Celecoxib

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Celecoxib
Celecoxib2DACS.svg
Celecoxib3Dan.gif
Systematic (IUPAC) name
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide
Clinical data
Trade names Celebrex
AHFS/Drugs.com monograph
MedlinePlus a699022
Licence data US FDA:link
Pregnancy cat. B3 (AU) C (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability Unknown[1]
Protein binding 97% (mainly to serum albumin)[1]
Metabolism Hepatic (mainly CYP2C9)[1]
Half-life 7.8 hours; 11 hours (mild hepatic impairment); 13 hours (moderate-severe hepatic impairment)[1]
Excretion Faeces (57%), urine (27%)[1]
Identifiers
CAS number 169590-42-5 YesY
ATC code L01XX33 M01AH01
PubChem CID 2662
DrugBank DB00482
ChemSpider 2562 YesY
UNII JCX84Q7J1L YesY
KEGG D00567 YesY
ChEBI CHEBI:41423 YesY
ChEMBL CHEMBL118 YesY
PDB ligand ID CEL (PDBe, RCSB PDB)
Chemical data
Formula C17H14F3N3O2S 
Mol. mass 381.373 g/mol
 YesY (what is this?)  (verify)

Celecoxib INN (/sɛlɨˈkɒksɪb/ SE-lə-KOK-sib) is a COX-2 selective nonsteroidal anti-inflammatory drugs (NSAID). It is used to treat the signs and symptoms of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute pain in adults, painful menstruation, juvenile rheumatoid arthritis in patients 2 years or older.[2]

It is also used to reduce colon and rectal polyps in people with familial adenomatous polyposis.

Side effects include a 37% increase in incidence of major vascular events, which include non-fatal myocardial infarction, non-fatal stroke or death from a vascular cause.[3] Additionally there is an 81% increase in incidence of upper gastrointestinal complications which include perforations, obstructions or bleeds.[3]

It is marketed by Pfizer. It is known under the brand name Celebrex or Celebra for arthritis and Onsenal for polyps. Celecoxib is available by prescription in capsule form.

Medical uses[edit]

Celecoxib is used for osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation, ankylosing spondylitis, and to reduce the number of colon and rectal polyps in people with familial adenomatous polyposis.[2] It may also be used in children with juvenile rheumatoid arthritis who are older than 2 years of age and weigh more than 10 kilograms (22 pounds).[2]

For post operative pain it is more or less equal to ibuprofen.[4] For pain relief it is similar to paracetamol (acetaminophen).[5] And in osteoarthritis acetaminophen is the first line treatment for OA.[6][7]

It was originally intended to relieve pain while minimizing the gastrointestinal adverse effects seen with conventional NSAIDs. In practice, its primary indication is in patients who need regular and long-term pain relief; there is probably no advantage to using celecoxib for short term or acute pain relief over conventional NSAIDs, except in the situation where nonselective NSAIDs or aspirin cause cutaneous reactions (urticaria or "hives").

Adverse effects[edit]

Anaphylactoid reactions: Contrary to the package insert and many other reviews the risk of Anaphylactoid reactions with Cox 2 inhibitors is decreased. Particularly Aspirin Triad Asthmatics tolerate highly selective Cox 2 inhibitors. (Stevenson DD et al. J Allergy Clin Immunol 2000;105;s273.) without exception. Celecoxib is actually safer than acetaminophen in Asprin Triad Asthma.

  • Cardiovascular events: [US Boxed Warning]: NSAIDs are associated with an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including myocardial infarction and stroke. Risk may be increased with duration of use or pre-existing cardiovascular risk factors or disease. Carefully evaluate individual cardiovascular risk profiles prior to prescribing. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may impair response to thiazide or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema or heart failure. Long-term cardiovascular risk in children has not been evaluated. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.[8]
  • Gastrointestinal events: [US Boxed Warning]: NSAIDs may increase risk of serious gastrointestinal (GI) ulceration, bleeding, and perforation (may be fatal). These events may occur at any time during therapy and without warning. Use caution with a history of GI disease (bleeding or ulcers), concurrent therapy with aspirin, anticoagulants and/or corticosteroids, smoking, use of alcohol, the elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with ≤325 mg of aspirin, a substantial increase in the risk of gastrointestinal complications (e.g., ulcer) occurs; concomitant gastroprotective therapy (e.g., proton pump inhibitors) is recommended.[2]
  • Hematologic effects: Anemia may occur; monitor hemoglobin or hematocrit in patients on long-term treatment. Celecoxib does not usually affect PT, PTT or platelet counts; it does not inhibit platelet aggregation at approved doses.
  • Skin reactions: NSAIDs may cause serious skin adverse events, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis; events may occur without warning and in patients without prior known sulfa allergy; discontinue use at first sign of rash (or any other hypersensitivity).

