Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-steroidal anti-inflammatory drugs (NSAID) target the enzyme cyclooxygenase (COX) thus affording relieve from pain, inflammation or fever. As COX-dependently formed prostanoids not only mediate signals involved in inflammation and pain, but also regulate important physiological cardiovascular functions, some NSAID have recently been reported to be associated with arterial thrombosis or hypertension. This is in contrast to the well-known antiplatelet effects of low-dose aspirin, but in coherence with the specific effects of some NSAID on prostanoid formation in the vasculature. A correlation between the intake of selective inhibitors of the cyclooxygenase 2 (COX-2) isoform and atherothrombotic events has recently been established. Large retrospective analyses of clinical data have repeatedly shown this effect and in some cases have also observed potential hazards for other, rather non-selective NSAID. This review evaluates potential prothrombotic effects of NSAID in vascular ischemic disease in comparison to low-dose aspirin and selective COX-2 inhibitors and discusses pathophysiological backgrounds for such observations.
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PMID:Prothrombotic potential of NSAID in ischemic heart disease. 1716 11

Cyclooxygenase plays a pivotal role in the transformation of the arachidonic acid to prostaglandins (PGs) and thromboxane. It is composed of two kinds of enzymes, namely cyclooxygenase 1 (COX-1) and cyclooxygenase 2 (COX-2). Cyclooxygenase 1 is the constructive enzyme whereas the cyclooxygenase 2 is the inducible enzyme. Inhibiting cyclooxygenase 1 is always associated with some undesirable side-effects, while inhibiting cyclooxygenase 2 can result in therapeutic effect. This has led the researchers to strive for searching the selective inhibitors inhibiting the COX-2 instead of COX-1. It is very well known that pain and inflammation are alleviated through the inhibition of COX-2 inhibitors such as Aspirin, which has resulted in the recent years, in the emergence of a range of COX-2 inhibitors. Moreover, while evaluating the functions of the COX-2 inhibitions, their significant role in treating glaucoma, preventing and suppressing cancer through their inhibitory activity was clearly revealed and many studies further demonstrated that COX-2 is not only related to the inflammation of peripheral tissues but also to the inflammation manifested in the central nervous system. In addition, the nervous disorders also found an effective treatment with the administration of COX-2 inhibitors. The above-mentioned findings delineate the role of the COX-2 inhibitors as promising agents to be exploited in the treatment of many illnesses. This review will elucidate the functions of the COX-2 inhibitors briefly and introduce some common selective inhibitors of COX-2.
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PMID:The function of the selective inhibitors of cyclooxygenase 2. 1716 13

Bradykinin is an important inflammatory mediator that can either activate and/or sensitise nociceptors to heat stimuli applied to the skin. Several studies have suggested that prostaglandins and thus the cyclooxygenase (cox) enzymes are important in the sensitisation process but little is known about the relative involvement of the two cox isoforms, cox-1 and cox-2. Extracellular recordings were made from C-mechanoheat-sensitive fibres in isolated rat skin-saphenous nerve preparations. Bradykinin-mediated sensitisation of heat responses in these afferents was significantly attenuated by the selective cox-1 inhibitor, SC-560, and by the selective cox-2 inhibitor, NS-398. In the same experiments, bradykinin-mediated induction of ongoing activity was reduced by SC-560 but not NS-398. In a second series of experiments, bradykinin-stimulated synthesis and release of prostaglandin E2 (PGE2) was measured in isolated skin-nerve preparations. Although the basal release of PGE2 appeared unaffected by either drug, bradykinin-stimulated PGE2 release from the skin was inhibited by both SC-560 and NS-398. Immunocytochemical evaluation revealed cox-1 immunostaining was present in large cutaneous nerve branches, small intradermal nerve bundles as well as nerve endings within the skin. Cox-1 labelling was also present in non-neuronal cell types such as mast cells. Cox-2 immunoreactivity was weak but where present was located in small nerve bundles, smaller intradermal nerve bundles and nerve endings. This study shows that both cox isoforms are present in skin and that they have an important role in mediating bradykinin-evoked heat sensitisation of C-MH sensitive fibres through cox-1 and cox-2 dependent prostaglandin synthesis.
Pain 2007 Jul
PMID:Bradykinin-induced nociceptor sensitisation to heat depends on cox-1 and cox-2 in isolated rat skin. 1719 38

