Evolving therapeutic strategies to improve nonsteroidal anti-inflammatory drug safety

American Journal of Therapeutics

Volumn 22, Issue 6, 2015, Pages e167-e178

  McCarberg, Bill H ^a,b   Cryer, Byron ^c,d,e  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b Elizabeth Hospice   (United States)

^c Neighborhood Healthcare   (United States)

^d UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^e VA NORTH TEXAS HEALTH CARE SYSTEM   (United States)

Author keywords

COX 2 selective; NSAIDs; Pain; Safety; SoluMatrix

Indexed keywords

ANTITHROMBOCYTIC AGENT; DICLOFENAC; DICLOFENAC EPOLAMINE; DICLOFENAC PLUS MISOPROSTOL; DICLOFENAC POTASSIUM; DISPERSANT; ESOMEPRAZOLE PLUS NAPROXEN; FAMOTIDINE PLUS IBUPROFEN; FLURBIPROFEN; HISTAMINE H2 RECEPTOR ANTAGONIST; HYDROGEN SULFIDE; INDOMETACIN; MACROGOL; MISOPROSTOL; NANOCARRIER; NANOSTRUCTURED LIPID CARRIER; NAPROXCINOD; NAPROXEN; NONSTEROID ANTIINFLAMMATORY AGENT; POLMACOXIB; PROTON PUMP INHIBITOR; SOLID LIPID NANOPARTICLE; UNCLASSIFIED DRUG; FURAN DERIVATIVE; NITRIC OXIDE DONOR; SULFONAMIDE;

AGE; ANTICOAGULANT THERAPY; DIGESTIVE SYSTEM ULCER; DRUG ABSORPTION; DRUG CHOICE; DRUG FORMULATION; DRUG INDUCED DISEASE; DRUG SAFETY; GEL; HELICOBACTER INFECTION; HUMAN; MEDICAL HISTORY; NANOPHARMACEUTICS; PATIENT RISK; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POWDER; PRACTICE GUIDELINE; PRESCRIPTION; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; STOMACH JUICE; STOMACH PROTECTION; SYSTEMATIC REVIEW; SYSTEMATIC REVIEW (TOPIC); TIME TO MAXIMUM PLASMA CONCENTRATION; UPPER GASTROINTESTINAL TRACT; DRUG DEVELOPMENT; MEDICINAL CHEMISTRY; NANOTECHNOLOGY; PHARMACEUTICS;

ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; CHEMISTRY, PHARMACEUTICAL; DRUG DISCOVERY; FURANS; HUMANS; NANOTECHNOLOGY; NITRIC OXIDE DONORS; SULFONAMIDES; TECHNOLOGY, PHARMACEUTICAL;

EID: 84947051206     PISSN: 10752765     EISSN: 15363686     Source Type: Journal    
DOI: 10.1097/MJT.0000000000000123     Document Type: Review

References (109)

