COX-2 inhibitor
Encyclopedia
COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug
(NSAID) that directly targets COX-2, an enzyme
responsible for inflammation
and pain
. Targeting selectivity for COX-2 reduces the risk of peptic ulcer
ation, and is the main feature of celecoxib
, rofecoxib
and other members of this drug class. COX-2 selectivity does not seem to reduce other adverse effects
of NSAIDs (most notably an increased risk of renal failure
), and some results have shown an increase in the risk for heart attack
, thrombosis
and stroke
by a relative increase in thromboxane
. Rofecoxib
(commonly known as Vioxx) was taken off the market in 2004 because of these concerns.
researcher formerly of Harvard University
. Dr. Simmons immediately understood the importance of his discovery. The same day the enzyme was sequenced, he had his notebook notarized as proof of his discovery. Subsequently, Pfizer, the research firm with whom Simmons had contracted, allegedly broke contract and refused to give Simmons any royalties and profits from his discovery. , a lawsuit is in progress by Simmons against the drug developers.
In the course of the search for a specific inhibitor
of the negative effects of prostaglandin
s which spared the positive effects, it was discovered that prostaglandins could indeed be separated into two general classes which 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 non-steroidal anti-inflammatory drugs (NSAIDs) differ in their relative specificities for COX-2 and COX-1; while aspirin
and ibuprofen
are equipotent at inhibiting COX-2 and COX-1 enzymes, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam
(Mobic). Studies of meloxicam 7.5 mg per day for 23 days find a level of gastric injury similar to that of a placebo
, and for meloxicam 15 mg per day a level of injury lower than that of other NSAIDs; however, in clinical practice meloxicam can still cause some ulcer
complications.
A search for COX-2-specific inhibitors resulted in promising candidates such as valdecoxib
, celecoxib
, etoricoxib
and rofecoxib
(marketed under the brand names Bextra, Celebrex, Arcoxia and Vioxx respectively). Valdecoxib and rofecoxib are about 300 times more potent at inhibiting COX-2, than COX-1, suggesting the possibility of relief from pain and inflammation, without gastrointestinal irritation, and promising to be a boon for those who had experienced such adverse effects previously 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.
Although individual reactions to particular NSAIDs vary, in general the efficacy
of COX-2 inhibitors has proved similar to that of other NSAIDs, as expected since both classes of drug inhibit the desired target, the action of COX-2 prostaglandins. The drugs effectiveness is similar to that of traditional NSAIDs such as ibuprofen, diclofenac, or naproxen.
) was withdrawn voluntarily from the market, due to an increased risk of myocardial infarction
and stroke. At present it is unclear whether this adverse drug reaction pertains also to other drugs of this group or is specific for rofecoxib.
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 physician
s (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.
The cause of the rapid widespread acceptance of Celebrex and Vioxx by physicians was the publication of two large trials, the Celecoxib Long-term Arthritis Safety Study CLASS study in JAMA
, and the Vioxx Gastrointestinal Outcomes Research VIGOR study in the New England Journal of Medicine
. Both publications concluded that COX-2 specific NSAIDs were associated with significantly fewer adverse gastrointestinal effects. In the CLASS trial comparing Celebrex 800 mg/day to ibuprofen 2400 mg/day and diclofenac 150 mg/day for osteoarthritis
or rheumatoid arthritis
for six months, Celebrex was significantly associated with fewer upper gastrointestinal complications (0.44% vs. 1.27%, P=0.04), with no significant difference in incidence of cardiovascular events in patients not taking aspirin
for cardiovascular prophylaxis. In the VIGOR trial testing Vioxx 50 mg/day versus naproxen
for rheumatoid arthritis, Vioxx reduced the risk of symptomatic ulcers and clinical upper gastrointestinal events (perforations
, obstructions
and bleeding
) by 54%, to 1.4% from 3%, the risk of complicated upper gastrointestinal events (complicated perforations, obstructions and bleeding in the upper gastrointestinal tract) by 57%, and the risk of bleeding from anywhere in the gastrointestinal tract by 62%. An enormous marketing effort capitalized on these publications; Vioxx was the most heavily advertised prescription drug in 2000, and Celebrex the seventh, according to IMS Health
.
because of adverse gastrointestinal events was 3.5% for Vioxx, compared to 4.8% for ibuprofen, diclofenac, or nabumetone
(Relafen). Endoscopic studies of patients receiving Celebrex 50–400 mg twice daily for 12–24 weeks found rates of upper gastrointestinal complications similar to placebo and significantly lower than naproxen
500 mg twice daily and ibuprofen 800 mg three times daily, but not statistically significantly different from patients receiving diclofenac
75 mg twice daily.11 The analysis found that Vioxx provided significant gastrointestinal benefits in patients both at high risk and at low risk of developing gastrointestinal problems; patients at low risk still had 88% fewer gastrointestinal problems with Vioxx.
