cyclooxygenase-2 inhibitor

• シクロオキシゲナーゼ-2阻害薬、シクロオキシゲナーゼ2阻害薬、シクロオキシゲナーゼ-2阻害剤、シクロオキシゲナーゼ2阻害剤

関

COX-2 inhibitor、coxib

WordNet

1. limit, block, or decrease the action or function of; "inhibit the action of the enzyme"; "inhibit the rate of a chemical reaction"
2. control and refrain from showing; of emotions, desires, impulses, or behavior (同)bottle up, suppress
3. limit the range or extent of; "Contact between the young was inhibited by strict social customs"
4. a substance that retards or stops an activity
5. either of two related enzymes that control the production of prostaglandins and are blocked by aspirin (同)Cox

PrepTutorEJDIC

1. 〈感情・欲望・行動・作用など〉‘を'抑制する / (…しないように)〈人〉‘を'抑制する,妨げる《+『名』+『from』+『名』(do『ing』)》
2. 抑制する人(物) / 化学反応抑制剤

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/24 03:12:55」(JST)

wiki en

[Wiki en表示]

COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug (NSAID) that directly targets cyclooxygenase-2, 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 drug class. 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 (commonly known as Vioxx) was taken off the market in 2004 because of these concerns and celecoxib and traditional NSAIDs received boxed warnings on their labels.

Medical uses

Some COX-2 inhibitors are used in a single dose to treat pain after surgery.

Etoricoxib appears as good as if not better than other pain medications. Celecoxib appears to be about as useful as ibuprofen.

NSAIDs are often used in treatment of acute gout attacks. COX-2 inhibitors appear to work as well as nonselective NSAIDS and may have fewer side effects. They have not been compared to other treatment options such as colchicine or glucocorticoids.

Adverse effects

Analysis of clinical trial data revealed that there was a significant increase in the rate of vascular events with COX-2 inhibitors compared with placebo; "vascular events" are non-fatal myocardial infarction (MI) or heart attack, non-fatal stroke, and death from a vascular event such as MI or stroke. 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. Traditional NSAIDs were also found to have cardiovascular risks, leading to similar boxed warnings.

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

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 polyposis (FAP) [1]. COX-2 inhibitors are currently being studied in breast cancer and appear to be beneficial.

Neuropsychiatric disorders

COX-2 inhibitors have been found to be effective in suppressing inflammatory neurodegenerative pathways in mental illness, with beneficial results in trials for major depressive disorder as well as schizophrenia.

Other targets

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. 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 analogs of celecoxib were generated with small alterations in their chemical structures. 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.

Research

Research history

For more details on this topic, see Discovery and development of cyclooxygenase 2 inhibitors.

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

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 Dr. Simmons work. A settlement was reached in April 2012 in which Pfizer agreed to pay $450 million. The other litigation is based on United States Pat. No. 6,048,850 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.

In the course of the search for a specific inhibitor of the negative effects of prostaglandins 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 inhibit COX-2 and COX-1 enzymes, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam (Mobic). Aspirin is ≈170-fold more potent in inhibiting COX-1 than COX-2. 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.

Many COX-2-specific inhibitors have been removed from the U.S. market. As of December 2011, only Celebrex (generic name is celecoxib) is still available for purchase.

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. Also, Tribulus terrestris was shown to have strong inhibitory activity on COX-2.

Research fraud

Between 1996 and 2009, anesthesiologist Scott Reuben conducted clinical research on the use of COX-2 inhibitors, often in combination with gabapentin or pregabalin, for the prevention and treatment of post-surgical pain, research which was found in 2009 to have been faked. Reuben pled guilty, paid fines and served six months in jail, and lost his medical license. A 2009 review of meta-articles used in evidence-based medicine found that while some reviews were no longer valid when the Reuben studies were removed, the conclusions in the majority of them remained unchanged. 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."

Early COX-2-inhibiting drugs

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.

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.

Neuroblastomas

Small tumors of the sympathetic nervous system (neuroblastoma) appear to 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 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 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.

