Naproxcinod

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Naproxcinod
Naproxcinod.png
Clinical data
Other namesAZD-3582, HCT-3012
ATC code
Identifiers
  • 4-nitrooxybutyl (2S)-2-(6-methoxynaphthalen-2-yl)propanoate
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
Formula C18H21NO6
Molar mass 347.367 g·mol−1
3D model (JSmol)
  • C[C@@H](C1=CC2=C(C=C1)C=C(C=C2)OC)C(=O)OCCCCO[N+](=O)[O-]
  • InChI=1S/C18H21NO6/c1-13(18(20)24-9-3-4-10-25-19(21)22)14-5-6-16-12-17(23-2)8-7-15(16)11-14/h5-8,11-13H,3-4,9-10H2,1-2H3/t13-/m0/s1 X mark.svgN
  • Key:AKFJWRDCWYYTIG-ZDUSSCGKSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Naproxcinod (nitronaproxen) is a nonsteroidal 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. [1] [2]

Contents

In December 2006, Scientific American distinguished naproxcinod as one of the ten most promising treatments for the world's biggest health threats. [3] However, in 2010 the U.S. Food and Drug Administration determined that further clinical trials would be needed to obtain approval. [4]

Current situation in pain treatment

There are people who are currently relying on traditional NSAIDs 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. [5] Therefore, there is a 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 ]

Indications

Three phase III clinical trials led by NicOx have shown that naproxcinod was effective to treat pain against knee osteoarthritis [6] [7] [8] and hip osteoarthritis. [9] A phase II study showed no significant differences in efficacy between naproxcinod and the COX-2 inhibitor rofecoxib in the treatment of pain. [10]

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. [11]

In July 2010 the FDA decided not to approve naproxcinod. [4]

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. [11]

Safety profile

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. [11] 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. [10] [12]

Clinical relevance of small increase in blood pressure

During a U.S. Food and Drug Administration (FDA) COX-2 advisory committee meeting, doctors have underlined the important role of small increase in blood pressure. [13] 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. [14] Clinical studies about rofecoxib have shown that this drug increases the systolic blood pressure. [15]

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. [16]

Gastrointestinal safety

NSAIDs 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, [17] [18] but a 2009 review has found only a slight and possibly not clinically relevant reduction of gastrointestinal side-effects. [19] [20]

Contraindications and adverse effects

Similarly to NSAIDs, adverse effects of naproxcinod include gastrointestinal bleedings. [19] [20]

Commercialization

Naproxcinod completed a phase III study needed for a New Drug Application (NDA). As a result, Nicox submitted its project to the FDA in September 2009. [21] In July 2010, the FDA decided not to approve naproxcinod without further clinical trials. [4] Nicox submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA) in December 2009. [22] Nicox and Fera Pharmaceuticals announced in November 2015 that they had entered into a license agreement for the development and commercialization of naproxcinod in the United States. [23]

See also

Related Research Articles

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<span class="mw-page-title-main">Nonsteroidal anti-inflammatory drug</span> Class of therapeutic drug for relieving pain and inflammation

Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

<span class="mw-page-title-main">Ibuprofen</span> Medication treating pain, fever, and inflammation

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<span class="mw-page-title-main">Cyclooxygenase</span> Class of enzymes

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid. A member of the animal-type heme peroxidase family, it is also known as prostaglandin G/H synthase. The specific reaction catalyzed is the conversion from arachidonic acid to prostaglandin H2 via a short-living prostaglandin G2 intermediate.

<span class="mw-page-title-main">Naproxen</span> Nonsteroidal anti-inflammatory drug (NSAID) used to treat pain

Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, and inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulations. Onset of effects is within an hour and lasts for up to twelve hours. Naproxen is also available in salt form, naproxen sodium, which has better solubility when taken orally.

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<span class="mw-page-title-main">Celecoxib</span> Nonsteroidal anti-inflammatory medication

Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. It may also be used to decrease the risk of colorectal adenomas in people with familial adenomatous polyposis. It is taken by mouth. Benefits are typically seen within an hour.

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<span class="mw-page-title-main">Nimesulide</span> Anti-inflammatory drug

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<span class="mw-page-title-main">Meloxicam</span> Nonsteroidal anti-inflammatory drug (NSAID)

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A prostaglandin antagonist is a hormone antagonist acting upon one or more prostaglandins, a subclass of eicosanoid compounds which function as signaling molecules in numerous types of animal tissues.

<span class="mw-page-title-main">NicOx</span>

Nicox S.A. is a French ophthalmology company developing treatments to maintain vision and improve ocular health. Nicox is headquartered in Sophia Antipolis, France, and its Chairman and CEO is Michele Garufi.

COX-inhibiting nitric oxide donators (CINODs), also known as NO-NSAIDs, are a new class of nonsteroidal anti-inflammatory drug (NSAID) developed with the intention of providing greater safety than existing NSAIDs.

<span class="mw-page-title-main">Licofelone</span> Analgesic and anti-inflammatory compound

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Cyclooxygenases are enzymes that take part in a complex biosynthetic cascade that results in the conversion of polyunsaturated fatty acids to prostaglandins and thromboxane(s). Their main role is to catalyze the transformation of arachidonic acid into the intermediate prostaglandin H2, which is the precursor of a variety of prostanoids with diverse and potent biological actions. Cyclooxygenases have two main isoforms that are called COX-1 and COX-2. COX-1 is responsible for the synthesis of prostaglandin and thromboxane in many types of cells, including the gastro-intestinal tract and blood platelets. COX-2 plays a major role in prostaglandin biosynthesis in inflammatory cells and in the central nervous system. Prostaglandin synthesis in these sites is a key factor in the development of inflammation and hyperalgesia. COX-2 inhibitors have analgesic and anti-inflammatory activity by blocking the transformation of arachidonic acid into prostaglandin H2 selectively.