Patients with prior history of ulcer disease or GI bleeding require special precaution. Moderate to severe hepatic impairment or GI toxicity can occur with or without warning symptoms in patients treated with NSAIDs.

Allergy[edit]

Celecoxib contains a sulfonamide moiety and may cause allergic reactions in those allergic to other sulfonamide-containing drugs. This is in addition to the contraindication in patients with severe allergies to other NSAIDs. However, it has a low (reportedly 4%) chance of inducing cutaneous reactions among persons who have a history of such reactions to aspirin or nonselective NSAIDs.

Drug interactions[edit]

Celecoxib is predominantly metabolized by cytochrome P450 2C9. Caution must be exercised with concomitant use of 2C9 inhibitors, such as fluconazole, which can greatly elevate celecoxib serum levels. In addition, celecoxib may increase the risk of renal failure with angiotensin converting enzyme-inhibitors, such as lisinopril, and diuretics, such as hydrochlorothiazide.[9]

Pregnancy[edit]

In the US FDA's pregnancy categories, the drug is category C prior to 30 weeks gestation, and category D starting at 30 weeks gestation.[9]

Heart attack and stroke[edit]

The coxibs (which includes celecoxib) increase the risk of major cardiovascular problems by about 37%.[3] The NSAID naproxen or paracetamol (acetaminophen) appears to be safer.[3]

The COX-2 inhibitor rofecoxib (Vioxx) was removed from the market in 2004 due to its risk. Like all NSAIDs on the US market, celecoxib carries an FDA-mandated "black box warning" for cardiovascular and gastrointestinal risk. In February 2007, the American Heart Association warned that with respect to "patients with a prior history of or at high risk for cardiovascular disease... use of COX-2 inhibitors for pain relief should be limited to patients for whom there are no appropriate alternatives, and then, only in the lowest dose and for the shortest duration necessary."[10]

In 2005, a study published in the Annals of Internal Medicine found that cardiovascular effects of COX-2 inhibitors differ, depending on the drug.[11] Other COX-2-selective inhibitors, such as rofecoxib, have significantly higher myocardial infarction rates than celecoxib.[12] In April 2005, after an extensive review of data, the FDA concluded it was likely "that there is a 'class effect' for increased CV risk for all NSAIDs".[13] In a 2006 meta-analysis of randomized control studies, the cerebrovascular events associated with COX-2 inhibitors were examined, but no significant risks were found when compared to nonselective NSAIDs or placebos.[14]

Mechanism of action[edit]

A highly selective inhibitor of the COX-2 isoform of cyclooxygenase, celecoxib inhibits the transformation of arachidonic acid to prostaglandin precursors. Therefore, it has anti-pyretic, analgesic and anti-inflammatory properties.[2] Nonselective NSAIDs (such as aspirin, naproxen, and ibuprofen) inhibit both COX-1 and COX-2. Cox-1 (which celecoxib does not inhibit at therapeutic concentrations) inhibits the production of prostaglandins and the production of thromboxane A2, a platelet activator.[2] COX-1 is traditionally defined as a constitutively expressed "housekeeping" enzyme and plays a role in the protection of the gastrointestinal mucosa, renal hemodynamics, and platelet thrombogenesis.[15][16] COX-2, on the contrary, is extensively expressed in cells involved in inflammation and is upregulated by bacterial lipopolysaccharides, cytokines, growth factors, and tumor promoters.[15][17] Celecoxib is approximately 10-20 times more selective for COX-2 inhibition over COX-1.[16][18] It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site.[19] In theory, this selectivity allows celecoxib and other COX-2 inhibitors to reduce inflammation (and pain) while minimizing gastrointestinal adverse drug reactions (e.g. stomach ulcers) that are common with nonselective NSAIDs.[20]

Medicinal chemistry[edit]

Synthesis[edit]

The synthesis of celecoxib was first described in 1997 by a team of researchers at Searle Research and Development. It is synthesized by a Claisen condensation reaction of an acetophenone with N-(trifluoroacetyl)imidazole catalyzed by the strong base, sodium bis(trimethylsilyl)amide to produce a 1,3-dicarbonyl adduct.[21] Condensation of the diketone with (4-sulfamoylaphenyl)hydrazine produces the 1,5-diarylpyrazole drug moiety.

