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COX-2 inhibitor

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Title: COX-2 inhibitor  
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Subject: Diclofenac, Etodolac, Nonsteroidal anti-inflammatory drug, Aspirin, Sulindac
Collection: Cox-2 Inhibitors, Experimental Medical Treatments, Non-Steroidal Anti-Inflammatory Drugs
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COX-2 inhibitor

COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug (NSAID) that directly targets cyclooxygenase-2, 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 drug class. After several COX-2 inhibiting drugs were approved for marketing, data from clinical trials revealed that COX-2 inhibitors caused a significant increase in heart attacks and strokes, with some drugs in the class having worse risks than others. Rofecoxib (commonly known as Vioxx) was taken off the market in 2004 because of these concerns and celecoxib and traditional NSAIDs received boxed warnings on their labels.


  • Medical uses 1
  • Adverse effects 2
    • Cancer 2.1
    • Neuropsychiatric disorders 2.2
    • Other targets 2.3
  • Research 3
    • Research history 3.1
    • Research fraud 3.2
    • Early COX-2-inhibiting drugs 3.3
    • Neuroblastomas 3.4
  • References 4
  • Further reading 5

Medical uses

Some COX-2 inhibitors are used in a single dose to treat pain after surgery.[1][2]

Etoricoxib appears as good as if not better than other pain medications.[3] Celecoxib appears to be about as useful as ibuprofen.[4]

NSAIDs are often used in treatment of acute gout attacks. COX-2 inhibitors appear to work as well as nonselective NSAIDS. [5] They have not been compared to other treatment options such as colchicine or glucocorticoids.[5][6]

Adverse effects

Analysis of clinical trial data revealed that there was a significant increase in the rate of vascular events with COX-2 inhibitors compared with placebo; "vascular events" are non-fatal myocardial infarction (MI) or heart attack, non-fatal stroke, and death from a vascular event such as MI or stroke.[7][8] These results led Merck to voluntarily withdraw (Rofecoxib) from the market in September 2004 and to regulatory authorities imposing a boxed warning on the label of celecoxib.[7] Traditional NSAIDs were also found to have cardiovascular risks, leading to similar boxed warnings.[7]

The cause of the cardiovascular problems became, and remains, a subject of intensive research.[9] As of 2012 results have been converging on the hypothesis that the adverse cardiovascular effects are most likely due to inhibition of COX-2 in blood vessels, which leads to a decrease in the production of prostacyclin in them. Prostacyclin usually prevents platelet aggregation and vasoconstriction, so its inhibition can lead to excess clot formation and higher blood pressure.[9]


COX-2 appears to be related to cancers and abnormal growths in the intestinal tract. COX inhibitors have been shown to reduce the occurrence of cancers and pre-cancerous growths. The National Cancer Institute has done some studies on COX-2 and cancer.[10] The FDA has approved Celebrex for treatment of familial adenomatous polyposis (FAP).[11] COX-2 inhibitors are currently being studied in breast cancer[12] and appear to be beneficial.[13]

Neuropsychiatric disorders

COX-2 inhibitors have been found to be effective in suppressing inflammatory neurodegenerative pathways in mental illness, with beneficial results in trials for major depressive disorder as well as schizophrenia.[14]

Other targets

The inhibition of COX-2 is paramount for the anti-inflammatory and analgesic function of the selective COX-2 inhibitor celecoxib. However, with regard to this drug’s promise for the therapy of advanced cancers, it is unclear whether the inhibition of COX-2 plays a dominant role, and this has become a controversial and intensely researched issue. In recent years, several additional intracellular components (besides COX-2) were discovered that appear to be important for mediating the anticancer effects of celecoxib in the absence of COX-2.[15] Moreover, a recent study with various malignant tumor cells showed that celecoxib could inhibit the growth of these cells, even though some of these cancer cells didn’t even contain COX-2.[16]

Additional support for the idea that other targets besides COX-2 are important for celecoxib’s anticancer effects has come from studies with chemically modified versions of celecoxib. Several dozen analogs of celecoxib were generated with small alterations in their chemical structures.[17] Some of these analogs retained COX-2 inhibitory activity, whereas many others didn’t. However, when the ability of all these compounds to kill tumor cells in cell culture was investigated, it turned out that the antitumor potency did not at all depend on whether or not the respective compound could inhibit COX-2, showing that inhibition of COX-2 was not required for the anticancer effects.[17][18] One of these compounds, 2,5-dimethyl-celecoxib, which entirely lacks the ability to inhibit COX-2, actually turned out to display stronger anticancer activity than celecoxib itself [19] and this anticancer effect could also be verified in highly drug-resistant tumor cells[20] and in various animal tumor models.[21][22]