References

Further reading

• Green GA (2001). "Understanding NSAIDs: from aspirin to COX-2". Clinical Cornerstone 3 (5): 50–60. doi:10.1016/S1098-3597(01)90069-9. PMID 11464731. 
• Malhotra S, Shafiq N, Pandhi P (2004). "COX-2 inhibitors: a CLASS act or Just VIGORously promoted". MedGenMed 6 (1): 6. PMC 1140734. PMID 15208519. 
• Montero Fernández MJ, Rodríguez Alcalá FJ, Valles Fernández N, López de Castro F, Esteban Tudela M, Cordero García B (Oct 2002). "[At what care level are cyclo-oxygenase-2 inhibitors prescribed?]". Atencion Primaria / Sociedad Española De Medicina De Familia Y Comunitaria (in Spanish) 30 (6): 363–7. doi:10.1016/s0212-6567(02)79048-3. PMID 12396942. 
• Francesca Lunzer Kritz (September 4, 2001). "You and A: Arthritis drugs. Pain and confusion". Washington Post. p. 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-2 selective NSAIDs come to fruition?". Drugs & Therapy Perspectives 17 (11): 6–10. 2001. doi:10.2165/00042310-200117110-00002. 
• Chancellor JV, Hunsche E, de Cruz E, Sarasin FP (2001). "Economic evaluation of celecoxib, a new cyclo-oxygenase 2 specific inhibitor, in Switzerland". PharmacoEconomics. 19 Suppl 1: 59–75. doi:10.2165/00019053-200119001-00005. PMID 11280106. 
• Kamath CC, Kremers HM, Vanness DJ, O'Fallon WM, Cabanela RL, Gabriel SE (2003). "The cost-effectiveness of acetaminophen, NSAIDs, and selective COX-2 inhibitors in the treatment of symptomatic knee osteoarthritis". Value in Health 6 (2): 144–57. doi:10.1046/j.1524-4733.2003.00215.x. PMID 12641865. 
• "Osteoarthritis drug Celebrex (celecoxib) less likely to cause increased blood pressure than Vioxx (rofecoxib)"; European League Against Rheumatism (EULAR) conference proceedings.
• Johnsen JI, Lindskog M, Ponthan F, Pettersen I, Elfman L, Orrego A, Sveinbjörnsson B, Kogner P (Oct 2004). "Cyclooxygenase-2 is expressed in neuroblastoma, and nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit tumor growth in vivo". Cancer Research 64 (20): 7210–5. doi:10.1158/0008-5472.CAN-04-1795. PMID 15492235. 
• Dai C, Stafford RS, Alexander GC (Jan 2005). "National trends in cyclooxygenase-2 inhibitor use since market release: nonselective diffusion of a selectively cost-effective innovation". Archives of Internal Medicine 165 (2): 171–7. doi:10.1001/archinte.165.2.171. PMID 15668363. 
• Solomon DH, Avorn J (Jan 2005). "Coxibs, science, and the public trust". Archives of Internal Medicine 165 (2): 158–60. doi:10.1001/archinte.165.2.158. PMID 15668360. 

UpToDate Contents

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• 1. COX-2選択的阻害剤の概要 overview of selective cox 2 inhibitors
• 2. COX-2選択的阻害剤：有害な心血管系への影響 cox 2 selective inhibitors adverse cardiovascular effects
• 3. COX-2阻害剤および胃十二指腸障害：大規模臨床試験 cox 2 inhibitors and gastroduodenal toxicity major clinical trials
• 4. 非ステロイド性抗炎症剤（NSAIDs）（アスピリンを含む）：胃十二指腸障害の一次予防 nsaids including aspirin primary prevention of gastroduodenal toxicity
• 5. 血管新生阻害剤の概要 overview of angiogenesis inhibitors

English Journal

• Efficient synthesis of apricoxib, CS-706, a selective cyclooxygenase-2 inhibitor, and evaluation of inhibition of prostaglandin E2 production in inflammatory breast cancer cells.

• Mandal PK, Freiter EM, Bagsby AL, Robertson FM, McMurray JS.SourceDepartment of Experimental Therapeutics, M.D. Anderson Cancer Center, 1862 East Road, Houston, TX 77054-3005, USA.
• Bioorganic & medicinal chemistry letters.Bioorg Med Chem Lett.2011 Oct 15;21(20):6071-3. Epub 2011 Aug 19.
• An efficient synthesis of apricoxib (CS-706), a selective cyclooxygenase inhibitor, was developed using copper catalyzed homoallylic ketone formation from methyl 4-ethoxybenzoate followed by ozonolysis to an aldehyde, and condensation with sulfanilamide. This method provided multi-gram access of apr
• PMID 21903394

• Endothelium-dependent vasoconstriction in isolated vessel grafts: a novel mechanism of vasospasm?

