 review has found only a slight and possibly not clinically relevant reduction of gastrointestinal side-effects.
[18][19]
[edit] Contraindications and adverse effects
This section requires
expansion.
Similarly to NSAIDs, adverse effects of naproxcinod include gastrointestinal bleedings.
[18][19]
[edit] Interactions
This section requires
expansion.
[edit] Commercialisation
Naproxcinod completed the pivotal phase III studies needed for a New Drug Application (NDA). As a result, NicOx submitted its project to the FDA in September 2009.
[20] If the FDA gives its agreement, the commercialisation may begin, with a partner, at the end of 2010.
NicOx has submitted a Marketing Authorization Application (MAA) to the
European Medicines Agency (EMEA) in December 2009.
[21]