Synthesis of celecoxib.gif

Structure-activity relationship[edit]

Monosubstituted 1,5-diarylpyrazoles.jpg
Enzyme data for monosubstituted 5-aryl analogs.jpg
Enzyme data for 4-substituted analogs.jpg
In vitro cox-I and cox-II enzyme data for disubstituted 5-aryl analogs.jpg

The Searle research group found the two appropriately substituted aromatic rings must reside on adjacent positions about the central ring for adequate COX-2 inhibition. Various modifications can be made to the 1,5-diarylpyrazole moiety to deduce the structure-activity relationship of celecoxib.[21] A para-sulfamoylphenyl at position 1 of the pyrazole was found to have a higher potency for COX-2 selective inhibition than a para-methoxyphenyl (see structures 1 and 2, below). In addition, a 4-(methylsulfonyl)phenyl or 4-sulfamoylphenyl is known to be necessary for COX-2 inhibition. For instance, replacing either of these entities with a –SO2NHCH3 substituent diminishes COX-2 inhibitory activity as noted with a very high inhibitory concentration-50 (see structures 3 - 5). At the 3-position of the pyrazole, a trifluoromethyl or difluoromethyl provides superior selectivity and potency compared to a fluoromethyl or methyl substitution (see structures 6 – 9).[21]

The fourth position of the pyrazole is readily affected by steric hindrance such that increasing the bulkiness of the substitution starkly decreases the potency. For example, by progressively increasing the size of R1, from a methyl to propyl, the potency for COX-2 inhibition decreases especially with moieties larger than an ethyl (see structures 10-12). In addition, incorporating a halo-atom at this position provides significantly potent COX-2 inhibition (see structures 13 and 14). While it is known there must be an aromatic system at the fifth position of the pyrazole, optimizing this substituent is difficult since it is not known what combination of modifications will provide the highest potency and selectivity due to the flexible nature of the 5-aryl system. It was found that substitutions at either the para (4-substitution) or ortho (2-substitution) sites have higher potency than meta (3-substitution) sites (see structures 15-17).

Electron withdrawing groups, such as –CN, at these positions have poor COX-1 and COX-2 inhibition; however, electron donating groups, such as methoxyl, have substantial COX-1 and COX-2 inhibitory effects which makes them inefficient as a COX-2 selective inhibitor (see structures 18 and 19 ). The strong COX-1 inhibition of the para-methoxyl can be corrected by substituting a halo-atom at the alpha position. For instance, the introduction of a 3-fluoro or 3-chloro decreases COX-1 inhibition by 43- and 33-folds, respectively (see structures 20 and 21). It is necessary to consider the steric hindrance created by a para-substitution of the 5-aromatic system. Consider the COX-2 inhibitory capacity of the 4-methyl and 4-ethyl modifications: 4-methyl can inhibit COX-2 such that the IC50 is 0.040 μM while that of the 4-ethyl is 0.86 μM which means the 4-methyl substituent is at least 20-fold more potent (see structures 22 and 23).

Celecoxib is compound 22; the 4-sulfamoylphenyl on the 1-pyrazol substituent is required for COX-2 inhibition and the 4-methyl on the 5-pyrazol system has low steric hindrance to maximize potency, while the 3-trifluoromethyl group provides superior selectivity and potency.[21] To explain the selectivity of celecoxib, it is necessary to analyze the free energy of binding difference between the drug molecule and COX-1 compared to COX-2 enzymes. The structural modifications highlight the importance of binding to residue 523 in the side binding pocket of the cyclooxygenase enzyme, which is an isoleucine in COX-1 and a valine in COX-2.[22] It appears that this mutation contributes to COX-2 selectivity by creating steric hindrance between the sulfonamide oxygen and the methyl group of Ile523 that effectively destabilizes the celecoxib-COX-1 complex.[22] Thus it is reasonable to expect COX-2 selective inhibitors to be more bulky than non-selective NSAIDs.