The results of the CLASS study were confirmed by the Successive Celecoxib Efficacy and Safety Studies (SUCCESS) study, which examined the effectiveness and safety of celecoxib 200 mg and 400 mg daily and how well it was tolerated by patients in terms of adverse effects, compared with the most common NSAID regimens in the countries studied (diclofenac 100 mg daily and naproxen 1000 mg daily). SUCCESS showed that celecoxib was as effective as the conventional NSAIDs in controlling the pain of arthritis, and caused fewer gastrointestinal ulcers or ulcer complications (such as perforations or bleeding) and fewer upper gastrointestinal adverse effects, e.g. 29% less chance of having nausea and 22% less chance of abdominal pain. In addition, hospitalization rates for upper gastrointestinal problems were 2 to 4 times lower with celecoxib, and because there were fewer adverse effects, there was 23% less chance of a celecoxib patient stopping treatment. The study also found that there was no real advantage to taking a
bigger dose of celecoxib: the 200 mg dose was found to be just as effective as the 400 mg dose.
The VIGOR study was followed by the Assessment of Difference between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness (ADVANTAGE) study, which showed that 9.1% of people taking Vioxx received a gastro-protective medicine compared with 11.2% of people taking naproxen, a reduction of 19%. In addition, after 3 months, 5.9% of people stopped taking Vioxx compared with 8.1% who stopped taking naproxen, a reduction of 27%. ADVANTAGE was the first study comparing the gastrointestinal tolerability of Vioxx and naproxen in a group that included patients taking low-dose aspirin for cardiovascular reasons. This was followed by the Experience with Vioxx in Arthritis (EVA) survey of 5,986 Belgian
physicians and 74,192 people with osteoarthritis, which found that, after 12.5 or 25 mg of Vioxx once daily for 30 days, 80% of the patients wished to continue treatment with Vioxx and more than 80% of doctors said they would continue prescribing Vioxx. The preference to
continue taking Vioxx was especially strong in people previously treated with older NSAIDs.
In a six week long study comparing Vioxx 25 mg once daily, Vioxx 12.5 mg once daily, Celebrex 200 mg once daily, and paracetamol
/acetaminophen 1,000 mg four times daily for osteoarthritis of the knee
, higher dose Vioxx was found to be superior to the other three treatments for reduction of nocturnal pain, and superior to Celebrex and acetaminophen/paracetamol for reduction of resting pain. At six weeks, 60% of high dose Vioxx patients reported a good or excellent response, compared to 46% of Celebrex patients and 39% of paracetamol patients. Low dose Vioxx was not found to be statistically significant from Celebrex at this dose. Similar results were found for early response to therapy.
However, when the Food and Drug Administration
(FDA) later presented more complete data from the CLASS and VIGOR trials on its web site, the results were less certain. The CLASS trial was revealed to also have twelve and fifteen month time points which had not been discussed in the JAMA publication; in this segment of the trial, the number of ulcer-related complications for Celebrex caught up to the control NSAID group. Similarly, the complete VIGOR study data revealed that in fact, when all adverse events, not just gastrointestinal, were tabulated, the patients receiving VIOXX had suffered (barely) significantly higher incidence of adverse events overall than the control NSAID group. In particular, the risk of serious cardiovascular thrombotic
events, e.g. myocardial infarction
, was 1.7% in the VIOXX patients versus 0.7% in the control group, and there were significantly more withdrawals in the Vioxx group for causes including hypertension
, edema
, hepatotoxicity
, heart failure, or pathological
laboratory findings. The mean increases in systolic
and diastolic blood pressure
in the Vioxx group were 4.6 mmHg and 1.7 mmHg respectively, compared to 1.0 and 0.1 mmHg in the control NSAID group. An estimated 43,000,000 Americans, nearly one out of six, suffers from arthritis
. However, 42% (18 million) of these also suffer from hypertension
. Therefore, the promise of better patient outcomes and lowered medical costs from use of COX-2 inhibitors may not be as great as previously hoped. Questions remain regarding the relative safety and cost effectiveness of this new class. While endoscopic
evidence of gastrointestinal damage is frequently seen in studies of nonspecific NSAIDs, the actual incidence of clinically evident symptoms and patient discomfort is much lower; furthermore, in cases of short-term therapy, any such damage generally reverses itself quickly after termination of the drug.
