Targeting selectivity for COX-2 reduces the risk of peptic ulceration and is the main feature of celecoxib, rofecoxib, and other members of this drug class.
[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.
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.
[25][26] 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.
[29] As of 2012 results have been converging on the hypothesis that the adverse cardiovascular effects are most likely due to inhibition of COX-2 in blood vessels, which leads to a decrease in the production of prostacyclin in them.
Prostacyclin usually prevents platelet aggregation and vasoconstriction, so its inhibition can lead to excess clot formation and higher blood pressure.
Brigham Young University has sued Pfizer, alleging breach of contract from relations BYU had with the company at the time of Simmons's work.
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.
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.
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.
[42] The review found that the key Reuben claims that needed to be re-examined were "the absence of detrimental effects of coxibs on bone healing after spine surgery, the beneficial long-term outcome after preemptive administration of coxibs including an allegedly decreased incidence of chronic pain after surgery, and the analgesic efficacy of ketorolac or clonidine when added to local anesthetics for intravenous regional anesthesia.
Sales and marketing efforts were supported by two large trials, the Celecoxib Long-term Arthritis Safety Study[44] (CLASS) in JAMA, and the Vioxx Gastrointestinal Outcomes Research (VIGOR).
In the CLASS trial which compared Celebrex 800 mg/day to ibuprofen 2400 mg/day and diclofenac 150 mg/day for osteoarthritis or rheumatoid arthritis for six months, Celebrex was associated with significantly 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.
[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).
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.
After treatment with a COX-2 inhibitor, the restored p53 function allows DNA damaged neuroblastoma cells to commit suicide through apoptosis reducing the size of growth of the tumor.