1. NSAIDs list. Available at: http://www.nsaids-list. com/. Accessed April 22, 2014.
2. Singh G. Gastrointestinal complications of prescription and over-the-counter nonsteroidal anti-inflammatory drugs: a view from the ARAMIS database. Arthritis, rheumatism, and aging medical information system. Am J Ther. 2000;7:115-121.
3. Koes BW, Scholten RJ, Mens JM, et al. Efficacy of non-steroidal anti-inflammatory drugs for low back pain: a systematic review of randomised clinical trials. Ann Rheum Dis. 1997;56:214-223.
4. Ahmad N, Grad HA, Haas DA, et al. The efficacy of nonopioid analgesics for postoperative dental pain: a meta-analysis. Anesth Prog. 1997;44:119-126.
5. Massey T, Derry S, Moore RA, et al. Topical NSAIDs for acute pain in adults. Cochrane Database Syst Rev. 2010;6: CD007402.
6. Bjordal JM, Ljunggren AE, Klovning A, et al. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ. 2004;329:1317.
7. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012;64:1447-1461.
8. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64:465-474.
9. Matchar DB, McCrory DC, Gray RN. Toward evidence-based management of migraine. JAMA. 2000;284: 2640-2641.
10. Coxib and Traditional NSAID Trialists' (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382:769-779.
11. Lewis SC, Langman MJ, Laporte JR, et al. Dose-response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a metaanalysis based on individual patient data. Br J Clin Pharmacol. 2002;54:320-326.
12. Garcia Rodriguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal antiinflammatory drugs in the general population. J Am Coll Cardiol. 2008;52:1628-1636.
13. McGettigan P, Henry D. Use of non-steroidal antiinflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med. 2013;10:e1001388.
14. Hippisley-Cox J, Coupland C, Logan R. Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ. 2005;331:1310-1316.
15. Schneider V, Levesque LE, Zhang B, et al. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: a population-based, nested case-control analysis. Am J Epidemiol. 2006;164:881-889.
16. Rostom A, Goldkind L, Laine L. Nonsteroidal antiinflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol. 2005;3:489-498.
17. Food and Drug Administration. Public health advisory-FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). 2005. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/ucm150314htm. Accessed April 11, 2014.
18. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232-235.
19. Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006;116:4-15.
20. Sinha M, Gautam L, Shukla PK, et al. Current perspectives in NSAID-induced gastropathy. Mediators Inflamm. 2013;2013:258209.
21. Miller TA. Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol. 1983;245(5 Pt 1): G601-G623.
22. Abraham NS, Hlatky MA, Antman EM, et al. AC-CF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/AC-G/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol. 2010;105:2533-2549.
23. Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ. 1996;312: 1563-1566.
24. Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343: 1075-1078.
25. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naprox-en in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000;343:1520-1528, 2 p following 1528.
26. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet. 2004;364: 665-674.
27. Jarupongprapa S, Ussavasodhi P, Katchamart W. Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis. J Gas-troenterol. 2013;48:830-838.
28. Solomon SD, Wittes J, Finn PV, et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation. 2008; 117:2104-2113.
29. Patrono C, Baigent C. Nonsteroidal anti-inflammatory drugs and the heart. Circulation. 2014;129:907-916.
30. Yu Y, Ricciotti E, Scalia R, et al. Vascular COX-2 modulates blood pressure and thrombosis in mice. Sci Transl Med. 2012;4:132-154.
31. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? meta-analysis of randomised trials. BMJ. 2006;332:1302-1308.
32. Chen YF, Jobanputra P, Barton P, et al. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodo-lac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecox-ib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation. Health Technol Assess. 2008;12:1-278, iii.
33. Haag MD, Bos MJ, Hofman A, et al. Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs and risk of stroke. Arch Intern Med. 2008;168:1219-1224.
34. Yu Y, Stubbe J, Ibrahim S, et al. Cyclooxygenase-2-dependent prostacyclin formation and blood pressure homeostasis: targeted exchange of cyclooxygenase iso-forms in mice. Circ Res. 2010;106:337-345.
35. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Engl J Med. 1994;331:1675-1679.
36. Walker AM. Quantitative studies of the risk of serious hepatic injury in persons using nonsteroidal antiinflam-matory drugs. Arthritis Rheum. 1997;40:201-208.
37. O'Connor N, Dargan PI, Jones AL. Hepatocellular damage from non-steroidal anti-inflammatory drugs. QJM. 2003;96:787-791.
38. Geis GS, Stead H, Wallemark CB, et al. Prevalence of mucosal lesions in the stomach and duodenum due to chronic use of NSAID in patients with rheumatoid arthritis or osteoarthritis, and interim report on prevention by misoprostol of diclofenac associated lesions. J Rheumatol Suppl. 1991;28:11-14.
39. Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev. 2002;4:CD002296.
40. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995;123: 241-249.
41. ARTHROTEC medical guide. Diclofenac sodium/miso-prostol tablets. 2013. Available at: http://labeling. pfizer.com/ShowLabeling.aspx?id5526. Accessed February 20, 2014.
42. Vimovo prescribing information. 2014. Available at: http://www.vimovo.com/pi/. Accessed May 9, 2014.
43. Duexis prescribing information. 2012. Available at: http://www.horizonpharma.com/pdf/DUEXIS-Fact- Sheet.pdf. Accessed June 25, 2014.
44. Bolten W, Gomes JA, Stead H, et al. The gastroduodenal safety and efficacy of the fixed combination of diclofe-nac and misoprostol in the treatment of osteoarthritis. Br J Rheumatol. 1992;31:753-758.
45. Bocanegra TS, Weaver AL, Tindall EA, et al. Diclofe-nac/misoprostol compared with diclofenac in the treatment of osteoarthritis of the knee or hip: a randomized, placebo controlled trial. Arthrotec Osteoarthritis Study Group. J Rheumatol. 1998;25:1602-1611.
46. Melo Gomes JA, Roth SH, Zeeh J, et al. Double-blind comparison of efficacy and gastroduodenal safety of diclofenac/misoprostol, piroxicam, and naproxen in the treatment of osteoarthritis. Ann Rheum Dis. 1993; 52:881-885.
47. Laine L, Kivitz AJ, Bello AE, et al. Double-blind randomized trials of single-tablet ibuprofen/high-dose famotidine vs. ibuprofen alone for reduction of gastric and duodenal ulcers. Am J Gastroenterol. 2012;107: 379-386.
48. Hochberg MC, Fort JG, Svensson O, et al. Fixed-dose combination of enteric-coated naproxen and immediate-release esomeprazole has comparable efficacy to celecoxib for knee osteoarthritis: two randomized trials. Curr Med Res Opin. 2011;27:1243-1253.
49. Cryer BL, Sostek MB, Fort JG, et al. A fixed-dose combination of naproxen and esomeprazole magnesium has comparable upper gastrointestinal tolerability to cele-coxib in patients with osteoarthritis of the knee: results from two randomized, parallel-group, placebo-controlled trials. Ann Med. 2011;43:594-605.
50. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology foundation task force on clinical expert consensus documents. J Am Coll Cardiol. 2008;52:1502-1517.
51. Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of G. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104:728-738.
52. Abraham NS, El-Serag HB, Johnson ML, et al. National adherence to evidence-based guidelines for the prescription of nonsteroidal anti-inflammatory drugs. Gas-troenterology. 2005;129:1171-1178.
53. Gill JM, Mainous AG III, Koopman RJ, et al. Impact of EHR-based clinical decision support on adherence to guidelines for patients on NSAIDs: a randomized controlled trial. Ann Fam Med. 2011;9:22-30.
54. Goldstein JL, Howard KB, Walton SM, et al. Impact of adherence to concomitant gastroprotective therapy on nonsteroidal-related gastroduodenal ulcer complications. Clin Gastroenterol Hepatol. 2006;4:1337-1345.
55. Arnstein PM. Evolution of topical NSAIDs in the guidelines for treatment of osteoarthritis in elderly patients. Drugs Aging. 2012;29:523-531.
56. Barkin RL. Topical nonsteroidal anti-inflammatory drugs: the importance of drug, delivery, and therapeutic outcome. Am J Ther. 2012 [epub ahead of print].
57. Voltaren gel 1% prescribing information. 2009. Available at: http://www.voltarengel.com/common/pdf/Voltaren-PI-10-19.pdf. Accessed November 1, 2013.
58. Pennsaid prescribing information. 2009. Available at: http://www.accessdata.fda.gov/drugsatfda-docs/label/2013/020947s008lbl.pdf. Accessed December 27, 2013.
59. Solaraze prescribing information. 2009. Available at: http://www.drugbank.ca/system/fda
60. Mason L, Moore RA, Edwards JE, et al. Topical NSAIDs for acute pain: a meta-analysis. BMC Fam Pract. 2004;5:10.
61. Altman RD, Dreiser RL, Fisher CL, et al. Diclofenac sodium gel in patients with primary hand osteoarthri-tis: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2009;36:1991-1999.
