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)

One of the features of inflammation is increased oxygenation of arachidonic acid which is metabolized by two enzymic pathways--the cyclooxygenase (CO) and the 5-lipoxygenase (5-LO)--leading to the production of prostaglandins and leukotrienes respectively. Amongst the CO products, PGE2 and amongst the 5-LO products, LTB4 are considered important mediators of inflammation. More than 200 potential drugs ranging from non-steroidal anti-inflammatory drugs, corticosteroids, gold salts, disease modifying anti-rheumatic drugs, methotrexate, cyclosporine are being tested. None of the drugs has been found safe; all are known to produce from mild to serious side-effects. Ginger is described in Ayurvedic and Tibb systems of medicine to be useful in inflammation and rheumatism. In all 56 patients (28 with rheumatoid arthritis, 18 with osteoarthritis and 10 with muscular discomfort) used powdered ginger against their afflictions. Amongst the arthritis patients more than three-quarters experienced, to varying degrees, relief in pain and swelling. All the patients with muscular discomfort experienced relief in pain. None of the patients reported adverse effects during the period of ginger consumption which ranged from 3 months to 2.5 years. It is suggested that at least one of the mechanisms by which ginger shows its ameliorative effects could be related to inhibition of prostaglandin and leukotriene biosynthesis, i.e. it works as a dual inhibitor of eicosanoid biosynthesis.
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PMID:Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders. 149 22

Ten patients with rheumatoid arthritis (RA) were evaluated in a placebo-controlled, double-blind study examining the clinical efficacy of a novel nonsteroidal anti-inflammatory agent: Tenidap (CP-66,248). RA patients receiving active drug therapy (n = 6) demonstrated clinically significant improvements in observer assessment of pain (p less than 0.025), painful joint count (p less than 0.010), and overall clinical assessment as based on a modified rheumatoid activity index, MRAI (p less than 0.025). In parallel laboratory assays, Tenidap was found to exhibit a significant in vitro dose-dependent inhibition of ionophore-stimulated neutrophil production of the 5-lipoxygenase product: [3H]leukotriene B4 (LTB4). Although more importantly, Tenidap was also found to exhibit an in vitro dose-dependent inhibition (IC50 20 microM) of the ionophore-stimulated release (deacylation) of the precursor [3H]arachidonic acid (AA) from membrane phospholipids. In further studies, Tenidap did not have any effect on fMLP-induced neutrophil chemotactic response. These results suggest that one of the possible mechanisms for the clinical effectiveness of this agent, may be through its effect at inhibiting the release of free AA from membrane phospholipids and therefore limiting its further metabolism into certain biologically-active inflammatory lipids.
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PMID:Evaluation of Tenidap (CP-66,248) on human neutrophil arachidonic acid metabolism, chemotactic potential and clinical efficacy in the treatment of rheumatoid arthritis. 212 72

Oxygenation of arachidonic acid is increased in inflamed tissues. In this condition products of two enzymic pathways--the cyclooxygenase and the 5-lipoxygenase producing respectively prostaglandins and leukotrienes--are elevated. Of the cyclooxygenase products, PGE2 and of the lipoxygenase products, LTB4 are the strongest candidates for mediating inflammation. Non-steroidal anti-inflammatory drugs which inhibit the cyclooxygenase, and corticosteroids are used to treat such disorders. Both types of drugs produce adverse side-effects on prolonged use. Ginger is reported in Ayurvedic and Tibb systems of medicine to be useful in rheumatic disorders. Seven patients suffering from such disorders reported relief in pain and associated symptoms on ginger administration.
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PMID:Ginger (Zingiber officinale) and rheumatic disorders. 250 34