, nonspecific NSAIDs alone, NSAIDs plus a proton pump inhibitor
, NSAIDs plus an H2 receptor antagonist, NSAIDs plus misoprostol
, and diclofenac/misoprostol, found the lowest probability of adverse gastrointestinal events for celecoxib, followed by NSAIDs plus a proton pump inhibitor, NSAIDs plus an H2 receptor antagonist, NSAID plus misoprostol, diclofenac/misoprostol, and NSAID alone. In total cost, including drug plus treatment of any gastrointestinal effects, the lowest cost treatment was celecoxib, followed by NSAIDs alone and diclofenac/misoprostol, with the other NSAID plus gastrointestinal protection regimens being much more costly. Similarly, a model of cost effectiveness of rofecoxib
and celecoxib compared to high-dose acetaminophen or ibuprofen
, with and without misoprostol, in patients with osteoarthritis of the knee found that acetaminophen had the
lowest cost for average patients. For those not responding to paracetamol, ibuprofen was the most cost effective treatment by a large margin, but for those who did not respond to acetaminophen and had a high risk of gastrointestinal damage, rofecoxib was the most cost effective treatment.
by the kidney
s. Therefore, cardiovascular effects of NSAIDs prescribed for arthritis pain and inflammation need to be considered when choosing the appropriate medication for each patient. A French
study of osteoarthritis patients over 65 years of age determined that, compared to Celebrex (200 mg once daily), patients taking Vioxx (25 mg once daily) suffered a two-fold increase in clinically significant edema
and 60% more frequent increases in systolic
blood pressure greater than 20 mmHg, as early as the second week of treatment. This has significant implications, since it has been estimated that every 2 mmHg increase in blood pressure raises the risk of stroke
by two thirds and the risk of myocardial infarction
by one third, suggesting that Celebrex may be a better choice for hypertensive
patients or those at risk
for edema. In addition, COX-2 inhibitors lack some of the platelet
inhibiting properties of aspirin
and other nonspecific NSAIDs and may, directly or indirectly, lead to increased risk of thrombosis
, particularly in high risk patients where low dose aspirin therapy is warranted. On the other hand, this property makes them a better choice for perisurgical pain management
, where inhibition of blood clotting would be problematic. Also, long-term use of COX-2 inhibitors is not safe, and for patients with chronic arthritis, the choices for prescription drugs for long-term treatment, is limited.
There are other differences between Celebrex and Vioxx that influence prescribing practices. Patients with known sensitivity to sulfa drug
s are likely to be sensitive to Celebrex as well, due to similarity in structure. Vioxx has a more rapid onset and is approved for acute pain as well as osteoarthritis, while Celebrex is approved for rheumatoid arthritis
as well as osteoarthritis.
75 mg twice daily; but this freedom from gastrointestinal complications was lost in patients taking concurrent low dose aspirin.
) have abnormal levels of COX-2 expressed. 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. 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. 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 phosphorylation and activation of the E3 ubiquitin ligase HDM2, a protein that mediates p53 ligation and tagged destruction, through ubiquitination. The mechanism for this neuroblastoma HDM2 hyperactivity is unknown. Studies have shown that COX-2 inhibitors block the phosphorylation of HDM2 preventing its activation. In vitro, the use of COX-2 inhibitors such as CELEBREX (celecoxib) lowers the level of active HDM2 found in neuroblastoma cells. The exact process of how COX-2 inhibitors block HDM2 phosphorylation is unknown, but this mediated reduction in active HDM2 concentration level restores the cellular p53 levels. After treatment with CELEBREX (celecoxib), the restored p53 function allows DNA damaged neuroblastoma cells to commit suicide through apoptosis reducing the size of growth of the tumor.
(FAP) http://www.fda.gov/bbs/topics/ANSWERS/ANS00992.html. COX-2 inhibitors are currently being studied breast cancer
and appear to be beneficial.
and analgesic
function of the selective COX-2 inhibitor celecoxib
, and quite likely also for its ability to prevent the development of cancerous growth. However, with regards 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. 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.
