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)

Our aim was to determine the amounts of eicosanoids in blood and synovial tissue of patients with knee arthrosis and to examine the effects of 2 doses of tepoxalin (50 mg twice, 200 mg twice), administered p.o. for 3.5 days. Concentrations of leukotriene B4 (LTB4, LTC4, and thromboxane B2 (TXB2) were measured in blood before and after oral administration of tepoxalin and release of prostaglandin E2 (PGE2), 6-keto-PGF1alpha, and LTC4 was measured in incubation media of synovial tissue, taken at surgery from patients treated with tepoxalin. Radioimmunoassay (RIA) was used to determine the levels of the eicosanoids. LT and TXB2 release was reduced by tepoxalin in both doses used. Under these conditions, PGE2, 6-keto-PGF1alpha, and LTC4 release from synovial tissue was detectable only after stimulation with calcium ionophore A23187. Washed synovial tissue, in which tepoxalin concentrations should be reduced, released higher amounts of all eicosanoids measured than directly incubated synovial tissue did. Pain after tepoxalin administration was significantly reduced. Relevant drug concentrations were detected in plasma and synovial fluid. Tepoxalin was well tolerated and had no marked adverse effects. At 400 mg, tepoxalin is a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5-LO) in blood and synovial tissue.
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PMID:Antiinflammatory effect of tepoxalin: blood and synovial tissue studied in patients with knee arthrosis. 970 7

The discovery of a second isoform of cyclooxygenase (cyclooxygenase-2) that is expressed in inflammatory cells and the central nervous system, but not in the gastric mucosa, offers the possibility of developing anti-inflammatory and analgesic agents that lack the gastrointestinal side effects of currently available nonsteroidal anti-inflammatory drugs. Lead compounds from several different structural classes have been identified and shown to be slow, tight-binding inhibitors that express their selectivity for cyclooxygenase-2 in the time-dependent step. The determination of structures of enzyme-inhibitor co-crystals along with site-directed mutagenesis experiments reveal the molecular basis for selectivity of some, but not all, inhibitors. Preclinical and clinical studies suggest cyclooxygenase-2 inhibitors are highly promising new agents for the treatment of pain and inflammation, and for the prevention of cancer.
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PMID:Design of selective inhibitors of cyclooxygenase-2 as nonulcerogenic anti-inflammatory agents. 973 21

Non steroidal antiinflammatory (NSAID) drugs are the most widely prescribed drugs against pain and inflammation. Problems of tolerance, particularly gastrointestinal toxicity, limit their use. The central mechanism of NSAID action is the reduction of prostaglandin production from arachidonic acid through cyclooxygenase inhibition. Although such a mechanism was already described 25 years ago, the recent discovery of two isoforms of cyclooxygenase, the cyclooxygenase 1 (COX-1) constitutively expressed in most tissues and the cyclooxygenase 2 (COX-2), inducible, has prompted research in developing new NSAID that would be safer whilst maintaining their efficacy. Nevertheless, their long term efficacy and safety need to be demonstrated in clinical practice. There are still unsolved questions, especially about the physiological role of COX-2.
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PMID:[New NSAIDS: COX-1, COX-2, what about them?]. 980 82

Prostaglandins are generated through two isoforms of the enzyme cyclooxygenase, the constitutively expressed cyclooxygenase (Cox)-1 and Cox-2, which is induced at sites of inflammation. Selective inhibition of Cox-2 is desirable as this may avoid the gastropathy and platelet inhibition seen with nonselective agents. Moreover, these agents will allow us to examine the relative contribution of the two isoforms to prostaglandin formation in man. We examined the activity of nimesulide, a Cox-2 selective nonsteroidal antiinflammatory drug, in vitro against purified enzymes and in vivo in man. Nimesulide 100 mg twice daily or aspirin 300 mg three times daily were administered randomly for 14 days to 20 subjects complaining of musculoskeletal pain. Serum thromboxane B2 was determined as an index of Cox-1 activity and endotoxin-induced prostaglandin E2 formation in whole blood as an index of Cox-2 activity. Urinary excretion of prostaglandin metabolites was determined by GC/MS. Nimesulide was highly selective against ovine Cox-2, so that at concentrations attained in vivo, it had no effect on Cox-1 but completely suppressed Cox-2. Aspirin markedly inhibited serum thromboxane B2 (181.92 +/- 19.77 to 2.83 +/- 0.96 ng/ml, P <. 002), whereas nimesulide had very little effect (207.53 +/- 47.30 to 181.15 +/- 54.59 ng/ml). In contrast, nimesulide suppresses endotoxin-induced prostaglandin E2 formation (35.03 +/- 8.73 to 2.62 +/- 0.95 ng/ml, P =.002). As expected, aspirin reduced TX metabolite excretion, whereas nimesulide had no significant effect. In contrast, both compounds suppressed PGI2 formation to the same extent. The findings suggest that TX is largely Cox-1 derived. Moreover, Cox-2 is expressed in man and generates prostaglandin I2.
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PMID:Selective cyclooxygenase-2 inhibition by nimesulide in man. 980 83

