Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostacyclin (PGI2) is known to cause vasorelaxation and inhibit platelet aggregation by receptor-mediated mechanisms. While cyclic (c) AMP is known to act as a second messenger for inhibition of platelet aggregation, vasorelaxation by hyperpolarization has been described only recently and may provide an explanation, in addition to stimulation of cAMP for the PGI2 mechanism of action on blood vessels. When PGI2 is infused into healthy volunteers it reduces blood pressure only at infusion rates that also cause significant side-effects, primarily, nausea, emesis, flushing, diaphoresis, and restlessness. In hypertensive patients blood-pressure responses are complex and are influenced to some extent by renin secretion. PGI2 stimulates renin secretion by a direct effect on the juxtaglomerular apparatus, and it also has an indirect effect by activating the sympathetic nervous system. Thus, it is useless as an antihypertensive agent even apart from its debilitating side-effects. Vascular PGI2 is synthesized endogenously by both the endothelial cells and the muscularis of arteries. While the endothelial cells undoubtedly synthesize large amounts of PGI2, the muscularis comprises a much larger tissue mass so that the overall synthesis is about equally distributed between the endothelial and muscle cells. In patients with pregnancy-induced hypertension and some patients with essential hypertension endogenous synthesis of PGI2 has been evaluated by measuring 2,3-dinor-6-keto-PGF1 alpha and has proved to be greatly reduced. Some drugs (thiazides, propranolol) have been shown to stimulate PGI2 synthesis, and inhibition of cyclooxygenase has been shown to reduce their antihypertensive effects. The effects of low- and high-dose aspirin on prostacyclin and thromboxane synthesis are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Prostacyclin in hypertension]. 149 51

Prostacyclin (PGI2) is known to cause vasorelaxation and inhibit platelet aggregation by receptor-mediated mechanisms. While cyclic (c)AMP is known to act as a second messenger for platelet aggregation, vasorelaxation by hyperpolarization has been described only recently and may provide an explanation, in addition to stimulation of cAMP, for the PGI2 mechanism of action on blood vessels. When PGI2 is infused into healthy volunteers it reduces blood pressure only at infusion rates that also cause significant side effects, primarily nausea, emesis, flushing, diphoresis and restlessness. In hypertensive patients blood pressure responses are complex and are influenced to some extent by secretion. PGI2 stimulates renin secretion by a direct effect on the juxtaglomerular apparatus, and also has an indirect effect by activating the sympathetic nervous system. Thus it is useless as an antihypertensive agent even apart from its debilitating side effects. Vascular PGI2 is synthesized endogenously by both the endothelial cells and the muscularis of arteries. While the endothelial cells undoubtedly synthesize larger amounts of PGI2, the muscularis comprises a much larger tissue mass so that the overall synthesis is about equally distributed between the endothelial and muscle cells. In patients with pregnancy-induced hypertension and some patients with essential hypertension, endogenous synthesis of PGI2 has been evaluated by measuring 2,3-dinor-6-keto-PGF1 alpha and has proved to be defective. Some drugs (cicletanine, thiazides, propranolol) have been shown to stimulate PGI2 synthesis, and inhibition of cyclooxygenase has been shown to abolish their antihypertensive effects. Whether stimulation of PGI2 synthesis affects the antihypertensive efficacy of these drugs is not yet known.
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PMID:Prostacyclin in hypertension. 225 88

