Celecoxib
Encyclopedia
Celecoxib INN
(icon) is a sulfa
non-steroidal anti-inflammatory drug
(NSAID) and selective COX-2 inhibitor
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.
, rheumatoid arthritis
, acute pain, painful menstruation
and menstrual symptoms, ankylosing spondylitis
and to reduce the number of colon and rectal polyps in patients with familial adenomatous polyposis
. It was originally intended to relieve pain while minimizing the gastrointestinal adverse effects usually seen with conventional NSAID
s. 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 non-selective NSAIDs or aspirin cause cutaneous reactions (urticaria or "hives"). In addition, the pain relief offered by celecoxib is similar to that offered by paracetamol (acetaminophen)
.
. The retracted studies were not submitted to either the U.S. 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."
sells celecoxib under the brand name Celebrex, and is available as oral capsules containing 50 mg, 100 mg, 200 mg or 400 mg of celecoxib.
Celecoxib is not currently available as a generic in the United States, because it is covered by unexpired Pfizer patents. However, in other countries, including India
and the Philippines
, it is legally available as a generic under the brand names Cobix, Celcoxx and Celexib.
XL Laboratories sells celecoxib under the brand name Selecap in Vietnam
and the Philippines
.
or diclofenac
, provided they were not on aspirin (Silverstein et al., 2000). However, this was not significant at 12 months (full study length).
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 non-selective NSAIDs.
(Vioxx) in 2004. Like all NSAIDs on the U.S. market, celecoxib carries an FDA-mandated "black box warning" for cardiovascular and gastrointestinal risk. In February 2007, the American Heart Association
warned that celecoxib should be used "as a last resort on patients who have heart disease or a risk of developing it", and suggested that paracetamol
(acetaminophen), or certain older NSAIDs, such as naproxen
, may be safer choices for chronic pain relief in these patients.
The cardiovascular risks of celecoxib are controversial, with apparently contradictory data produced from different clinical trials. In December 2004, "APC", the first of two trials of celecoxib for colon cancer prevention, found that long-term (33 months) use of high-dose Celebrex (400 and 800 mg daily) demonstrated an increased cardiovascular risk compared with placebo.
A similar trial, named PreSAP, did not demonstrate an increased risk. Still, the APC trial, combined with the recent Vioxx findings, suggested that there might be serious cardiovascular risks specific to the COX-2 inhibitors. On the other hand, a large Alzheimer's
prevention trial, called ADAPT, was terminated early after preliminary data suggested that the nonselective NSAID naproxen
, but not celecoxib, was associated with increased cardiovascular risk. In 2005, a study published in the Annals of Internal Medicine
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 that it was likely "that there is a 'class effect' for increased CV risk for all NSAIDs". 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 non-selective NSAIDs or placebos.
Two studies on the cardiovascular risks of celecoxib and other NSAIDs were meta-analyses
, published in 2006. The first of these, published in the British Medical Journal
, looked at the incidence of cardiovascular events in all previous randomized controlled trials of COX-2 inhibitors, as well as some trials of other NSAIDs. The authors concluded that a significant increased risk did exist for celecoxib, as well as some other selective and nonselective NSAIDS. However, the increased cardiovascular risk in celecoxib was noted only at daily doses of 400 mg or greater. A second meta-analysis published in the Journal of the American Medical Association
, which included observational rather than randomized studies (mostly at lower doses) did not find an increased cardiovascular risk of celecoxib vs placebo.
The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial presented a five-fold increase in atherothrombotic cardiovascular events associated with rofecoxib compared to naproxen. Although, the Celecoxib Long-Term Arthritis Safety Study (CLASS) did not present an increase in occurrence of such events, many experts believe that the risk associated with rofecoxib long-term use also applies to celecoxib based on the pharmacology in three distinct mechanisms. It is suggested that prostacyclin (PGI2) inhibition with relatively unopposed platelet-derived thromboxane (TxA2) generation may lead to thrombotic risks. PGI2 from endothelial cells by COX-2 catalysis has anti-aggregating, anti-proliferative, and vasodilating properties. Conversely, TxA2 from platelets maintain vascular homeostasis by irreversible platelet aggregating, vasoconstricting, and smooth muscle proliferating properties. The imbalance of PGI2 may promote TxA2 thrombosis. In addition, COX-2 selective inhibitors can elevate blood pressure by allowing a normal amount of the vasoconstrictor, TxA2, and a stark decrease in the levels of the vasodilator, PGI2., Furthermore, a third postulate for promoting atherothombotic events includes that the upregulation of COX-2 plays a key role in cardioprotection of the last phase of ischemic preconditioning. Due to the controversy, it is advised that prescribers use caution when prescribing celecoxib and present rational care plans that demonstrate a clear indication for the medication.