62. Flector prescribing information. 2011. Available at: http://www.flectorpatch.com/pdf/Flector-PI-M110029. pdf. Accessed August 26, 2014.
63. Barthel HR, Haselwood D, Longley S III, et al. Randomized controlled trial of diclofenac sodium gel in knee osteoarthritis. Semin Arthritis Rheum. 2009;39:203-212.
64. Baraf HS, Gloth FM, Barthel HR, et al. Safety and efficacy of topical diclofenac sodium gel for knee osteoarthritis in elderly and younger patients: pooled data from three randomized, double-blind, parallel-group, placebo-controlled, multicentre trials. Drugs Aging. 2011;28:27-40.
65. Baer PA, Thomas LM, Shainhouse Z. Treatment of osteo-arthritis of the knee with a topical diclofenac solution: a randomised controlled, 6-week trial [ISRCTN53366886]. BMC Musculoskelet Disord. 2005;6:44.
66. Roth SH, Shainhouse J. Efficacy and safety of a topical diclofenac solution (Pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med. 2004;164:2017-2023.
67. Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2012;9:CD007400.
68. Lin J, Zhang W, Jones A, et al. Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials. BMJ. 2004;329:324.
69. Fuller P, Roth S. Diclofenac sodium topical solution with dimethyl sulfoxide, a viable alternative to oral nonsteroidal anti-inflammatories in osteoarthritis: review of current evidence. J Multidiscip Healthc. 2011; 4:223-231.
70. Cambia prescribing information. 2010. Available at: http://www.bcbsnc.com/assets/services/public/pdfs/formulary/cambia-um-criteria.pdf. Accessed November 18, 2013.
71. Reiner V, Reiner A, Reiner G, et al. Increased absorption rate of diclofenac from fast acting formulations containing its potassium salt. Arzneimittelforschung. 2001;51: 885-890.
72. Diener HC, Montagna P, Gacs G, et al. Efficacy and tolerability of diclofenac potassium sachets in migraine: a randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo. Cephalalgia. 2006;26:537-547.
73. Lipton RB, Grosberg B, Singer RP, et al. Efficacy and tolerability of a new powdered formulation of diclofe-nac potassium for oral solution for the acute treatment of migraine: results from the International Migraine Pain Assessment Clinical Trial (IMPACT). Cephalalgia. 2010;30:1336-1345.
74. Zipsor full prescribing information. 2012. Available at: http://www.zipsor.com/files/PI.pdf. Accessed November 18, 2013.
75. Lissy M, Scallion R, Stiff DD, et al. Pharmacokinetic comparison of an oral diclofenac potassium liquid-filled soft gelatin capsule with a diclofenac potassium tablet. Expert Opin Pharmacother. 2010;11:701-708.
76. Hersh EV, Levin LM, Adamson D, et al. Dose-ranging analgesic study of prosorb diclofenac potassium in postsurgical dental pain. Clin Ther. 2004;26:1215-1227.
77. Zuniga JR, Phillips CL, Shugars D, et al. Analgesic safety and efficacy of diclofenac sodium softgels on postoperative third molar extraction pain. J Oral Maxillofac Surg. 2004;62:806-815.
78. Daniels SE, Baum DR, Clark F, et al. Diclofenac potassium liquid-filled soft gelatin capsules for the treatment of postbunionectomy pain. Curr Med Res Opin. 2010;26: 2375-2384.
79. Riff DS, Duckor S, Gottlieb I, et al. Diclofenac potassium liquid-filled soft gelatin capsules in the management of patients with postbunionectomy pain: a phase III, mul-ticenter, randomized, double-blind, placebo-controlled study conducted over 5 days. Clin Ther. 2009;31:2072-2085.
80. Zorvolex full prescribing information. 2013. Available at: https://www.iroko.com/wp-content/uploads/2013/10/Zorvolex-PI-10-18-2013.pdf. Accessed November 08, 2013.
81. Low dose diclofenac (Zorvolex) for pain. The Medical Letter on Drugs and Therapeutics. 2014;56:19-20.
82. Iroko Pharmaceuticals Gains FDA Approval of ZORVOLEX® for Management of Osteoarthritis Pain [press release]. Philadelphia, PA: Iroko Pharmaceuticals LLC; August 25, 2014. http://www.iroko.com/press-releases/iroko-pharmaceuticals-gains-fda-approval-of-zorvolex-for-management-of-osteoarthritis-pain/. Accessed August 26, 2014.
83. Altman R, Daniels S, Young CL. Indomethacin submi-cron particle capsules provide effective pain relief in patients with acute pain: a phase 3 study. Phys Sportsmed. 2013;41:7-15.
84. Gibofsky A, Hochberg MC, Jaros M, et al. Efficacy and safety of low-dose submicron diclofenac for the treatment of osteoarthritis pain: A 12-week, phase 3 study. Curr Med Res Opin. 2014;1-29.
85. Tivorbex prescribing information. 2014. Available at: http://www.accessdata.fda.gov/drugsatfda-docs/label/2014/204768s000lbl.pdf. Accessed March 19, 2014.