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 and this anticancer effect could also be verified in highly drug-resistant tumor cells and in various animal tumor models.
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) that directly targets COX-2, an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
responsible for 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
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
. Targeting selectivity for COX-2 reduces the risk of peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
ation, and is the main feature of celecoxib
Celecoxib
Celecoxib INN is a sulfa non-steroidal anti-inflammatory drug 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...
, 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...
and other members of this drug class. COX-2 selectivity does not seem to reduce other adverse effects
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...
of NSAIDs (most notably an increased risk of renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
), and some results have shown an increase in the risk for heart attack
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...
, thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
by a relative increase in 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....
. 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...
(commonly known as Vioxx) was taken off the market in 2004 because of these concerns.
Research history
The mouse COX-2 gene was cloned by UCLA scientist Dr. Harvey Herschman. The enzyme was discovered in 1988 by Daniel Simmons, a Brigham Young UniversityBrigham 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...
researcher formerly of Harvard University
Harvard University
Harvard University is a private Ivy League university located in Cambridge, Massachusetts, United States, established in 1636 by the Massachusetts legislature. Harvard is the oldest institution of higher learning in the United States and the first corporation chartered in the country...
. Dr. Simmons immediately understood the importance of his discovery. The same day the enzyme was sequenced, he had his notebook notarized as proof of his discovery. Subsequently, Pfizer, the research firm with whom Simmons had contracted, allegedly broke contract and refused to give Simmons any royalties and profits from his discovery. , a lawsuit is in progress by Simmons against the drug developers.
In the course of the search for a specific inhibitor
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of the negative effects of prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
s which spared the positive effects, it was discovered that prostaglandins could indeed be separated into two general classes which could loosely be regarded as "good prostaglandins" and "bad prostaglandins", according to the structure of a particular enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
involved in their biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
, 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...
.
Prostaglandins whose synthesis involves the cyclooxygenase-I
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...
enzyme, or COX-1, are responsible for maintenance and protection of the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
, while prostaglandins whose synthesis involves the cyclooxygenase-II enzyme, or COX-2, are responsible for inflammation and pain.
The existing non-steroidal anti-inflammatory drugs (NSAIDs) differ in their relative specificities for COX-2 and COX-1; while aspirin
Aspirin
Aspirin , 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...
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....
are equipotent at inhibiting COX-2 and COX-1 enzymes, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam
Meloxicam
Meloxicam is a nonsteroidal anti-inflammatory drug with analgesic and fever reducer effects. It is a derivative of oxicam, closely related to piroxicam, and falls in the enolic acid group of NSAIDs...
(Mobic). Studies of meloxicam 7.5 mg per day for 23 days find a level of gastric injury similar to that of a placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
, and for meloxicam 15 mg per day a level of injury lower than that of other NSAIDs; however, in clinical practice meloxicam can still cause some ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
complications.
A search for COX-2-specific inhibitors resulted in promising candidates such as valdecoxib
Valdecoxib
Valdecoxib is a non-steroidal anti-inflammatory drug used in the treatment of osteoarthritis, rheumatoid arthritis, and painful menstruation and menstrual symptoms. It is a cyclooxygenase-2 selective inhibitor....
, celecoxib
Celecoxib
Celecoxib INN is a sulfa non-steroidal anti-inflammatory drug 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...
, etoricoxib
Etoricoxib
Etoricoxib is a COX-2 selective inhibitor from Merck & Co...
and 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...
(marketed under the brand names Bextra, Celebrex, Arcoxia and Vioxx respectively). Valdecoxib and rofecoxib are about 300 times more potent at inhibiting COX-2, than COX-1, suggesting the possibility of relief from pain and inflammation, without gastrointestinal irritation, and promising to be a boon for those who had experienced such adverse effects previously or had comorbidities
Comorbidity
In medicine, comorbidity is either the presence of one or more disorders in addition to a primary disease or disorder, or the effect of such additional disorders or diseases.- In medicine :...
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.
Although individual reactions to particular NSAIDs vary, in general the efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
of COX-2 inhibitors has proved similar to that of other NSAIDs, as expected since both classes of drug inhibit the desired target, the action of COX-2 prostaglandins. The drugs effectiveness is similar to that of traditional NSAIDs such as ibuprofen, diclofenac, or naproxen.
