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)

Acetylsalicylic acid (ASA) is one of the most commonly used substances in the treatment of headache and other pain syndromes. It is only recently that its efficacy in the treatment of acute attacks and in the prophylaxis of migraine has been proven in clinical trials. Various peripheral and central mechanisms have been proposed for the analgesic effects of acetylsalicylic acid and its mode of action in migraine. The possible actions of acetylsalicylic acid in migraine include local analgesic effects, changes in cerebral serotonin turnover, modulation of antinociceptive neurons in the hypothalamus and inhibition of the release of algogenic peptides during neurogenic inflammation. In this study trigeminal somatosensory evoked potentials and single unit activity of central trigeminal neurons in the dorsolateral C2 spinal cord were monitored during electrical stimulation of the superior sagittal sinus in the cat. Intravenous administration of the soluble acetylsalicylic salt (acetylsalicylic lysinate, 30 mg/kg) reduced the peak-to-peak amplitudes of somatosensory evoked potentials from 219 +/- 11 mV by 18% after 45 minutes and by 26% after 60 minutes. Naloxone injection (0.5 mg/kg and 1.5 mg/kg) did not reverse the inhibition caused by ASA. The probability of trigeminal cell tiring was reduced in 63% percent of the monitored single units. The effect was not mediated through naloxone-sensitive opioid receptors and was independent from ASA-induced peripheral blockade of neuropeptides during neurogenic inflammation. The non-steroidal anti-inflammatory agent ketorolac (0.4 mg/kg, IVI) a new cyclooxygenase inhibitor, also reduced the somatosensory evoked potentials by 30% following the same time course.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intravenous acetylsalicylic acid inhibits central trigeminal neurons in the dorsal horn of the upper cervical spinal cord in the cat. 829 91

There is experimental evidence that inhibition of cyclooxygenase with nonsteroidal anti-inflammatory drugs may decrease cholesterol gallstone formation and mitigate biliary pain in gallstone patients. The mechanisms by which NSAIDs exert these effect are unclear. In a prospective, controlled clinical trial we examined the effects of oral indomethacin on the composition of human gallbladder bile. The study included 28 patients with symptomatic cholesterol or mixed gallstones. Of these, 8 were treated with 3 x 25 mg indomethacin daily for 7 days prior to elective cholecystectomy while 20 received no treatment and served as controls. Bile and tissue samples from the gallbladder were obtained during cholecystectomy. Indomethacin tissue levels in the gallbladder mucosa, as assessed by HPLC, were 1.05 +/- 0.4 ng/mg wet weight, a concentration known to inhibit effectively cyclooxygenase activity. Nevertheless, no differences between the treated and untreated groups were found in the concentrations of biliary mucus glycoprotein (0.94 +/- 0.27 versus 0.93 +/- 0.32 mg/ml) or total protein (5.8 +/- 0.9 versus 6.4 +/- 1.3 mg/ml), cholesterol saturation (1.3 +/- 0.2 versus 1.5 +/- 0.2), or nucleation time (2.0 +/- 3.0 versus 1.5 +/- 2.0 days). However, biliary viscosity, measured using a low-shear rotation viscosimeter, was significantly lower in patients receiving indomethacin treatment (2.9 +/- 0.6 versus 5.6 +/- 1.2 mPa.s; P < 0.02). In conclusion, in man oral indomethacin decreases bile viscosity without alteration of bile lithogenicity or biliary mucus glycoprotein content.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Indomethacin decreases viscosity of gallbladder bile in patients with cholesterol gallstone disease. 831 87

Aspirin is one of the oldest and most commonly used nonprescription drugs in the world. Although commonly it is used for relief from common headache and muscular pain, its use in the prevention and treatment of platelet related complications in cardiovascular diseases (CVD) and cerebrovascular disease (CBVD) is quite controversial. A brief review of the major aspirin trials indicated that a full strength aspirin taken daily had no significant beneficial effect in reducing mortality of patients with CVD/CBVD. However, two major trials (ISIS-2, PHS) in which either low dose aspirin (160 mg) or one aspirin administered every other day, have demonstrated significant reduction in fatal and nonfatal cardiovascular events. Even a dose as low as 1 mg aspirin per day significantly lowers platelet thromboxane synthesis. As a result of these studies, low dose aspirin should be the choice of prophylactic therapy aimed at the inhibition of platelet cyclooxygenase activity. Controlled-release low dose aspirin may favorably reduce platelet thromboxane production and spare vascular prostacyclin synthesis. At least 100 mgs of aspirin per day are essential to completely inhibit steady state thromboxane formation. Low dose aspirin (160 mgs) has been shown to be as effective as the full strength aspirin (325 mgs) in reducing clinical complications related to platelet activation. The antithrombotic effect of aspirin is well established and improved formulations, well thought out therapeutic protocols, customized dosage, appropriate timing of delivery, a better understanding of platelet function and pathophysiology of CUD/CBUD will facilitate maximization of the beneficial effects of aspirin.
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PMID:Aspirin in ischemic heart disease--an overview. 836 57