• Hoenicka M, Keyser A, Rupprecht L, Puehler T, Hirt S, Schmid C.SourceDepartment of Cardiothoracic Surgery, University of Regensburg Medical Center, Regensburg, Germany.
• The Annals of thoracic surgery.Ann Thorac Surg.2011 Oct;92(4):1299-306.
• BACKGROUND: YC-1 (3-(5'-hydroxymethyl-2'furyl)-1-benzyl-indazole) is an allosteric activator of soluble guanylyl cyclase (sGC) and a vasodilator. This study describes a paradoxical action of YC-1 in isolated vessels of patients with coronary artery disease (CAD) that appears to trigger an endotheliu
• PMID 21958775

Japanese Journal

• Prostaglandin E2 signaling and bacterial infection recruit tumor-promoting macrophages to mouse gastric tumors

• Oshima Hiroko,Hioki Kyoji,Popivanova Boryana K.,Oguma Keisuke,Rooijen Nico van,Ishikawa Tomoo,Oshima Masanobu
• Gastroenterology 140(2), 596-607, 2011-02
• … Induction of cyclooxygenase-2 (COX-2) results in production of prostaglandin E2 (PGE2), which mediates inflammation. … We investigated the roles of bacterial infection and PGE2 signaling in gastric tumorigenesis in mice. … Methods We generated a germfree (GF) colony of K19-Wnt1/C2mE mice (Gan mice); …
• NAID 120002829318

• COX-2選択的阻害薬によるNSAID起因性小腸粘膜傷害の治療・予防 (特集 小腸疾患の診断と治療の進歩)

• 井上 隆弘,飯島 英樹,白石 衣里 [他]
• 消化器内科 53(1), 29-34, 2011-07
• NAID 40018961538

Related Links

• COX-2 inhibitor - Wikipedia, the free encyclopedia

For more details on this topic, see Discovery and development of cyclooxygenase 2 inhibitors. The mouse COX-2 gene was cloned by UCLA scientist Dr. Harvey Herschman. The enzyme was discovered in 1988 by Daniel Simmons, ...

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★リンクテーブル★

リンク元	「シクロオキシゲナーゼ-2阻害薬」「シクロオキシゲナーゼ-2阻害剤」「シクロオキシゲナーゼ2阻害薬」「シクロオキシゲナーゼ2阻害剤」「COX-2 inhibitor」
関連記事	「inhibit」「inhibitor」「cyclooxygenase」

「シクロオキシゲナーゼ-2阻害薬」

　　[★]

英

cyclooxygenase-2 inhibitor、COX-2 inhibitor

関

シクロオキシゲナーゼ2阻害薬、コキシブ、シクロオキシゲナーゼ2阻害剤、シクロオキシゲナーゼ-2阻害剤

「シクロオキシゲナーゼ-2阻害剤」

　　[★]

英

cyclooxygenase-2 inhibitor、COX-2 inhibitor

関

シクロオキシゲナーゼ2阻害薬、シクロオキシゲナーゼ2阻害剤、シクロオキシゲナーゼ-2阻害薬

「シクロオキシゲナーゼ2阻害薬」

　　[★]

英

cyclooxygenase-2 inhibitor

関

コキシブ、シクロオキシゲナーゼ2阻害剤、シクロオキシゲナーゼ-2阻害剤、シクロオキシゲナーゼ-2阻害薬

「シクロオキシゲナーゼ2阻害剤」

　　[★]

英

cyclooxygenase-2 inhibitor

関

シクロオキシゲナーゼ2阻害薬、シクロオキシゲナーゼ-2阻害剤、シクロオキシゲナーゼ-2阻害薬

「COX-2 inhibitor」

　　[★]

• シクロオキシゲナーゼ-2阻害薬、シクロオキシゲナーゼ-2阻害剤

関

coxib、cyclooxygenase-2 inhibitor

「inhibit」

　　[★]

• v.

• 抑制する、阻害する、阻止する

関

abrogate、block、depress、depression、deter、inhibition、interdict、prevent、prevention、repress、repression、restrain、restraint、suppress、suppression

　 　 　 　

「inhibitor」

　　[★]

• n.

• 阻害剤、阻害薬、抑制薬、抑制剤、(内在性物質について)インヒビター、抑制物質

関

blocker、depressant、suppressant

　 　

「cyclooxygenase」

　　[★] シクロオキシゲナーゼ