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)

Acute cholecystitis is associated with increased gallbladder prostanoid formation and the inflammatory changes and prostanoid increases can be inhibited by nonsteroidal anti-inflammatory agents. Recent information indicates that prostanoids are produced by two cyclooxygenase (COX) enzymes, COX-1 and COX-2. The purpose of this study was to determine the COX enzymatic pathway in gallbladder mucosal cells involved in the production of prostanoids stimulated by inflammatory agents. Human gallbladder mucosal cells were isolated from cholecystectomy specimens and maintained in cell culture and studied in comparison with cells from a well differentiated gallbladder mucosal carcinoma cell line. COX enzymes were evaluated by Western immunoblotting and prostanoids were measured by ELISA. Unstimulated and stimulated cells were exposed to specific COX-1 and COX-2 inhibitors. In both normal and transformed cells constitutive COX-1 was evident and in gallbladder cancer cells lysophosphatidyl choline (LPC) induced the formation of constitutive COX-1 enzyme. While not detected in unstimulated normal mucosal cells and cancer cells, COX-2 protein was induced by both lipopolysaccharide (LPS) and LPC. Unstimulated gallbladder mucosal cells and cancer cells produced prostaglandin E2 (PGE2) and prostacyclin (6-keto prostaglandin F1alpha, 6-keto PGF1alpha) continuously. In freshly isolated normal gallbladder mucosal cells, continuously produced 6 keto PGF1alpha was inhibited by both COX-1 and COX-2 inhibitors while PGE2 levels were not affected. Both LPS and LPC stimulated PGE2 and 6 keto PGF1alpha formation were blocked by COX-2 inhibitors in freshly isolated, normal human gallbladder mucosal cells and in the gallbladder cancer cells. The prostanoid response of gallbladder cells stimulated by proinflammatory agents is inhibited by COX-2 inhibitors suggesting that these agents may be effective in treating the pain and inflammation of gallbladder disease.
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PMID:Synthetic pathways of gallbladder mucosal prostanoids: the role of cyclooxygenase-1 and 2. 1032 26

Prostaglandins are formed from arachidonic acid by the action of cyclooxygenase (COX) and subsequent downstream synthetases. Recently, it has been found that there are two closely related forms of COX, which are now known as COX-1 and COX-2. Although both isoforms of this enzyme convert arachidonate to prostaglandins, there are significant differences in their distribution in the body and their roles in health and disease. The basis for these important differences lies in the genes for COX-1 and COX-2 and the regulation of these genes. COX-1, the predominantly constitutive form of the enzyme, is expressed throughout the body and provides certain homeostatic functions, such as maintaining normal gastric mucosa, influencing renal blood flow, and aiding in blood clotting by abetting platelet aggregation. In contrast, COX-2, the inducible form, is expressed in response to inflammatory and other physiologic stimuli and growth factors and is involved in the production of those prostaglandins that mediate pain and support the inflammatory process. All conventional nonsteroidal anti-inflammatory drugs (NSAIDs) nonspecifically inhibit both COX-1 and COX-2 at standard anti-inflammatory doses. The beneficial anti-inflammatory and analgesic effects occur through the inhibition of COX-2, but the gastrointestinal toxicities and the mild bleeding diathesis occur as a result of concurrent inhibition of COX-1. It is important that physicians fully understand the pharmacologic basis for the differential actions of NSAIDs when prescribing them for pain and inflammation. This understanding is also important so that physicians can critically evaluate the basis for, and the emerging data on, COX-2-specific inhibitors and their potential role in clinical medicine. Agents that would inhibit COX-2 while sparing COX-1 represent an attractive therapeutic development and could represent a major advance in the treatment of rheumatoid arthritis and osteoarthritis, as well as a diverse array of other conditions.
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PMID:Role and regulation of cyclooxygenase-2 during inflammation. 1039 Jan 26