<span class="mw-page-title-main">Otenaproxesul</span> Chemical compound

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References

  1. ↑ Ellis JL, Augustyniak ME, Cochran ED, Earl RA, Garvey DS, Gordon LJ, et al. (2005). "NMI-1182, a gastro-protective cyclo-oxygenase-inhibiting nitric oxide donor". Inflammopharmacology. 12 (5–6): 521–534. doi:10.1163/156856005774382661. PMID   16259719. S2CID   3231846.
  2. ↑ Cirino G, Distrutti E, Wallace JL (April 2006). "Nitric oxide and inflammation". Inflammation & Allergy - Drug Targets. 5 (2): 115–119. CiteSeerX   10.1.1.628.532 . doi:10.2174/187152806776383143. PMID   16613570.
  3. ↑ Special Report: 10 Promising Treatments for World's Biggest Health Threats, By Charles Q. Choi. 2006
  4. 1 2 3 NicOx Shares Plummet as FDA Says Osteoarthritis Drug Not Ready for Approval
  5. ↑ Baron JA, Sandler RS, Bresalier RS, Lanas A, Morton DG, Riddell R, et al. (November 2008). "Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial". Lancet. 372 (9651): 1756–1764. doi:10.1016/S0140-6736(08)61490-7. PMID   18922570. S2CID   39981292.
  6. ↑ "NicOx Announces Top-Line Results From Naproxcinod 52-Week 301 Safety Extension". 24 July 2008. Retrieved 2 February 2010.
  7. ↑ Clinical trial number NCT00542555 for "Analgesic Efficacy and Safety Study of Naproxcinod in Subjects With Osteoarthritis of the Knee" at ClinicalTrials.gov
  8. ↑ Clinical trial number NCT00504127 for "Efficacy and Safety Study of Naproxcinod in Subjects With Osteoarthritis of the Knee" at ClinicalTrials.gov
  9. ↑ Clinical trial number NCT00541489 for "Efficacy and Safety Study of Naproxcinod in Subjects With Osteoarthritis of the Hip" at ClinicalTrials.gov
  10. 1 2 Karlsson J, Pivodic A, Aguirre D, Schnitzer TJ (June 2009). "Efficacy, safety, and tolerability of the cyclooxygenase-inhibiting nitric oxide donator naproxcinod in treating osteoarthritis of the hip or knee". The Journal of Rheumatology. 36 (6): 1290–1297. doi: 10.3899/jrheum.081011 . PMID   19411388.
  11. 1 2 3 White WB, Schnitzer TJ, Fleming R, Duquesroix B, Beekman M (September 2009). "Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis". The American Journal of Cardiology. 104 (6): 840–845. doi:10.1016/j.amjcard.2009.05.014. PMID   19733721.
  12. ↑ Wallace JL, Viappiani S, Bolla M (March 2009). "Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis". Trends in Pharmacological Sciences. 30 (3): 112–117. doi:10.1016/j.tips.2009.01.001. PMID   19230986.
  13. ↑ "Analysis of FDA COX-2 Advisory Committee Meeting" (PDF). 2005. p. 21.
  14. ↑ Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, et al. (November 2004). "Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial". JAMA. 292 (18): 2217–2225. doi:10.1001/jama.292.18.2217. PMID   15536108.
  15. ↑ Whelton A (September 2002). "COX-2-specific inhibitors and the kidney: effect on hypertension and oedema". Journal of Hypertension Supplement. 20 (6): S31 –S35. PMID   12683425.
  16. ↑ Grover SA, Coupal L, Zowall H (January 2005). "Treating osteoarthritis with cyclooxygenase-2-specific inhibitors: what are the benefits of avoiding blood pressure destabilization?". Hypertension. 45 (1): 92–97. CiteSeerX   10.1.1.576.8621 . doi:10.1161/01.HYP.0000149684.01903.b8. PMID   15545508. S2CID   19825259.
  17. ↑ Wilder-Smith CH, Jonzon B, Fornstedt-Wallin B, Hedman A, Karlsson P (March 2006). "Dose-effect comparisons of the CINOD AZD3582 and naproxen on upper gastrointestinal tract mucosal injury in healthy subjects". Scandinavian Journal of Gastroenterology. 41 (3): 264–273. doi:10.1080/00365520510024197. PMID   16497612. S2CID   8025524.
  18. ↑ Hawkey CJ, Jones JI, Atherton CT, Skelly MM, Bebb JR, Fagerholm U, et al. (November 2003). "Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans". Gut. 52 (11): 1537–1542. doi:10.1136/gut.52.11.1537. PMC   1773862 . PMID   14570719.
  19. 1 2 Geusens P (May 2009). "Naproxcinod, a new cyclooxygenase-inhibiting nitric oxide donator (CINOD)". Expert Opinion on Biological Therapy. 9 (5): 649–657. doi:10.1517/14712590902926071. PMID   19392579. S2CID   70711735.
  20. 1 2 Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2010
  21. ↑ Michelson M (25 September 2009). "NicOx submits naproxcinod application to FDA". Reuters. Retrieved 3 February 2010.
  22. ↑ "MAA for naproxcinod submitted to EMEA through centralized procedure". NewsMedical.net. 22 December 2009. Retrieved 2 February 2010.[ dead link ]
  23. ↑ "Fera Pharmaceuticals - Press Releases". www.ferapharma.com. Retrieved 20 April 2016.
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