Nonsteroidal anti-inflammatory drugs have been associated with hepatotoxicity in susceptible patients. One such example is nimesulide, a preferential cyclooxygenase 2-inhibitor, widely used for the treatment of inflammation and pain. It was suggested that nimesulide could exert its hepatotoxicity by altering hepatic mitochondrial function, which was demonstrated in vitro. The objective of this study was to verify whether liver mitochondria isolated from rats treated with doses of nimesulide well above therapeutic levels possessed decreased calcium tolerance and oxidative phosphorylation, which indicates in vivo nimesulide mitochondrial toxicity. Male and female rats received nimesulide or its vehicle twice daily, for 5 days, and were killed on the seventh day for the isolation of liver mitochondria. Mitochondrial respiration, transmembrane electric potential, and calcium tolerance were characterized in all experimental groups. Nimesulide had no effect on liver mitochondrial function. Indexes of mitochondrial integrity, calcium loading capacity, and oxidative phosphorylation efficiency were unchanged between liver mitochondria from treated and control animals. In the animals tested, no evidence of degraded mitochondrial function due to nimesulide administration could be found. The results corroborate the notion that despite recognized in vitro mitochondrial toxicity, nimesulide does not cause detectable mitochondrial dysfunction in Wistar rats, even when administered in much higher concentrations than those known to have anti-inflammatory effects.
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PMID:Unaltered hepatic oxidative phosphorylation and mitochondrial permeability transition in wistar rats treated with nimesulide: Relevance for nimesulide toxicity characterization. 1799 79

The use of combined oral contraceptives (COCs) is associated with a reduced risk of developing endometriosis, myomas, and endometrial and ovarian carcinoma. The mechanisms involved are multiple; next to ovulation suppression, a reduction in inflammation in the genital tract is involved. This is accomplished through inhibition of the endometrial expression of enzymes related to the biosynthesis of prostaglandin and oestrogen, particularly cyclooxygenase type II (Cox-2) and aromatase. The blockade of these enzymatic systems by COCs explains the beneficial effects of these compounds in treating the symptoms, and halting the progression of myomas, endometriosis and adenomyosis, all of which are characterized by increased inflammation. Inhibition of aromatase and Cox-2 expression in the endometrium by COCs may explain their efficacy in controlling the pain and excessive uterine bleeding caused by these pathologies. The reduction of inflammation in the endometrium may also be the mechanism behind the lower incidence of endometrial carcinoma in COC users. The blockade of ovulation and ovarian steroidogenesis, on the other hand, may explain the lesser incidence of ovarian cancer and the improvement of acne in users. In conclusion, inflammation appears to play a pivotal role in the development of various benign and malignant gynecological diseases. COCs reduce inflammation in the female genital tract by blocking enzymes such as Cox-2 and aromatase.
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PMID:Non-contraceptive health benefits of oral contraceptives. 1796 79

