Celecoxib, sold under the brand name Celebrex among others, is a
COX-2 inhibitor and
nonsteroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
(NSAID).
It is used to treat the
pain
Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
and
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
in
osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
,
acute pain in adults,
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
,
ankylosing spondylitis
Ankylosing spondylitis (AS) is a type of arthritis characterized by long-term inflammation of the joints of the spine typically where the spine joins the pelvis. Occasionally areas affected may include other joints such as the shoulders or hip ...
,
painful menstruation, and
juvenile rheumatoid arthritis.
[ It may also be used to decrease the risk of ]colorectal adenoma
The colorectal adenoma is a benign glandular tumor of the colon and the rectum. It is a precursor lesion of the colorectal adenocarcinoma (colon cancer). They often manifest as colorectal polyps.
Comparison table
Tubular adenoma
In contrast t ...
s in people with familial adenomatous polyposis.[ It is taken by mouth.][ Benefits are typically seen within an hour.][
Common side effects include ]abdominal pain
Abdominal pain, also known as a stomach ache, is a symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than ...
, nausea, and diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
.[ Serious side effects may include ]heart attacks
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tra ...
, stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
s, gastrointestinal perforation, gastrointestinal bleeding, kidney failure
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
, and anaphylaxis
Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...
.[ Use is not recommended in people at high risk for heart disease.] The risks are similar to other NSAIDs, such as ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arte ...
and naproxen. Use in the later part of pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
or during breastfeeding
Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...
is not recommended.
Celecoxib was patented in 1993 and came into medical use in 1999. It is available as a generic medication
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. In 2020, it was the 98th most commonly prescribed medication in the United States, with more than 7million prescriptions.
Medical uses
Celecoxib is indicated for the treatment of osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
, rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
, acute pain, musculoskeletal pain
Musculoskeletal disorders (MSDs) are injuries or pain in the human musculoskeletal system, including the joints, ligaments, muscles, nerves, tendons, and structures that support limbs, neck and back. MSDs can arise from a sudden exertion (e.g., li ...
, painful menstruation
Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and mucosal tissue from the inner lining of the uterus through the vagina. The menstrual cycle is characterized by the rise and fall of hor ...
, ankylosing spondylitis
Ankylosing spondylitis (AS) is a type of arthritis characterized by long-term inflammation of the joints of the spine typically where the spine joins the pelvis. Occasionally areas affected may include other joints such as the shoulders or hip ...
, juvenile rheumatoid arthritis, and to reduce the number of colon and rectal polyps in people with familial adenomatous polyposis.[ It may be used in children with juvenile rheumatoid arthritis who are older than two years of age and weigh more than 10 kg (22 lb).][
For postoperative pain, it is more or less equal to ]ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arte ...
. For pain relief, it is similar to paracetamol
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
(acetaminophen), which is the first line treatment for osteoarthritis.
Evidence of effects are not clear as a number of studies done by the manufacturer have not been released for independent analysis.
Familial adenomatous polyposis
It has been used to reduce colon and rectal polyps in people with familial adenomatous polyposis, but it is not known if it decreases rates of cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
,[ so it is not a good choice for this reason.][
]
Adverse effects
* Cardiovascular events: 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. Individual cardiovascular risk profiles should be evaluated prior to prescribing. New-onset hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
or exacerbation of hypertension
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
may occur (NSAIDs may impair response to thiazide or loop diuretics), and may contribute to cardiovascular events; monitor blood pressure and 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; alternative therapies should be considered for patients at high risk. The increased risk is about 37%.[
* Gastrointestinal events: 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.] The increased risk is about 81%.[
* Hematologic effects: Anemia may occur; monitor hemoglobin or hematocrit in people on long-term treatment. Celecoxib does not usually affect prothrombin time, partial thromboplastin time or platelet counts; it does not inhibit platelet aggregation at approved doses.
People with prior history of ulcer disease or GI bleeding require special precaution. Moderate to severe liver impairment or GI toxicity can occur with or without warning symptoms in people treated with NSAIDs.
In October 2020, the U.S. ]Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[ ][ ]
Allergy
Celecoxib contains a sulfonamide
In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this group is unreactive. ...
moiety and may cause allergic reactions in those allergic to other sulfonamide-containing drugs. This is in addition to the contraindication in people 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. 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. Use should be discontinued at first sign of rash (or any other hypersensitivity).