Research history

The COX-2 enzyme was discovered in 1988 by Daniel Simmons, a Brigham Young University researcher.[23] The mouse COX-2 gene was cloned by UCLA scientist Dr. Harvey Herschman, a finding published in 1991.[24]

The basic research leading to the discovery of COX-2 inhibitors has been the subject of at least two lawsuits. Brigham Young University has sued Pfizer, alleging breach of contract from relations BYU had with the company at the time of Dr. Simmons work.[25][26] A settlement was reached in April 2012 in which Pfizer agreed to pay $450 million.[27][28] The other litigation is based on United States Pat. No. 6,048,850[29] owned by University of Rochester, which claimed a method to treat pain without causing gastro-intestinal distress by selectively inhibiting COX-2. When the patent issued, the university sued Searle (later Pfizer) in a case called, University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004). The court ruled in favor of Searle in 2004, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid.[30][31]

In the course of the search for a specific inhibitor of the negative effects of prostaglandins which spared the positive effects, it was discovered that prostaglandins could indeed be separated into two general classes which could loosely be regarded as "good prostaglandins" and "bad prostaglandins", according to the structure of a particular enzyme involved in their biosynthesis, cyclooxygenase.

Prostaglandins whose synthesis involves the cyclooxygenase-I enzyme, or COX-1, are responsible for maintenance and protection of the gastrointestinal tract, while prostaglandins whose synthesis involves the cyclooxygenase-II enzyme, or COX-2, are responsible for inflammation and pain.

The existing non-steroidal anti-inflammatory drugs (NSAIDs) differ in their relative specificities for COX-2 and COX-1; while aspirin and ibuprofen inhibit COX-2 and COX-1 enzymes, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam (Mobic). Aspirin is ≈170-fold more potent in inhibiting COX-1 than COX-2.[32] Studies of meloxicam 7.5 mg per day for 23 days find a level of gastric injury similar to that of a placebo, and for meloxicam 15 mg per day a level of injury lower than that of other NSAIDs; however, in clinical practice meloxicam can still cause some ulcer complications.

Many COX-2-specific inhibitors have been removed from the U.S. market. As of December 2011, only Celebrex (generic name is celecoxib) is still available for purchase.

Valdecoxib and rofecoxib are about 300 times more potent at inhibiting COX-2, than COX-1, suggesting the possibility of relief from pain and inflammation, without gastrointestinal irritation, and promising to be a boon for those who had experienced such adverse effects previously or had comorbidities that could lead to such complications. Celecoxib is approximately 30 times more potent at inhibiting COX-2 than COX-1, with etoricoxib being 106 times more potent. Also, Tribulus terrestris was shown to have strong inhibitory activity on COX-2.[33]

Research fraud

Between 1996 and 2009, anesthesiologist Scott Reuben conducted clinical research on the use of COX-2 inhibitors, often in combination with gabapentin or pregabalin, for the prevention and treatment of post-surgical pain, research which was found in 2009 to have been faked. Reuben pled guilty, paid fines and served six months in jail, and lost his medical license.[34] A 2009 review of meta-articles used in evidence-based medicine found that while some reviews were no longer valid when the Reuben studies were removed, the conclusions in the majority of them remained unchanged.[35] The review found that the key Reuben claims that needed to be re-examined were "the absence of detrimental effects of coxibs on bone healing after spine surgery, the beneficial long-term outcome after preemptive administration of coxibs including an allegedly decreased incidence of chronic pain after surgery, and the analgesic efficacy of ketorolac or clonidine when added to local anesthetics for intravenous regional anesthesia."[35]

Early COX-2-inhibiting drugs

Celebrex (and other brand names for celecoxib) was introduced in 1999 and rapidly became the most frequently prescribed new drug in the United States. By October 2000, its US sales exceeded 100 million prescriptions per year for $3 billion, and was still rising. Sales of Celebrex alone reached $3.1 billion in 2001. A Spanish study found that between January 2000 and June 2001, 7% of NSAID prescriptions and 29% of NSAID expenditures were for COX-2 inhibitors. Over the period of the study, COX-2 inhibitors rose from 10.03% of total NSAIDs prescribed by specialty physicians to 29.79%, and from 1.52% to 10.78% of NSAIDs prescribed by primary care physicians (98.23% of NSAIDs and 94.61% of COX-2 inhibitors were prescribed by primary care physicians). For specialty physicians, rofecoxib and celecoxib were third and fifth most frequently prescribed NSAIDs but first and second in cost, respectively; for primary-care physicians they were ninth and twelfth most frequently prescribed NSAIDs and first and fourth in cost.