CI-986 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)- thione-2-hydroxy-N,N,N-trimethylethanaminium salt) is a novel anti-inflammatory compound classified as a dual inhibitor of cyclooxygenase and 5-lipoxygenase. Studies were undertaken to characterize the preclinical toxicology of the compound. CI-986 was administered to rats for 2 weeks (0, 50, 250, 750, and 1500 mg/kg) or 13 weeks (0, 20, 250, 500, and 1000 mg/kg), dogs for 2 weeks (0, 50, 150, and 500 mg/kg) or 13 weeks (0, 20, 100, and 200 mg/kg), and to monkeys for 2 weeks (0, 50, 250, and 1000 mg/kg). No drug-related deaths resulted. Mild clinical signs of toxicity were noted in rats given doses of 250 mg/kg and above. Drug-related emesis and diarrhea were absent at the low dose in the dog and monkey but increased in incidence and severity at higher doses. Severe clinical signs in monkeys (emesis and diarrhea) necessitated the lowering of the top dose to 500 mg/kg/day (administered b.i.d.) during the second week of the monkey study. Slight decreases (< 23%) in serum protein and/or albumin were noted in all studies at the higher doses. A dose-related increase in alkaline phosphatase was noted in both dog studies, with no other drug-related effect on clinical pathology parameters. A gastric ulcer occurred in one rat administered 500 mg/kg CI-986 for 13 weeks. Gastrointestinal ulcers were not noted at any other dose in rats or at any dose in dogs or monkeys. A dose-related eosinophilia of glandular stomach submucosa was noted in rats after 2 and 13 weeks of drug administration but not in dogs or monkeys. In the 2-week rat study, mean combined sex plasma drug concentrations monitored 2 hr after dose on Day 14 were 0.59, 1.10, 2.64, and 3.43 micrograms/ml for the 50, 250, 750, and 1,500 mg/kg dose groups, respectively. In the 2-week dog studies, maximum plasma drug concentrations on Day 10 or Day 11 were achieved within 2 hr of dose with mean combined sex Cmax values of 0.73, 2.05, and 2.62 micrograms/ml for the 50, 250, and 750 mg/kg groups, respectively. Hepatic microsomal induction characterized by increased microsomal protein, increased microsomal cytochrome P450 content, and increased p-nitroanisole O-demethylation activity was noted in dogs and monkeys but not rats. CI-986 was well tolerated in rats and dogs at the doses employed and in monkeys at doses up to 500 mg/kg (b.i.d.).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Subacute and subchronic toxicology studies of CI-986, a novel anti-inflammatory compound. 831 60

Headache is known to be the predominant symptom in acute mountain sickness which is also frequently accompanied by nausea, vomiting and insomnia. Nowadays, every year millions of skiers and mountaineers are attracted to mountains all over the world. At altitudes between 2500 m and 5000 m about 20% to 90% of those who are not adapted to high altitude will experience high altitude headache (HAH). It is well documented that HAH can be best prevented by observance of the golden rule: not to go too high too fast. Although many mountaineers are aware of this rule, its observance is complicated by unknown individual susceptibility, the location of mountain huts, the use of cable cars, limited holiday time, unfavorable weather or avalanche conditions. Therefore, there is a widespread use of drugs for the treatment and prevention of HAH. In the past, the increase in cerebral blood flow during acute hypoxia was thought to be the main cause of HAH. More recent findings, however, have caused this hypothesis to be reduced in importance and have supported the pathogenetic consequence of sensitization of intracranial pain-sensitive structures. The effectiveness of cyclooxygenase inhibition for the treatment and prevention of HAH suggests that especially prostaglandins may be an important mediator between hypoxia and HAH. Besides oxygen, acetazolamide, dexamethasone and especially inhibitors of prostaglandin synthesis such as ibuprofen and naproxen are approved for the treatment of HAH. Acetazolamide, dexamethasone, and aspirin were also found to prevent HAH. The most beneficial effects however, may be achieved by the combined application of acetazolamide and aspirin. This combination increases oxygenation and reduces prostaglandin synthesis.
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PMID:[High altitude headache: epidemiology, pathophysiology, therapy and prophylaxis]. 1058 87

