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Celecoxib

Description of Celecoxib: Celecoxib was developed by G. D. Searle & Company and 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. 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. 

Celecoxib is a sulfa non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis. 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.

Pfizer sells celecoxib under the brand name Celebrex. Celecoxib is not currently available as a generic in the United States, because the intellectual property is still controlled by Pfizer. However, in other countries, including India and the Philippines, it is legally available as a generic under the brand names Cobix and Celcoxx. XL Laboratories sells celecoxib under the brand name Selecap in Vietnam and the Philippines. See http://en.wikipedia.org/wiki/Celecoxib.

History

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.  Pfizer resumed advertising Celebrex in magazines in 2006,  and resumed television advertising in April 2007 with an unorthodox, 2½ 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. Pfizer has 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.

In late 2007, Pfizer released another U.S. television ad for Celebrex, which also discussed celecoxib's adverse effects in comparison with those of other anti-inflammatory drugs. Dr. Simmons of Brigham Young University, who discovered the COX-2 enzyme, is suing Pfizer to be credited with discovery of the technique in 1989 that eventually led to the drug, and for $1 billion USD, (The company has made about $30 billion from the drug as of 2006).

Research into cancer prevention

The role that celecoxib might have in reducing the rates of certain cancers has been the subject of many studies. However, given the side effects of anti-COX-2 on rates of heart disease, there is no current medical recommendation to use this drug for cancer reduction. Colorectal cancer risk is clearly reduced in people regularly taking a NSAID like aspirin or celecoxib. In addition, some epidemiological studies, and most preclinical studies pointed out that specific COX-2 inhibitors like celecoxib are more potent and less toxic than "older" NSAIDs. Twelve carcinogenesis studies support that celecoxib is strikingly potent to prevent intestinal cancer in rats or mice (data available on the Chemoprevention Database). Small-scale clinical trials in very high risk people (belonging to FAP families) also indicate that 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. 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, has demonstrated cardioprotective effects and is significantly cheaper, but there have been no head-to-head clinical trials comparing the two drugs.

Research into cancer treatment

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. 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 via the inhibition of COX-2 became contentious.

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 that 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 don’t even contain COX-2. 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. 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.  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.

Current developer:    Pfizer

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4: Arakawa Y, Nakai N, Katoh N. Celecoxib-induced erythema multiforme-type drug eruption with a positive patch test. J Dermatol. 2011 Dec;38(12):1185-8. doi: 10.1111/j.1346-8138.2010.01182.x. Epub 2011 Mar 21. Review. PubMed PMID: 22103805.

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11: Derry S, Barden J, McQuay HJ, Moore RA. Single dose oral celecoxib for acute postoperative pain in adults. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD004233. Review. Update in: Cochrane Database Syst Rev. 2012;3:CD004233. PubMed PMID: 18843655.

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14: Schönthal AH, Chen TC, Hofman FM, Louie SG, Petasis NA. Celecoxib analogs that lack COX-2 inhibitory function: preclinical development of novel anticancer drugs. Expert Opin Investig Drugs. 2008 Feb;17(2):197-208. Review. PubMed PMID: 18230053.

15: Doggrell SA. Celecoxib to prevent restenosis--results from the COREA-TAXUS trial. Expert Opin Pharmacother. 2008 Feb;9(2):339-41. Review. PubMed PMID: 18201156.

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17: Schönthal AH. Direct non-cyclooxygenase-2 targets of celecoxib and their potential relevance for cancer therapy. Br J Cancer. 2007 Dec 3;97(11):1465-8. Epub 2007 Oct 23. Review. PubMed PMID: 17955049; PubMed Central PMCID: PMC2360267.

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19: Futagami S, Suzuki K, Hiratsuka T, Shindo T, Hamamoto T, Ueki N, Kusunoki M, Miyake K, Gudis K, Tsukui T, Sakamoto C. Chemopreventive effect of celecoxib in gastric cancer. Inflammopharmacology. 2007 Feb;15(1):1-4. Review. PubMed PMID: 17323186.

20: Gajraj NM. COX-2 inhibitors celecoxib and parecoxib: valuable options for postoperative pain management. Curr Top Med Chem. 2007;7(3):235-49. Review. PubMed PMID: 17305567.

21: Chen JT, Pucino F, Resman-Targoff BH. Celecoxib versus a non-selective NSAID plus proton-pump inhibitor: what are the considerations?. J Pain Palliat Care Pharmacother. 2006;20(4):11-32. Review. PubMed PMID: 17182503.

