The Role of Cyclooxygenase in Gastric Mucosal Protection

Gudis, Katya; Sakamoto, Choitsu

doi:10.1007/s10620-005-2802-7

Cited by 79 publications

(61 citation statements)

References 55 publications

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“…Although more highly variable, COX-2 protein was found in nearly all tissues and was most often localized to parenchymal cells (13). Constitutive COX-2 expression is well recognized in brain, kidney, and the female reproductive tract, and evidence for induction of COX-1 during the lipopolysaccharide (LPS)-mediated inflammatory response and cellular differentiation has been reported (14)(15)(16)(17)(18). Although these data generally support the COX-2 hypothesis, they also show that expression of neither enzyme fully fits the paradigm.…”

Section: Differential Expression Of Cox-1 and Cox-2mentioning

confidence: 99%

Cyclooxygenases: structural and functional insights

Rouzer

Marnett

2009

Journal of Lipid Research

562

471

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Cyclooxygenase (COX; prostaglandin G/H synthase, EC 1.14.99.1) catalyzes the first two steps in the biosynthesis of prostaglandins (PGs). The two COX isoforms COX-1 and COX-2 are the targets of the widely used nonsteroidal anti-inflammatory drugs, indicating a role for these enzymes in pain, fever, inflammation, and tumorigenesis. The ubiquitous constitutive expression of COX-1 and inducible expression of COX-2 have led to the widely held belief that COX-1 produces homeostatic PGs, while PGs produced by COX-2 are primarily pathophysiological. However, recent discoveries call this paradigm into question and reveal as yet underappreciated functions for both enzymes. This review focuses on some of these new insights.-Rouzer, C. A., and L. J. Marnett. Cyclooxygenases: structural and functional insights. J. Lipid Res. 2009. 50: S29-S34. Supplementary key words prostaglandinThe cyclooxygenase isoforms (COX-1 and COX-2) are among the most thoroughly studied and best understood mammalian oxygenases. Possessing two separate but linked active sites, the COXs catalyze the bis-dioxygenation and subsequent reduction of arachidonic acid (AA) to prostaglandin (PG)G 2 and PGH 2 (Fig. 1A). The mechanism of oxygenation has been well characterized through kinetics, mutagenesis, and X-ray crystallography (1-3). PGH 2 is subject to metabolism by downstream enzymes yielding the family of PGs, each member of which exerts a range of physiologic effects through specific G-protein-coupled receptors (Fig. 1B) (4, 5). The discovery that the COXs are the target of the nonsteroidal anti-inflammatory drugs (NSAIDs), which play a primary therapeutic role in the treatment of pain, fever, and inflammation (6), promulgated the first wave of experimentation on the constitutively expressed COX-1 during the 1970s and 1980s. Then, just as interest began to wane, the discovery of the inducible isoform, COX-2, rekindled a massive new effort that ultimately led to new insights about both isoforms. A search of PubMed over the past 2 years indicates that there have been over 70 review articles containing "cyclooxygenase" in their title, leading one to question the need for yet another. However, despite the overwhelming mass of data available on these enzymes, recent discoveries suggest that some original assumptions concerning their roles in physiology and pathophysiology require reexamination. This review will emphasize these issues. STRUCTURE OF THE COX ENZYMESHuman COX-1 and COX-2 are homodimers of 576 and 581 amino acids, respectively. Both enzymes contain three high mannose oligosaccharides, one of which facilitates protein folding. A fourth oligosaccharide, present only in COX-2, regulates its degradation. Considering the 60% identity in sequence between COX-1 and COX-2, it is not surprising that their three-dimensional structures are nearly superimposable. Each subunit of the dimer consists of three domains, the epidermal growth factor domain (residues 34-72), the membrane binding domain (residues 73-116), and the catalytic domain comprisi...

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Section: Differential Expression Of Cox-1 and Cox-2mentioning

confidence: 99%

Cyclooxygenases: structural and functional insights

Rouzer

Marnett

2009

Journal of Lipid Research

562

471

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“…Nonselective NSAIDs such as ketoprofen reduce pain and inflammation by inhibiting the cyclooxygenase (COX) enzyme (3). The COX enzyme exists in two distinct isoforms: COX-1, the primary site of action for nsNSAIDs, is present in many tissues and is necessary for physiological (homeostatic) functions such as gastric mucosal protection and normal platelet aggregation (4,5); COX-2 is an inducible form of the COX enzyme and is expressed locally in inflamed tissues (6,7). Although nsNSAIDs have been shown to be effective for acute and chronic pain relief, a number of adverse events (AEs) have been associated with their use.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of parecoxib in the treatment of acute renal colic: a randomized clinical trial

Glina¹,

Damião²,

Afif-Abdo³

et al. 2011

Int. braz j urol.