The emetic response to intraperitoneal (i.p., 0.5, 2, 8 mg kg(-1)) and intravenous (i.v., 200 microg kg(-1)) administration of bacterial lipopolysaccharides (LPS) was characterized in conscious piglets observed for 4 h. The latencies and the incidence of the emetic response to LPS (i.p.) decreased and increased, respectively, in a dose-dependent manner. In 14 additional piglets, a bilateral vagotomy performed 4 h prior to LPS administration abolished the vomiting induced by i.p. LPS (2 mg kg(-1)), and decreased its incidence by 77% in the i.v. injected animals. Sham-operated animals (n=6) exhibited a similar emetic pattern to the controls injected intraperitoneally with LPS (2 mg kg(-1)). In 7 piglets, the administration of granisetron, a 5-HT(3) receptor antagonist (i.v., 2 mg kg(-1)), 30 min prior to the i.p. LPS injection (2 mg kg(-1)) failed to reduce significantly the emetic activity; whereas, in 6 animals, a combination of meloxicam (0.3 mg kg(-1)) and indomethacin (5 mg kg(-1)), two cyclooxygenase (COX) inhibitors, administered per os 1.5 h prior to the i.p. LPS (2 mg kg(-1)) abolished the emetic response to endotoxins. The present results show that the activation of the medullary "vomiting centre" in response to i.p. administration of LPS is mediated via vagal afferents and is likely to involve prostaglandins.
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PMID:Characterization of lipopolysaccharide-induced emesis in conscious piglets: effects of cervical vagotomy, cyclooxygenase inhibitors and a 5-HT(3) receptor antagonist. 1097 16

Cannabinoids, including the endogenous cannabinoid or endocannabinoid, anandamide, modulate several gastrointestinal functions. To date, the gastrointestinal effects of the second putative endocannabinoid 2-arachidonoylglycerol (2-AG) have not been studied. In the present study using a shrew (Cryptotis parva) emetic model, 2-AG (0.25-10 mg/kg, i.p.) potently and dose-dependently increased vomiting frequency (ED(50) = 1.13 mg/kg) and the number of animals vomiting (ED(50) = 0.48 mg/kg). In contrast, neither anandamide (2.5-20 mg/kg) nor methanandamide (5-10 mg/kg) induced a dose-dependent emetogenic response, but both could partially block the induced emetic effects. Delta(9)-Tetrahydrocannabinol and its synthetic analogs reduced 2-AG-induced vomiting with the rank order potency: CP 55,940 > WIN 55,212-2 > Delta(9)-tetrahydrocannabinol. The nonpsychoactive cannabinoid, cannabidiol, was inactive. Nonemetic doses of SR 141716A (1-5 mg/kg) also blocked 2-AG-induced vomiting. The 2-AG metabolite arachidonic acid also caused vomiting. Indomethacin, a cyclooxygenase inhibitor, blocked the emetogenic effects of both arachidonic acid and 2-AG. CP 55,940 also blocked the emetic effects of arachidonic acid. 2-AG (0.25-10 mg/kg) reduced spontaneous locomotor activity (ED(50) = 11 mg/kg) and rearing frequency (ED(50) = 4.3 mg/kg) in the shrew, whereas such doses of both anandamide and methanandamide had no effect on locomotor parameters. The present study indicates that: 1) 2-AG is an efficacious endogenous emetogenic cannabinoid involved in vomiting circuits, 2) the emetic action of 2-AG and the antiemetic effects of tested cannabinoids are mediated via CB(1) receptors, and 3) the emetic effects of 2-AG occur in lower doses relative to its locomotor suppressant actions.
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PMID:The potent emetogenic effects of the endocannabinoid, 2-AG (2-arachidonoylglycerol) are blocked by delta(9)-tetrahydrocannabinol and other cannnabinoids. 1175 94