Several currently available nonsteroidal anti-inflammatory drugs (NSAIDs) have been evaluated for their relative selectivity in inhibiting the two cyclooxygenase (COX) isozymes, COX-1 and COX-2. Arguments have been made that more selective inhibitors of COX-2 will be safer than less selective ones. Rankings of the COX-2/COX-1 inhibition ratios of various NSAIDs as they relate to the agents' toxicities have been used as evidence that COX-2 selectivity is an important factor in the upper gastrointestinal (GI) safety of some NSAIDs. Unfortunately, none of these claims has been supported by endoscopy studies in treated patients. Since all NSAIDs inhibit COX-1, they all cause upper GI mucosal damage. What is needed are specific COX-2 inhibitors that do not inhibit COX-1. Such agents are currently under development. Ongoing clinical trials will determine the potential role for specific COX-2 inhibitors in the treatment of arthritis and pain. If specific COX-2 inhibitors are shown to be both safe and effective, the treatment of rheumatic diseases will be revolutionized.
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PMID:COX-2: separating myth from reality. 1042 43

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective for the relief of pain and inflammation, yet their use is tempered by the development of side effects, primarily in the gastrointestinal (GI) tract. It is now known that inhibition of the enzyme cyclooxygenase (COX) is the principal mechanism for both the efficacy and the toxicity of NSAIDs. Recent research has shown that COX exists as at least two isoenzymes, COX-1 and COX-2. Compelling evidence suggests that COX-1 synthesizes prostaglandins that are involved in the regulation of normal cell activity (including GI cytoprotection), whereas COX-2 appears to produce prostaglandins mainly at sites of inflammation. These findings led to the search for compounds that would inhibit COX-2 without affecting COX-1. Several agents are under investigation in this new therapeutic category, including celecoxib (SC-58635). Celecoxib was developed as an anti-inflammatory and analgesic agent, and has been studied in preclinical studies and in clinical trials. This paper focuses on the results of five key clinical trials of celecoxib: an efficacy trial in dental pain, a 2-week osteoarthritis (OA) efficacy trial, a 4-week rheumatoid arthritis (RA) efficacy trial, a 1-week endoscopic study of GI mucosal effects, and a 10-day study of effects on platelet function. The arthritis trials identified celecoxib doses that were effective in treating OA and RA and that were distinguished from placebo on standard arthritis scales. In the upper GI endoscopy study, no ulcers occurred in subjects receiving celecoxib or placebo, whereas 19% of subjects receiving naproxen developed gastric ulcers. In the platelet effects trial, no statistically significant difference from placebo was seen in the effect of celecoxib on platelet aggregation or bleeding time. In contrast, naproxen caused statistically significant reductions in platelet aggregation and a statistically significant increase in bleeding time. These preliminary trials show that celecoxib achieves analgesic and anti-inflammatory efficacy in arthritis through specific COX-2 inhibition without showing evidence of two of the toxic effects of COX-1 inhibition associated with NSAIDs.
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PMID:Update on clinical developments with celecoxib, a new specific COX-2 inhibitor: what can we expect? 1042 44

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of agents with similar action but diverse chemical structures and mechanism of action. There is considerable interpatient variability in the pain relief obtained from NSAIDs even when these agents belong to the same chemical family. The reasons for this interpatient variability include pharmacodynamic actions, pharmacokinetic parameters, or a combination of both. Furthermore, two distinct forms of the key enzyme cyclo-oxygenase (COX) have been identified. The constitutive enzyme COX-1 is found in most tissues and is believed to confer gastric mucosal protective action, and COX-2, the inducible enzyme, is implicated in pain and inflammation. Selective inhibition of COX-1 and COX-2 may allow prediction of drugs' major effects. By definition, NSAIDs are expected to modulate synovial inflammation present in the arthritic joints. Whether NSAIDs can positively influence the progression of arthritic disorders by modifying the underlying pathology remains to be answered. This review provides guidelines on how to choose NSAIDs rationally keeping in view the mechanism of tissue injury, the mode of action of NSAIDs, and their adverse effects.
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PMID:Nonsteroidal anti-inflammatory drugs in the management of pain and inflammation: a basis for drug selection. 1042 41