Adverse effects
On September 27, 2004 Vioxx (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...
) was withdrawn voluntarily from the market, due to an increased risk of 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...
and stroke. At present it is unclear whether this adverse drug reaction pertains also to other drugs of this group or is specific for rofecoxib.
Early COX-2-inhibiting drugs
Celebrex and celebra were introduced in 1999 and rapidly became the most frequently prescribed new drugs in the United States. By October 2000, their US sales exceeded 100 million prescriptions per year for $3 billion, and were still rising, sales of Celebrex alone reaching $3.1 billion in 2001. A SpanishSpain
Spain , officially the Kingdom of Spain languages]] under the European Charter for Regional or Minority Languages. In each of these, Spain's official name is as follows:;;;;;;), is a country and member state of the European Union located in southwestern Europe on the Iberian Peninsula...
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 physician
Primary care physician
A primary care physician, or PCP, is a physician/medical doctor who provides both the first contact for a person with an undiagnosed health concern as well as continuing care of varied medical conditions, not limited by cause, organ system, or diagnosis....
s (98.23% of NSAIDs and 94.61% of COX-2 inhibitors were prescribed by primary care physicians). For specialty physicians, 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...
and celecoxib
Celecoxib
Celecoxib INN is a sulfa non-steroidal anti-inflammatory drug 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...
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.
The cause of the rapid widespread acceptance of Celebrex and Vioxx by physicians was the publication of two large trials, the Celecoxib Long-term Arthritis Safety Study CLASS study in JAMA
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 ...
, and the Vioxx Gastrointestinal Outcomes Research VIGOR study in the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
. Both publications concluded that COX-2 specific NSAIDs were associated with significantly fewer adverse gastrointestinal effects. In the CLASS trial comparing Celebrex 800 mg/day to ibuprofen 2400 mg/day and diclofenac 150 mg/day for 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...
or 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...
for six months, Celebrex was significantly associated with fewer upper gastrointestinal complications (0.44% vs. 1.27%, P=0.04), with no significant difference in incidence of cardiovascular events in patients not taking aspirin
Aspirin
Aspirin , 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...
for cardiovascular prophylaxis. In the VIGOR trial testing Vioxx 50 mg/day versus 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:...
for rheumatoid arthritis, Vioxx reduced the risk of symptomatic ulcers and clinical upper gastrointestinal events (perforations
Gastrointestinal perforation
Gastrointestinal perforation is a complete penetration of the wall of the stomach, small intestine or large bowel, resulting in intestinal contents flowing into the abdominal cavity. Perforation of the intestines results in the potential for bacterial contamination of the abdominal cavity...
, obstructions
Gastric outlet obstruction
Gastric outlet obstruction is a medical condition where there is an obstruction at the level of the pylorus, which is the outlet of the stomach. Individuals with gastric outlet obstruction will often have recurrent vomiting of food that has accumulated in the stomach, but which cannot pass into...
and bleeding
Upper gastrointestinal bleeding
Upper gastrointestinal bleeding refers to hemorrhage in the upper gastrointestinal tract. The anatomic cut-off for upper GI bleeding is the ligament of Treitz, which connects the fourth portion of the duodenum to the diaphragm near the splenic flexure of the colon.Upper GI bleeds are considered...
) by 54%, to 1.4% from 3%, the risk of complicated upper gastrointestinal events (complicated perforations, obstructions and bleeding in the upper gastrointestinal tract) by 57%, and the risk of bleeding from anywhere in the gastrointestinal tract by 62%. An enormous marketing effort capitalized on these publications; Vioxx was the most heavily advertised prescription drug in 2000, and Celebrex the seventh, according to IMS Health
IMS Health
IMS Health is an international company that supplies the pharmaceutical industry with sales data and consulting services. IMS Health was founded in 1954 by Bill Froch and David Dubow. Today IMS has operations in more than 100 countries, a global workforce of 7,600+ employees, and revenues of $2...
.
Comparative studies
In a metaanalysis of eight osteoarthritis studies, the incidence of withdrawalWithdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
because of adverse gastrointestinal events was 3.5% for Vioxx, compared to 4.8% for ibuprofen, diclofenac, or nabumetone
Nabumetone
Nabumetone is a non-steroidal anti-inflammatory drug , the only 1-naphthaleneacetic acid derivative. Nabumetone has been developed by Beecham...