Heart attack and stroke
A 2013 meta-analysis of hundreds of clinical trials found that coxibs (the class of drugs that includes celecoxib) increase the risk of major cardiovascular problems by about 37% over placebo. In 2016, a randomized trial provided strong evidence that treatment with celecoxib is not more likely to result in poor cardiovascular outcomes than treatment with naproxen or ibuprofen. As a result, in 2018 an FDA advisory panel concluded that celecoxib poses no greater risk for causing heart attacks and strokes than the commonly-used NSAIDs ibuprofen or naproxen and recommended that the FDA consider changing its advice to physicians regarding celecoxib's safety.[
The COX-2 inhibitor ]rofecoxib
Rofecoxib is a COX-2 inhibitor, COX-2 selective nonsteroidal anti-inflammatory drug (NSAID). It was marketed by Merck & Co. to treat osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, acute pain conditions, migraine, and dysmenor ...
(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
The American Heart Association (AHA) is a nonprofit organization in the United States that funds cardiovascular medical research, educates consumers on healthy living and fosters appropriate cardiac care in an effort to reduce disability and death ...
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."
In 2005, a study published in the ''Annals of Internal Medicine
''Annals of Internal Medicine'' is an academic medical journal published by the American College of Physicians (ACP). It is one of the most widely cited and influential specialty medical journals in the world. ''Annals'' publishes content relevan ...
'' found that cardiovascular effects of COX-2 inhibitors differ, depending on the drug. Other COX-2-selective inhibitors, such as rofecoxib, have significantly higher myocardial infarction rates than celecoxib. 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". In a 2006 meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
of randomized control studies, the cerebrovascular events
Stroke (also known as a cerebrovascular accident (CVA) or brain attack) is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, d ...
associated with COX-2 inhibitors were examined, but no significant risks were found when compared to nonselective NSAIDs or placebos.
Drug interactions
Celecoxib is predominantly metabolized by cytochrome
Cytochromes are redox-active proteins containing a heme, with a central Fe atom at its core, as a cofactor. They are involved in electron transport chain and redox catalysis. They are classified according to the type of heme and its mode of bin ...
P450 2C9. Caution must be exercised with concomitant use of 2C9 inhibitors, such as fluconazole
Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidiodomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and pityriasis versicolor. It is also used to prevent ...
, which can greatly elevate celecoxib serum levels. If used concomitantly with lithium, celecoxib increases lithium plasma levels. If used concomitantly with warfarin, celecoxib may result in increased risk of bleeding complications. The risk of bleeding and gastric ulcers also increase further when SSRIs are used in combination with celecoxib. The drug may increase the risk of kidney failure with angiotensin-converting enzyme-inhibitors, such as lisinopril, and diuretic
A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
s, such as hydrochlorothiazide.
Pregnancy
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.
Mechanism of action
Anti-inflammatory
A highly selective reversible inhibitor of the COX-2 isoform of cyclooxygenase, celecoxib inhibits the transformation of arachidonic acid to prostaglandin precursors. Therefore, it has analgesic and anti-inflammatory properties. Nonselective NSAIDs (such as aspirin, naproxen, and ibuprofen) inhibit both COX-1 and COX-2. Inhibition of COX-1 (which celecoxib does not inhibit at therapeutic concentrations) inhibits the production of prostaglandins and the production of thromboxane A2, a platelet activator. COX-1 is traditionally defined as a constitutively expressed "housekeeping" enzyme and plays a role in the protection of the gastrointestinal mucosa, kidney hemodynamics, and platelet thrombogenesis. 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. Celecoxib is approximately 10-20 times more selective for COX-2 inhibition over COX-1. It binds with its polar sulfonamide side chain to a hydrophilic side pocket region close to the active COX-2 binding site. In theory, this selectivity allows celecoxib and other COX-2 inhibitors to reduce inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
(and pain) while minimizing gastrointestinal adverse drug reactions (e.g. stomach ulcers) that are common with nonselective NSAIDs.
Anti-cancer
For its use in reducing colon polyps, celecoxib affects genes and pathways involved in inflammation and malignant transformation in tumors, but not normal tissues.