The use of non steroidal anti-inflammatory drugs as analgesic or anti-inflammatory agents is primarily limited by their toxicity to the gastrointestinal tract. Two strategies have been developed recently in order to improve the safety of these drugs. The first approach is the linking of a nitric oxide-releasing moiety to the available compounds. The rationale is that nitric oxide may prevent non steroidal anti-inflammatory drugs-induced ulcerations by preventing mucosal ischemia. The second approach is based on the discovery of two isoforms (COX-1 and COX-2) of the cyclo-oxygenase enzyme. It was hypothesized that the constitutively expressed COX-1 isoenzyme leads to the synthesis of prostaglandins with homeostatic functions whereas COX-2 is merely responsible for the production of prostaglandins mediating pain, fever and inflammation. Accordingly, selective COX-2 inhibitors have been developed. Clinical trials indicate that these compounds are roughly as effective as the available non steroidal anti-inflammatory agents without causing acute gastrointestinal damage. There is some evidence that both COX-1 and COX-2 isoforms are involved in the production of prostaglandins associated with inflammation and homeostatic functions. Finally, the true benefit/risk ratio of these new non steroidal anti-inflammatory drugs remains to be assessed.
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PMID:[New nonsteroidal anti-inflammatory agents: nitric oxide donors and selective cyclooxygenase-2 inhibitors]. 1048 Jan 84

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs, despite their well-established association with gastroduodenal injury. Recent discovery of the cyclooxygenase (COX) isoenzymes COX-1 and COX-2 has improved our knowledge of the action of NSAIDs. COX-1 is continuously expressed in almost all tissues, where it converts arachidonate to the prostaglandins (PGs) important in homeostatic function; COX-2 is present in immune cells, blood vessel endothelial cells, and synovial fibroblasts. Classic NSAIDs inhibit both COX isoenzymes by occupying the cyclooxygenase-active site, preventing access by arachidonic acid. In theory, a drug such as celecoxib that selectively inhibited COX-2 might block inflammation, pain, and fever while reducing the side effects (gastric erosions and ulcers) associated with inhibition of COX-1. In animal models of inflammation and pain, celecoxib has shown marked suppression of PG production and inflammation compared with indomethacin, the standard COX-1/COX-2 inhibitor. In clinical trials, celecoxib dosed at 100, 200, and 400 mg BID was found to significantly reduce the signs and symptoms of rheumatoid arthritis (RA) and osteoarthritis. In one RA study, celecoxib was found to be as clinically effective as diclofenac after 24 weeks of treatment; at the end of the study, gastroduodenal ulcers occurred significantly more frequently in the diclofenac group (15%) than in the celecoxib group (4%). In a 1-week endoscopy study comparing celecoxib with naproxen and placebo, the incidence of gastric erosions/ulcers was significantly greater in the naproxen group than in the celecoxib or placebo group. The most common adverse effects of celecoxib in clinical studies were headache, diarrhea, abdominal discomfort, and dizziness. Celecoxib has shown significant equivalent anti-inflammatory and analgesic efficacy and has produced less endoscopically apparent gastrointestinal (GI) ulceration or erosion than have 3 classic NSAIDs. Whether it will have long-term GI adverse effects or interact with other medications to cause serious adverse responses (eg, increased GI bleeding or rash in conjunction with other sulfonamide-like drugs) is unknown and remains to be established.
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PMID:Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis. 1050 45