History[edit]

Two lawsuits arose over discovery of celecoxib. Daniel L. Simmons of Brigham Young University discovered the COX-2 enzyme,[23] and BYU entered into a collaboration with Monsanto to develop drugs to inhibit it. BYU ended up suing Pfizer for breach of contract.[24] A settlement was reached in April 2012 in which Pfizer agreed to pay $450 million.[25][26] Other important discoveries in COX-2 were made at University of Rochester, which patented the discoveries.[27] 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.[28][29]

Celecoxib was discovered and[30] developed by G. D. Searle & Company and was approved by the FDA on December 31, 1998.[31] It was co-promoted by Monsanto Company (parent company of Searle) and Pfizer under the brand name Celebrex. Monsanto merged with Pharmacia, from which the Medical Research Division was acquired by Pfizer, giving Pfizer ownership of Celebrex. The drug was at the core of a major patent dispute that was resolved in Searle's favor (later Pfizer) in 2004.[28][29] In University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004), the University of Rochester claimed that United States Pat. No. 6,048,850 (which claimed a method of inhibiting COX-2 in humans using a compound, without actually disclosing what that compound might be) covered drugs such as celecoxib. The court ruled in favor of Searle, 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.

After the withdrawal of rofecoxib (Vioxx) from the market in September 2004, Celebrex enjoyed a robust increase in sales. However, the results of the APC trial in December of that year raised concerns that Celebrex might carry risks similar to those of Vioxx, and Pfizer announced a moratorium on direct-to-consumer advertising of Celebrex soon afterwards. After a significant drop, sales of Celebrex have recovered, and reached $2 billion in 2006.[10] Pfizer resumed advertising Celebrex in magazines in 2006,[32] and resumed television advertising in April 2007 with an unorthodox, 2 12-minute advertisement which extensively discussed the adverse effects of Celebrex in comparison with other anti-inflammatory drugs. The ad drew criticism from the consumer advocacy group Public Citizen, which called the ad's comparisons misleading.[33] Pfizer responded to Public Citizen's concerns with assurances that they are truthfully advertising the risk and benefits of Celebrex as set forth by the FDA.[33]

In late 2007, Pfizer released another US television ad for Celebrex, which also discussed celecoxib's adverse effects in comparison with those of other anti-inflammatory drugs.

Society and culture[edit]

Fabricated efficacy studies[edit]

On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Massachusetts, revealed that the data for 21 studies he had authored for the efficacy of the drug (along with others such as Vioxx) had been fabricated. The analgesic effects of the drugs had been exaggerated. Reuben was also a former paid spokesperson for Pfizer. None of the retracted studies were submitted to either the US Food and Drug Administration or the European Union's regulatory agencies prior to the drug's approval. Pfizer issued a public statement declaring, "It is very disappointing to learn about Dr. Scott Reuben's alleged actions. When we decided to support Dr. Reuben's research, he worked for a credible academic medical center and appeared to be a reputable investigator."[34][35]

Availability[edit]

Pfizer markets celecoxib under the brand name Celebrex, and is available as oral capsules containing 50, 100, 200 or 400 mg of celecoxib.[36]

As of March 2013 Celecoxib is not available as a generic in the United States, because it is covered by unexpired Pfizer patents.[37] However, in other countries, including India and the Philippines, it is legally available as a generic under several brand names.[38]

Research[edit]

Cancer prevention[edit]

The role celecoxib might have in reducing the rates of certain cancers has been the subject of many studies. However, there is no current medical recommendation to use this drug for cancer reduction.

The use of celecoxib to reduce the risk of colorectal cancer has been investigated, but neither celecoxib nor any other drug is indicated for this use.[39] Twelve carcinogenesis studies in rats of mice showed celecoxib prevented intestinal cancer in those experimental settings.[40] Small-scale clinical trials in very high risk people (belonging to FAP families) also showed celecoxib can prevent polyp growth. Hence, large-scale randomized clinical trials were undertaken and results published by N. Arber and M. Bertagnolli in The New England Journal of Medicine, August 2006.[41] Results show a 33 to 45% polyp recurrence reduction in people taking 400–800 mg celecoxib each day. However, serious cardiovascular events were significantly more frequent in the celecoxib-treated groups (see above, cardiovascular toxicity). Aspirin shows a similar (and possibly larger) protective effect,[42][43][44] has demonstrated cardioprotective effects and is significantly cheaper, but there have been no head-to-head clinical trials comparing the two drugs.