The cause of the rapid widespread acceptance of Celebrex and Vioxx by physicians was the publication of two large trials, the Celecoxib Long-term Arthritis Safety Study [36] CLASS study in JAMA, and the Vioxx Gastrointestinal Outcomes Research[37] VIGOR study in the New England Journal of Medicine. Both publications concluded that COX-2 specific NSAIDs were associated with significantly fewer adverse gastrointestinal effects. In the CLASS trial comparing Celebrex 800 mg/day to ibuprofen 2400 mg/day and diclofenac 150 mg/day for osteoarthritis or rheumatoid arthritis for six months, Celebrex was significantly associated with fewer upper gastrointestinal complications (0.44% vs. 1.27%, P=0.04), with no significant difference in incidence of cardiovascular events in patients not taking aspirin for cardiovascular prophylaxis. In the VIGOR trial testing Vioxx 50 mg/day versus naproxen for rheumatoid arthritis, Vioxx reduced the risk of symptomatic ulcers and clinical upper gastrointestinal events (perforations, obstructions and bleeding) by 54%, to 1.4% from 3%, the risk of complicated upper gastrointestinal events (complicated perforations, obstructions and bleeding in the upper gastrointestinal tract) by 57%, and the risk of bleeding from anywhere in the gastrointestinal tract by 62%. An enormous marketing effort capitalized on these publications; Vioxx was the most heavily advertised prescription drug in 2000, and Celebrex the seventh, according to IMS Health.


Small tumors of the sympathetic nervous system (neuroblastoma) appear to have abnormal levels of COX-2 expressed.[38] These studies report that overexpression of the COX-2 enzyme has an adverse effect on the tumor suppressor, p53. p53 is an apoptosis transcription factor normally found in the cytosol. When cellular DNA is damaged beyond repair, p53 is transported to the nucleus where it promotes p53 mediated apoptosis.[39] Two of the metabolites of COX-2, prostaglandin A2 (PGA2) and A1 (PGA1), when present in high quantities bind to p53 in the cytosol and inhibit its ability to cross into the nucleus. This essentially sequesters p53 in the cytosol and prevents apoptosis.[39] Coxibs such as Celebrex (celecoxib), by selectively inhibiting the overexpressed COX-2, allow p53 to work properly. Functional p53 allows DNA damaged neuroblastoma cells to commit suicide through apoptosis, halting tumor growth.

COX-2 up-regulation has also been linked to the phosphorylation and activation of the E3 ubiquitin ligase HDM2, a protein that mediates p53 ligation and tagged destruction, through ubiquitination.[39] The mechanism for this neuroblastoma HDM2 hyperactivity is unknown. Studies have shown that COX-2 inhibitors block the phosphorylation of HDM2 preventing its activation. In vitro, the use of COX-2 inhibitors lowers the level of active HDM2 found in neuroblastoma cells. The exact process of how COX-2 inhibitors block HDM2 phosphorylation is unknown, but this mediated reduction in active HDM2 concentration level restores the cellular p53 levels. After treatment with a COX-2 inhibitor, the restored p53 function allows DNA damaged neuroblastoma cells to commit suicide through apoptosis reducing the size of growth of the tumor.[39]