Oxphaman and particularly oxphalin, among other phenolic azomethines, have been proven as strong inhibitors of lipoxygenases (LOX) from reticulocytes, soybean, thrombocytes as well as of quasi-LOX (hemoglobin) with IC50 values which correspond with those of known LOX inhibitors. The 5-LOX is likewise strongly, the cyclooxygenase of sheep seminal vesicles only weakly inhibited. Nevertheless, antiinflammatory effectivity was found in some carrageenin-induced inflammatory models of the rat as well as in the arachidonic acid- and croton oil-induced ear oedema of the mouse. Adjuvant arthritis, experimental pain, skin permeability and allergy models (anaphylactic paw oedema, cutaneous anaphylaxis, asthma, picryl chloride ear oedema) were not, only weakly or irregularly influenced. In the guinea pig ileum a certain antihistaminic, anticholinergic and leukotriene antagonistic activity was found. An inflammation-induced vasodepression (anaphylactic shock, dextran paw oedema. UV irradiation) was dose-dependently prevented or even reversed, obviously on the basis of oxygen radical scavenging.
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PMID:[The pharmacology of the lipoxygenase inhibitors oxphaman (1-(2,5-dihydroxybenzylidene)aminoadamantane) and oxphalin (1-(3,4-dihydroxybenzylidene)-2,4,6-trimethylaniline]. 251 86

Platelet-activating factor (PAF), a potent inflammatory mediator, decreases the nociceptive threshold in the rat hindpaw. Pain sensitivity, measured by the applied pressure necessary to induce vocalization, was increased maximally at 3 and 4 hr after injection of synthetic PAF. The hyperalgesic response to PAF was specifically inhibited by agents that interfere with the lipoxygenase pathway of arachidonic acid metabolism and was not affected by cyclooxygenase inhibitors. BW-755C (3-30 mg/kg, p.o.) and L-615,919 (0.01-0.3 mg/kg, p.o.) significantly reduced PAF-induced hyperalgesia, whereas indomethacin had no effect. The finding that L-615,919, a specific 5-lipoxygenase inhibitor, was a potent inhibitor of this model of hyperalgesia leads to speculation that leukotrienes are important mediators of inflammatory pain.
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PMID:Pharmacological evidence for a role of lipoxygenase products in platelet-activating factor (PAF)-induced hyperalgesia. 282 47

L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3-methyl-5-propyl-4-benzofuranol) was a potent inhibitor of leukotriene biosynthesis in intact rat and human leukocytes and CXBG mastocytoma cells (IC50 values, 18-240 nM) and of crude human leukocyte and highly purified porcine leukocyte 5-lipoxygenase (IC50 value, 4 X 10(-7) M). The selectivity of L-656,224 for 5-lipoxygenase was shown through the relative lack of activity of the compound on 12-lipoxygenase, 15-lipoxygenase, cyclooxygenase, catalase, and myeloperoxidase. The compound showed (i) oral activity against hyperalgesia induced in the rat paw by injection of yeast or platelet-activating factor, (ii) dyspnea in sensitized inbred rats induced by an aerosol of antigen, and (iii) bronchoconstriction induced by an aerosol of Ascaris in squirrel monkeys, suggesting a role for 5-lipoxygenase inhibitors in the treatment of asthma and peripheral pain.
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PMID:L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3- methyl-5-propyl-4-benzofuranol): a novel, selective, orally active 5-lipoxygenase inhibitor. 283 37

Leukotrienes are novel mediators derived from arachidonic acid through the 5-lipoxygenase enzyme system. Leukotriene B4 has potent effects on leukocyte function and in vivo induces leukocyte accumulation and changes in vascular permeability and modulates pain responses. Peptido-lipid leukotrienes are potent smooth muscle--contracting agents. They may have important cardiovascular actions through mechanisms involving either vasoconstriction or indirect vasodilatation. Evidence for leukotriene production has been found in subjects with allergic conditions and psoriasis, indicating a putative role for these substances in human disease.
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PMID:Biological actions of leukotrienes. State of the art lecture. 301 71

