Naproxcinod

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Naproxcinod
File:Naproxcinod.png
Systematic (IUPAC) name
4-nitrooxybutyl (2S)-2-(6-methoxynaphthalen-2-yl)propanoate
Identifiers
ATC code none
PubChem CID 9884642
Synonyms AZD-3582, HCT-3012
Chemical data
Formula C18H21NO6
Molar mass 347.362 g/mol[[Script error: No such module "String".]]
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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], but in 2010 the FDA said further clinical trials would be needed to obtain approval.[4]

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.[5] 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]

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 osteoarthrtis[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 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.[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

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,[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]

Interactions

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.[21] In July 2010 the FDA decided not to approve naproxcinod without further clinical trials[4].

NicOx has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA) in December 2009.[22]

References

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Non-steroidal anti-inflammatory drug (NSAID) products (primarily M01A and M02A, also N02BA)
Salicylates
Arylalkanoic acids
2-Arylpropionic acids
(profens)
N-Arylanthranilic acids
(fenamic acids)
Pyrazolidine derivatives
Oxicams
COX-2 inhibitors
Sulfonanilides
Topically used products
COX-inhibiting nitric oxide donators
Naproxcinod
Others
Items listed in bold indicate initially developed compounds of specific groups. †Withdrawn drugs. ‡Veterinary use medications.
fr:Naproxcinod
  1. ↑ Ellis JL, Augustyniak ME, Cochran ED, Earl RA, Garvey DS, Gordon LJ, Janero DR, Khanapure SP, Letts LG, Melim TL, Murty MG, Schwalb DJ, Shumway MJ, Selig WM, Trocha AM, Young DV, Zemtseva IS. NMI-1182, a gastro-protective cyclo-oxygenase-inhibiting nitric oxide donor. Inflammopharmacology. 2005;12(5-6):521-34. PMID 16259719
  2. ↑ Cirino G, Distrutti E, Wallace JL. Nitric oxide and inflammation. Inflammation and Allergy Drug Targets. 2006 Apr;5(2):115-9. PMID 16613570
  3. ↑ Special Report: 10 Promising Treatments for World's Biggest Health Threats, By Charles Q. Choi. 2006
  4. ↑ 4.0 4.1 4.2 http://www.genengnews.com/gen-news-highlights/nicox-shares-plummet-as-fda-says-osteoarthritis-drug-not-ready-for-approval/81243699/
  5. ↑ Baron, J.; Sandler, R.; Bresalier, R.; Lanas, A.; Morton, D.; Riddell, R.; Iverson, E.; Demets, D. (2008). "Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial". The Lancet. 372: 1756–1764. doi:10.1016/S0140-6736(08)61490-7.  edit
  6. ↑ "NicOx Announces Top-Line Results From Naproxcinod 52-Week 301 Safety Extension". 24 July 2008. Retrieved 2 February 2010. 
  7. ↑ ClinicalTrials.gov NCT00542555 Analgesic Efficacy and Safety Study of Naproxcinod in Subjects With Osteoarthritis of the Knee
  8. ↑ ClinicalTrials.gov NCT00504127 Efficacy and Safety Study of Naproxcinod in Subjects With Osteoarthritis of the Knee
  9. ↑ ClinicalTrials.gov NCT00541489 Efficacy and Safety Study of Naproxcinod in Subjects With Osteoarthritis of the Hip
  10. ↑ 10.0 10.1 Karlsson, J.; Pivodic, A.; Aguirre, D.; Schnitzer, T. (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.  edit
  11. ↑ 11.0 11.1 11.2 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  12. ↑ Wallace, J.; Viappiani, S.; Bolla, M. (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.  edit
  13. ↑ "Analysis of FDA COX-2 Advisory Committee Meeting" (PDF). 2005. p. 21. 
  14. ↑ Nissen, Steven E (2004). "Effect of Antihypertensive Agents on Cardiovascular Events in Patients With Coronary Disease and Normal Blood Pressure". JAMA. 292: 2217–25. PMID 15536108. 
  15. ↑ Whelton, A (2002). "COX-2-specific inhibitors and the kidney: effect on hypertension and oedema". Journal of hypertension. Supplement : official journal of the International Society of Hypertension. 20 (6): S31–5. PMID 12683425.  edit
  16. ↑ Grover, S. A.; Coupal, L.; Zowall, H. (2004). "Treating Osteoarthritis with Cyclooxygenase-2-Specific Inhibitors. What Are the Benefits of Avoiding Blood Pressure Destabilization?". Hypertension. 45 (1): 92–97. doi:10.1161/01.HYP.0000149684.01903.b8. PMID 15545508.  edit
  17. ↑ Wilder-Smith, C. H.; Jonzon, B.; Fornstedt-Wallin, B.; Hedman, A.; Karlsson, P. R. (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. doi:10.1080/00365520510024197. PMID 16497612.  edit
  18. ↑ Hawkey, CJ; Jones, JI; Atherton, CT; Skelly, MM; Bebb, JR; Fagerholm, U; Jonzon, B; Karlsson, P; Bjarnason, IT (2003). "Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans". Gut. 52 (11): 1537–42. doi:10.1136/gut.52.11.1537. PMC 1773862 Freely accessible. PMID 14570719.  edit
  19. ↑ 19.0 19.1 Geusens, P. (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.  edit
  20. ↑ 20.0 20.1 Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2010
  21. ↑ "NicOx submits naproxcinod application to FDA". Reuters. 25 September 2009. Retrieved 3 February 2010. 
  22. ↑ "MAA for naproxcinod submitted to EMEA through centralized procedure". NewsMedical.net. 22 December 2009. Retrieved 2 February 2010. 
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