To establish more conclusively the true cardiovascular risk profile of celecoxib, Pfizer agreed to fund a large, randomized trial specifically designed for that purpose. The trial, centered at the Cleveland Clinic
, with a planned enrollment of 20,000 high-risk patients. Celecoxib will be compared with the non-selective NSAIDS naproxen and ibuprofen. Since all patients have arthritis, ethical considerations make it difficult to have a placebo group. This trial has began enrollment in 2006 according to the Clinical Trials database, and is not scheduled to be completed until May 2014. Ultimately, this trial will help answer the question as to whether Celebrex has a riskier cardiovascular profile compared with naproxen or ibuprofen.
and primarily inhibits this isoform of cyclooxygenase
(and thus causes inhibition of prostaglandin production), whereas nonselective NSAIDs (like asprin, naproxen
and ibuprofen
) inhibit both COX-1 and COX-2. COX-1, traditionally defined as a constitutively-expressed “housekeeping” enzyme, is the only isoenzyme found in platelets and plays a role in the protection of the gastrointestinal mucosa, renal 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
(and pain) while minimizing gastrointestinal adverse drug reaction
s (e.g. stomach ulcers) that are common with non-selective NSAIDs.
Celecoxib inhibits COX-2 without affecting COX-1. COX-1 is involved in synthesis of prostaglandins and thromboxane
, but COX-2 is only involved in the synthesis of prostaglandin. Therefore, inhibition of COX-2 inhibits only prostaglandin synthesis without affecting thromboxane (TXA2) and thus offer no cardioprotective effects of non-selective NSAIDs.
reaction of an acetophenone with N-(trifluoroacetyl)imidazole catalyzed by the strong base, sodium bis(trimethylsilyl)amide to produce a 1,3-dicarbonyl adduct. Condensation of the diketone with (4-sulfamoylaphenyl)hydrazine produces the 1,5-diarylpyrazole drug moiety.
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 that 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 it 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 0.040μM while that of the 4-ethyl is 0.86μM which means that 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. 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. 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. . Thus it is reasonable to expect COX-2 selective inhibitors to be more bulky than non-selective NSAIDs.
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.
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.
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 analog
s of celecoxib were generated with small alterations in their chemical structure
s. 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.
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 post-surgical adhesions in mice taking the drug celecoxib. Multi-institutional trials in adult human patients are planned.
The initially suggested course of treatment is a mere 7–10 days following surgery.
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
(icon) is a sulfa
SULFA
SULFA, short for Surrendered ULFA, i.e. members of the United Liberation Front of Asom that surrendered to the government.Beginning with 1990, the Government of India has attempted to wean away members of ULFA. In 1992 a large section of second rank leaders and members surrendered to government...
non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
(NSAID) and selective COX-2 inhibitor
COX-2 inhibitor
COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug that directly targets 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...
used in the treatment of osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
, rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, acute pain, painful menstruation
Menstruation
Menstruation is the shedding of the uterine lining . It occurs on a regular basis in sexually reproductive-age females of certain mammal species. This article focuses on human menstruation.-Overview:...
and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis
Familial adenomatous polyposis
Familial adenomatous polyposis is an inherited condition in which numerous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when not treated....
. It is marketed by Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
. It is known under the brand name Celebrex or Celebra for arthritis and Onsenal for polyps. Celecoxib is available by prescription
Medical prescription
A prescription is a health-care program implemented by a physician or other medical practitioner in the form of instructions that govern the plan of care for an individual patient. Prescriptions may include orders to be performed by a patient, caretaker, nurse, pharmacist or other therapist....
in capsule form.