Substance P (SP) is synthesized in the dorsal root ganglion (DRG) and released from primary afferent neurons to convey information regarding noxious stimuli. The effects of the proinflammatory cytokine interleukin-1 (IL-1) beta on the release of SP were investigated using primary cultured rat DRG cells. Recombinant mouse IL-1beta added to the cells at 0.1 ng/ml increased the SP-like immunoreactivity (SPLI) in the culture medium after incubation for 6 h by approximately 50% as compared with that of nontreated DRG cells. The effect of IL-1beta was Ca(2+)-dependent and significantly inhibited by 100 ng/ml IL-1 receptor-specific antagonist (IL-1r antagonist), cyclooxygenase (COX) inhibitors such as 0.1 mM aspirin, 1 microg/ml indomethacin, and 1 microM NS-398 (specific for COX-2), and 1 microM dexamethasone. Furthermore, a 1-h incubation with IL-1beta markedly increased the inducible COX-2 mRNA level, which was inhibited by an IL-1r antagonist and dexamethasone, whereas IL-1beta showed no effect on the level of constitutive COX-1 mRNA. These observations indicated that IL-1beta induced the release of SP from the DRG cells via specific IL-1 receptors, the mechanism of which might involve prostanoid systems produced by COX-2. This could be responsible for the hyperalgesic action with reference to inflammatory pain in the primary afferent neuron to spinal cord pathway.
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PMID:Interleukin-1beta induces substance P release from primary afferent neurons through the cyclooxygenase-2 system. 1053 81

Angiogenesis, the formation of new capillary blood vessels, is essential not only for the growth and metastasis of solid tumors, but also for wound and ulcer healing, because without the restoration of blood flow, oxygen and nutrients cannot be delivered to the healing site. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used drugs for pain, arthritis, cardiovascular diseases and, more recently, the prevention of colon cancer and Alzheimer disease. However, NSAIDs produce gastroduodenal ulcers in about 25% of users (often with bleeding and/or perforations) and delay ulcer healing, presumably by blocking prostaglandin synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both selective and nonselective NSAIDs inhibit angiogenesis through direct effects on endothelial cells. We also show that this action involves inhibition of mitogen-activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear translocation, is independent of protein kinase C and has prostaglandin-dependent and prostaglandin-independent components. Finally, we show that both COX-1 and COX-2 are important for the regulation of angiogenesis. These findings challenge the premise that selective COX-2 inhibitors will not affect the gastrointestinal tract and ulcer/wound healing.
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PMID:Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. 1058 Oct 68

NSAIDs/Corticosteroids are the most used and maybe misused drugs against "aches and pains of the musculoskeletal system". Their effectiveness to reduce (not cure) inflammation and related pain is without doubt. The problem is that of their side effects in particular of the GI-tract and other body systems. It is clear that these side effects occur more often and more seriously in a number of patients, the so-called high risk group: elderly women, patients with previous history of gastro-intestinal ulcer and corticosteroid users. The discovery that there are two pathways to influence cyclooxygenase activity and prostaglandin production and that some NSAIDs have a more marked COX-2 and COX-1 inhibition opens new perspectives. COX-1 is present in normal tissues and is responsible for the production of protective prostaglandins in the gastric mucosa and other tissues. COX-2 is induced by inflammatory cytokines and plays a role in the inflammatory cascade. Therefore more specific COX-2 antagonists should be safer for the gastro-intestinal mucosa and kidney function. The risk of hip fracture is 50% higher in patients receiving long-term corticosteroid therapy, and 30-35% of corticosteroid patients have vertebral fractures. The renewed interest in osteoporosis and increased number of papers on bone loss in RA reflect on the one hand the advances in technology to measure bone mineral density (BMD) accurately and precisely, and on the other hand the availability of effective drugs to stop bone loss and reverse the process. The possible deleterious effect of low dose corticosteroids continues to be a subject of concern, particularly in rheumatology where serum levels of free cortisone may be higher because of low albumen and other protein changes. Recently, several editorials and conflicting data obtained from cross-sectional and longitudinal studies in RA on steroid-induced osteoporosis have been published. Because the pathogenesis of steroid osteoporosis is distinct from that of entities such as postmenopausal osteoporosis, each therapy requires specific assessment in steroid treated patients. In recent years a wide variety of therapies, for example hormone replacement therapy, calcium supplements administered with vitamin D metabolites, thiazides, diuretics, anabolic steroids, tibolone, calcitonin and bisphosphonates, have been proposed to prevent osteoporosis in patients receiving longterm corticosteroid therapy, but there have been few carefully controlled trials, except for vitamin D and bisphosphonates.
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PMID:NSAIDs/corticosteroids--primum non nocere. 1059 63


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