Inflammation enhances release of neuropeptides from sensory nerve terminals in the spinal cord, and this may contribute to the development of hyperalgesia. In a similar manner, proinflammatory prostaglandins also augment peptide release from sensory neurons. To ascertain whether the inflammation-induced increase in peptide release from spinal cord slices is mediated by production of these eicosanoids, we examined whether intrathecal administration of nonsteroidal antiinflammatory drugs (NSAIDS) could attenuate the effects of inflammation. Unilateral injection of 150 microl of complete Freund's adjuvant (CFA) into the hindpaw of adult Sprague-Dawley rats resulted in a lower threshold for paw withdrawal (hyperalgesia) on 1, 4, and 5 days after injection. Five days after the induction of inflammation, capsaicin-evoked release of immunoreactive substance P (iSP) and immunoreactive calcitonin gene-related peptide (iCGRP) was increased approximately 2-fold in slices of cord tissue from the side ipsilateral to CFA injection, compared to spinal cord slices from the non-inflamed side. Intrathecal administration of 1 microl/h of 10 nmol/microl solution of the NSAID, ketorolac, for 1 day prior to and throughout the inflammation significantly attenuated the inflammation-induced increase in capsaicin-evoked release of both peptides without altering release in cord tissue from the non-inflamed side. Systemic administration of the same amount of ketorolac did not attenuate the effect of inflammation on peptide release. Intrathecal administration of 16 nmol/h (S)-ibuprofen, before and throughout the inflammation, also significantly attenuated the increase in evoked neuropeptide release associated with inflammation, whereas (R)-ibuprofen was ineffective. These results suggest that inhibition of cyclooxygenase at the level of the spinal cord attenuates the augmentation of neuropeptide release induced by peripheral inflammation, and provide further evidence for an action of prostaglandins at central terminals of sensory neurons during inflammation.
Pain 1998 Oct
PMID:Intrathecal NSAIDS attenuate inflammation-induced neuropeptide release from rat spinal cord slices. 982 10

Nonsteroidal anti-inflammatory drugs (NSAIDs) produce their therapeutic activities through inhibition of cyclooxygenase (COX), the enzyme that makes prostaglandins (PGs). They share, to a greater or lesser degree, the same side effects, including gastric and renal toxicity. Recent research has shown that there are at least two COX isoenzymes. COX-1 is constitutive and makes PGs that protect the stomach and kidney from damage. COX-2 is induced by inflammatory stimuli, such as cytokines, and produces PGs that contribute to the pain and swelling of inflammation. Thus, selective COX-2 inhibitors should be anti-inflammatory without side effects on the kidney and stomach. Of course, selective COX-2 inhibitors may have other side effects and perhaps other therapeutic potential. For instance, COX-2 (and not COX-1) is thought to be involved in ovulation and in labor. In addition, the well-known protective action of aspirin on colon cancer may be through an action on COX-2, which is expressed in this disease. Moreover, NSAIDs delay the progress of Alzheimer's disease. Thus, selective COX-2 inhibitors may demonstrate new important therapeutic benefits as anticancer agents, as well as in preventing premature labor and perhaps even retarding the progression of Alzheimer's disease.
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PMID:Anti-inflammatory drugs and their mechanism of action. 983 28

The pharmacological profile of a novel and newly discovered non-steroidal anti-inflammatory and analgesic compound, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (FR140423), was investigated. In recombinant human cyclooxygenase enzyme assays, the inhibition of prostaglandin E2 formation by FR140423 was 150 times more selective for cyclooxygenase-2 than cyclooxygenase-1. Oral administration of FR140423 dose dependently reduced carrageenin-induced paw edema and adjuvant arthritis. These effects were two- to three-fold more potent than those of indomethacin. Unlike indomethacin, FR140423 did not induce mucosal lesions in the stomach. FR140423 showed dose-dependent anti-hyperalgesic effects in the yeast-induced hyperalgesic model. This effect was five-fold more potent than that of indomethacin. Furthermore, FR140423 increased the pain threshold in non-inflamed paws and, unlike indomethacin, it produced an analgesic effect in the tail-flick test. These analgesic effects were blocked by the mu-opioid antagonist naloxone. These results suggest that FR140423, a selective cyclooxygenase-2 inhibitor, is a potent non-steroidal anti-inflammatory drug (NSAID) without gastrointestinal side effects and is a unique compound having morphine-like analgesic effects.
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PMID:Anti-inflammatory and analgesic effects of a novel pyrazole derivative, FR140423. 998 10

