UMLS:C0344307 - FACTA Search

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Query: UMLS:C0344307 (analgesia)
28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel series of 5,6-diarylspiro[2.4]hept-5-enes was shown to provide highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. A study of structure-activity relationships in this series suggests that 3,4-disubstituted phenyl analogs are generally more selective than 4-substituted phenyl analogs and that replacement of the methyl sulfone group on the 6-phenyl ring with a sulfonamide moiety results in compounds with superior in vivo pharmacological properties, although with lower COX-2 selectivity. Several compounds have been shown to possess promising pharmacological properties in adjuvant-induced arthritis and edema analgesia models. The absence of gastrointestinal (GI) toxicity at 200 mpk of several selected compounds in rats and mice corresponds well with the weak potency for inhibition of COX-1 observed in the enzyme assay. Methyl sulfone 55 and sulfonamide 24 were shown to have superior in vivo pharmacological profiles, low GI toxicity, and good oral bioavailability and duration of action.
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PMID:Diarylspiro[2.4]heptenes as orally active, highly selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationships. 856 15

Traditionally, the analgesic action of nonsteroidal anti-inflammatory drugs (NSAIDs) has been explained on the basis of their inhibition of the enzymes that synthesise prostaglandins. However, it is clear that NSAIDs exert their analgesic effect not only through peripheral inhibition of prostaglandin synthesis but also through a variety of other peripheral and central mechanisms. It is now known that there are 2 structurally distinct forms of the cyclo-oxygenase enzyme (COX-1 and COX-2). COX-1 is a constitutive member of normal cells and COX-2 is induced in inflammatory cells. Inhibition of COX-2 activity represent the most likely mechanism of action for NSAID-mediated analgesia, while the ratio of inhibition of COX-1 to COX-2 by NSAIDs should determine the likelihood of adverse effects. In addition, some NSAIDs inhibit the lipoxygenase pathway, which may itself result in the production of algogenic metabolites. Interference with G-protein-mediated signal transduction by NSAIDs may form the basis of an analgesic mechanism unrelated to inhibition of prostaglandin synthesis. These is increasing evidence that NSAIDs have a central mechanism of action that augments the peripheral mechanism. This effect may be the result of interference with the formation of prostaglandins within the CNS. Alternatively, the central action may be mediated by endogenous opioid peptides or blockade of the release of serotonin (5-hydroxytryptamine; 5-HT). A mechanism involving inhibition of excitatory amino acids of N-methyl-D-aspartate receptor activation has also been proposed.
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PMID:The mechanisms of action of NSAIDs in analgesia. 892 54

Pain is the major symptom that leads patients to consult their physicians for the treatment of arthritis; therefore, effective pain control is an important goal in the management of this disorder. Pharmacologic therapy begins with simple analgesics and education. In many patients, simple analgesics do not adequately control moderate arthritis pain, and nonsteroidal antiinflammatory drugs (NSAID) are substituted for or added to the analgesic therapy. While NSAID are effective in controlling pain in mild to moderate osteoarthritis (OA), they are associated with significant toxicity (most frequently gastrointestinal) and may even cause complications that result in death. Patients who experience the pain associated with arthritis would therefore benefit from the antiinflammatory and analgesic actions of agents that are devoid of significant toxicities. Cyclooxygenase-2 (COX-2) inhibitors are being evaluated in clinical trials or are in development. These agents appear to inhibit only the COX-2 isoenzyme, which is produced largely during inflammation and is responsible for the biosynthesis of prostaglandins and other mediators of inflammation as well as sensitizers to pain. Because COX-2 inhibitors do not inhibit COX-1 isoenzyme activity at pharmacologic concentrations, they are devoid of many of the toxicities that are typical side effects of NSAID. Short term studies in dental pain, OA, and rheumatoid arthritis found that the COX-2 inhibitor celecoxib was an effective analgesic but did not cause gastroduodenal erosions. It has the potential to provide analgesia and antiinflammatory action in patients with arthritis without the side effects of NSAID. Further studies are required to substantiate these findings.
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PMID:Pain management in osteoarthritis: the role of COX-2 inhibitors. 924 47