Celecoxib binds to Cadherin-11
Cadherin-11 is a protein that in humans is encoded by the ''CDH11'' gene.
Function
This gene encodes a type II classical cadherin from the cadherin superfamily, integral membrane proteins that mediate calcium-dependent cell-cell adhesion. Mat ...
(which may explain the reduction in cancer progression).
Structure-activity relationship
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. 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).
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. 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. This mutation appears to contribute 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.
History
It was initially marketed by Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
for arthritis. Celecoxib and other COX-2 selective inhibitors, valdecoxib, parecoxib, and mavacoxib, were discovered by a team at the Searle Searle may refer to:
__NOTOC__ Persons
* Searle (surname)
* J. Searle Dawley (1877–1949), American film director, producer, screenwriter, stage actor and playwright
* Searle Turton (born 1979), Canadian politician
Places
* Serle, a comune in Lomb ...
division of Monsanto led by John Talley.
Two lawsuits arose over discovery of celecoxib. Daniel L. Simmons of Brigham Young University
Brigham Young University (BYU, sometimes referred to colloquially as The Y) is a private research university in Provo, Utah. It was founded in 1875 by religious leader Brigham Young and is sponsored by the Church of Jesus Christ of Latter-day ...
(BYU) discovered the COX-2 enzyme in 1988, and in 1991, BYU entered into a collaboration with Monsanto to develop drugs to inhibit it. Monsanto's pharmaceutical division was later purchased by Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
, and in 2006, BYU sued Pfizer for breach of contract, claiming Pfizer did not properly pay contractual royalties back to BYU. A settlement was reached in April 2012, in which Pfizer agreed to pay $450 million. Other important discoveries in COX-2 were made at University of Rochester
The University of Rochester (U of R, UR, or U of Rochester) is a private research university in Rochester, New York. The university grants undergraduate and graduate degrees, including doctoral and professional degrees.
The University of Roc ...
, which patented the discoveries. 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.[Ranjana Kadle (2004]
CAFC Court Decision Reach-Through Claims Declared Invalid
/ref>
According to the National Academy of Sciences
The National Academy of Sciences (NAS) is a United States nonprofit, non-governmental organization. NAS is part of the National Academies of Sciences, Engineering, and Medicine, along with the National Academy of Engineering (NAE) and the Nati ...
, Philip Needleman
Philip Needleman is an American pharmacologist and academic. Needleman was a professor and associate dean at the Washington University School of Medicine and he served as an executive at Monsanto/Searle. He is credited with discovering the first ...
, who was vice president of Monsanto in 1989 and president of Searle Searle may refer to:
__NOTOC__ Persons
* Searle (surname)
* J. Searle Dawley (1877–1949), American film director, producer, screenwriter, stage actor and playwright
* Searle Turton (born 1979), Canadian politician
Places
* Serle, a comune in Lomb ...
in 1993 oversaw research into COX-2 that led to the development of the anti-inflammatory drug celecoxib (Celebrex). He became senior executive vice president and chief scientist of Pharmacia from 2000 to 2003. Celecoxib was discovered and developed by G. D. Searle & Company and was approved by the FDA on 31 December 1998. 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. In ''University of Rochester v. G.D. Searle & Co.'', 358 F.3d 916 (Fed. Cir. 2004), the University of Rochester
The University of Rochester (U of R, UR, or U of Rochester) is a private research university in Rochester, New York. The university grants undergraduate and graduate degrees, including doctoral and professional degrees.
The University of Roc ...
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 from the market in September 2004, celecoxib 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 rofecoxib, and Pfizer announced a moratorium on direct-to-consumer advertising of Celebrex soon afterwards. Sales reached $2 billion in 2006. Prior to its availability in generic form, it was one of Pfizer's "best-selling drugs, amounting to more than $2.5 billion in sales y 2012
Y, or y, is the twenty-fifth and penultimate letter of the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. According to some authorities, it is the sixth (or seventh ...
and was prescribed to 2.4 million" people in 2011. By 2012, 33 million Americans had taken celecoxib.
Pfizer resumed advertising Celebrex in magazines in 2006, and resumed television advertising in April 2007 with an unorthodox, -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
Public Citizen is a non-profit, progressive consumer rights advocacy group and think tank based in Washington, D.C., United States, with a branch in Austin, Texas.
