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)

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

To test the hypothesis that the postoperative abdominal pain of tubal occlusion is mediated by prostaglandins, the effects of meclofenamate, an analgesic and a potent inhibitor of cyclooxygenase, on postoperative analgesia and incidence of abdominal pain were compared with those of acetaminophen, a weak inhigitor of prostaglandin activity. 100 patients undergoing tubal occlusion under local anesthesia in a Kentucky health facility were studied. Tge patients were randomly divided into 4 equal groups: 1) control; 2) acetaminophen, 1300 mg; 3) meclofenamate, 100 mg; 4) meclofenamate, 200 mg. The fallopian tubes were occluded by electrocautery in 47 patients and by application of Falope rings in 53 patients. Both acetaminophen and meclofenamate provided substantial analgesia for 4 hours after the operation (p0.05). Meclofenamate reduced the incidence of abdominal pain by 1/2 (p0.02), but acetaminophen did not. These results suggest that a portion of pain relief achieved by meclofenamate may be due to suppression of myosalpingian and/or myometrial contractions, a process mediated by prostaglandins.
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PMID:Effects of meclofenamate and acetaminophen on abdominal pain following tubal occlusion. 294 86

Washed platelets of patients with familial Mediterranean fever (FMF) were incubated with I-14C arachidonic acid (AA). Only 10% of AA were transformed into thromboxane A2, 12(S)-12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE) and 12(S)-12-hydroxy-5Z,8Z,10E-heptadecatrienoic acid (HHT), which strongly indicates the suppression of platelet lipoxygenase and cyclooxygenase or the deficit in these enzymes in FMF. However, there were no noticeable alterations in AA platelet metabolism during attacks of fever and immediately after hyperbaric oxygenation used to relieve pain and fever. The data obtained suggest that arachidonic acid metabolism plays an important role in the pathogenesis of FMF.
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PMID:[Metabolism of arachidonic acid in the thrombocytes of patients with periodic disease]. 309 98

Interleukin-1 (IL-1) has been shown to induce inflammatory reactions in part through increased prostaglandin production. Prostaglandins of the E- and I-type sensitize nociceptors in peripheral tissues. We have therefore investigated the effect of IL-1 perfusion in the isolated rabbit ear, a model which allows the assessment of peripheral pain. Natural IL-1 from human monocytes, IL-1 from glioblastoma cells as well as recombinant IL-1 alpha or beta, increased the pain reflex induced by acetylcholine in a concentration dependent manner. The PGE2 levels were measured in the perfusate and were found to be enhanced more than 10-fold after the infusion of IL-1 alpha or IL-1 beta. This effect was paralleled by the enhanced pain reflexes and persisted for at least one hour after cessation of the IL-1 perfusion. Both the increased pain reflexes as well as the enhanced PGE2 levels were abolished by addition of the cyclooxygenase inhibitor diclofenac-Na (Voltaren) to the perfusion fluid. These results show that besides the numerous known physiological functions of IL-1, it may also play a role in peripheral pain sensations.
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PMID:Interleukin-1 enhances pain reflexes. Mediation through increased prostaglandin E2 levels. 326 68

