Селекоксиб: Қолданылуы, қауіптері мен ескертулер

Nonsteroidal anti inflammatory medication

Celecoxib is indicated for the treatment of osteoarthritis, rheumatoid arthritis, psoriatic arthritis, acute pain, musculoskeletal pain, painful menstruation, ankylosing spondylitis, juvenile rheumatoid arthritis, and to reduce the number of colon and rectal polyps in people with familial adenomatous polyposis. For pain relief, it is similar to paracetamol (acetaminophen) at 3990 mg per day, which is the first line treatment for osteoarthritis. Evidence of effects is not clear as a number of studies done by the manufacturer have not been released for independent analysis.

It has been used to reduce colon and rectal polyps in people with familial adenomatous polyposis, but it is not known if it decreases rates of cancer, The increased risk is about 37%. The increased risk is about 81%.

Celecoxib contains a sulfonamide moiety and may cause allergic reactions in those allergic to other sulfonamide containing drugs. This is in addition to the contraindication in people with severe allergies to other NSAIDs. However, it has a low (reportedly 4%) chance of inducing cutaneous reactions among persons who have a history of such reactions to aspirin or nonselective NSAIDs. NSAIDs may cause serious skin adverse events, including exfoliative dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis; events may occur without warning and in patients without prior known sulfa allergy. Use should be discontinued at first sign of rash (or any other hypersensitivity).

A 2013 meta analysis of hundreds of clinical trials found that coxibs (the class of drugs that includes celecoxib) increase the risk of major cardiovascular problems by about 37% over placebo. In 2016, a randomized trial provided strong evidence that treatment with celecoxib is not more likely to result in poor cardiovascular outcomes than treatment with naproxen or ibuprofen. As a result, in 2018 an FDA advisory panel concluded that celecoxib poses no greater risk for causing heart attacks and strokes than the commonly used NSAIDs ibuprofen or naproxen and recommended that the FDA consider changing its advice to physicians regarding celecoxib's safety. Other COX 2 selective inhibitors, such as rofecoxib, have significantly higher myocardial infarction rates than celecoxib. In April 2005, after an extensive review of data, the FDA concluded it was likely "that there is a 'class effect' for increased CV risk for all NSAIDs". In a 2006 meta analysis of randomized control studies, the cerebrovascular events associated with COX 2 inhibitors were examined, but no significant risks were found when compared to nonselective NSAIDs or placebos.

Celecoxib is predominantly metabolized by cytochrome P450 2C9. Caution must be exercised with concomitant use of 2C9 inhibitors, such as fluconazole, which can greatly elevate celecoxib serum levels. The drug may increase the risk of kidney failure with angiotensin converting enzyme inhibitors, such as lisinopril, and diuretics, such as hydrochlorothiazide. 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 reactions (e. g. stomach ulcers) that are common with nonselective NSAIDs.

For its use in reducing colon polyps, celecoxib affects genes and pathways involved in inflammation and malignant transformation in tumors, but not normal tissues. Celecoxib binds to Cadherin 11 (which may explain the reduction in cancer progression).

