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)

The availability of radiolabelled ligands selective for various putative neurotransmitter receptor sites and the development of quantitative autoradiography has led to a greater understanding of the neuronal pathway and receptor subtypes involved in the vomiting reflex induced by various mechanisms both within the central nervous system and the periphery. Receptors for acetylcholine, dopamine, histamine and serotonin have been detected in a number of brain regions associated with the vomiting reflex, and provide a rational basis for the antiemetic action of drugs that inhibit receptor subtypes for these neurotransmitters. The basis of the antiemetic action of other drugs such as dexamethasone and the cannabinoids is still obscure. Some drugs act on more than 1 receptor subtype. Metoclopramide may inhibit both dopamine D2- and 5-HT3 receptors in producing its antiemetic effect. Both metoclopramide and domperidone appear to have additional peripheral actions that contribute to their effectiveness. The cannabinoids are effective in cytotoxic-induced vomiting, perhaps acting via endorphin receptors or by inhibiting prostaglandin synthesis. The effectiveness of 5-HT3 receptor antagonists may depend on the block of both central and peripheral neuronal 5-HT3 receptors. Vomiting constitutes a major disadvantage to the use of many drugs; vomiting induced by aminoglycoside antibiotics appears to be due to ototoxicity and is relieved by histamine H1-receptor antagonists. The protracted vomiting associated with the use of some cytotoxics in cancer chemotherapy may involve psychic components, the chemoreceptor trigger zone and peripheral sensory neurons. Both 5-HT3 and dopamine D2-receptor antagonists exert some control, the former being more effective with cytotoxics of high emetogenic potential, such as cisplatin. Serotonin 5-HT3 receptor antagonists or high doses of metoclopramide in combination with anxiolytics and steroids as well as greater attention to pharmacokinetic profiles of the drugs involved would appear to offer improved control. The use of dopamine receptor antagonists in controlling emesis induced by dopamine agonists used in Parkinson's disease poses theoretical problems which can be overcome by using drugs with selectivity for the chemoreceptor trigger zone, such as domperidone or metoclopramide. However, higher doses of these drugs may produce some impairment of therapeutic responses to the agonists. Muscarinic and nicotinic agonists currently under investigation in Alzheimer's disease pose another therapeutic dilemma as emesis is due to a central action of these compounds. Several sites may be involved including the chemoreceptor trigger zone and frontal lobes. Opiates may act through dopamine receptors or mu-receptors on dopaminergic nerves, but serotonergic mechanisms may also be involved in the action of some opiates.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacological agents affecting emesis. A review (Part I). 137 16

Ondansetron (GR 38032) has potent and highly selective antagonist properties at the 5-hydroxytryptamine (5-HT, serotonin) 5-HT3 receptor. The selectivity ratio for ondansetron on 5-HT3 receptors compared with actions on other neurotransmitter receptor types is greater than 1,000. The antiemetic properties of ondansetron have been determined in ferrets against the nausea and vomiting induced by cisplatin, cyclophosphamide, and whole-body radiation. Ondansetron (intravenous 0.01 to 0.1 mg/kg or subcutaneous 0.1 to 0.5 mg/kg) or metoclopramide (1.0 to 4.0 mg/kg) cause dose-dependent inhibitions of the vomiting induced by each of these procedures. Unlike ondansetron, the effects of metoclopramide are accompanied by moderate to marked behavioral depression. Since metoclopramide is 50 times more potent on dopamine D2 receptors than on 5-HT3 receptors, the behavioral depression is likely due to profound blockade of dopamine receptors. The 5-HT3 receptors have been shown to be present peripherally on vagal afferent fibers and are densely located in the vomiting center of the hindbrain. The current hypothesis is that there may be both a peripheral and a central site of action for ondansetron and other 5-HT3 antagonists. The lack of antagonist activity on dopamine and other non-5-HT3 receptors indicates that, unlike metoclopramide, ondansetron will not cause extrapyramidal or other dose-limiting side effects.
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PMID:Pharmacology and preclinical antiemetic properties of ondansetron. 138 45