Lobbying efforts
Public Citizen advocates before all three branches of the Unit ...
, which called the ad's comparisons misleading. 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.
Society and culture
Fabricated efficacy studies
Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
and its partner, Pharmacia presented findings from their study that Celebrex was "better in protecting the stomach from serious complications than other drugs." This became Celebrex's main selling point. However, following federal investigations it was revealed that Pfizer and Pharmacia "only presented the results from the first six months of a year long study rather than the whole thing." These partial results were then published in The Journal of the American Medical Association
''The Journal of the American Medical Association'' (''JAMA'') is a peer-reviewed medical journal published 48 times a year by the American Medical Association. It publishes original research, reviews, and editorials covering all aspects of biom ...
. In 2001, the US Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) released the full results of the Pfizer and Pharmacia study which showed that they had withheld crucial data. By 2012, a federal judge unsealed "thousands of pages of internal documents and depositions" in a "long-running securities fraud case against Pfizer."
On 11 March 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center
Baystate Health is a not-for-profit integrated health system headquartered in Springfield, Massachusetts, serving Western Massachusetts and the Knowledge Corridor Region of Massachusetts and Connecticut. The system has 5 hospitals, over 80 medical ...
, 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. Although from 2002 to 2007 Pfizer underwrote much of Dr. Reuben's research and "many of his trials found that Celebrex and Lyrica, Pfizer drugs, were effective against postoperative pain," Pfizer was not aware of the fraudulent data. None of the retracted studies were submitted to either the US Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
or the European Union's regulatory agencies prior to the drug's approval. Although 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", the documents unsealed in 2012, revealed that by February 2000, Pharmacia employees had devised a strategy to present the findings.
Availability
Pfizer markets celecoxib under the brand name Celebrex, and it is available as oral capsules containing 50, 100, 200 or 400 mg of celecoxib.
It is legally available in many jurisdictions as a generic under several brand names. In the US, celecoxib was covered by three patents, two of which expired on 30 May 2014, and one of which (US RE44048) was due to expire 2 December 2015. On 13 March 2014, that patent was found to be invalid for double patenting. Upon the patent expiry on 30 May 2014, the FDA approved the first versions of generic celecoxib.
Research
Psychiatry
On the theory that inflammation plays a role in the pathogenesis of major mental disorders, celecoxib has been trialed for a number of psychiatric disorders, including major depression, bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
, and schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
.
Bipolar disorder
A meta-analysis considering trials of celecoxib as an adjunctive treatment in bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
was inconclusive citing low evidence quality.
Familial adenomatous polyposis
It has been used to reduce colon and rectal polyps in people with familial adenomatous polyposis, but it is not known if it decreases rates of cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
,[ so it is not a good choice for this reason.][
]
Cancer prevention
The use of celecoxib to reduce the risk of colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
has been investigated, but neither celecoxib nor any other drug is indicated for this use. Small-scale clinical trials in very high-risk people (belonging to FAP
FAP may refer to:
Technology and industry
* FORTRAN Assembly Program, the macro assembler for some IBM mainframe computers
* Fair Access Policy, a term for a bandwidth cap, limiting Internet usage
* Femtocell (Femto Access Point), a small ...
families) showed celecoxib can prevent polyp growth. Hence, large-scale randomized clinical trials were undertaken. Results show a 33 to 45% polyp recurrence reduction in people treated with celecoxib each day. However, serious cardiovascular events were significantly more frequent in the celecoxib-treated groups. Aspirin shows a similar (and possibly larger) protective effect, has demonstrated cardioprotective effects and is significantly cheaper, but no head-to-head clinical trials have compared the two drugs.
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 going on 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, 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.
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
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'', 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. Karen Seibert and colleagues have published research showing antiangiogenic and antitumor activity of celecoxib in animal models.
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 analog
Analog or analogue may refer to:
Computing and electronics
* Analog signal, in which information is encoded in a continuous variable
** Analog device, an apparatus that operates on analog signals
*** Analog electronics, circuits which use analo ...
s of celecoxib were generated with small alterations in their chemical structure
A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of at ...
s. 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
Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This te ...
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. One of these compounds, 2,5-dimethyl-celecoxib, which entirely lacks the ability to inhibit COX-2, actually displayed stronger anticancer activity than celecoxib.
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