22: Schönthal AH. Antitumor properties of dimethyl-celecoxib, a derivative of celecoxib that does not inhibit cyclooxygenase-2: implications for glioma therapy. Neurosurg Focus. 2006 Apr 15;20(4):E21. Review. PubMed PMID: 16709027.

23: Caldwell B, Aldington S, Weatherall M, Shirtcliffe P, Beasley R. Risk of cardiovascular events and celecoxib: a systematic review and meta-analysis. J R Soc Med. 2006 Mar;99(3):132-40. Review. PubMed PMID: 16508052; PubMed Central PMCID: PMC1383759.

24: Brophy JM. Celecoxib and cardiovascular risks. Expert Opin Drug Saf. 2005 Nov;4(6):1005-15. Review. PubMed PMID: 16255660.

25: Moore RA, Derry S, Makinson GT, McQuay HJ. Tolerability and adverse events in clinical trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-analysis of information from company clinical trial reports. Arthritis Res Ther. 2005;7(3):R644-65. Epub 2005 Mar 24. Review. Erratum in: Arthritis Res Ther. 2006;8(1):401. PubMed PMID: 15899051; PubMed Central PMCID: PMC1174947.

26: Gore E. Celecoxib and radiation therapy in non-small-cell lung cancer. Oncology (Williston Park). 2004 Dec;18(14 Suppl 14):10-4. Review. PubMed PMID: 15685827.

27: Goeschke B, Braathen LR. Acute generalized exanthematic pustulosis: a case and an overview of side effects affecting the skin caused by celecoxib and other COX-2 inhibitors reported so far. Dermatology. 2004;209(1):53-6. Review. PubMed PMID: 15237269.

28: Kismet K, Akay MT, Abbasoglu O, Ercan A. Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention. Cancer Detect Prev. 2004;28(2):127-42. Review. PubMed PMID: 15068837.

29: Perna AG, Woodruff CA, Markus RF, Hsu S. Toxic epidermal necrolysis as a complication of treatment with celecoxib. Dermatol Online J. 2003 Dec;9(5):25. Review. PubMed PMID: 14996398.

30: Phelan KM, Mosholder AD, Lu S. Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry. 2003 Nov;64(11):1328-34. Review. PubMed PMID: 14658947.

31: Coulter DM, Clark DW, Savage RL. Celecoxib, rofecoxib, and acute temporary visual impairment. BMJ. 2003 Nov 22;327(7425):1214-5. Review. PubMed PMID: 14630760; PubMed Central PMCID: PMC274063.

32: Oviedo JA, Wolfe MM. Gastroprotection by coxibs: what do the Celecoxib Long-Term Arthritis Safety Study and the Vioxx Gastrointestinal Outcomes Research Trial tell us? Rheum Dis Clin North Am. 2003 Nov;29(4):769-88. Review. PubMed PMID: 14603582.

33: Poza-Guedes P, González-Pérez R, Canto G. Celecoxib-induced lupus-like syndrome. Rheumatology (Oxford). 2003 Jul;42(7):916-7. Review. PubMed PMID: 12826720.

34: Barden J, Edwards JE, McQuay HJ, Moore RA. Single dose oral celecoxib for postoperative pain. Cochrane Database Syst Rev. 2003;(2):CD004233. Review. Update in: Cochrane Database Syst Rev. 2008;(4):CD004233. PubMed PMID: 12804506.

35: Gibofsky A. Clinical profiles of celecoxib and rofecoxib in the rheumatic diseases. J Hypertens Suppl. 2002 Sep;20(6):S25-30. Review. PubMed PMID: 12683424.

36: Garner S, Fidan D, Frankish R, Judd M, Shea B, Towheed T, Wells G, Tugwell P. Celecoxib for rheumatoid arthritis. Cochrane Database Syst Rev. 2002;(4):CD003831. Review. PubMed PMID: 12519610.

37: Jordan KM, Edwards CJ, Arden NK. Allergic vasculitis associated with celecoxib. Rheumatology (Oxford). 2002 Dec;41(12):1453-5. Review. PubMed PMID: 12468830.

38: Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ. 2002 Sep 21;325(7365):619. Review. PubMed PMID: 12242171; PubMed Central PMCID: PMC126301.

39: Lander SA, Wallace DJ, Weisman MH. Celecoxib for systemic lupus erythematosus: case series and literature review of the use of NSAIDs in SLE. Lupus. 2002;11(6):340-7. Review. PubMed PMID: 12139371.

40: Ahmad SR, Kortepeter C, Brinker A, Chen M, Beitz J. Renal failure associated with the use of celecoxib and rofecoxib. Drug Saf. 2002;25(7):537-44. Review. PubMed PMID: 12093311.