This review covers eicosanoid metabolism in human uterine tissues, in normal menstrual cycles, menorrhagia, and IUD contraception. Since measuring tissue level of prostaglandins (PGs) leads to artifacts, recent studies have involved tissue culture, superfusion and histochemistry, to analyze arachidonic acid metabolism, in endometrium, its tissues, and myometrium. First, it was established that Pgf2alpha and PGE2 are the primary PGs elaborated by human endometrium. The enzyme that produces Pgf2alpha, cyclooxygenase, is located primarily in the glandular endothelium. Pgf2alpha is under estrogen receptor control. Progesterone reduces Pgf2alpha and antiprogestogens increase it. In normal menstrual cycles, both PGs are highest in late luteal phase. In women with menorrhagia, defined as menstrual blood loss over 90 ml, the Pgf2alpha:PGE2 ratio is abnormally low, a reasonable finding since Pgf2alpha is vasoconstrictive, and PGE2 is a vasodilator. Another vasodilator PG, prostacyclin or PGI2, may be abnormally high in women with excessive bleeding. Some experiments on endometrium and myometrium, cultured apart and together, suggest that there may be flow of substrates of the PG pathways such that less Pgf2alpha is available in this condition. Using radiolabelled arachidonic acid, researchers concluded that the Pgf2alpha pathway may be saturated because of substrate being incorporated into excess triglycerides, leading to alternative PG release. Another theory proposes that PG antagonist drugs which block menstrual pain may also lower synthesis of leukotrienes, an eicosanoid that causes vasoconstriction as well as inflammation and pain. There have been no studies comparable to the tissue culture work cited above concerning IUDs. Some explorations of leukocyte PG metabolism and the effects of copper are relevant to the conclusions about PGE2 as a vasodilator. There could also be an alteration of locally produced thromboxanes and prostacyclins on blood clotting in IUD wearers.
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PMID:The role of prostaglandins and allied substances in uterine haemostasis. 331 24

Phenylbutazone is an acidic, lipophilic, non-steroidal anti-inflammatory drug (NSAID). It is extensively metabolized in the horse. The metabolites so far identified, oxyphenbutazone, gamma-hydroxyoxyphenbutazone, account for some 25-30% of administered dose over 24 h. The plasma half-life of phenylbutazone and termination of its pharmacological action are determined primarily by its rate of hepatic metabolism. Phenylbutazone acts by inhibiting the cyclooxygenase enzyme system, which is responsible for synthesis of prostanoids such as PGE2. It appears to act on prostaglandin-H synthase and prostacyclin synthase, after conversion by prostaglandin-H synthase to reactive intermediates. It markedly reduces prostanoid-dependent swelling, edema, erythema, and hypersensitivity to pain in inflamed tissues. Its principal use in the horse is for treatment of soft tissue inflammation. Phenylbutazone is highly bound (greater than 98%) to plasma protein. After i.v. injection, blood levels decline with an elimination half-life of 3-10 h. The plasma kinetics of phenylbutazone may be dose dependent, with the plasma half-life increasing as the drug dosage level increases. Plasma residues of the drug at 24 h after a single i.v. dose of 2 g/450 kg average about 0.9 microgram/ml, but considerable variation occurs. If dosing is repeated, the plasma residue accumulates to give mean residual blood levels of approximately 4.5 microgram/ml on Day 5 after 4 days of dosing. Approximately similar blood levels are found after a combination of oral and i.v. dosing. Experiments on large numbers of horses in training have been undertaken to ascertain the population distributions of residual blood levels after such dosing schedules. Absorption of phenylbutazone from the gastrointestinal tract is influenced by the dose administered and the relationship of dosing to feeding. Access to hay can delay the time of peak plasma concentration to 18 h or longer. Under optimal conditions, the bioavailability of oral phenylbutazone is probably in the region of 70%. Paste preparations may be more slowly absorbed than other preparations and yield higher residual plasma levels at 24 h after dosing, but further controlled studies are required. Phenylbutazone is easily detected in the plasma and urine of horses but concentrations in saliva are low. It is quantitated for forensic purposes by HPLC. The variability of this method between laboratories is about +/- 25%. Increasing urinary pH increases the urinary concentration of phenylbutazone and its metabolites up to 200-fold.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phenylbutazone in the horse: a review. 351 82

Primary dysmenorrhea may affect as many as 40 percent of all adult women, temporarily disabling one-tenth of them. The etiology of this condition may be related to excess production of prostaglandins by the endometrium following decline in progesterone levels consequent to corpus luteum regression. It is proposed that increased prostaglandin levels produce increased myometrial contractility and uterine ischemia and sensitization of pain fibers, resulting in pelvic pain. Administration of nonsteroidal anti-inflammatory agents which block the cyclooxygenase enzyme of the arachidonic acid cascade is an effective treatment for primary dysmenorrhea, as is oral contraceptive therapy. Criteria for an ideal prostaglandin synthetase inhibitor are described.
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PMID:Current concepts in the etiology and treatment of primary dysmenorrhea. 354 8

