Cyclooxygenase-2 inhibitor

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Cyclooxygenase-2 inhibitors (COX-2 inhibitors), also known as coxibs, are a type of

After several COX-2–inhibiting drugs were approved for marketing, data from clinical trials revealed that COX-2 inhibitors caused a significant increase in heart attacks and strokes, with some drugs in the class having worse risks than others. Rofecoxib (sold under the brand name Vioxx) was taken off the market in 2004 because of these concerns, while celecoxib (sold under the brand name Celebrex) and traditional NSAIDs received boxed warnings on their labels. Many COX-2–specific inhibitors have been removed from the US market. As of December 2011, only Celebrex (celecoxib) is still available for purchase in the United States. In the European Union, celecoxib, parecoxib, and etoricoxib have been approved for use by the European Medicines Agency.^[2]

Paracetamol (acetaminophen) inhibits COX-2 almost exclusively within the brain and only minimally in the rest of the body, although it is not considered an NSAID, since it has only minor anti-inflammatory activity.^[3][4]

Medical uses

Some COX-2 inhibitors are used in a single dose to treat pain after surgery.^[5][6] In this role etoricoxib appears as good as, if not better than, other pain medications, and celecoxib appears to be about as useful as ibuprofen.^[7][8]

NSAIDs are often used in treatment of acute

The inhibition of COX-2 is paramount for the anti-inflammatory and analgesic function of the selective COX-2 inhibitor celecoxib. However, with regard to this drug's promise for the therapy of advanced cancers, it is unclear whether the inhibition of COX-2 plays a dominant role, and this has become a controversial and intensely researched issue. In recent years, several additional intracellular components (besides COX-2) were discovered that appear to be important for mediating the anticancer effects of celecoxib in the absence of COX-2.^[19] Moreover, a recent study with various malignant tumor cells showed that celecoxib could inhibit the growth of these cells, even though some of these cancer cells didn't even contain COX-2.^[20]

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

Analysis of clinical trial data revealed that there was a significant increase in the rate of vascular events like myocardial infarction or stroke with COX-2 inhibitors compared with placebo.^[27][28] These results led Merck to voluntarily withdraw (rofecoxib) from the market in September 2004 and to regulatory authorities imposing a boxed warning on the label of celecoxib.^[27] Traditional NSAIDs were also found to have cardiovascular risks, leading to similar boxed warnings.^[27]

The cause of the cardiovascular problems became, and remains, a subject of intensive research.

The COX-2 enzyme was discovered in 1988 by Daniel Simmons, a Brigham Young University researcher.^[30] The mouse COX-2 gene was cloned by UCLA scientist Harvey Herschman, a finding published in 1991.^[31]

The basic research leading to the discovery of COX-2 inhibitors has been the subject of at least two lawsuits. Brigham Young University has sued Pfizer, alleging breach of contract from relations BYU had with the company at the time of Simmons's work.^[32][33] A settlement was reached in April 2012 in which Pfizer agreed to pay $450 million.^[34][35] The other litigation is based on United States Pat. No. 6,048,850^[36] owned by University of Rochester, which claimed a method to treat pain without causing gastro-intestinal distress by selectively inhibiting COX-2. When the patent issued, the university sued Searle (later Pfizer) in a case called, University of Rochester v. G.D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004). The court ruled in favor of Searle in 2004, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid.^[37][38]

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

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

The existing nonsteroidal anti-inflammatory drugs (

Valdecoxib and rofecoxib were about 300 times more potent at inhibiting COX-2 than COX-1, but too toxic for the heart, suggesting the possibility of relief from pain and inflammation without gastrointestinal irritation, and promising to be a boon for those who had previously experienced adverse effects or had comorbidities that could lead to such complications. Celecoxib is approximately 30 times more potent at inhibiting COX-2 than COX-1, with etoricoxib being 106 times more potent.

Research fraud

Between 1996 and 2009,

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

Sales and marketing efforts were supported by two large trials, the Celecoxib Long-term Arthritis Safety Study

The VIGOR trial results were published in 2000 in the New England Journal of Medicine[47] Bombardier and his research team claimed that there was "an increase in myocardial infarction in the patients given rofecoxib (0.4%) compared with those given naproxen (0.1%)" and "patients given naproxen experienced 121 side effects compared with 56 in the patients taking rofecoxib," a "marvellous result for Merck" which "contributed to huge sales of rofecoxib."^[46] Merck's scientists incorrectly interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks "is primarily due to" this protective effect.^[48] In September 2001, the United States Food and Drug Administration (FDA) sent a warning letter to the CEO of Merck, stating, "Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator nonsteroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen)."^[49] This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke). By 2005 The New England Journal of Medicine published an editorial accusing the Bombardier et al. of deliberately withholding data.^[50]

Claire Bombardier, a University of Toronto rheumatologist, had claimed that the VIGOR trial showed that

Small tumors of the sympathetic nervous system (neuroblastoma) appear to have abnormal levels of COX-2 expressed.^[51] These studies report that overexpression of the COX-2 enzyme has an adverse effect on the tumor suppressor, p53. p53 is an apoptosis transcription factor normally found in the cytosol. When cellular DNA is damaged beyond repair, p53 is transported to the nucleus where it promotes p53 mediated apoptosis.^[52] Two of the metabolites of COX-2, prostaglandin A2 (PGA2) and A1 (PGA1), when present in high quantities, bind to p53 in the cytosol and inhibit its ability to cross into the nucleus. This essentially sequesters p53 in the cytosol and prevents apoptosis.^[52] Coxibs such as Celebrex (celecoxib), by selectively inhibiting the overexpressed COX-2, allow p53 to work properly. Functional p53 allows DNA damaged neuroblastoma cells to commit suicide through apoptosis, halting tumor growth.

COX-2 up-regulation has also been linked to the