Cancer treatment[edit]

Different from cancer prevention, cancer treatment is focused on the therapy of tumors that have already formed and have established themselves inside the patient. Many studies are ongoing to determine whether celecoxib might be useful for this latter condition.[45] However, during molecular studies in the laboratory, it became apparent that celecoxib could interact with other intracellular components besides its most famous target, cyclooxygenase 2 (COX-2). The discovery of these additional targets has generated much controversy, and the initial assumption that celecoxib reduces tumor growth primarily by the inhibition of COX-2 became contentious.[46]

Certainly, the inhibition of COX-2 is paramount for the anti-inflammatory and analgesic function of celecoxib. However, whether inhibition of COX-2 also plays a dominant role in this drug’s anticancer effects is unclear. For example, a recent study with malignant tumor cells showed celecoxib could inhibit the growth of these cells in vitro, but COX-2 played no role in this outcome; even more strikingly, the anticancer effects of celecoxib were also obtained with the use of cancer cell types that do not even contain COX-2.[47]

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.[48] Some of these analogs retained COX-2 inhibitory activity, whereas many others did not. However, when the ability of all these compounds to kill tumor cells in cell culture was investigated, the antitumor potency did not at all depend on whether or not the respective compound could inhibit COX-2, showing the inhibition of COX-2 was not required for the anticancer effects.[48][49] One of these compounds, 2,5-dimethyl-celecoxib, which entirely lacks the ability to inhibit COX-2, actually displayed stronger anticancer activity than celecoxib.[50]

Adhesion prevention[edit]

Celocoxib may prevent intra-abdominal adhesion formation. Adhesions are a common complication of surgery, especially abdominal surgery, and major cause of bowel obstruction and infertility. Publishing in 2005, researchers in Boston noticed a "dramatic" reduction in postsurgical adhesions in mice taking the drug celecoxib.[51] Multi-institutional trials in adult human patients are planned.[52] The initially suggested course of treatment is a mere seven to 10 days following surgery.[53]

References[edit]