Since their synthesis in the late 1800s paracetamol (acetaminophen) and phenacetin have followed divergent pathways with regard to their popularity as mild analgesic/antipyretic drugs. Initially, paracetamol was discarded in favour of phenacetin because the latter drug was supposedly less toxic. Today the opposite is true, and paracetamol, along with aspirin, has become one of the two most popular 'over-the-counter' non-narcotic analgesic agents. This marked increase in the wide approval attained by paracetamol has been accompanied by the virtual commercial demise of phenacetin because of its role, albeit somewhat circumstantial, in causing analgesic nephropathy. Both paracetamol and phenacetin are effective mild analgesics, suitable for treating mild to moderate pain, and their actions are broadly comparable with those of aspirin and related salicylates, although they do not appear to possess significant anti-inflammatory activity. Since a major portion of a dose of phenacetin is rapidly metabolised to paracetamol, it seems possible that phenacetin owes some of its therapeutic activity to its main metabolite, paracetamol, whereas its most troublesome side effect (methaemoglobinaemia) is due to another metabolite, p-phenetidine. The mechanism of action of paracetamol is poorly defined, although it has been speculated that it may selectively inhibit prostaglandin production in the central nervous system, which would account for its analgesic/antipyretic properties. The lack of any significant influence on peripheral cyclooxygenase would explain the absence of anti-inflammatory activity. At therapeutic doses paracetamol is well tolerated and produces fewer side effects than aspirin. The most frequently reported adverse effect associated with paracetamol is hepatotoxicity, which occurs after acute overdosage (usually doses greater than 10 to 15g are needed) and, very rarely, during long term treatment with doses at the higher levels of the therapeutic range. Paracetamol damages the liver through the formation of a highly reactive metabolite which is normally inactivated by conjugation with glutathione. Overdoses of paracetamol exhaust glutathione stores, thus allowing the accumulation of this toxic metabolite which covalently binds with vital cell elements and can result in liver necrosis. Glutathione precursors (notably intravenous N-acetylcysteine) have proved remarkably successful in treating paracetamol overdose, as long as treatment is initiated within 10 hours.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Paracetamol and phenacetin. 355 85

Leukotriene D4 (LTD4) increased the blood flow rate in human skin, equipotent to histamine in the dose range of 3.1-200 pmol. The vasodilatation lasted for up to 60 min, and no late reactions occurred. Indomethacin did not affect the LTD4-induced blood flow rate. H1 and H2 antagonists reduced the increase in blood flow rate, but did not abolish the response to LTD4. Local nerve block inhibited the axon reflex-mediated flare component of the LTD4-induced blood flow rate, leaving a local red reaction. This local red reaction was not affected by H1 and H2 antagonists. These results indicate histamine as a mediator of the axon reflex, and show that LTD4 causes a direct vasodilatory effect that is not mediated via histamine or cyclooxygenase products. The laser-Doppler flowmeter was applied for dynamic studies of the vasopressor response in the skin during a Valsalva maneuver, and the relative changes in blood flow were confirmed by control estimates of the blood flow rate by a 133xenon washout method. The pressor response to a Valsalva maneuver was reversed by local nerve block, but not affected by LTD4. Therefore LTD4 did not interfere with the sympathetic activity on the cutaneous vessels. Leukotriene D4 caused a dose-dependent wheal reaction, equipotent to histamine in the dose range of 0.2-200 pmol. Only minor whealing occurred when the vasculature to the test arm was occluded before injection of LTD4 and the circulation restored 30 min later. Most of the LTD4 was apparently metabolized within this period. Subsequent injections of LTD4 into the same sites demonstrated the development of tachyphylaxis with respect to whealing. This evidence suggests that LTD4 cannot mediate sustained inflammation. The injections of LTD4 caused neither pain nor itching. In conclusion, the elucidated properties point to LTD4 as a possible mediator of microvascular changes during acute inflammation.
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PMID:Vascular effects of leukotriene D4 in human skin. 380 52


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