When used appropriately, non-steroidal anti-inflammatory drugs (NSAIDs) are safe and effective for treating pain and inflammation. NSAIDs that block both the lipoxygenase and cyclooxygenase pathways may be advantageous in some patients. New classes of NSAIDs that may have a more favorable safety profile than older agents may improve patient outcome. However, all patients receiving NSAIDs, especially the elderly, should be carefully monitored for possible drug-related complications.
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PMID:Nonsteroidal anti-inflammatory drugs. Tailoring therapy to achieve results and avoid toxicity. 844 44

Ketorolac tromethamine (Toradol [Syntex, Palo Alto]), a new commercially available nonsteroidal antiinflammatory drug (NSAID), has appropriate solubility and minimal tissue irritation, making it suitable for intramuscular injection. Previously, NSAID have only been available for oral use in the United States for the treatment of pain. Ketorolac, the most potent NSAID known, relieves pain through inhibition of arachidonic acid synthesis at the cyclooxygenase level and has no central opioid effects. The results of previous studies using parenteral ketorolac in combination with patient administered narcotics have shown a 40 percent reduction in narcotic requirements. However, ketorolac is presently only approved for intramuscular injection and oral use in the United States. In a prospective, randomized study, we compared intramuscular ketorolac in combination with patient controlled intravenous narcotic analgesia (morphine) (PCA-M) to PCA-M alone for the control of pain after extensive colonic resections. The combination of intramuscular ketorolac and PCA-M provided equal pain relief with no increased side effects when compared with narcotics alone. However, narcotic requirements of the patients were decreased by an average of 45 percent. Ketorolac and narcotics in combination provide effective postoperative pain relief and significantly decrease narcotic requirements. This combination may be particularly beneficial in the subpopulation of patients especially prone to narcotic related complications.
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PMID:Ketorolac and patient controlled analgesia in the treatment of postoperative pain. 848 Feb 64

The recent discovery of an alternative form cyclooxygenase (cyclooxygenase-2, COX-2), which has been proposed to play a significant role in inflammatory conditions, may provide an opportunity to develop anti-inflammatory drugs with fewer side effects than existing non-steroidal anti-inflammatory drugs (NSAIDs). We have now identified 6-[(2,4-difluorophenyl)-thio]-5-methanesulfonamido-1-indanone++ + (20) (L-745,337) as a potent, selective, and orally active COX-2 inhibitor. The structure-activity relationships in this series have been extensively studied. Ortho- and para-substituted 6-phenyl substitutents are optimal for in vitro potency. Replacement of this phenyl ring by a variety of heterocycles gave compounds that were less active. The methanesulfonamido group seems to be the optimal group at the 5-position of the indanone system. Compound 20 has an efficacy profile that is superior or comparable to that of the nonselective COX inhibitor indomethacin in animal models of inflammation, pain, and fever and appears to be nonulcerogenic within the dosage ranges required for functional efficacy. Although 20 and its oxygen linkage analog 2 (flosulide) are equipotent in the in vitro assays, compound 20 is more potent in the rat paw edema assay, has a longer t1/2 in squirrel monkeys, and seems less ulcergenic than 2 in rats.
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PMID:Cyclooxygenase-2 inhibitors. Synthesis and pharmacological activities of 5-methanesulfonamido-1-indanone derivatives. 852 3

Sensitization of primary afferent neurons underlies much of the pain and tenderness associated with tissue injury and inflammation. The increase in excitability is caused by chemical agents released at the site of injury. Because recent studies suggest that an increase in voltage-gated Na+ currents may underlie increases in neuronal excitability associated with injury, we have tested the hypothesis that a tetrodotoxin-resistant voltage-gated Na+ current (TTX-R INa), selectively expressed in a subpopulation of sensory neurons with properties of nociceptors, is a target for hyperalgesic agents. Our results indicate that three agents that produce tenderness or hyperalgesia in vivo, prostaglandin E2, adenosine, and serotonin, modulate TTX-R INa. These agents increase the magnitude of the current, shift its conductance-voltage relationship in a hyperpolarized direction, and increase its rate of activation and inactivation. In contrast, thromboxane B2, a cyclooxygenase product that does not produce hyperalgesia, did not affect TTX-R INa. These results suggest that modulation of TTX-R INa is a mechanism for sensitization of mammalian nociceptors.
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PMID:Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. 857 23