  1. ^ a b c d e McCormack, PL (December 2011). "Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.". Drugs 71 (18): 2457–89. doi:10.2165/11208240-000000000-00000. PMID 22141388. 
  2. ^ a b c d e f "Drug Label". 
  3. ^ a b c d Coxib and traditional NSAID Trialists' (CNT), Collaboration; Bhala, N; Emberson, J; Merhi, A; Abramson, S; Arber, N; Baron, JA; Bombardier, C; Cannon, C; Farkouh, ME; FitzGerald, GA; Goss, P; Halls, H; Hawk, E; Hawkey, C; Hennekens, C; Hochberg, M; Holland, LE; Kearney, PM; Laine, L; Lanas, A; Lance, P; Laupacis, A; Oates, J; Patrono, C; Schnitzer, TJ; Solomon, S; Tugwell, P; Wilson, K; Wittes, J; Baigent, C (Aug 31, 2013). "Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials". Lancet 382 (9894): 769–79. doi:10.1016/S0140-6736(13)60900-9. PMC 3778977. PMID 23726390. 
  4. ^ Derry, S; Moore, RA (Mar 14, 2012). "Single dose oral celecoxib for acute postoperative pain in adults". In Derry, Sheena. The Cochrane database of systematic reviews 3: CD004233. doi:10.1002/14651858.CD004233.pub3. PMID 22419293. 
  5. ^ Yelland MJ, Nikles CJ, McNairn N, Del Mar CB, Schluter PJ, Brown RM (2007). "Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials". Rheumatology 46 (1): 135–40. doi:10.1093/rheumatology/kel195. PMID 16777855. 
  6. ^ Zhang W, Moskowitz RW, Nuki G et al. (September 2007). "OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence". Osteoarthr. Cartil. 15 (9): 981–1000. doi:10.1016/j.joca.2007.06.014. PMID 17719803. 
  7. ^ Flood, J (March 2010). "The role of acetaminophen in the treatment of osteoarthritis". The American journal of managed care. 16 Suppl Management: S48–54. PMID 20297877. 
  8. ^ Solomon, S.; McMurray, J.; Pfeffer, M.; Wittes, J.; Fowler, R.; Finn, P.; Anderson, W.; Zauber, A.; Hawk, E.; Bertagnolli, M.; Adenoma Prevention with Celecoxib (APC) Study Investigators (2005). "Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention". The New England Journal of Medicine 352 (11): 1071–1080. doi:10.1056/NEJMoa050405. PMID 15713944.  edit
  9. ^ a b Celebrex label Accessed December 27, 2012
  10. ^ a b Antman EM, et al Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007 Mar 27;115(12):1634-42. Epub 2007 Feb 26.
  11. ^ Kimmel SE, Berlin JA, Reilly M, Jaskowiak J, Kishel L, Chittams J, Strom BL. Patients Exposed to Rofecoxib and Celecoxib Have Different Odds of Nonfatal Myocardial Infarction" Ann Intern Med 2005;142:157-164.
  12. ^ Mukherjee D, Nissen SE, Topol EJ. Inhibitors Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors" JAMA 2001;286(8) 954-959 doi:10.1001/jama.286.8.954.
  13. ^ Jenkins JK, Seligman PJ. (2005-04-06). "Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk [decision memorandum]" (PDF). FDA Center for Drug Evaluation and Research. 
  14. ^ Chen LC, Ashcroft DM. Do selective COX-2 inhibitors increase the risk of cerebrovascular events? A meta-analysis of randomized controlled trials.Journal of Clinical Pharmacy and Therapeutics (2006) 31, 565–576.
  15. ^ a b Mathew, ST; Devi S, G; Prasanth, VV; Vinod, B (2011). "Efficacy and Safety of COX-2 Inhibitors in the Clinical Management of Arthritis: Mini Review.". ISRN pharmacology 2011: 480291. PMID 22084715. 
  16. ^ a b Katzung, edited by Bertram G. (2007). Basic & clinical pharmacology (10th ed. ed.). New York: McGraw-Hill Medical. p. 579. ISBN 9780071451536. 
  17. ^ Shi, S; Klotz, U (2008 Mar). "Clinical use and pharmacological properties of selective COX-2 inhibitors.". European journal of clinical pharmacology 64 (3): 233–52. PMID 17999057. 
  18. ^ Conaghan, PG (2012 Jun). "A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity.". Rheumatology international 32 (6): 1491–502. PMID 22193214. 
  19. ^ DiPiro, Joseph T., Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, and L. Michael Posey. Pharmacotherapy A Pathophysiologic Approach (Pharmacotherapy (Dipiro) Pharmacotherapy (Dipiro)). New York: McGraw-Hill Medical, 2008. Print.
  20. ^ Bhatt, DL; Scheiman, J; Abraham, NS; Antman, EM; Chan, FK; Furberg, CD; Johnson, DA; Mahaffey, KW; Quigley, EM; Harrington, RA; Bates, ER; Bridges, CR; Eisenberg, MJ; Ferrari, VA; Hlatky, MA; Kaul, S; Lindner, JR; Moliterno, DJ; Mukherjee, D; Schofield, RS; Rosenson, RS; Stein, JH; Weitz, HH; Wesley, DJ; American College of Cardiology Foundation Task Force on Clinical Expert Consensus, Documents (2008 Oct 28). "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.". Journal of the American College of Cardiology 52 (18): 1502–17. PMID 19017521. 