Adverse reactions to acetylsalicylic acid (aspirin, ASA) and other non-steroidal anti-inflammatory drugs (NSAIDs) are the second most important cause of adverse drug reactions (ARDs) after beta-lactams. They produce various clinical manifestations and can affect different organs. Gastrointestinal reactions (pyrosis, vomiting, gastralgia), neurological reactions (tinnitus, deafness, vertigo), blood dyscrasias, and nephrotoxic and hepatotoxic reactions are well known.NSAIDs are the drugs of choice in the treatment of chronic arthropathies and other childhood connective-tissue diseases and are also commonly used in the treatment of febrile and acute inflammatory processes. Not all NAIDs are authorized for use in the pediatric population but their spectrum of use varies according to the entity for which they are indicated and the legislation of the country. Published studies on the prevalence of aspirin intolerance in patients with bronchial asthma show a fair amount of disagreement. This may be due to (i) the method of selecting asthmatic patients for the study, which differs according to whether all asthmatic patients are included or only those dependent on corticoids; (ii) the diagnostic method used, whether based on clinical criteria or oral provocation tests, which will affect the number of patients with a diagnosis of intolerance. In children aged less than 10 years, including children with asthma, the prevalence is low, while among children and young adults aged 10-20 years old, the prevalence is estimated at 10 %. Some hypotheses attempt to explain the mechanisms through which adverse reactions to NAIDs take place. One hypothesis attributes the reaction to a reaginic immunological mechanism but this hypothesis has only been confirmed in exceptional cases. The theory of the cyclooxygenase pathway, currently the most widely accepted, is based on the ability of NSAIDs to inhibit the cyclooxygenase pathway of arachidonic acid metabolism, leading to prostaglandin depletion and an increase in leukotrienes. The discovery of two isoforms of the cyclooxygenase enzymes, COX-1 and COX-2, has represented a great advance in our understanding of the mechanism of action of NSAIDs and has also elucidated the problem of cross-reactivities. According to the theory of viral infection, aspirin-induced asthma could be caused by chronic viral infection since, after initial exposure to the virus, cytotoxic lymphocytes are produced. Their activity is inhibited by prostaglandin E2 (PGE2); aspirin and other NSAIDs block PGE2 production and allow cytotoxic lymphocytes to attack and eliminate the respiratory tract cells infected by the virus. During this reaction lysosomal enzymes and mediators are released, which could precipitate an asthmatic crisis.Clinically, five types of reaction have been identified: 1. Respiratory illness with aspirin sensitivity. 2. Aspirin-induced urticarial disease. 3. Allergic reactions to NSAIDs and aspirin. 4 and 5. Aseptic meningitis and pneumonitis due to hypersensitivity. The latter are exceptional and are published as case reports. They have never been associated with aspirin or acetaminophen and usually occur in patients undergoing prolonged treatment. Diagnosis is based on a detailed history. Skin tests are not valid and in vitro tests are not widely used. Provocation tests with aspirin and NSAIDs definitively identify sensitized patients but their indications and limitations should be kept in mind. In children, certain features of adverse reactions to NSAIDs are observed in relation to their incidence and clinical manifestations. Acetaminophen is considered the drug of choice but further studies of other alternatives in children are required.
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PMID:[Special features of NSAID intolerance in children]. 1278 61

The chemotherapeutic agent cisplatin may produce emesis via release of several neurotransmitters such as serotonin (5-HT), substance P and/or dopamine as well as production of prostaglandins (PGs). Administration of synthetic 2-arachidonoylglycerol (2-AG) but not of anandamide, which are two putative endocannabinoids, causes vomiting via its downstream metabolites such as arachidonic acid (AA) and PGs in the least shrew (Cryptotis parva). We report here that cisplatin (0, 5, 10 and 20 mg/kg, i.p.) causes dose- and time-dependent increases in brain tissue levels of 2-AG but not anandamide in this vomiting species. Concomitantly, intestinal tissue levels of both endocannabinoids are relatively reduced. Selective inhibitors [arachidonoyl-serotonin (AA-5-HT) and URB597, 0-5 and 0-10 mg/kg, i.p.] of one of the major endocannabinoid metabolic enzymes, the intracellular fatty acid amide hydrolase (FAAH), do not significantly prevent vomiting produced by emetic doses of i.p.-administered 2-AG, cisplatin or the dopamine receptor agonist apomorphine. At large doses (10 and 20 mg/kg, respectively), both FAAH inhibitors caused emesis per se. Administration of one selective uptake inhibitor of endocannabinoids, OMDM1 (0-5 mg/kg, i.p.), also did not significantly prevent emesis by the direct and indirect emetic stimuli, and likewise caused emesis by itself at a high (10 mg/kg) dose. However, another selective uptake inhibitor, VDM11, did not produce significant emesis per se and prevented emesis caused by apomorphine. Both the corticosteroid dexamethasone, and the cyclooxygenase inhibitor indomethacin, reduced vomiting produced by cisplatin. These data: (a) provide the first evidence that cisplatin causes a selective increase in 2-AG levels in the brain, and (b) support the established notion that 2-AG may produce some of its effects, including emesis, via downstream metabolites produced independently of FAAH.
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PMID:Cisplatin increases brain 2-arachidonoylglycerol (2-AG) and concomitantly reduces intestinal 2-AG and anandamide levels in the least shrew. 1592 9