(Relafen). Endoscopic studies of patients receiving Celebrex 50–400 mg twice daily for 12–24 weeks found rates of upper gastrointestinal complications similar to placebo and significantly lower than 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:...
500 mg twice daily and ibuprofen 800 mg three times daily, but not statistically significantly different from patients receiving diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
75 mg twice daily.11 The analysis found that Vioxx provided significant gastrointestinal benefits in patients both at high risk and at low risk of developing gastrointestinal problems; patients at low risk still had 88% fewer gastrointestinal problems with Vioxx.
The results of the CLASS study were confirmed by the Successive Celecoxib Efficacy and Safety Studies (SUCCESS) study, which examined the effectiveness and safety of celecoxib 200 mg and 400 mg daily and how well it was tolerated by patients in terms of adverse effects, compared with the most common NSAID regimens in the countries studied (diclofenac 100 mg daily and naproxen 1000 mg daily). SUCCESS showed that celecoxib was as effective as the conventional NSAIDs in controlling the pain of arthritis, and caused fewer gastrointestinal ulcers or ulcer complications (such as perforations or bleeding) and fewer upper gastrointestinal adverse effects, e.g. 29% less chance of having nausea and 22% less chance of abdominal pain. In addition, hospitalization rates for upper gastrointestinal problems were 2 to 4 times lower with celecoxib, and because there were fewer adverse effects, there was 23% less chance of a celecoxib patient stopping treatment. The study also found that there was no real advantage to taking a
bigger dose of celecoxib: the 200 mg dose was found to be just as effective as the 400 mg dose.
The VIGOR study was followed by the Assessment of Difference between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness (ADVANTAGE) study, which showed that 9.1% of people taking Vioxx received a gastro-protective medicine compared with 11.2% of people taking naproxen, a reduction of 19%. In addition, after 3 months, 5.9% of people stopped taking Vioxx compared with 8.1% who stopped taking naproxen, a reduction of 27%. ADVANTAGE was the first study comparing the gastrointestinal tolerability of Vioxx and naproxen in a group that included patients taking low-dose aspirin for cardiovascular reasons. This was followed by the Experience with Vioxx in Arthritis (EVA) survey of 5,986 Belgian
Belgium
Belgium , officially the Kingdom of Belgium, is a federal state in Western Europe. It is a founding member of the European Union and hosts the EU's headquarters, and those of several other major international organisations such as NATO.Belgium is also a member of, or affiliated to, many...
physicians and 74,192 people with osteoarthritis, which found that, after 12.5 or 25 mg of Vioxx once daily for 30 days, 80% of the patients wished to continue treatment with Vioxx and more than 80% of doctors said they would continue prescribing Vioxx. The preference to
continue taking Vioxx was especially strong in people previously treated with older NSAIDs.
In a six week long study comparing Vioxx 25 mg once daily, Vioxx 12.5 mg once daily, Celebrex 200 mg once daily, and 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 1,000 mg four times daily for osteoarthritis of the knee
Knee
The knee joint joins the thigh with the leg and consists of two articulations: one between the fibula and tibia, and one between the femur and patella. It is the largest joint in the human body and is very complicated. The knee is a mobile trocho-ginglymus , which permits flexion and extension as...
, higher dose Vioxx was found to be superior to the other three treatments for reduction of nocturnal pain, and superior to Celebrex and acetaminophen/paracetamol for reduction of resting pain. At six weeks, 60% of high dose Vioxx patients reported a good or excellent response, compared to 46% of Celebrex patients and 39% of paracetamol patients. Low dose Vioxx was not found to be statistically significant from Celebrex at this dose. Similar results were found for early response to therapy.
However, when the 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...
(FDA) later presented more complete data from the CLASS and VIGOR trials on its web site, the results were less certain. The CLASS trial was revealed to also have twelve and fifteen month time points which had not been discussed in the JAMA publication; in this segment of the trial, the number of ulcer-related complications for Celebrex caught up to the control NSAID group. Similarly, the complete VIGOR study data revealed that in fact, when all adverse events, not just gastrointestinal, were tabulated, the patients receiving VIOXX had suffered (barely) significantly higher incidence of adverse events overall than the control NSAID group. In particular, the risk of serious cardiovascular thrombotic
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
events, e.g. 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...