  1. ^ Tirunagari SK, Derry S, Moore RA, McQuay HJ (2009). "Single dose oral etodolac for acute postoperative pain in adults". The Cochrane Database of Systematic Reviews (3): CD007357.  
  2. ^ Bulley S, Derry S, Moore RA, McQuay HJ (2009). "Single dose oral rofecoxib for acute postoperative pain in adults". The Cochrane Database of Systematic Reviews (4): CD004604.  
  3. ^ Clarke R, Derry S, Moore RA (May 8, 2014). "Single dose oral etoricoxib for acute postoperative pain in adults". The Cochrane Database of Systematic Reviews 5: CD004309.  
  4. ^ Derry S, Moore RA (Oct 22, 2013). "Single dose oral celecoxib for acute postoperative pain in adults". The Cochrane Database of Systematic Reviews 10: CD004233.  
  5. ^ a b van Durme, CM; Wechalekar, MD; Buchbinder, R; Schlesinger, N; van der Heijde, D; Landewé, RB (16 September 2014). "Non-steroidal anti-inflammatory drugs for acute gout.". The Cochrane database of systematic reviews 9: CD010120.  
  6. ^ van Durme, CM; Wechalekar, MD; Landewé, RB (9 June 2015). "Nonsteroidal anti-inflammatory drugs for treatment of acute gout.". JAMA 313 (22): 2276–7.  
  7. ^ a b c Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA (Mar 2007). "Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association". Circulation 115 (12): 1634–42.  
  8. ^ Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C (Jun 2006). "Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials". Bmj 332 (7553): 1302–8.  
  9. ^ a b Cannon CP, Cannon PJ (Jun 2012). "Physiology. COX-2 inhibitors and cardiovascular risk". Science 336 (6087): 1386–7.  
  10. ^ "COX-2 Inhibitors and Cancer". Fact Sheet. United States National Cancer Institute. 
  11. ^ [1]
  12. ^ Chow LW, Loo WT, Toi M (Oct 2005). "Current directions for COX-2 inhibition in breast cancer". Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie. 59 Suppl 2: S281–4.  
  13. ^ Farooqui M, Li Y, Rogers T, Poonawala T, Griffin RJ, Song CW, Gupta K (Dec 2007). "COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia". British Journal of Cancer 97 (11): 1523–31.  
  14. ^ Müller N (Jan 2010). "COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence". Current Opinion in Investigational Drugs 11 (1): 31–42.  
  15. ^ Schönthal AH (Dec 2007). "Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy". British Journal of Cancer 97 (11): 1465–8.  
  16. ^ Chuang HC, Kardosh A, Gaffney KJ, Petasis NA, Schönthal AH (2008). "COX-2 inhibition is neither necessary nor sufficient for celecoxib to suppress tumor cell proliferation and focus formation in vitro". Molecular Cancer 7: 38.  
  17. ^ a b Zhu J, Song X, Lin HP, Young DC, Yan S, Marquez VE, Chen CS (Dec 2002). "Using cyclooxygenase-2 inhibitors as molecular platforms to develop a new class of apoptosis-inducing agents". Journal of the National Cancer Institute 94 (23): 1745–57.  
  18. ^ Schönthal AH, Chen TC, Hofman FM, Louie SG, Petasis NA (Feb 2008). "Celecoxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs". Expert Opinion on Investigational Drugs 17 (2): 197–208.  
  19. ^ Schönthal AH (2006). "Antitumor properties of dimethyl-celecoxib, a derivative of celecoxib that does not inhibit cyclooxygenase-2: implications for glioma therapy". Neurosurgical Focus 20 (4): E21.  
  20. ^ Kardosh A, Soriano N, Liu YT, Uddin J, Petasis NA, Hofman FM, Chen TC, Schönthal AH (Dec 2005). "Multitarget inhibition of drug-resistant multiple myeloma cell lines by dimethyl-celecoxib (DMC), a non-COX-2 inhibitory analog of celecoxib". Blood 106 (13): 4330–8.  
  21. ^ Pyrko P, Kardosh A, Liu YT, Soriano N, Xiong W, Chow RH, Uddin J, Petasis NA, Mircheff AK, Farley RA, Louie SG, Chen TC, Schönthal AH (Apr 2007). "Calcium-activated endoplasmic reticulum stress as a major component of tumor cell death induced by 2,5-dimethyl-celecoxib, a non-coxib analogue of celecoxib". Molecular Cancer Therapeutics 6 (4): 1262–75.  
  22. ^ Kardosh A, Wang W, Uddin J, Petasis NA, Hofman FM, Chen TC, Schönthal AH (May 2005). "Dimethyl-celecoxib (DMC), a derivative of celecoxib that lacks cyclooxygenase-2-inhibitory function, potently mimics the anti-tumor effects of celecoxib on Burkitt's lymphoma in vitro and in vivo". Cancer Biology & Therapy 4 (5): 571–82.  
  23. ^ Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL (Apr 1991). "Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing". Proceedings of the National Academy of Sciences of the United States of America 88 (7): 2692–6.  
  24. ^ Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR (Jul 1991). "TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue". The Journal of Biological Chemistry 266 (20): 12866–72.  
  25. ^ Yajnik J (2006-10-27). "University sues Pfizer over COX-2 research". The Scientist. Retrieved 2010-11-11. 
  26. ^ Tom Harvey (2010-09-21). "BYU spices up Celebrex lawsuit against Pfizer".  
  27. ^ Tom Harvey (May 1, 2012). "Pfizer, BYU settle Celebrex lawsuit for $450M". The Salt Lake Tribune. 
  28. ^ Associated Press, May 1, 2012 Pfizer Settles B.Y.U. Lawsuit Over Development of Celebrex
  29. ^ US Patent 6048850,
  30. ^ "Publications: Hodgson Russ LLP". Retrieved 2015-05-23. 
  31. ^ Ranjana Kadle (2004) CAFC Court Decision Reach-Through Claims Declared Invalid
  32. ^ Awtry EH, Loscalzo J (Mar 2000). "Aspirin". Circulation 101 (10): 1206–18.  
  33. ^ Hong CH, Hur SK, Oh OJ, Kim SS, Nam KA, Lee SK (Nov 2002). "Evaluation of natural products on inhibition of inducible cyclooxygenase (COX-2) and nitric oxide synthase (iNOS) in cultured mouse macrophage cells". Journal of Ethnopharmacology 83 (1-2): 153–9.  
  34. ^ A Medical Madoff: Anesthesiologist Faked Data in 21 Studies, Scientific American, March 10, 2009
  35. ^ a b Marret E, Elia N, Dahl JB, McQuay HJ, Møiniche S, Moore RA, Straube S, Tramèr MR (Dec 2009). "Susceptibility to fraud in systematic reviews: lessons from the Reuben case". Anesthesiology 111 (6): 1279–89.  
  36. ^ Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, Burr AM, Zhao WW, Kent JD, Lefkowith JB, Verburg KM, Geis GS (Sep 2000). "Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study". Jama 284 (10): 1247–55.  
  37. ^ Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ (Nov 2000). "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group". The New England Journal of Medicine 343 (21): 1520–8, 2 p following 1528.  
  38. ^ Johnsen JI, Lindskog M, Ponthan F, Pettersen I, Elfman L, Orrego A, Sveinbjörnsson B, Kogner P (Oct 2004). "Cyclooxygenase-2 is expressed in neuroblastoma, and nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit tumor growth in vivo". Cancer Research 64 (20): 7210–5.  
  39. ^ a b c d Lau L, Hansford LM, Cheng LS, Hang M, Baruchel S, Kaplan DR, Irwin MS (Mar 2007). "Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma". Oncogene 26 (13): 1920–31.  