41: Blanke CD. Celecoxib with chemotherapy in colorectal cancer. Oncology (Williston Park). 2002 Apr;16(4 Suppl 3):17-21. Review. PubMed PMID: 12014863.

42: Koki AT, Masferrer JL. Celecoxib: a specific COX-2 inhibitor with anticancer properties. Cancer Control. 2002 Mar-Apr;9(2 Suppl):28-35. Review. PubMed PMID: 11965228.

43: Graham GG, Graham RI, Day RO. Comparative analgesia, cardiovascular and renal effects of celecoxib, rofecoxib and acetaminophen (paracetamol). Curr Pharm Des. 2002;8(12):1063-75. Review. PubMed PMID: 11945151.

44: North GL. Celecoxib as adjunctive therapy for treatment of colorectal cancer. Ann Pharmacother. 2001 Dec;35(12):1638-43. Review. PubMed PMID: 11793634.

45: Ashcroft DM, Chapman SR, Clark WK, Millson DS. Upper gastroduodenal ulceration in arthritis patients treated with celecoxib. Ann Pharmacother. 2001 Jul-Aug;35(7-8):829-34. Review. PubMed PMID: 11485128.

46: Nachimuthu S, Volfinzon L, Gopal L. Acute hepatocellular and cholestatic injury in a patient taking celecoxib. Postgrad Med J. 2001 Aug;77(910):548-50. Review. PubMed PMID: 11470953; PubMed Central PMCID: PMC1742098.

47: Davies NM, Gudde TW, de Leeuw MA. Celecoxib: a new option in the treatment of arthropathies and familial adenomatous polyposis. Expert Opin Pharmacother. 2001 Jan;2(1):139-52. Review. PubMed PMID: 11336575.

48: Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients who are allergic to sulfonamides? Revisiting the meaning of 'sulfa' allergy. Drug Saf. 2001;24(4):239-47. Review. PubMed PMID: 11330653.

49: Whelton A, Maurath CJ, Verburg KM, Geis GS. Renal safety and tolerability of celecoxib, a novel cyclooxygenase-2 inhibitor. Am J Ther. 2000 May;7(3):159-75. Review. Erratum in: Am J Ther 2000 Sep;7(5):341. PubMed PMID: 11317165.

50: Maddrey WC, Maurath CJ, Verburg KM, Geis GS. The hepatic safety and tolerability of the novel cyclooxygenase-2 inhibitor celecoxib. Am J Ther. 2000 May;7(3):153-8. Review. Erratum in: Am J Ther 2000 Sep;7(5):341. PubMed PMID: 11317164.

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53: Pettitt D, Goldstein JL, McGuire A, Schwartz JS, Burke T, Maniadakis N. Overview of the arthritis Cost Consequence Evaluation System (ACCES): a pharmacoeconomic model for celecoxib. Rheumatology (Oxford). 2000 Dec;39 Suppl 2:33-42; discussion 57-9. Review. PubMed PMID: 11276801.

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58: Celecoxib. Dimens Crit Care Nurs. 2001 Mar-Apr;20(2):13. Review. PubMed PMID: 22076292.

59: Are rofecoxib and celecoxib safer NSAIDS? Drug Ther Bull. 2000 Nov;38(11):81-6. Review. PubMed PMID: 11138599.

60: Goldstein JL. Significant upper gastrointestinal events associated with conventional NSAID versus celecoxib. J Rheumatol Suppl. 2000 Oct;60:25-8. Review. PubMed PMID: 11032099.

61: Luong BT, Chong BS, Lowder DM. Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and infliximab. Ann Pharmacother. 2000 Jun;34(6):743-60. Review. PubMed PMID: 10860137.

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64: Tindall E. Celecoxib for the treatment of pain and inflammation: the preclinical and clinical results. J Am Osteopath Assoc. 1999 Nov;99(11 Suppl):S13-7. Review. PubMed PMID: 10643176.

65: Goldenberg MM. Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis. Clin Ther. 1999 Sep;21(9):1497-513; discussion 1427-8. Review. PubMed PMID: 10509845.

66: Geis GS. Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? Scand J Rheumatol Suppl. 1999;109:31-7. Review. PubMed PMID: 10422544.

67: Geis GS. Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? J Rheumatol Suppl. 1999 Apr;56:31-6. Review. PubMed PMID: 10225538.

68: Fort J. Celecoxib, a COX-2--specific inhibitor: the clinical data. Am J Orthop (Belle Mead NJ). 1999 Mar;28(3 Suppl):13-8. Review. PubMed PMID: 10193998.