, was 1.7% in the VIOXX patients versus 0.7% in the control group, and there were significantly more withdrawals in the Vioxx group for causes including hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
, hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
, heart failure, or pathological
laboratory findings. The mean increases in systolic
Systole (medicine)
Systole is the contraction of the heart. Used alone, it usually means the contraction of the left ventricle.In all mammals, the heart has 4 chambers. The left and right ventricles pump together. The atria and ventricles pump in sequence...
and diastolic blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
in the Vioxx group were 4.6 mmHg and 1.7 mmHg respectively, compared to 1.0 and 0.1 mmHg in the control NSAID group. An estimated 43,000,000 Americans, nearly one out of six, suffers from arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
. However, 42% (18 million) of these also suffer from hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
. Therefore, the promise of better patient outcomes and lowered medical costs from use of COX-2 inhibitors may not be as great as previously hoped. Questions remain regarding the relative safety and cost effectiveness of this new class. While endoscopic
Endoscopy
Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
evidence of gastrointestinal damage is frequently seen in studies of nonspecific NSAIDs, the actual incidence of clinically evident symptoms and patient discomfort is much lower; furthermore, in cases of short-term therapy, any such damage generally reverses itself quickly after termination of the drug.
Combination drugs
A model comparing the theoretical relative frequency of gastrointestinal adverse effects and cost effectiveness of celecoxibCelecoxib
Celecoxib INN is a sulfa non-steroidal anti-inflammatory drug 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...
, nonspecific NSAIDs alone, NSAIDs plus a proton pump inhibitor
Proton pump inhibitor
Proton-pump inhibitors are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar...
, NSAIDs plus an H2 receptor antagonist, NSAIDs plus misoprostol
Misoprostol
Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...
, and diclofenac/misoprostol, found the lowest probability of adverse gastrointestinal events for celecoxib, followed by NSAIDs plus a proton pump inhibitor, NSAIDs plus an H2 receptor antagonist, NSAID plus misoprostol, diclofenac/misoprostol, and NSAID alone. In total cost, including drug plus treatment of any gastrointestinal effects, the lowest cost treatment was celecoxib, followed by NSAIDs alone and diclofenac/misoprostol, with the other NSAID plus gastrointestinal protection regimens being much more costly. Similarly, a model of cost effectiveness of 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...
and celecoxib compared to high-dose acetaminophen or 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....
, with and without misoprostol, in patients with osteoarthritis of the knee found that acetaminophen had the
lowest cost for average patients. For those not responding to paracetamol, ibuprofen was the most cost effective treatment by a large margin, but for those who did not respond to acetaminophen and had a high risk of gastrointestinal damage, rofecoxib was the most cost effective treatment.
Risks and adverse effects
This cardiovascular risk of COX-2 specific inhibitors is not surprising since prostaglandins are involved in regulation of blood pressureBlood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
by the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s. Therefore, cardiovascular effects of NSAIDs prescribed for arthritis pain and inflammation need to be considered when choosing the appropriate medication for each patient. A French
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
study of osteoarthritis patients over 65 years of age determined that, compared to Celebrex (200 mg once daily), patients taking Vioxx (25 mg once daily) suffered a two-fold increase in clinically significant edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
and 60% more frequent increases in systolic
Systole (medicine)
Systole is the contraction of the heart. Used alone, it usually means the contraction of the left ventricle.In all mammals, the heart has 4 chambers. The left and right ventricles pump together. The atria and ventricles pump in sequence...
blood pressure greater than 20 mmHg, as early as the second week of treatment. This has significant implications, since it has been estimated that every 2 mmHg increase in blood pressure raises the risk of stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
by two thirds and the risk of 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...
by one third, suggesting that Celebrex may be a better choice for hypertensive
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
patients or those at risk
for edema. In addition, COX-2 inhibitors lack some of the platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
inhibiting properties of aspirin
Aspirin
Aspirin , 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...
and other nonspecific NSAIDs and may, directly or indirectly, lead to increased risk of thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
, particularly in high risk patients where low dose aspirin therapy is warranted. On the other hand, this property makes them a better choice for perisurgical pain management
Pain management
Pain management is a branch of medicine employing an interdisciplinary approach for easing the suffering and improving the quality of life of those living with pain. The typical pain management team includes medical practitioners, clinical psychologists, physiotherapists, occupational therapists,...
, where inhibition of blood clotting would be problematic. Also, long-term use of COX-2 inhibitors is not safe, and for patients with chronic arthritis, the choices for prescription drugs for long-term treatment, is limited.