1. The responses of wide dynamic range spinal dorsal horn neurones to noxious mechanical stimulation of the ankle or knee joint were tested before and after spinal administration of the non-selective cyclooxygenase (COX) inhibitors, indomethacin and meclofenamic acid. Neither of these drugs altered the responses of these neurones to noxious mechanical stimulation. 2. Wind-up of a spinal nociceptive reflex evoked by electrical stimulation of the sural nerve at C-fibre strength was dose-dependently inhibited by intravenous administration of indomethacin, a non-selective COX inhibitor, and SC58125, a selective COX-2 inhibitor. Intrathecal administration of indomethacin also reduced the wind-up of this nociceptive reflex. 3. Western blot analysis of proteins extracted from normal rat spinal cord revealed the presence of both cyclo-oxygenase (COX)-1 and COX-2 proteins. 4. Immunocytochemistry of sections of normal rat spinal cord with specific COX-1 antiserum revealed little specific COX-1-like immunoreactivity in the grey matter. With the same antiserum, intense COX-1-like immunoreactivity was observed in the cytoplasm, nuclear membrane and axonal processes of small to medium sized (< 1000 microns2) dorsal root ganglion (DRG) cell bodies. 5. Immunocytochemistry of sections of normal rat spinal cord incubated with specific COX-2 antiserum showed intense COX-2-like immunoreactivity (COX-2-li) in the superficial dorsal horn of the spinal cord (laminae I and II) and around the central canal (lamina X). COX-2-li was also observed in some neurones in deep dorsal horn and in individual motor neurones in ventral horn. COX-2-li was not observed in the cell bodies of DRG. 6. Superfusion of the lumbar spinal cord of normal rats with artificial CSF and subsequent radioimmunoassay revealed the presence of prostaglandin D2 (PGD2) < PGE2, but not PGI2 (determined by measurement of the stable metabolite, 6-keto-PGF1 alpha) or PGF2 alpha. 7. These data suggest that eicosanoids synthesized by an active COX pathway in the spinal cord of normal animals may contribute to nociceptive processing, but only when the spinal cord neurones are rendered hyperexcitable following C-fibre stimulation. Selective inhibition of one or both of the COX isoforms in normal animals may represent a novel target for spinal analgesia.
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PMID:Prostanoids synthesized by cyclo-oxygenase isoforms in rat spinal cord and their contribution to the development of neuronal hyperexcitability. 942 3

Two enzymes, cyclo-oxygenase (COX) and 5-lipoxygenase, act upon arachidonic acids to produce prostaglandins and leukotrienes. Inhibition of COX-2 by non-steroidal anti-inflammatory drugs (NSAIDs) lowers synthesis of proinflammatory prostaglandins and produces analgesia. COX-2 is highly inducible by endotoxin, IL-1, hypoxia, epidermal growth factor (EGF), benzo[a]pyrene, and transforming growth factor beta 1(TGF-beta 1). COX-1 in constitutively expressed. Conventional NSAIDs also inhibit the synthesis of cytoprotective prostaglandins by COX-1 in the gastrointestinal tract. Surplus arachidonic acids accumulate and enhance the generation of leukotrienes via the lipoxygenase pathway inducing neutrophil adhesion to endothelium and vasoconstriction. The NSAIDs harboring a carboxyl group also inhibit oxidative phosphorylation (OXPHOS) lowering adenosine-triphosphate (ATP) generation leading to loss of mucosal cell tight junctions and increased mucosal permeability. Administration of NSAIDs that do not interfere with OXPHOS, and concomitant use of prostaglandin analogues to restore cytoprotection reduces complications of NSAID use. However, no NSAID that lacks potential for serious gastrointestinal toxicity is currently available. Selective inhibitors of COX-2 and 5-lipoxygenase are newer, promising drugs. Surprisingly, COX-2 null mice are able to mount an inflammatory response, suffering however, from kidney dysfunction and a shortened life span. Results of clinical studies on the long-term use of NSAID drugs such as selective inhibitors are still pending.
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PMID:Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal system. 955 45