Opiates are the primary treatment for pain management in cancer patients reporting moderate to severe pain, and are being increasingly used for non-cancer chronic pain. However, prolonged administration of opiates is associated with significant problems including the development of antinociceptive tolerance, wherein higher doses of the drug are required over time to elicit the same amount of analgesia. High doses of opiates result in serious side effects such as constipation, nausea, vomiting, dizziness, somnolence, and impairment of mental alertness. In addition, sustained exposure to morphine has been shown to result in paradoxical pain in regions unaffected by the initial pain complaint, and which may also result in dose escalation, i.e. 'analgesic tolerance'. A concept that has been gaining considerable experimental validation is that prolonged use of opioids elicits paradoxical, abnormal pain. This enhanced pain state requires additional opioids to maintain a constant level of antinociception, and consequently may be interpreted as antinociceptive tolerance. Many substances have been shown to block or reverse antinociceptive tolerance. A non-inclusive list of examples of substances reported to block or reverse opioid antinociceptive tolerance include: substance P receptor (NK-1) antagonists, calcitonin gene-related peptide (CGRP) receptor antagonists, nitric oxide (NO) synthase inhibitors, calcium channel blockers, cyclooxygenase (COX) inhibitors, protein kinase C inhibitors, competitive and non-competitive antagonists of the NMDA (N-methyl-D-aspartate) receptor, AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) antagonists, anti-dynorphin antiserum, and cholecystokinin (CCK) receptor antagonists. Without exception, these substances are also antagonists of pain-enhancing agents. Prolonged opiate administration indeed induces upregulation of substance P (SP) and calcitonin gene-related peptide (CGRP) within sensory fibers in vivo, and this is accompanied by an enhanced release of excitatory neurotransmitters and neuropeptides from primary afferent fibers upon stimulation. The enhanced evoked release of neuropeptides is correlated with the onset of abnormal pain states and opioid antinociceptive tolerance. Importantly, the descending pain modulatory pathway from the brainstem rostral ventromedial medulla (RVM) via the dorsolateral funiculus (DLF) is critical for maintaining the changes observed in the spinal cord, abnormal pain states and antinociceptive tolerance, because animals with lesion of the DLF did not show enhanced evoked neuropeptide release, or develop abnormal pain or antinociceptive tolerance upon sustained exposure to opiates. Microinjection of either lidocaine or a CCK antagonist into the RVM blocked both thermal and touch hypersensitivity as well as antinociceptive tolerance. Thus, prolonged opioid exposure enhances a descending pain facilitatory pathway from the RVM that is mediated at least in part by CCK activity and is essential for the maintenance of antinociceptive tolerance.
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PMID:Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? 1621 2

Given the expanding role of ambulatory surgery and the need to facilitate an earlier hospital discharge, improving postoperative pain control has become an increasingly important issue for all anesthesiologists. As a result of the shift from inpatient to outpatient surgery, the use of IV patient-controlled analgesia and continuous epidural infusions has steadily declined. To manage the pain associated with increasingly complex surgical procedures on an ambulatory or short-stay basis, anesthesiologists and surgeons should prescribe multimodal analgesic regimens that use non-opioid analgesics (e.g., local anesthetics, nonsteroidal antiinflammatory drugs, cyclooxygenase inhibitors, acetaminophen, ketamine, alpha 2-agonists) to supplement opioid analgesics. The opioid-sparing effects of these compounds may lead to reduced nausea, vomiting, constipation, urinary retention, respiratory depression and sedation. Therefore, use of non-opioid analgesic techniques can lead to an improved quality of recovery for surgical patients.
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PMID:The changing role of non-opioid analgesic techniques in the management of postoperative pain. 1633 89


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