Non-steroidal anti-inflammatory drugs (NSAIDs) currently attract large interest. Next to pain relief, NSAIDs have important anti-thrombotic and anti-oncogenic effects. NSAIDs exert their action by inhibition of cyclooxygenase, the enzyme responsible for the production of prostanoids. Prostanoid signal transduction is still poorly understood, but it has become clear that these inflammatory lipids influence cellular physiology at three different levels: (1) activation of a 7 x transmembrane receptor coupled to heterotrimeric G proteins, (2) the inhibition of inflammation by activating corticosteroid-like receptors, (3) participation in receptor protein tyrosine kinase signal transduction. In this review prostanoid signalling at these three different levels will be reviewed and the relevance in (patho)physiological processes will be evaluated.
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PMID:Cyclooxygenase-dependent signalling: molecular events and consequences. 1006 62

Plants used by Southern African traditional healers for the treatment of menstrual pains were screened for prostaglandin-synthesis inhibitors and the ability to reduce isolated uterine muscle contraction using the cyclooxygenase and in vitro uterine bioassays respectively. Prostaglandins are synthesized from arachidonic acid and the enzyme that drives this reaction is cyclooxygenase. The excessive production of prostaglandins by the myometrium and endometrium induces uterine contractions. Inhibition of cyclooxygenase and hence of the prostaglandin biosynthetic pathway may lead to relief of menstrual pain. Ten plants used by traditional healers for menstrual pains were assayed for cyclooxygenase inhibitory activity. Several plant extracts exhibited high inhibitory activity in the assay. The highest activities were obtained with ethanolic extracts of Siphonochilus aethiopicus, Cenchrus ciliaris and Solanum mauritianum. Generally ethanolic extracts gave higher activity than the aqueous extracts. None of the ethanolic plant extracts were able to relax or reduce the contractions of the precontracted guinea pig uterus.
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PMID:Screening of plants used by Southern African traditional healers in the treatment of dysmenorrhoea for prostaglandin-synthesis inhibitors and uterine relaxing activity. 1007 17

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of arthritis and pain. These drugs tend to cause significant side effects, however, including gastric and intestinal toxicity. The mechanism of action of NSAIDs is through their inhibition of the key enzyme of prostaglandin biosynthesis, the cyclooxygenase. Recently, two forms of cyclooxygenase have been found to exist: COX-1 and COX-2, the constitutive and inducible forms, respectively. COX-1 exists in the stomach, intestine, kidneys and platelets, while COX-2, the inducible form, is expressed during inflammation. The therapeutic effects of NSAIDs are largely the result of inhibition of the enzyme cyclooxygenase-2 (COX-2), whereas the toxic effects (e.g., gastrointestinal, renal and platelet effects) are primarily due to the inhibition of COX-1. Individual NSAIDs show different potencies against COX-1 compared with COX-2 and this explains the variations in the side effects of NSAIDs at their anti-inflammatory doses. Drugs with high potency against COX-2 and a better COX-2-/COX-1 activity ratio will have anti-inflammatory activity with fewer gastrointestinal side effects. In contrast piroxicam and indomethacin, which drugs have a much higher potency against COX-1 than against COX-2, are amongst those with the highest gastrointestinal toxicity. Based on these findings, COX-2 seems to be an ideal target for the development of new anti-inflammatory drugs. Several compounds with preferential or specific COX-2 inhibiting properties have been synthesized and evaluated in pre-clinical and clinical studies i.e. Meloxicam, Celecoxib, MK-966, Flusolid and L-745, 337. The COX-2 selectivity of these novel NSAIDs relate well to their favorable gastrointestinal tolerability profile. Clinical trials have shown meloxicam and celecoxib to be as effective as currently available NSAIDs, but with an improved gastrointestinal tolerability profile. Further clinical trials and large-scale postmarketing surveillance programs are needed, however, to confirm the potential therapeutic benefits of these novel preferential or specific COX-2 inhibitors.
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PMID:[Preferential COX-2 inhibition: its clinical relevance for gastrointestinal non-steroidal anti-inflammatory rheumatic drug toxicity]. 1009 Dec 84


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