There are other differences between Celebrex and Vioxx that influence prescribing practices. Patients with known sensitivity to sulfa drug
Sulfonamide (medicine)
Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame...
s are likely to be sensitive to Celebrex as well, due to similarity in structure. Vioxx has a more rapid onset and is approved for acute pain as well as osteoarthritis, while Celebrex is approved for 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...
as well as osteoarthritis.
Considerations for prescription
A key assumption made in early COX-2 cost-effectiveness studies was lower cost due to a reduction in coprescription of agents used to protect the gastrointestinal tract from traditional NSAIDs. However, if gastroprotective agents continue to be coprescribed along with COX-2 inhibitors, there would seem to be no advantage to the use of these higher cost NSAIDs. Similarly, in patients who take aspirin for cardiovascular benefit, with its attendant gastrointestinal irritation, prescription of COX-2 inhibitors to avoid gastrointestinal irritation would seem to offer no advantage. This was confirmed by the CLASS study, which found significantly lower incidence of upper gastrointestinal complications alone and combined with symptomatic ulcers in patients taking Celebrex 400 mg twice daily, compared to ibuprofen 800 mg three times daily or diclofenacDiclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
75 mg twice daily; but this freedom from gastrointestinal complications was lost in patients taking concurrent low dose aspirin.
Neuroblastomas
Recent studies have shown that small tumors of the sympathetic nervous system (neuroblastomaNeuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
) have abnormal levels of COX-2 expressed. 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. 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. 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 phosphorylation and activation of the E3 ubiquitin ligase HDM2, a protein that mediates p53 ligation and tagged destruction, through ubiquitination. The mechanism for this neuroblastoma HDM2 hyperactivity is unknown. Studies have shown that COX-2 inhibitors block the phosphorylation of HDM2 preventing its activation. In vitro, the use of COX-2 inhibitors such as CELEBREX (celecoxib) lowers the level of active HDM2 found in neuroblastoma cells. The exact process of how COX-2 inhibitors block HDM2 phosphorylation is unknown, but this mediated reduction in active HDM2 concentration level restores the cellular p53 levels. After treatment with CELEBREX (celecoxib), the restored p53 function allows DNA damaged neuroblastoma cells to commit suicide through apoptosis reducing the size of growth of the tumor.
Cancer
COX-2 appears to be related to cancers and abnormal growths in the intestinal tract. COX inhibitors have been shown to reduce the occurrence of cancers and pre-cancerous growths. The National Cancer Institute has done some studies on COX-2 and Cancer. And the FDA has approved Celebrex for treatment of familial adenomatous polyposisFamilial 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....
(FAP) http://www.fda.gov/bbs/topics/ANSWERS/ANS00992.html. COX-2 inhibitors are currently being studied breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and appear to be beneficial.
Other targets
The inhibition of COX-2 is paramount for the anti-inflammatoryAnti-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 the selective COX-2 inhibitor celecoxib
Celecoxib
Celecoxib INN is a sulfa non-steroidal anti-inflammatory drug 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...
, and quite likely also for its ability to prevent the development of cancerous growth. However, with regards 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
Celecoxib
Celecoxib INN is a sulfa non-steroidal anti-inflammatory drug 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...
in the absence of COX-2. 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.
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 and this anticancer effect could also be verified in highly drug-resistant tumor cells and in various animal tumor models.
Further reading
- "You and A: Arthritis drugs. Pain and confusion"; Francesca Lunzer Kritz; Washington Post; Sept. 4, 2001; HE01.
- "Vioxx (rofecoxib) reduces night-time osteoarthritis pain better than celecoxib or acetaminophen"; European League Against Rheumatism (EULAR) conference proceedings.
- "Will the promise of the COX-II selective NSAIDs come to fruition?"; Drug Ther Perspect 17(11); 6-10, 2001.
- "Osteoarthritis drug Celebrex (celecoxib) less likely to cause increased blood pressure than Vioxx (rofecoxib)"; European League Against Rheumatism (EULAR) conference proceedings.
- Dai C, Stafford RS, Alexander GC. National Trends in Cox-2 inhibitor use since market release: non-selective diffusion of a selectively cost-effective innovation Archives of Internal Medicine. 2005; 165: 171-177.
- Editorial: Solomon DH, Avorn J. Coxibs, science, and the public trust Archives of Internal Medicine. 2005;165:158-160