The new class of antiinflammatory and analgesic drugs, the selective cyclooxygenase (COX-2) inhibitors, which promise to be devoid of the types of toxicity associated with nonsteroidal antiinflammatory drugs (NSAID), especially adverse gastrointestinal effects, are under clinical trial but are not yet available for use. All NSAID, including those most recently introduced, exhibit nonselectivity of action, producing therapeutic blood levels that inhibit constitutive COX-1 and deplete tissue protective prostaglandins. Among NSAID, the diclofenac/misoprostol combination (Arthrotec) is unique in possessing an active component, misoprostol, to help prevent NSAID induced gastrointestinal damage. Ulcer damage and associated serious complications probably represent only the tip of the iceberg in relation to clinically significant side effects associated with the use of NSAID. In this context, metaanalysis of 8 large multicenter studies reported here has shown that patients taking NSAID show a mean decrease in hemoglobin over 4 - 12 weeks' assessment, with some 10-20% of patients exhibiting clinically significant decreases (> or = 1 g/dl) early in treatment. Patients taking diclofenac/misoprostol showed significantly less of a decline in hemoglobin and up to 50% fewer clinically significant decreases than patients receiving diclofenac alone. The misoprostol component of diclofenac/misoprostol may also help to restore homeostasis in tissues other than the gut. Inhibition of the activity or release of various tissue damaging agents and inflammatory cytokines, e.g., thromboxane and interleukin 1, are described, as are in vivo animal studies that have revealed synergistic or potentiating analgesic and antiinflammatory activities between misoprostol and NSAID, particularly diclofenac. Clinical studies in postsurgical dental pain in more than 500 patients have now shown enhanced analgesia, with greater relief over a longer period, for the diclofenac/misoprostol combination compared with diclofenac alone. The relevance of these findings to pain and inflammation control in arthritis is discussed. Enhanced control of morning stiffness provided by diclofenac/misoprostol, possibly also the result of misoprostol/diclofenac synergy, is also reported, and the development of an objective system that measures 24 hour ambulatory activity is described. Using this Numact recorder, improved mobility in patients receiving diclofenac 75 mg/misoprostol 200 microg was observed compared with patients treated with diclofenac 75 mg slow release. Further studies are being performed employing magnetic resonance imaging both to assess antiinflammatory effects in joint soft tissue architecture and to assess whether the synergistic stimulatory effects of diclofenac and misoprostol on human osteoarthritic cartilage that have been reported in vitro are clinically evident. A growing body of evidence supports the view that the diclofenac/misoprostol combination provides an improved therapeutic ratio over diclofenac alone, not only by improving gastrointestinal safety but also by enhancing analgesic/antiinflammatory effects.
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PMID:Diclofenac/misoprostol: novel findings and their clinical potential. 959 52

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs and their widespread use is associated with increased gastro-intestinal toxic effects such as ulceration, haemorrhage, perforation and death. They result in these complications mainly by reducing cytoprotective prostaglandins (PGE2 and PGI2) in the stomach, through the inhibition of cyclo-oxygenase (COX) enzyme. The increased morbidity and mortality, in addition to enormous cost, associated with NSAID-associated side effects, necessitates a need for safer GI-friendly NSAID. Various approaches have been used to counteract NSAID associated side effects with varying degrees of success and acceptance. These include the use of alternative analgesia, anti-acid secretory agents like proton pump inhibitors, sucralfate and prostaglandin analogues. In addition, new types of NSAIDs are being developed, based on new understanding of their mechanism of action and the pathogenesis of inflammation. These include a new class of NSAIDs called "selective Cox-2 inhibitors". These agents preserve the COX-1 that is responsible for the production of cytoprotective prostaglandins in the stomach and selectively inhibit COX-2 induced at the sites of inflammation. Selective COX-2 inhibitors exert the same analgesic and anti-inflammatory effects as the existing NSAIDs but may be less toxic to the stomach. In this review the background development and well-structured clinical trials on this new generation NSAIDs are discussed.
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PMID:Non-steroidal anti-inflammatory drugs (NSAIDs) and gastro-intestinal toxicity: current issues. 1062 61