Indications
Celecoxib is licensed for use in osteoarthritisOsteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
, rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, acute pain, painful menstruation
Menstruation
Menstruation is the shedding of the uterine lining . It occurs on a regular basis in sexually reproductive-age females of certain mammal species. This article focuses on human menstruation.-Overview:...
and menstrual symptoms, ankylosing spondylitis
Ankylosing spondylitis
Ankylosing spondylitis , previously known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strümpell disease is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures...
and to reduce the number of colon and rectal polyps in patients with familial adenomatous polyposis
Familial adenomatous polyposis
Familial adenomatous polyposis is an inherited condition in which numerous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when not treated....
. It was originally intended to relieve pain while minimizing the gastrointestinal adverse effects usually seen with conventional NSAID
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...
s. 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 non-selective NSAIDs or aspirin cause cutaneous reactions (urticaria or "hives"). In addition, the pain relief offered by celecoxib is similar to that offered by paracetamol (acetaminophen)
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
.
Fabricated efficacy studies
On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that 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 being exaggerated. Dr. Reuben was also a former paid spokesperson for PfizerPfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
. The retracted studies were not submitted to either the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
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."
Availability
PfizerPfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
sells celecoxib under the brand name Celebrex, and is available as oral capsules containing 50 mg, 100 mg, 200 mg or 400 mg of celecoxib.
Celecoxib is not currently available as a generic in the United States, because it is covered by unexpired Pfizer patents. However, in other countries, including India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
and the Philippines
Philippines
The Philippines , officially known as the Republic of the Philippines , is a country in Southeast Asia in the western Pacific Ocean. To its north across the Luzon Strait lies Taiwan. West across the South China Sea sits Vietnam...
, it is legally available as a generic under the brand names Cobix, Celcoxx and Celexib.
XL Laboratories sells celecoxib under the brand name Selecap in Vietnam
Vietnam
Vietnam – sometimes spelled Viet Nam , officially the Socialist Republic of Vietnam – is the easternmost country on the Indochina Peninsula in Southeast Asia. It is bordered by China to the north, Laos to the northwest, Cambodia to the southwest, and the South China Sea –...
and the Philippines
Philippines
The Philippines , officially known as the Republic of the Philippines , is a country in Southeast Asia in the western Pacific Ocean. To its north across the Luzon Strait lies Taiwan. West across the South China Sea sits Vietnam...
.
Dosing
The usual adult dose of celecoxib is 100 to 200 mg once or twice a day. The lowest effective dose should be used.Gastrointestinal ADRs
In theory the COX-2 selectivity should result in a significantly lower incidence of gastrointestinal ulceration than traditional NSAIDs. The main items of evidence cited to support this theory were the preliminary (6 month) results of the Celecoxib Long-term Arthritis Safety Study (CLASS) as published in 2000, which demonstrated a significant reduction in the combination of symptomatic ulcers plus ulcer complications in those taking celecoxib versus ibuprofenIbuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....
or diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
, provided they were not on aspirin (Silverstein et al., 2000). However, this was not significant at 12 months (full study length).
Special precaution
Patients with prior history of ulcer disease or GI bleeding. Moderate to severe hepatic impairment, GI toxicity can occur with or without warning symptoms in patients treated with NSAIDsAllergy
Celecoxib contains a sulfonamideSulfonamide (chemistry)
In chemistry, the sulfonamide functional group is -S2-NH2, a sulfonyl group connected to an amine group.A sulfonamide is a compound that contains this group. The general formula is RSO2NH2, where R is some organic group. For example, "methanesulfonamide" is CH3SO2NH2...
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 non-selective NSAIDs.
Drug Interactions
Celecoxib is predominantly metabolized by cytochrome P450 2D6. Caution must be exercised with concomitant use of 2D6 inhibitors, such as fluconazole, which can greatly elevate celecoxib serum levels. In addition, celecoxib may antagonize or increase the risk of renal failure with angiotensin converting enzyme-inhibitors, such as lisinopril, and diuretics, such as hydrochlorothiazide.Pregnancy
Celecoxib is labeled as pregnancy category C. It is contraindicated during the third trimester of pregnancy due to teratogenic potential.Risk of heart attack and stroke
There has been much concern about the possibility of increased risk for heart attack and stroke in users of NSAID drugs, particularly COX-2 selective NSAIDs such as celecoxib, since the withdrawal of the COX-2 inhibitor rofecoxibRofecoxib
Rofecoxib is a nonsteroidal anti-inflammatory drug that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea...