  21. ^ a b c d Penning TD, Talley JJ, Bertenshaw SR et al. (1997). "Synthesis and Biological Evaluation of the 1.5 Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors: Identification of 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzenesulfonamide (SC-58634, Celecoxib)". Journal of Medicinal Chemistry 40 (9): 1347–1365. doi:10.1021/jm960803q. PMID 9135032. 
  22. ^ a b Price MLP, Jorgensen WL. Rationale for the Observed COX-2/COX-1 Selectivity of Celecoxibfrom Monte Carlo Simulations. Bioorganic and Medicinal Chemistry Lectures. 2001; 11: 1541-1544.
  23. ^ Yajnik J (2006-10-27). "University sues Pfizer over COX-2 research". The Scientist. Retrieved 2010-11-11. 
  24. ^ Linda Thomson (October 28, 2009). "Judge orders Pfizer to pay BYU $852K for suit delays". Deseret News. 
  25. ^ Tom Harvey (May 1, 2012). "Pfizer, BYU settle Celebrex lawsuit for $450M". The Salt Lake Tribune. 
  26. ^ Associated Press, May 1, 2012 Pfizer Settles B.Y.U. Lawsuit Over Development of Celebrex
  27. ^ U.S. Patent 6,048,850
  28. ^ a b Reach-Through Claims Declared Invalid
  29. ^ a b Ranjana Kadle (2004) CAFC Court Decision Reach-Through Claims Declared Invalid
  30. ^ U.S. Patent 5,466,823
  31. ^ Drug Approval Package, Food and Drug Administration
  32. ^ Berenson A (April 29, 2006). "Celebrex Ads Are Back, Dire Warnings and All". The New York Times. 
  33. ^ a b Saul S (April 10, 2007). "Celebrex Commercial, Long and Unconventional, Draws Criticism". The New York Times. 
  34. ^ Winstein, Keith J. (March 11, 2009). "Top Pain Scientist Fabricated Data in Studies, Hospital Says". The Wall Street Journal. 
  35. ^ "Associated Press, Mar 11, 2009, Mass. doctor accused of faking pain pill data". [dead link]
  36. ^ CELEBREX indications and dosing: Official Pfizer site
  37. ^ Reuters, March 5, 2013 Pfizer gets Celebrex patent extension, sues generic companies
  38. ^ Celecoxib at drugs.com
  39. ^ Rial NS et al (2012) Clinical end points for developing pharmaceuticals to manage patients with a sporadic or genetic risk of colorectal cancer. Expert Rev Gastroenterol Hepatol. 2012 Aug;6(4):507-17
  40. ^ data available on the Chemoprevention Database
  41. ^ Bertagnolli MM, Eagle CJ, Zauber AG, et al. (August 2006). "Celecoxib for the prevention of sporadic colorectal adenomas". N. Engl. J. Med. 355 (9): 873–84. doi:10.1056/NEJMoa061355. PMID 16943400. 
  42. ^ Baron JA, Cole BF, Sandler RS, et al. (2003). "A randomized trial of aspirin to prevent colorectal adenomas". N. Engl. J. Med. 348 (10): 891–9. doi:10.1056/NEJMoa021735. PMID 12621133. 
  43. ^ Sandler RS, Halabi S, Baron JA, et al. (2003). "A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer". N. Engl. J. Med. 348 (10): 883–90. doi:10.1056/NEJMoa021633. PMID 12621132. 
  44. ^ Bosetti C, Talamini R, Franceschi S, Negri E, Garavello W, La Vecchia C (2003). "Aspirin use and cancers of the upper aerodigestive tract". British Journal of Cancer 88 (5): 672–4. doi:10.1038/sj.bjc.6600820. PMC 2376339. PMID 12618872. 
  45. ^ Dannenberg AJ, Subbaramaiah K (December 2003). "Targeting cyclooxygenase-2 in human neoplasia: rationale and promise". Cancer Cell 4 (6): 431–6. doi:10.1016/S1535-6108(03)00310-6. PMID 14706335. 
  46. ^ Schönthal AH (December 2007). "Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy". Br. J. Cancer 97 (11): 1465–8. doi:10.1038/sj.bjc.6604049. PMC 2360267. PMID 17955049. 
  47. ^ Chuang, Huan-Ching; 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 (1): 38. doi:10.1186/1476-4598-7-38. PMC 2396175. PMID 18485224. 
  48. ^ a b Zhu J, Song X, Lin HP, et al. (December 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. doi:10.1093/jnci/94.23.1745. PMID 12464646. 
  49. ^ Schönthal AH, Chen TC, Hofman FM, Louie SG, Petasis NA (February 2008). "Celecoxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs". Expert Opinion on Investigational Drugs 17 (2): 197–208. doi:10.1517/13543784.17.2.197. PMID 18230053. 
  50. ^ 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. doi:10.3171/foc.2006.20.4.14. PMID 16709027. 
  51. ^ Arin K. Greene, MD, MMSc,Ian P. J. Alwayn, MD, PhD, Vania Nose, MD, PhD, Evelyn Flynn, MA, David Sampson, BA, David Zurakowski, PhD, Judah Folkman, MD, and Mark Puder, MD (July 2005). "Prevention of Intra-abdominal Adhesions Using the Antiangiogenic COX-2 Inhibitor Celecoxib". Ann Surg. 242 (1): 140–146. doi:10.1097/01.sla.0000167847.53159.c1. PMC 1357715. PMID 15973112. 
  52. ^ "Celebrex Prevents Adhesions After Surgery". Children's Hospital Boston. January 26, 2005. Retrieved 2009-03-11. 
  53. ^ Viinikka, Tai (February 25, 2005). "COX-2 Inhibitors May Prevent Common Surgical Complication". Focus Online. Harvard Medical, Dental, and Public Health Schools. Retrieved 2009-03-11. 

External links[edit]