Even at the beginning of the next millennium, aspirin will still offer surprises. Its relatively young pharmacological history compares with the early use of salicylate-containing plants since antiquity. The Assyrians and the Egyptians were aware of the analgesic effects of a decoction of myrtle or willow leaves for joint pains. Hippocrates recommended chewing willow leaves for analgesia in childbirth and the Reverend Edward Stones is acknowledged as the first person to scientifically define the beneficial antipyretic effects of willow bark. At the beginning of the 19th century salicin was extracted from willow bark and purified. Although a French chemist, Charles Gerhardt, was the first to synthesize aspirin in a crude form, the compound was ignored, and later studied by Felix Hoffmann. He reportedly tested the rediscovered agent on himself and on his father, who suffered from chronic arthritis--a legend was born and Bayer Laboratories rose to the heights of the pharmacological world. First used for its potent analgesic, antipyretic and anti-inflammatory properties, aspirin was successfully used as an antithrombotic agent. Sir John Vane elucidated aspirin's active mechanism as an inhibitor of prostaglandin synthetase and received the Nobel Price in Medicine for this work in 1982. Two isoform of cyclooxygenase (COX-1 and COX-2) have now been identified, each possessing similar activities, but differing in characteristic tissue expression. The cox enzyme is now a target of drug interventions against the inflammatory process. After two centuries of evaluation, aspirin remains topical, and new therapeutic indications are increasingly being studied.
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PMID:[Aspirin throughout the ages: a historical review]. 1076

The role of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain has been well established in the treatment of mild pain and also alone or in association with opioids for the treatment of moderate to severe pain. Acutely, NSAIDs may be more than mild analgesics, and may provide additional analgesia when combined with opioids. However, NSAIDs have ceiling effects and there is no therapeutic gain from increasing dosages beyond those recommended. As there is no clearly superior NSAID, the choice should be based on experience and the toxicity profile that probably relates to the COX-1:COX-2 ratio. Among the older drugs, ibuprofen seems to have these properties.Non-steroidal anti-inflammatory drugs have been shown to have an opioid-sparing effect. Although the value of a simple narcotic-sparing effect may be questioned in cancer pain treatment, the use of NSAIDs may be useful when the increase in opioid dosage determine the occurrence of opioid toxicity. Like opioids, NSAIDs should not be considered analgesics for a specific type or cause of pain. There is a lack of evidence for any difference between different routes of NSAIDs administration. The long-term toxicity of NSAIDs in cancer pain is poorly defined due to a lack of studies. A variety of strategies have been used in an attempt to reduce the risks associated with NSAID therapy. Those NSAIDs that are weak COX-1 inhibitors may be preferred. In addition, concomitant administration of misoprostol is recommended in patients at increased risk for upper gastrointestinal complications.
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PMID:The use of anti-inflammatory drugs in cancer pain. 1123 77

Non-steroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) enzyme and so they are effective analgesic, antiinflammatory and antipyretic drugs. The discovery of COX-2 led to the search for new NSAIDs with a selective action over this isoenzyme. The experiments performed to date have shown either more, less or no different efficacy of new COX-2 selective NSAIDs when compared to the non-selective inhibitors, probably because the comparison has not been performed under similar conditions. We have therefore compared the analgesic activity of six NSAIDs with different selectivity for the COX isoenzymes. The experiments were performed using the recording of spinal cord nociceptive reflexes in anaesthetised rats and in awake mice. The non-selective COX inhibitors, such as dexketoprofen trometamol, were effective in reducing nociceptive responses both in normal and monoarthritic rats (ED50s: 0.31 and 3.97 micromol/kg, respectively), and in mice with paw inflammation (12.5 micromol/kg, p < 0.01). The COX-1 selective inhibitor SC-58560 showed efficacy in normal rats (ED50: 0.8 micromol/kg) and in mice with paw inflammation (15 micromol/kg, p < 0.05), but not in monoarthritic rats. The COX-2 selective inhibitors celecoxib (105 micromol/kg) and rofecoxib (128 micromol/kg) however, were not effective in any of the groups studied. We conclude that inhibition of both COX isoenzymes is needed to achieve an effective analgesia in inflammation.
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PMID:Cyclooxygenase-1 vs. cyclooxygenase-2 inhibitors in the induction of antinociception in rodent withdrawal reflexes. 1137 64

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