(Vioxx) in 2004. Like all NSAIDs on the U.S. market, celecoxib carries an FDA-mandated "black box warning" for cardiovascular and gastrointestinal risk. In February 2007, the American Heart Association
American Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
warned that celecoxib should be used "as a last resort on patients who have heart disease or a risk of developing it", and suggested that paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
(acetaminophen), or certain older NSAIDs, such as naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
, may be safer choices for chronic pain relief in these patients.
The cardiovascular risks of celecoxib are controversial, with apparently contradictory data produced from different clinical trials. In December 2004, "APC", the first of two trials of celecoxib for colon cancer prevention, found that long-term (33 months) use of high-dose Celebrex (400 and 800 mg daily) demonstrated an increased cardiovascular risk compared with placebo.
A similar trial, named PreSAP, did not demonstrate an increased risk. Still, the APC trial, combined with the recent Vioxx findings, suggested that there might be serious cardiovascular risks specific to the COX-2 inhibitors. On the other hand, a large Alzheimer's
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
prevention trial, called ADAPT, was terminated early after preliminary data suggested that the nonselective NSAID naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
, but not celecoxib, was associated with increased cardiovascular risk. In 2005, a study published in the Annals of Internal Medicine
Annals of Internal Medicine
Annals of Internal Medicine is an academic medical journal published by the American College of Physicians . It publishes research articles and reviews in the area of internal medicine. Its current editor is Christine Laine...
found that cardiovascular effects of COX-2 inhibitors differ, depending on the drug. Other COX-2 selective inhibitors, such as rofecoxib
Rofecoxib
Rofecoxib is a nonsteroidal anti-inflammatory drug that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea...
, have significantly higher myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
rates than celecoxib. In April 2005, after an extensive review of data, the FDA concluded that it was likely "that there is a 'class effect' for increased CV risk for all NSAIDs". In a 2006 meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
of randomized control studies, the cerebrovascular events
Cerebrovascular disease
Cerebrovascular disease is a group of brain dysfunctions related to disease of the blood vessels supplying the brain. Hypertension is the most important cause; it damages the blood vessel lining, endothelium, exposing the underlying collagen where platelets aggregate to initiate a repairing process...
associated with COX-2 inhibitors were examined, but no significant risks were found when compared to non-selective NSAIDs or placebos.
Two studies on the cardiovascular risks of celecoxib and other NSAIDs were meta-analyses
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
, published in 2006. The first of these, published in the British Medical Journal
British Medical Journal
BMJ is a partially open-access peer-reviewed medical journal. Originally called the British Medical Journal, the title was officially shortened to BMJ in 1988. The journal is published by the BMJ Group, a wholly owned subsidiary of the British Medical Association...
, looked at the incidence of cardiovascular events in all previous randomized controlled trials of COX-2 inhibitors, as well as some trials of other NSAIDs. The authors concluded that a significant increased risk did exist for celecoxib, as well as some other selective and nonselective NSAIDS. However, the increased cardiovascular risk in celecoxib was noted only at daily doses of 400 mg or greater. A second meta-analysis published in the Journal of the American Medical Association
Journal of the American Medical Association
The Journal of the American Medical Association is a weekly, peer-reviewed, medical journal, published by the American Medical Association. Beginning in July 2011, the editor in chief will be Howard C. Bauchner, vice chairman of pediatrics at Boston University’s School of Medicine, replacing ...
, which included observational rather than randomized studies (mostly at lower doses) did not find an increased cardiovascular risk of celecoxib vs placebo.