Further reading

  • Green GA (2001). "Understanding NSAIDs: from aspirin to COX-2". Clinical Cornerstone 3 (5): 50–60.  
  • Malhotra S, Shafiq N, Pandhi P (2004). "COX-2 inhibitors: a CLASS act or Just VIGORously promoted". MedGenMed 6 (1): 6.  
  • Montero Fernández MJ, Rodríguez Alcalá FJ, Valles Fernández N, López de Castro F, Esteban Tudela M, Cordero García B (Oct 2002). "[At what care level are cyclo-oxygenase-2 inhibitors prescribed?]". Atencion Primaria / Sociedad Española De Medicina De Familia Y Comunitaria (in Spanish) 30 (6): 363–7.  
  • Francesca Lunzer Kritz (September 4, 2001). "You and A: Arthritis drugs. Pain and confusion". Washington Post. p. HE01. 
  • "Vioxx (rofecoxib) reduces night-time osteoarthritis pain better than celecoxib or acetaminophen"; European League Against Rheumatism (EULAR) conference proceedings.
  • "Will the promise of the COX-2 selective NSAIDs come to fruition?". Drugs & Therapy Perspectives 17 (11): 6–10. 2001.  
  • Chancellor JV, Hunsche E, de Cruz E, Sarasin FP (2001). "Economic evaluation of celecoxib, a new cyclo-oxygenase 2 specific inhibitor, in Switzerland". PharmacoEconomics. 19 Suppl 1: 59–75.  
  • Kamath CC, Kremers HM, Vanness DJ, O'Fallon WM, Cabanela RL, Gabriel SE (2003). "The cost-effectiveness of acetaminophen, NSAIDs, and selective COX-2 inhibitors in the treatment of symptomatic knee osteoarthritis". Value in Health 6 (2): 144–57.  
  • "Osteoarthritis drug Celebrex (celecoxib) less likely to cause increased blood pressure than Vioxx (rofecoxib)"; European League Against Rheumatism (EULAR) conference proceedings.
  • Johnsen JI, Lindskog M, Ponthan F, Pettersen I, Elfman L, Orrego A, Sveinbjörnsson B, Kogner P (Oct 2004). "Cyclooxygenase-2 is expressed in neuroblastoma, and nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit tumor growth in vivo". Cancer Research 64 (20): 7210–5.  
  • Dai C, Stafford RS, Alexander GC (Jan 2005). "National trends in cyclooxygenase-2 inhibitor use since market release: nonselective diffusion of a selectively cost-effective innovation". Archives of Internal Medicine 165 (2): 171–7.  
  • Solomon DH, Avorn J (Jan 2005). "Coxibs, science, and the public trust". Archives of Internal Medicine 165 (2): 158–60.  
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