86. Manvelian G, Daniels S, Altman R. A phase I study evaluating the pharmacokinetic profile of a novel, proprietary, nano-formulated, lower-dose oral indomethacin. Postgrad Med. 2012;124:197-205.
87. Manvelian G, Daniels S, Gibofsky A. The pharmacokinetic parameters of a single dose of a novel nano-formulated, lower-dose oral diclofenac. Postgrad Med. 2012;124:117-123.
88. Manvelian G, Daniels S, Gibofsky A. A phase 2 study evaluating the efficacy and safety of a novel, proprietary, nano-formulated, lower dose oral diclofenac. Pain Med. 2012;13:1491-1498.
89. Manvelian G, Hochberg MC, Daniels SE, et al. A phase 2 study of lower-dose, indomethacin submicron particle capsules demonstrates early onset of acute pain relief. Clin J Pain. 2013 [epub ahead of print].
90. Gibofsky A, Silberstein S, Argoff C, et al. Lower-dose diclofenac submicron particle capsules provide early and sustained acute patient pain relief in a phase 3 study. Postgrad Med. 2013;125:130-138.
91. Uaesoontrachoon K, Quinn JL, Tatem KS, et al. Long-term treatment with naproxcinod significantly improves skeletal and cardiac disease phenotype in the mdx mouse model of dystrophy. Hum Mol Genet. 2014;23:3239-3249.
92. Skarke C, Alamuddin N, Lawson JA, et al. Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649. Clin Pharmacol Ther. 2012;91:986-993.
93. Fiorucci S, Santucci L. Hydrogen sulfide-based therapies: focus on H2S releasing NSAIDs. Inflamm Allergy Drug Targets. 2011;10:133-140.
94. Bhaskar K, Anbu J, Ravichandiran V, et al. Lipid nano-particles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies. Lipids Health Dis. 2009;8:6.
95. Gonzalez-Mira E, Egea MA, Souto EB, et al. Optimizing flurbiprofen-loaded NLC by central composite factorial design for ocular delivery. Nanotechnology. 2011;22:045101.
96. Gonzalez-Mira E, Nikolic S, Garcia ML, et al. Potential use of nanostructured lipid carriers for topical delivery of flurbiprofen. J Pharm Sci. 2011;100:242-251.
97. Rosseto R, Hajdu J. Synthesis of oligo(ethylene glycol) substituted phosphatidylcholines: secretory PLA2-targeted precursors of NSAID prodrugs. Chem Phys Lip-ids. 2010;163:110-116.
98. Makris UE, Kohler MJ, Fraenkel L. Adverse effects of topical nonsteroidal antiinflammatory drugs in older adults with osteoarthritis: a systematic literature review. J Rheumatol. 2010;37:1236-1243.
99. Stefano F, Distrutti E. Cyclo-oxygenase (COX) inhibiting nitric oxide donating (CINODs) drugs: a review of their current status. Curr Top Med Chem. 2007;7:277-282.
100. Karlsson J, Pivodic A, Aguirre D, et al. Efficacy, safety, and tolerability of the cyclooxygenase-inhibiting nitric oxide donator naproxcinod in treating osteoarthritis of the hip or knee. J Rheumatol. 2009;36:1290-1297.
101. Schnitzer TJ, Hochberg MC, Marrero CE, et al. Efficacy and safety of naproxcinod in patients with osteoarthritis of the knee: a 53-week prospective randomized multi-center study. Semin Arthritis Rheum. 2011;40:285-297.
102. Schnitzer TJ, Kivitz A, Frayssinet H, et al. Efficacy and safety of naproxcinod in the treatment of patients with osteoarthritis of the knee: a 13-week prospective, randomized, multicenter study. Osteoarthritis Cartilage. 2010;18:629-639.
103. Baerwald C, Verdecchia P, Duquesroix B, et al. Efficacy, safety, and effects on blood pressure of naproxcinod 750 mg twice daily compared with placebo and naproxen 500 mg twice daily in patients with osteoarthritis of the hip: a randomized, double-blind, parallel-group, multi-center study. Arthritis Rheum. 2010;62:3635-3644.
104. White WB, Schnitzer TJ, Bakris GL, et al. Effects of nap-roxcinod on blood pressure in patients with osteoarthri-tis. Am J Cardiol. 2011;107:1338-1345.
105. Carroll J. NicOx shares pummeled after EU panel rejects naproxcinod 2011. Available at: http://www. fiercebiotech.com/story/nicox-shares-pummeled-after-eu-panel-rejects-naproxcinod/2011-04-20#ixzz30Io5pDQL. Accessed June 19, 2014.
106. Naproxcinod: muscular dystrophy. 2013. Available at: http://www.nicox.com/index.php/en/rd/other-therapeutic-areas/naproxcinod-muscular-dystrophy. Accessed April 29, 2014.
107. Fiorucci S, Distrutti E. COXIBs, CINODs and H(2)S-releasing NSAIDs: current perspectives in the development of safer non steroidal anti-inflammatory drugs. Curr Med Chem. 2011;18:3494-3505.
108. Cudaback E, Jorstad NL, Yang Y, et al. Therapeutic implications of the prostaglandin pathway in Alzheimer's disease. Biochem Pharmacol. 2014;88:565-572.
109. Nevalainen TJ, Haapamaki MM, Gronroos JM. Roles of secretory phospholipases A(2) in inflammatory diseases and trauma. Biochim Biophys Acta. 2000;1488:83-90.