The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial presented a five-fold increase in atherothrombotic cardiovascular events associated with rofecoxib compared to naproxen. Although, the Celecoxib Long-Term Arthritis Safety Study (CLASS) did not present an increase in occurrence of such events, many experts believe that the risk associated with rofecoxib long-term use also applies to celecoxib based on the pharmacology in three distinct mechanisms. It is suggested that prostacyclin (PGI2) inhibition with relatively unopposed platelet-derived thromboxane (TxA2) generation may lead to thrombotic risks. PGI2 from endothelial cells by COX-2 catalysis has anti-aggregating, anti-proliferative, and vasodilating properties. Conversely, TxA2 from platelets maintain vascular homeostasis by irreversible platelet aggregating, vasoconstricting, and smooth muscle proliferating properties. The imbalance of PGI2 may promote TxA2 thrombosis. In addition, COX-2 selective inhibitors can elevate blood pressure by allowing a normal amount of the vasoconstrictor, TxA2, and a stark decrease in the levels of the vasodilator, PGI2., Furthermore, a third postulate for promoting atherothombotic events includes that the upregulation of COX-2 plays a key role in cardioprotection of the last phase of ischemic preconditioning. Due to the controversy, it is advised that prescribers use caution when prescribing celecoxib and present rational care plans that demonstrate a clear indication for the medication.
To establish more conclusively the true cardiovascular risk profile of celecoxib, Pfizer agreed to fund a large, randomized trial specifically designed for that purpose. The trial, centered at the Cleveland Clinic
Cleveland Clinic
The Cleveland Clinic is a multispecialty academic medical center located in Cleveland, Ohio, United States. The Cleveland Clinic is currently regarded as one of the top 4 hospitals in the United States as rated by U.S. News & World Report...
, with a planned enrollment of 20,000 high-risk patients. Celecoxib will be compared with the non-selective NSAIDS naproxen and ibuprofen. Since all patients have arthritis, ethical considerations make it difficult to have a placebo group. This trial has began enrollment in 2006 according to the Clinical Trials database, and is not scheduled to be completed until May 2014. Ultimately, this trial will help answer the question as to whether Celebrex has a riskier cardiovascular profile compared with naproxen or ibuprofen.
Pharmacology
Celecoxib is a highly selective COX-2 inhibitorCOX-2 inhibitor
COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug that directly targets 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...
and primarily inhibits this isoform of cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
(and thus causes inhibition of prostaglandin production), whereas nonselective NSAIDs (like asprin, naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
and ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....
) inhibit both COX-1 and COX-2. COX-1, traditionally defined as a constitutively-expressed “housekeeping” enzyme, is the only isoenzyme found in platelets and plays a role in the protection of the gastrointestinal mucosa, renal 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
Sulfonamide (chemistry)
In chemistry, the sulfonamide functional group is -S2-NH2, a sulfonyl group connected to an amine group.A sulfonamide is a compound that contains this group. The general formula is RSO2NH2, where R is some organic group. For example, "methanesulfonamide" is CH3SO2NH2...
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
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
(and pain) while minimizing gastrointestinal adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (e.g. stomach ulcers) that are common with non-selective NSAIDs.
Celecoxib inhibits COX-2 without affecting COX-1. COX-1 is involved in synthesis of prostaglandins and thromboxane
Thromboxane
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring....
, but COX-2 is only involved in the synthesis of prostaglandin. Therefore, inhibition of COX-2 inhibits only prostaglandin synthesis without affecting thromboxane (TXA2) and thus offer no cardioprotective effects of non-selective NSAIDs.
Synthesis
The synthesis of celecoxib was first described in 1997 by a team of researchers at Searle Research and Development. Celecoxib is synthesized by a Claisen condensationClaisen condensation
The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone...
reaction of an acetophenone with N-(trifluoroacetyl)imidazole catalyzed by the strong base, sodium bis(trimethylsilyl)amide to produce a 1,3-dicarbonyl adduct. Condensation of the diketone with (4-sulfamoylaphenyl)hydrazine produces the 1,5-diarylpyrazole drug moiety.
Structure-Activity Relationship
The Searle research group found that 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. It was found that a para-sulfamoylphenyl at position 1 of the pyrazole has a higher potency for COX-2 selective inhibition than a para-methoxyphenyl (see structures 1 and 2, below). In addition, it is known that a 4-(methylsulfonyl)phenyl or 4-sulfamoylphenyl is 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).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 that 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 it 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 0.040μM while that of the 4-ethyl is 0.86μM which means that 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. 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. 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. . Thus it is reasonable to expect COX-2 selective inhibitors to be more bulky than non-selective NSAIDs.