The Searle research group found the two appropriately substituted aromatic rings must reside on adjacent positions about the central ring for adequate COX 2 inhibition. Various modifications can be made to the 1,5 diarylpyrazole moiety to deduce the structure activity relationship of celecoxib. A para sulfamoylphenyl at position 1 of the pyrazole was found to have a higher potency for COX 2 selective inhibition than a para methoxyphenyl (see structures 1 and 2, below). In addition, a 4 (methylsulfonyl)phenyl or 4 sulfamoylphenyl is known to be necessary for COX 2 inhibition. For instance, replacing either of these entities with a –SO2NHCH3 substituent diminishes COX 2 inhibitory activity as noted with a very high inhibitory concentration 50 (see structures 3 – 5). At the 3 position of the pyrazole, a trifluoromethyl or difluoromethyl provides superior selectivity and potency compared to a fluoromethyl or methyl substitution (see structures 6 – 9). This mutation appears to contribute to COX 2 selectivity by creating steric hindrance between the sulfonamide oxygen and the methyl group of Ile523 that effectively destabilizes the celecoxib COX 1 complex. Two lawsuits arose over discovery of celecoxib. Daniel L. Simmons of Brigham Young University (BYU) discovered the COX 2 enzyme in 1988, and in 1991, BYU entered into a collaboration with Monsanto to develop drugs to inhibit it. Monsanto's pharmaceutical division was later purchased by Pfizer, and in 2006, BYU sued Pfizer for breach of contract, claiming Pfizer did not properly pay contractual royalties back to BYU. A settlement was reached in April 2012, in which Pfizer agreed to pay $450 million. Other important discoveries in COX 2 were made at University of Rochester, which patented the discoveries. When the patent issued, the university sued Searle (later Pfizer) in a case called, University of Rochester v. G. D. Searle & Co., 358 F.3d 916 (Fed. Cir. 2004). The court ruled in favor of Searle in 2004, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX 2 and therefore the patent was invalid. According to the National Academy of Sciences, Philip Needleman, who was vice president of Monsanto in 1989 and president of Searle in 1993 Celecoxib was discovered and developed by G. D. Searle & Company and was approved by the FDA on 31 December 1998. It was co promoted by Monsanto Company (parent company of Searle) and Pfizer under the brand name Celebrex. Monsanto merged with Pharmacia, from which the Medical Research Division was acquired by Pfizer, giving Pfizer ownership of Celebrex. The drug was at the core of a major patent dispute that was resolved in Searle's favor (later Pfizer) in 2004. Pfizer resumed advertising Celebrex in magazines in 2006, and resumed television advertising in April 2007 with an unorthodox, 2 1/2 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 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. None of the retracted studies were submitted to either the US Food and Drug Administration or the European Union's regulatory agencies prior to the drug's approval. Although Pfizer issued a public statement declaring, "It is very disappointing to learn about Dr. Scott Reuben's alleged actions. When we decided to support Dr. Reuben's research, he worked for a credible academic medical center and appeared to be a reputable investigator", the documents unsealed in 2012, revealed that by February 2000, Pharmacia employees had devised a strategy to present the findings. In the US, celecoxib was covered by three patents, two of which expired on 30 May 2014, and one of which (US RE44048) was due to expire 2 December 2015. On 13 March 2014, that patent was found to be invalid for double patenting. Upon the patent expiry on 30 May 2014, the FDA approved the first versions of generic celecoxib.

On the theory that inflammation plays a role in the pathogenesis of major mental disorders, celecoxib has been trialed for a number of psychiatric disorders, including major depression, bipolar disorder, and schizophrenia.

A meta analysis considering trials of celecoxib as an adjunctive treatment in bipolar disorder was inconclusive citing low evidence quality. Small scale clinical trials in very high risk people (belonging to FAP families) showed celecoxib can prevent polyp growth. Hence, large scale randomized clinical trials were undertaken. Results show a 33 to 45% polyp recurrence reduction in people treated with celecoxib each day. However, serious cardiovascular events were significantly more frequent in the celecoxib treated groups. Aspirin shows a similar (and possibly larger) protective effect, has demonstrated cardioprotective effects and is significantly cheaper, but no head to head clinical trials have compared the two drugs.

Different from cancer prevention, cancer treatment is focused on the therapy of tumors that have already formed and have established themselves inside the patient. Many studies are going on to determine whether celecoxib might be useful for this latter condition. However, during molecular studies in the laboratory, it became apparent that celecoxib could interact with other intracellular components besides its most famous target, COX 2. The discovery of these additional targets has generated much controversy, and the initial assumption that celecoxib reduces tumor growth primarily by the inhibition of COX 2 became contentious. Certainly, the inhibition of COX 2 is paramount for the anti inflammatory and analgesic function of celecoxib. However, whether inhibition of COX 2 also plays a dominant role in this drug's anticancer effects is unclear. For example, a recent study with malignant tumor cells showed celecoxib could inhibit the growth of these cells in vitro, but COX 2 played no role in this outcome; even more strikingly, the anticancer effects of celecoxib were also obtained with the use of cancer cell types that do not even contain COX 2. Karen Seibert and colleagues have published research showing antiangiogenic and antitumor activity of celecoxib in animal models. Additional support for the idea that other targets besides COX 2 are important for celecoxib's anticancer effects has come from studies with chemically modified versions of celecoxib. Several dozen analogs of celecoxib were generated with small alterations in their chemical structures. Some of these analogs retained COX 2 inhibitory activity, whereas many others did not. However, when the ability of all these compounds to kill tumor cells in cell culture was investigated, the antitumor potency did not at all depend on whether or not the respective compound could inhibit COX 2, showing the inhibition of COX 2 was not required for the anticancer effects. One of these compounds, 2,5 dimethyl celecoxib, which entirely lacks the ability to inhibit COX 2, actually displayed stronger anticancer activity than celecoxib.