Tebufelone is a novel nonsteroidal anti-inflammatory drug (NSAID), of the di-tert-butylphenol (DTBP) class, which displays potent anti-inflammatory, analgesic and anti-pyretic properties in a variety of animal models. In this report, the effects of Tebufelone on arachidonic acid (AA) metabolism are reviewed. Tebufelone potently inhibits the formation of prostaglandins (PGE2) a key mediator of pain and inflammation, in isolated enzyme preparations (IC50 = 1.5 microM, KI = 0.35 microM), two in vitro cellular systems: rat peritoneal macrophages (IC50 = 0.02 microM) and human whole blood (IC50 = 0.08 microM), and ex vivo in man. In addition to PGE2 inhibition, which is common to all NSAIDs, higher concentrations of Tebufelone block the in vitro formation of products of the lipoxygenase pathway [leukotrienes (LTB4)] in rat macrophages (IC50 = 20 microM) and human whole blood (IC50 = 22 microM). Substrate incorporation studies (14C-AA) indicate that Tebufelone reversibly inhibits cyclooxygenase (CO) and 5-lipoxygenase (5-LO) enzymes rather than regulating the release of AA. Tebufelone was shown to be a more potent CO inhibitor than indomethacin and a less potent 5-LO inhibitor than RG-5901. Comparisons to structurally related compounds under development (E-5110, Esai; KME-4, Kanagafuchi), found Tebufelone to be the most potent CO inhibitor in vitro. All three DTBP compounds were equipotent 5-LO inhibitors. It is likely that Tebufelone's inhibitory effects on AA metabolism are, in part, responsible for its in vivo efficacy and enhanced safety profile.
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PMID:Effects of tebufelone (NE-11740), a new anti-inflammatory drug, on arachidonic acid metabolism. 794 23

Prostaglandins and thromboxanes are products of arachidonic acid metabolism via the cyclooxygenase (CO) enzyme and are responsible for the pain and swelling common to sites of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of these substances and are used in the treatment of inflammatory diseases such as arthritis. However, one of the major side-effects of NSAID therapy is gastric ulceration. It is possible that inhibition of prostaglandin production and a related increase in the formation of leukotrienes via the 5-lipoxygenase (5-LO) enzymatic pathway are responsible for attracting inflammatory cells, causing local sites of inflammation and producing ulceration. To determine the effects of 5-LO inhibition on this hypothesis, studies were performed in rats to evaluate the effects of tepoxalin, a dual CO/LO inhibitor on leukotriene B4 levels in gastric mucosa and neutrophil adhesion in mesenteric venules. In rats, chronic oral administration of an NSAID, indomethacin (2 mg/kg daily over 4 days), resulted in 40% mortality, accompanied by intestinal adhesions and perforations when evaluated 24 h after the fourth dose of drug. Additionally, neutrophil adhesion was increased in the mesenteric venules and cell infiltration was evident in the mesenteric interstitium. These gastrointestinal side-effects were inhibited in a separate group of rats administered tepoxalin (20 mg/kg, p.o) 30 min prior to each daily indomethacin treatment. Further studies were performed to determine tepoxalin's effects on early events associated with NSAID-induced gastrointestinal inflammation, including neutrophil adhesion, lipid peroxide generation and LTB4 production. Indomethacin (100 mg/kg, p.o.) produced elevated levels of LTB4 in rat gastric mucosa 90 min after administration. Additionally, neutrophil adhesion in mesenteric venules was increased at this dose and with the administration of another NSAID, naproxen. No generation of lipid peroxides was evident in the gastric mucosa at this timepoint. Tepoxalin (up to 400 mg/kg, p.o.) did not have an effects on gastric mucosal LTB4 generation and lipid peroxide levels. A decrease in neutrophil adhesion was observed at the highest dose. In another study, pretreatment with tepoxalin (ED50=7.5 mg/kg, p.o.) or the selective 5-LO inhibitor zileuton (100 mg/kg, p.o.) prevented the increases in gastric mucosal LTB4 levels and neutrophil adhesion induced by indomethacin (100 mg/kg, p.o.). These data suggest that LO inhibition may play a vital role in the prevention of NSAID-induced gastric inflammation, providing insight into the lack of ulcerogenicity with tepoxalin and new approaches to anti-inflammatory therapy which may prevent gastric side effects.
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PMID:Effects of tepoxalin, a dual inhibitor of cyclooxygenase/5-lipoxygenase, on events associated with NSAID-induced gastrointestinal inflammation. 922 51

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


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