The therapeutic utility of cyclooxygenase (CO) inhibitors, such as ketorolac, in reducing the inflammatory events associated with allergic conjunctivitis is not unexpected since prostanoids (PG) elicit conjunctival redness (PGD2, PGE2, PGF2 alpha), edema (PGD2, TxA2), eosinophil infiltration (PGD2, PGJ2) and mucous cell discharge (PGD2, PGJ2, TxA2). Recently, topically administered ketorolac has also been reported to alleviate the itching associated with allergic conjunctivitis. This was viewed as intriguing since CO inhibitors are not regarded as useful for treating itching dermatoses and PGs do not elicit itching when applied to the skin. In order to investigate the antipruritic activity of ketorolac, we developed a model for reproducibly measuring ocular surface itch responses. The model involves itch-scratch responses to pruritogens applied locally to the ocular surface. Painful and foreign body stimuli do not produce an itch-scratch response. Unlike reported skin studies, PGE2 was a potent itch-producing substances in the conjunctiva. PGD2 was weakly pruritogenic but PGF2 alpha and the TxA2-mimetic U-46619 were inactive. The PG precursor arachidonic acid was also a potent pruritogen and its effects were inhibited by ketorolac pretreatment. Ketorolac also dose-dependently inhibited the itching associated with experimental allergic conjunctivitis. It appears that PGs are potent itch-producing substances in the conjunctiva and the anti-itch efficacy of ketorolac in allergic conjunctivitis appears to involve inhibition of conjunctival PG biosynthesis from arachidonic acid.
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PMID:The pruritogenic and inflammatory effects of prostanoids in the conjunctiva. 859 Feb 66

Conventional drug therapy in rheumatoid arthritis (RA) has failed to control the longterm morbidity and mortality associated with RA. Similarly, drug therapy for osteoarthritis (OA) can relieve symptoms, but it is not clear that it alters progression of disease. Three classes of drugs are widely used for treatment of RA: nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and the slow-acting agents. In most patients, pharmacologic therapy is initiated with NSAIDs. These drugs can relieve symptoms but do not alter the course of the disease. The gastrointestinal and other side effects attributed to these compounds are well known. Similarly, use of corticosteroids can provide rapid pain relief to patients with RA and, if used in low doses, pose limited risk of toxicity. Slow-acting agents, including gold, d-penicillamine, and methotrexate, appear to decrease radiographic progression and improve clinical and biochemical indicators of RA. Therefore, newer treatment philosophies encourage use of slow-acting agents earlier in the course of the disease in order to prevent or diminish bone and joint erosions and destruction and other manifestations of disease progression. Drugs under investigation for the treatment of arthritis appear to exhibit disease-modifying or immunomodulating properties. Tenidap is a novel agent that possesses a dual mechanism of action: cyclooxygenase inhibition and modulation of cytokine activity. In addition, several biologic agents, including antibodies to tumor necrosis factor-alpha (TNF-alpha) and to intercellular adhesion molecule-1, may prove useful. These immunotherapeutic strategies are based on knowledge of the role of cytokines in the inflammatory process in arthritis. Osteoarthritis may be managed using drug and nondrug modalities. Weight loss is especially important when OA is in the weight-bearing joints. Biopsies of synovium from patients with OA show evidence of inflammation, but whether this disease should be treated with analgesics alone or with anti-inflammatory drugs remains controversial. Other treatment modalities, including tissue transplants and cytokine-modulating drugs, are emerging for the potential therapy of OA. Surgery may also be appropriate if drug treatment fails to control symptoms.
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PMID:Management of osteoarthritis and rheumatoid arthritis: prospects and possibilities. 860 23

In a pilot study we investigated the association between concentrations of various eicosanoids in menstrual blood with pain and oral contraceptive use. Menstrual fluid was collected on tampons by 12 women who did not use an oral contraceptive but suffered from slight primary dysmenorrhea and by three pain-free women who used an oral contraceptive. Eicosanoids (cyclooxygenase products: 6-ketoprostaglandin F1 alpha, thromboxane B2, prostaglandin E2, prostaglandin F2 alpha, 13,14-dihydro-15-ketoprostaglandin F2 alpha, 12-hydroxy-heptadecatrienoic acid; lipoxygenase products: 5-, 12-, 15-hydroxy-eicosatetraenoic acid (HETE), leukotriene B4, leukotriene C4, leukotriene D4, leukotriene E4) and female sex steroids (17 beta-estradiol and progesterone) were analyzed by the combined use of high-performance liquid chromatography and radioimmunoassay. 12-HETE was the main arachidonic acid metabolite. An increased metabolism of arachidonic acid was associated with pain, especially when synthesis of 12-HETE was elevated. Oral contraceptive use decreased the synthesis of prostaglandins as well as leukotrienes. The concordant changes of cyclooxygenase and lipoxygenase products in dysmenorrhea or in oral contraceptive use may be explained by an increased or decreased phospholipid metabolism, respectively.
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PMID:Concentrations of various arachidonic acid metabolites in menstrual fluid are associated with menstrual pain and are influenced by hormonal contraceptives. 862 59


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