Our objective was to investigate the therapeutic potential of peripheral opioid antagonism with alvimopan and anti-inflammatory cyclooxygenase 2 (COX-2) inhibition in an animal model of postoperative ileus with pain management. Intestinal manipulation was conducted in mice and rats with or without postoperative morphine injection. Rodents were orally fed non-digestible fluorescein (FITC)-labelled dextran and transit measured after a period of 90 min. The immunomodulatory effects of morphine and alvimopan were determined on nitric oxide released from the organ cultured muscularis externa. Surgical manipulation of the intestine resulted in a delay in gastrointestinal transit after 24 h that worsened with exogenous morphine. Alvimopan did not significantly alter transit of control or manipulated animals, but significantly antagonized the transit delaying effects of morphine. However, when the inflammatory component was robust enough to obscure a further opioid induced delay in gastrointestinal transit, alvimopan ceased to be effective in improving postoperative intestinal function. Cyclooxygenase 2 inhibition significantly diminished the inflammatory component of postoperative ileus. Surgical manipulation resulted in an increased release of nitric oxide from the inflamed isolated muscularis externa in 24-h organ culture which was not altered by morphine or alvimopan. Two distinct mechanisms exist which participate in postoperative bowel dysfunction: a local inflammatory response which is antagonized by COX-2 inhibition, and a morphine-induced alteration in neural function which can be blocked with alvimopan.
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PMID:Alvimopan and COX-2 inhibition reverse opioid and inflammatory components of postoperative ileus. 1826 13

Previous evidence has implicated E prostanoid receptor 4 (EP4) in mechanical hyperalgesia induced by subplantar inflammation. However, its role in chronic arthritis remains to be further defined because previous attempts have generated two conflicting lines of evidence, with one showing a marked reduction of arthritis induced by a collagen antibody in mice lacking EP4, but not EP1-EP3, and the other showing no impact of EP4 antagonism on arthritis induced by collagen. Here, we assessed the effect of a novel and selective EP4 antagonist MF498 [N-{[4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide] on inflammation in adjuvant-induced arthritis (AIA), a rat model for rheumatoid arthritis (RA), and joint pain in a guinea pig model of iodoacetate-induced osteoarthritis (OA). In the AIA model, MF498, but not the antagonist for EP1, MF266-1 [1-(5-{3-[2-(benzyloxy)-5-chlorophenyl]-2-thienyl}pyridin-3-yl)-2,2,2-trifluoroethane-1,1-diol] or EP3 MF266-3 [(2E)-N-[(5-bromo-2-methoxyphenyl)sulfonyl]-3-[5-chloro-2-(2-naphthylmethyl)phenyl]acrylamide], inhibited inflammation, with a similar efficacy as a selective cyclooxygenase 2 (COX-2) inhibitor MF-tricyclic. In addition, MF498 was as effective as an nonsteroidal anti-inflammatory drug, diclofenac, or a selective microsomal prostaglandin E synthase-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro[9,10-d]imidazol-2-yl)isophthalonitrile], in relieving OA-like pain in guinea pigs. When tested in rat models of gastrointestinal toxicity, the EP4 antagonist was well tolerated, causing no mucosal leakage or erosions. Lastly, we evaluated the renal effect of MF498 in a furosemide-induced diuresis model and demonstrated that the compound displayed a similar renal effect as MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone], reducing furosemide-induced natriuresis by approximately 50%. These results not only suggest that EP4 is the major EP receptor in both RA and OA but also provide a proof of principle to the concept that antagonism of EP4 may be useful for treatment of arthritis.
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PMID:MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a selective E prostanoid receptor 4 antagonist, relieves joint inflammation and pain in rodent models of rheumatoid and osteoarthritis. 1828 10

Prostaglandins (PGs), particularly PGE2 and prostacyclin (PGI2), are potent mediators of pain and inflammation. Both atherosclerosis and aortic aneurysm exhibit the hallmarks of inflammation. However, randomized trials of inhibitors of PG synthesis--nonsteroidal anti-inflammatory drugs--reveal that they predispose to cardiovascular risk. This appears to be consequent to inhibition of PGI2 and PGE2 formed by cyclooxygenase-2 (COX-2). Inhibitors of microsomal PGE synthase-1 (mPGES-1) are being developed for relief of pain and interest has focused on their potential impact on the cardiovascular system. Deletion of mPGES-1 retards atherogenesis and limits aortic aneurysm formation in hyperlipidaemic mice. However, it does not predispose to thrombogenesis and has a limited impact on blood pressure compared to inhibition of COX-2. This occurs despite the potential of the suppressed PGE2 in affording cardioprotection via its EP2 and EP4 receptors. However, deletion of mPGES-1 permits rediversion of the PGH2 substrate to other PG synthases and augmented formation of PGI2 and PGD2 mitigates this effect. However, increased PGI2 may also attenuate relief of pain. Pain relief seems likely to be a nuanced indication for mPGES-1 inhibitors, but they have therapeutic potential in syndromes of cardiovascular inflammation, cancer and perhaps in neurodegenerative disease. However, as the products of substrate rediversion vary according to cell type, these drugs may have contrasting impact amongst individuals at varied stages of disease evolution.
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PMID:Microsomal prostaglandin E synthase-1 inhibition in cardiovascular inflammatory disease. 1841 May 93

