Naproxcinod
Encyclopedia
Naproxcinod is a non-steroidal anti-inflammatory drug
(NSAID) developed by the French pharmaceutical company NicOx
. It is a derivative
of naproxen
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 in 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.
On December 2006, Scientific American
distinguished naproxcinod as one of the ten most promising treatments for the world's biggest health threats; however, in 2010 the U.S. Food and Drug Administration determined that further clinical trials would be needed to obtain approval.
s (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 stroke
s or heart attacks. 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.
s led by NicOx have shown that naproxcinod was effective to treat pain against knee osteoarthritis
and hip osteoarthrtis. A phase II study showed no significant differences in efficacy
between naproxcinod and the COX-2 inhibitor rofecoxib
in the treatment of pain.
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.
In July 2010 the FDA decided not to approve naproxcinod.
actions as well as the inhibition of vascular smooth muscle
proliferation
that serves to maintain normal vascular tone.
. 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.
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.
NicOx has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency
(EMEA) in December 2009.
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
(NSAID) developed by the French pharmaceutical company NicOx
NicOx
NicOx S.A. is a French pharmaceutical company. Its headquarters are at Sophia Antipolis...
. It is a derivative
Derivative (chemistry)
In chemistry, a derivative is a compound that is derived from a similar compound by some chemical or physical process. In the past it was also used to mean a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms, but modern...
of naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
with a nitroxybutyl ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
to allow it to also act as a nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
(NO) donor. This second mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
makes naproxcinod the first in a new class of drugs, the cyclooxygenase inhibiting nitric oxide donators (CINODs), that are hoped to produce similar analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
efficacy to traditional NSAIDs, but with less gastrointestinal and cardiovascular side effects.
On December 2006, Scientific American
Scientific American
Scientific American is a popular science magazine. It is notable for its long history of presenting science monthly to an educated but not necessarily scientific public, through its careful attention to the clarity of its text as well as the quality of its specially commissioned color graphics...
distinguished naproxcinod as one of the ten most promising treatments for the world's biggest health threats; however, in 2010 the U.S. Food and Drug Administration determined that further clinical trials would be needed to obtain approval.
Current situation in pain treatment
Many people are currently relying on traditional non-steroidal anti-inflammatory drugs and COX-2 inhibitorCOX-2 inhibitor
COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug that directly targets COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this...
s (for example celecoxib
Celecoxib
Celecoxib INN is a sulfa non-steroidal anti-inflammatory drug and selective COX-2 inhibitor used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial...
) to treat chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
and inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. COX-2 inhibitors have been associated with an increased risk of serious cardiovascular events such as stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
s or heart attacks. 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.
Indications
Three phase III clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s led by NicOx have shown that naproxcinod was effective to treat pain against knee osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
and hip osteoarthrtis. A phase II study showed no significant differences in efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
between naproxcinod and the COX-2 inhibitor rofecoxib
Rofecoxib
Rofecoxib is a nonsteroidal anti-inflammatory drug that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea...
in the treatment of pain.
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.
In July 2010 the FDA decided not to approve naproxcinod.
Mechanism of action
Naproxcinoid is metabolized to naproxen and a nitric oxide donating moiety. NO has various cardiovascular effects, including vasodilatory and platelet-inhibitoryAntiplatelet drug
An antiplatelet drug is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation...
actions as well as the inhibition of vascular smooth muscle
Vascular smooth muscle
Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood vessels.Vascular smooth muscle contracts or relaxes to both change the volume of blood vessels and the local blood pressure, a mechanism that is responsible for the...
proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
that serves to maintain normal vascular tone.
Blood pressure profile
According to some experts, 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 placeboPlacebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. 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.
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. 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. Clinical studies about rofecoxib have shown that this drug increases the systolic blood pressure.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
Coronary disease
Coronary disease refers to the failure of coronary circulation to supply adequate circulation to cardiac muscle and surrounding tissue. It is already the most common form of disease affecting the heart and an important cause of premature death in Europe, the Baltic states, Russia, North and South...
, resulting in more than 449,000 person years of life saved and 1.4 billion US$ in direct health care cost savings.
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, but a 2009 review has found only a slight and possibly not clinically relevant reduction of gastrointestinal side-effects.Contraindications and adverse effects
Similarly to NSAIDs, adverse effects of naproxcinod include gastrointestinal bleedings.Commercialization
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. In July 2010, the FDA decided not to approve naproxcinod without further clinical trials.NicOx has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
(EMEA) in December 2009.