The serotonin 5-HT3 receptor antagonist effects of DAT-582, the (R) enantiomer of AS-5370 ((+/-)-N-[1-methyl-4-(3-methyl-benzyl)hexahydro-1H-1,4-diazepin-6- yl]-1H- indazole-3-carboxamide dihydrochloride), and its antipode were compared with those of AS-5370 and existing 5-HT3 receptor antagonists. In anesthetized rats, DAT-582 antagonized 2-methyl-5-HT-induced bradycardia with an ED50 value of 0.25 microgram/kg i.v., whereas the (S) enantiomer was without effect even at 1000 micrograms/kg i.v. In antagonizing the bradycardia, DAT-582 was as potent as granisetron, slightly more potent than AS-5370, and 2, 5 and 18 times more potent than ondansetron, ICS 205-903 and renzapride, respectively, although it was less potent than zacopride. DAT-582 inhibited cisplatin (10 mg/kg i.v.)-induced emesis in ferrets with an ED50 value of 3.2 micrograms/kg i.v. twice. The antiemetic activity of DAT-582 was more potent than that of the existing 5-HT3 receptor antagonists examined, except zacopride. In contrast, the (S) enantiomer had little effect at 1000 micrograms/kg i.v. twice. In isolated guinea-pig ileum, DAT-582 inhibited 5-HT-induced contractions with an IC50 value of 91 nM, whereas the (S) enantiomer hardly inhibited them even at 1000 nM. These results suggest that DAT-582, the (R) enantiomer of AS-5370, potently and selectively blocks 5-HT3 receptors.
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PMID:5-HT3 receptor antagonist effects of DAT-582, (R) enantiomer of AS-5370. 142 31

In the present study, the emetic effect of the anticancer drug cisplatin, and the protective effects of 5-HT3 receptor antagonists against cisplatin emesis were investigated in the pigeon. The experimental set-up involved the i.v. administration of drugs and subsequent observation of the percentage of vomiting animals and the number of emetic episodes per vomiting animal. It was observed that cisplatin induced dose-dependent emesis in the pigeon. 5-HT3 receptor antagonists afforded partial protection against cisplatin emesis, although some of them, i.e. indole, indole-like derivatives and zacopride, displayed intrinsic emetic activity. A serotonergic mechanism appears to be involved in both cisplatin- and 5-HT3 receptor antagonist-induced emesis, since pretreatment with an inhibitor of 5-HT synthesis, para-chlorophenylalanine (pCPA), prevented vomiting induced by either cisplatin or 5-HT3 receptor antagonists. It is concluded that the intrinsic emetic effects of 5-HT3 receptor antagonists provide pharmacological evidence of species differences in the properties of 5-HT3 receptors.
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PMID:The effects of 5-HT3 receptor antagonists on cisplatin-induced emesis in the pigeon. 142 10

The involvement of visceral afferent fibers and 5-HT3 receptors in the emesis induced by cisplatin was studied in beagle dogs. The emesis induced by cisplatin (3 mg/kg, i.v.) was inhibited by the intravenous administration of ICS205930 (2 x 0.01 or 2 x 0.1 mg/kg) and MDL72222 (2 x 0.5 mg/kg), 5-HT3 receptor antagonists, but not by the intravenous administration of metoclopramide (2 x 0.5 mg/kg), a dopamine D2 receptor antagonist. The cisplatin-induced emesis was also suppressed by the intravenous administration of para-chlorophenylalanine (300 mg/kg/day for 3 days), an inhibitor of 5-HT synthesis. On the other hand, the administration of ICS205930 into the IVth ventricle (2 x 0.01 mg/animal) had no effects on the cisplatin-induced emesis. The cisplatin-induced emesis was completely inhibited by abdominal vagotomy and splanchnicectomy, but not by splanchnicectomy alone. On the contrary, the emesis induced by apomorphine was suppressed by the intravenous (0.1 mg/kg) or intracerebroventricular (0.05 mg/animal) administration of metoclopramide, but not by visceral nerve section. These results strongly suggest that cisplatin evokes emesis mainly by acting on the vagal afferent terminals through the release of 5-HT and that peripheral 5-HT3 receptors are involved in this action.
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PMID:Vagal afferent fibers and peripheral 5-HT3 receptors mediate cisplatin-induced emesis in dogs. 143 18