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Purpose: Although nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs) and opioids are effective treatments for acute renal colic, they are associated with adverse events (AEs). As cyclooxygenase-2 selective NSAIDs may provide a safer alternative, we compared the efficacy and safety of parecoxib versus an nsNSAID in subjects with acute renal colic. Materials and Methods: Phase i.v., multicenter, double-blind, noninferiority, active-controlled study: 338 subjects with acute renal colic were randomized to parecoxib 40 mg i.v. plus placebo (n = 174) or ketoprofen 100 mg i.v. plus placebo (n = 164). 338 subjects with acute renal colic were randomized to parecoxib 40 mg i.v. (n = 174) or ketoprofen 100 mg i.v. (n = 164) plus placebo. Subjects were evaluated 15, 30, 45, 60, 90 and 120 minutes after treatment start and 24 hours after discharge. Primary endpoint was the mean pain intensity difference (PID) at 30 minutes by visual analog scale (VAS) (per-protocol population). An ANCOVA model was used with treatment group, country, and baseline score as covariates. Noninferiority of parecoxib to ketoprofen was declared if the lower bound of the 95% confidence interval (CI) for the difference between the two groups excluded the pre-established margin of 10 mm for the primary endpoint. Results: Baseline demographics were similar. The mean (SD) mPID30 min was 33.84 (24.61) and 35.16 (26.01) for parecoxib and ketoprofen, respectively. For treatment difference (parecoxib-ketoprofen) the lower bound of the 95% CI was 6.53. The mean change from baseline in VAS 30 minutes after study medication was ~43 mm; AEs were comparable between treatments.Conclusions: Parecoxib is as effective as ketoprofen in the treatment of pain due to acute renal colic, is well tolerated and has a comparable safety profile.

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“…The arrows indicate the location of the bleeding. The area (mm enzyme and COX-2 enzyme 18,19) in the stomach. Aspirin prevents thromboxane A 2 (TXA 2 ) synthesis in platelets 20) and prostacyclin (PGI 2 ) in endothelial cells by the inhibition of COX-1 21) at different concentrations.…”

Section: Fig 4 Effect Of Combination Of Low-dose Aspirin and Paroxementioning

confidence: 99%

The Coadministration of Paroxetine and Low-Dose Aspirin Synergistically Enhances Gastric Ulcerogenic Risk in Rats

Yamaguchi

Hidaka

Suemaru

et al. 2008

Biological & Pharmaceutical Bulletin

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Cerebral infarction (CI) is one of the highly mortal diseases. It has been reported that the use of an anti-platelet drug for the treatment of CI significantly decreased the patient's risk of a future stroke by 23%.1) Low-dose aspirin, the most frequently used anti-platelet drug in Japan, could reduce the risk of future strokes with dose range in the 50 to 200 mg per day range. 2,3) On the other hand, depression is the major co-morbid disorders in CI sequelae. Selective serotonin reuptake inhibitors (SSRI) are the major antidepressants used to treat depression. Therefore, it is likely to coadminister low-dose aspirin and SSRIs in order to prevent future strokes and to treat depression. Only a few clinical studies have examined the risk associated with the coadministration of low-dose aspirin and SSRIs, 4,5) even though both drugs have similar adverse effects on gastric mucosa. [6][7][8] Former 2 studies indicated that the coadministration of lowdose aspirin and SSRIs increased the risk of abnormal bleeding in stomach, which is closely related to gastric ulcers. In the present study, we investigated the ulcerogenic effect induced by the coadministration of low-dose aspirin and paroxetine, major one of the SSRIs in rats. MATERIALS AND METHODS AnimalsMale Wistar rats (200-250 g) were used. Animals were fed on diet with free access to water under standard humidity and temperature. Animals were fasted for 24 h before ulcerogenic experiments.Drugs Paroxetine hydrochroride (GlaxoSmithKline), low-dose aspirin (Merck), indomethacin (Sigma Chemicals, St. Louis, MO, U.S.A.) and serotonin (Nacalai, Japan) were used. We used Paxil ® tablets as paroxetine hydrochroride. Paxil ® tablets contain calcium hydrogen phosphate, sodium carboxymethylstarch, magnesium stearate, hydroxypropyl methylcellulose 2910, macrogol 400, iron and sesquioxide, polysorbate 80, titanium dioxide. However, these ingredients were not enough to express their actions. A dose of 50 mg/kg of aspirin was selected as low-dose aspirin.9) Low-dose aspirin was suspended and paroxetine and indomethacin were dissolved in the distillated water, and we administrated them (2 ml/kg) orally, and serotonin was subcutaneously administered at 1, 5 or 10 ml/kg. Distillated water (2 ml/kg) or saline (5 ml/kg) were orally or subcutaneously administered to the control animals.Determination of Gastric Acid Secretion In order to measure the gastric acid secretion, a pylorus-ligation method was used. A pylorus ligature was performed 30 min after orally or subcutaneously administration of the drugs. Paroxetine (1, 3 or 10 mg/kg) or serotonin (1, 5 or 10 mg/kg) was selected as proper doses from many published papers. Animals were sacrificed 2 h after pylorus ligature by cervical dislocation, the abdomen was opened and oesophagus was held by clamp. The stomach was removed, and was inspected external apparence. Its content was drained into a centrifuge tube and centrifuged at 3000 rpm for 5 min. The supernatant volume was measured with micropipette and pH was recorded with a digita...

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The Role of Cyclooxygenase in Gastric Mucosal Protection

Cited by 79 publications

References 55 publications

Cyclooxygenases: structural and functional insights

Cyclooxygenases: structural and functional insights

Efficacy and safety of parecoxib in the treatment of acute renal colic: a randomized clinical trial

The Coadministration of Paroxetine and Low-Dose Aspirin Synergistically Enhances Gastric Ulcerogenic Risk in Rats

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