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Naproxcinod
Systematic (IUPAC) name
4-nitrooxybutyl (2S)-2-(6-methoxynaphthalen-2-yl)propanoate
Identifiers
CAS number  ?
ATC code none
PubChem 9884642
Chemical data
Formula C 18H21NO6  
Mol. mass 347.362 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability  ?
Metabolism  ?
Half life  ?
Excretion  ?
Therapeutic considerations
Pregnancy cat.  ?
Legal status
Routes  ?

Naproxcinod (nitronaproxen, AZD-3582, HCT-3012) 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 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

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 often 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.[5]

Indications

Three phase III clinical trials led by NicOx have shown that naproxcinod was effective to treat pain against knee osteoarthritis (301, 302) but also against hip osteoarthrtis (303).[6] Furthermore, phase II studies have demonstrated that naproxcinod was as effective as the COX-2 inhibitor rofecoxib to treat pain.[7]

Safety profile

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 2800 patients to have a blood pressure profile similar to placebo.[8]

Clinical relevance of small increase in blood pressure

During COX-2 meetings, the U.S. Food and Drug Administration (FDA) has underlined the important role of small increase in blood pressure.[9] Clinical studies about rofecoxib have shown that this drug clearly increases the systolic blood pressure.[10] The blood pressure profile of naproxcinod could lead to decrease cardiovascular risks. Indeed, it might be possible to avoid around 30,000 strokes if blood pressure does not increase.[11] The CAMELOT trial has concluded that even a small decrease in systolic blood pressure could lead to a reduction of cardiovascular events. A reduction of 5 mmHg in systolic blood pressure could lead to a relative reduction of 31% in cardiovascular events.[12]

An analysis completed in Grover & al, Hypertension 2005 shows that a decrease of 3.1 mmHG could avoid >30 000 stroke deaths and 25 000 coronary deaths resulting in >449 000 person years of life saved and US$ 1.4 billion in direct health care cost savings.[13]

Gastrointestinal safety

Cardiovascular safety is a key preoccupation for the use of NSAIDs but these products have also been associated with gastrointestinal risks such as bleedings. Several studies demonstrated that naproxcinod had a better gastrointestinal profile than naproxen, especially for the gastroduodenal mucosa.[14]

Contraindications and adverse effects

Interactions

End of development and commercialisation

Naproxcinod ended successfully his program of clinical studies and completed all pivotal phase III studies needed for a New Drug Application (NDA). As a result, NicOx plans to submit its project to the FDA in mid 2009. If the FDA gives its agreement, the commercialisation may begin, with a partner, at the end of 2010.

References

  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. ^ 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
  5. ^ Naproxcinod Development, 2008
  6. ^ Press releases about phase III studies, 2008
  7. ^ Press releases about phase II studies, 2008
  8. ^ NicOx' naproxcinod shows robust blood pressure results in phase 3 pooled analysis, 12/17/2008
  9. ^ http://www.masterdocs.com/PDF/Analysis%20of%20FDA%20COX-2%20Advisory%20Committee%20Meeting.pdf, Analysis of FDA COX-2 Advisory Committee Meeting, 2005
  10. ^ http://www.adrugrecall.com/vioxx/high-blood-pressure.html, Vioxx High Blood Pressure ,2008
  11. ^ http://www.medicinaoral.com/medoralfree01/v13i11/medoralv13i11p717.pdf , "Interactions between ibuprofen and antihypertensive drugs: incidence and clinical relevance in dental practice", Salort-Llorca C, Mínguez-Serra MP, Silvestre-Donat FJ, 1: Med Oral Patol Oral Cir Bucal. 2008 Nov 1;13(11):E717-21
  12. ^ http://jama.ama-assn.org/cgi/content/full/292/18/2217 , Effect of Antihypertensive Agents on Cardiovascular Events in Patients With Coronary Disease and Normal Blood Pressure, Steven E. Nissen, MD; E. Murat Tuzcu, MD; Peter Libby, MD; Paul D. Thompson, MD; Magdi Ghali, MD; Dahlia Garza, MD; Lance Berman, MD; Harry Shi, MS; Ethel Buebendorf, BSN; Eric J. Topol, MD; for the CAMELOT Investigators JAMA. 2004;292:2217-2225
  13. ^ http://hyper.ahajournals.org/cgi/content/abstract/45/1/92, Treating Osteoarthritis With Cyclooxygenase-2–Specific Inhibitors, Steven A. Grover; Louis Coupal; Hanna Zowall, 2005
  14. ^ Dose-effect comparisons of the CINOD AZD3582 and naproxen on upper gastrointestinal tract mucosal injury in healthy subjects, Wilder-Smith CH, Jonzon B, Fornstedt-Wallin B, Hedman A, Karlsson P, 2006 Mar;41(3):264-73







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