History
Celecoxib was developed by G. D. Searle & CompanyG. D. Searle & Company
G.D. Searle & Company or just Searle was a company focusing on life sciences, specifically pharmaceuticals, agriculture, and animal health. It is now part of Pfizer.- History :...
and co-promoted by Monsanto Company (parent company of Searle) and Pfizer under the brand name Celebrex. Monsanto merged with Pharmacia
Pharmacia
Pharmacia was a pharmaceutical and biotechnological company in Sweden.-History:Pharmacia was founded in 1911 in Stockholm, Sweden by pharmacist Gustav Felix Grönfeldt at the Elgen Pharmacy. The company is named after the Greek word φαρμακεία, transliterated pharmakeia, which means 'sorcery'...
, 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
University of Rochester
The University of Rochester is a private, nonsectarian, research university in Rochester, New York, United States. The university grants undergraduate and graduate degrees, including doctoral and professional degrees. The university has six schools and various interdisciplinary programs.The...
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
Direct-to-consumer advertising
Direct-to-consumer advertising usually refers to the marketing of pharmaceutical products but can apply in other areas as well. This form of advertising is directed toward patients, rather than healthcare professionals. The Food and Drug Administration holds responsibility of regulating DTC...
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
Public Citizen
Public Citizen is a non-profit, consumer rights advocacy group based in Washington, D.C., United States, with a branch in Austin, Texas. Public Citizen was founded by Ralph Nader in 1971, headed for 26 years by Joan Claybrook, and is now headed by Robert Weissman.-Lobbying Efforts: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
Brigham Young University
Brigham Young University is a private university located in Provo, Utah. It is owned and operated by The Church of Jesus Christ of Latter-day Saints , and is the United States' largest religious university and third-largest private university.Approximately 98% of the university's 34,000 students...
, 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 cancerColorectal cancerColorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
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). AspirinAspirinAspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
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, cyclooxygenaseCyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...
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
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
and analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
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
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
, 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 analog
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
s of celecoxib were generated with small alterations in their chemical structure
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
s. 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
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...
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.
Research into adhesion prevention
Celocoxib may prevent intra-abdominal adhesionAdhesion (medicine)
Adhesions are fibrous bands that form between tissues and organs, often as a result of injury during surgery. They may be thought of as internal scar tissue that connect tissues not normally connected.-Pathophysiology:...
formation. Adhesions are a common complication of surgery, especially abdominal surgery
Abdominal surgery
The term abdominal surgery broadly covers surgical procedures that involve opening the abdomen. Surgery of each abdominal organ is dealt with separately in connection with the description of that organ Diseases affecting the abdominal cavity are dealt with generally under their own names The term...
, and major cause of bowel obstruction
Bowel obstruction
Bowel obstruction is a mechanical or functional obstruction of the intestines, preventing the normal transit of the products of digestion. It can occur at any level distal to the duodenum of the small intestine and is a medical emergency...
and infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
. Publishing in 2005, researchers in Boston noticed a "dramatic" reduction in post-surgical adhesions in mice taking the drug celecoxib. Multi-institutional trials in adult human patients are planned.
The initially suggested course of treatment is a mere 7–10 days following surgery.
See also
- TilmacoxibTilmacoxibTilmacoxib or JTE-522 is a COX-2 inhibitor and is an effective chemopreventive agent against rat experimental liver fibrosis....
- COX-2 selective inhibitor
- Cyclooxygenase 2 inhibitors: drug discovery and developmentCyclooxygenase 2 inhibitors: drug discovery and developmentCyclooxygenases are enzymes that take part in a complex biosynthetic cascade that results in the conversion of polyunsaturated fatty acids to prostaglandins and thromboxane....
External links
- Celebrex website run by PfizerPfizerPfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
- FDA Alert for Practitioners on Celebrex (celecoxib), published December 17, 2004
- FDA Alert for Healthcare Professionals published July 4, 2005
- Largest systematic review of adverse renal and arrhythmia risk of Celecoxib and other COX-2 inhibitors, in JAMA 2006
- U.S. National Library of Medicine: Drug Information Portal - Celecoxib