Etoricoxib is a cyclooxygenase 2 (COX-2) inhibitor that selectively inhibits the COX-2 enzyme and decreases the incidences of side effects associated with these agents. It is commonly prescribed for acute pain, gouty arthritis, and rheumatoid arthritis. Conventional tablets of etoricoxib are not capable of rapid action, which is required for faster drug effect onset and immediate relief from pain. Thus, the aim of the present investigation is to formulate orally disintegrating tablets (ODTs) of etoricoxib. A combination of the superdisintegrants with a sublimation technique was used to prepare the tablets. Tablets were prepared using a direct compression method employing superdisintegrants such as low substituted hydroxylpropyl methyl cellulose (L-HPMC), low substituted hydroxyl-propyl cellulose (L-HPC), crospovidone, croscarmellose sodium, and sodium starch glycolate. Tablets of etoricoxib prepared using L-HPC exhibited the least friability and disintegration time (approximately 65 s). To decrease the disintegration time further, a sublimation technique was used along with the superdisintegrants for the preparation of ODTs. The use of sublimating agents including camphor, menthol, and thymol was explored. The addition of camphor lowered the disintegration time (approximately 30 s) further, but the percent friability was increased. A 3(2) full factorial design was employed to study the joint influence of the amount of superdisintegrant (L-HPC) and the amount of sublimating agent (camphor) on the percent of friability and the disintegration time. The results of multiple linear regression analysis revealed that for obtaining an effective ODT of etoricoxib, higher percentages of L-HPC and camphor should be used. Checkpoint batches were prepared to validate the evolved mathematical model. A response surface plot is also presented to graphically represent the effect of the independent variables on the percent of friability and the disintegration time. The approach using the optimization technique helped to produce a detailed understanding of the effects of formulation parameters.
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PMID:Design, development, and optimization of orally disintegrating tablets of etoricoxib using vacuum-drying approach. 1866 71

Neuropathic pain (NeP) is a debilitating disease afflicting mostly the aged population. Inflammatory responses in injured nerves play a pivotal role in the pathogenesis of NeP. Injured nerve derived cyclooxygenase 2/prostaglandin E2 (COX2/PGE2) contributes to the genesis of NeP at the early stage in young rats. Here we show that COX2/PGE2 is involved in the maintenance of NeP at a chronic stage in aged rats. Eighteen months after partial sciatic nerve ligation (PSNL), NeP remained prominent in aged rats. COX2 expressing macrophages and PGE2 levels were increased in injured nerves. PGE2 receptors (EP1 and EP4) and pain-related ion channel transient receptor potential vanilloid-1 (TRPV1) were increased in the ipsilateral dorsal root ganglion (DRG) neurons of aged PSNL rats. Perineural injection of a selective COX2 inhibitor NS-398 relieved NeP, reversed PSNL increased expression of EP1, EP4 and TRPV1 and suppressed the levels of pain-related peptide substance P and calcitonin gene-related peptide in DRG neurons. These data suggest that injured nerve-derived PGE2 contributes to the maintenance of NeP at the chronic stage in aged rats. Chronically facilitating the synthesis of pain-related molecules in nociceptive DRG neurons is a novel mechanism underpinning the contribution of PGE2.
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PMID:Injured nerve-derived COX2/PGE2 contributes to the maintenance of neuropathic pain in aged rats. 1878 48


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