Pancopride ((+-)N-(1-azabicyclo-[2,2,2]-oct-3-yl)-2-cyclopropylmethoxy-4-ami no-5-chlorobenzamide) is a new potent and selective 5-HT3 receptor antagonist, orally and parenterally effective against cytotoxic drug-induced emesis. In vitro, pancopride displayed high affinity (Ki = 0.40 nM) for [3H]GR65630-labelled 5-HT3 recognition sites in membranes from the cortex of rat brains. In vivo, pancopride antagonized 5-HT-induced bradycardia in anaesthetized rats when administered i.v. 5 min (ID50 = 0.56 microgram/kg) or p.o. 60 min (ID50 = 8.7 micrograms/kg) before 5-HT challenge. A single oral dose (10 micrograms/kg) of pancopride produced a significant inhibition of the bradycardic reflex over an 8-h period. Pancopride dose dependently inhibited the number of vomiting episodes and delayed the onset of vomiting induced by cisplatin in dogs (ID50 = 3.6 micrograms/kg i.v. and 7.1 micrograms/kg p.o.). Pancopride was also effective in blocking mechlorethamine- and dacarbazine-induced emesis. Unlike metoclopramide, pancopride was shown to lack any measurable antidopaminergic activity both in vitro and in vivo. These results support clinical data, indicating that pancopride will be a useful drug for treating cytostatic-induced emesis in humans.
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PMID:Pancopride, a potent and long-acting 5-HT3 receptor antagonist, is orally effective against anticancer drug-evoked emesis. 145 37

In the present study, the emetic effect of the anticancer drug cisplatin, and protective effects of 5-HT3 receptor antagonists against cisplatin emesis were investigated in the pigeon. The experimental setting involved the i.v. administration of drugs and subsequent observation of the percentage of vomiting animals and number of emetic episodes per vomiting animal over a period of 5 h. In some experiments, the 5-HT and 5-HIAA content in tissues was estimated by the HPLC technique. It was observed that cisplatin (2.5-10 mg/kg) is able to induce dose-dependent emesis in the pigeon. 5-HT3 receptor antagonists (500 micrograms/kg) afford partial protection against cisplatin emesis, although some of them, i.e. indolic derivatives and zacopride, display intrinsic emetic activity at doses of 50-500 micrograms/kg. A serotonergic mechanism appears to be involved in both cisplatin- and 5-HT3 receptor antagonist-induced emesis, since pretreatment with an inhibitor of 5-HT synthesis, para-chlorophenylalanine (300 mg/kg x 3 days), is able to hamper vomiting induced by either cisplatin or 5-HT3 receptor antagonists. It is concluded that the intrinsic emetic effects of 5-HT3 receptor antagonists in the pigeon provide pharmacological evidence of species differences in the properties of 5 HT3 receptors.
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PMID:A dual effect of some 5-HT3 receptor antagonists on cisplatin-induced emesis in the pigeon. 147 Dec 30

Fractionated radiotherapy of malignancies in the abdomen induces nausea and vomiting in approximately 50% of the patients. During abdominal irradiation the damaged gastrointestinal mucosa releases 5-HT with ensuing activation of 5-HT3 receptors which may explain the nausea and vomiting. Ondansetron is a new 5-HT3-antagonist with antiemetic properties. In this consecutive study, 33 patients receiving fractionated upper abdominal irradiation (> or = 100 cm2, 1,8-4 Gy daily dose for a mean of 13 days) were treated with ondansetron (8 mg t.d.s. p.o.). Emesis was completely controlled in 26/33 (79%) patients throughout their radiation course, which embraced 628 (94%) treatment days. Ondansetron was well tolerated. Eleven patients developed mild constipation. No patients experienced diarrhoea (a common distressing side-effect of abdominal irradiation). It is suggested that ondansetron can be of value in preventing emesis in patients receiving fractionated radiotherapy. The possible beneficial effect in preventing diarrhoea must be further evaluated.
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PMID:The effect of ondansetron on radiation-induced emesis and diarrhoea. 147 56

In this review it has been speculated that PONV is induced by the anaesthetic and by the trauma and perturbations associated with surgery. Indeed, it is unlikely that PONV is caused by any one pathophysiological input, but is multifactorial in origin. These perturbations may be peripheral, central, or both, and involve direct effects on the vomiting system together with afferent inputs in the vagal, splanchnic and trigeminal nerves. A proposed scheme summarizing these inputs is given in figure 1. The precise mechanisms through which 5-HT and 5-HT3 receptors contribute to the control of PONV is unknown, but their involvement is demonstrated by the antiemetic effect of ondansetron.
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PMID:The role of 5-HT in postoperative nausea and vomiting. 148 15

5-HT3 receptor antagonists, ondansetron, granisetron and tropisetron are highly specific for the 5-HT3 receptor and have a selectivity ratio of approximately 1000:1 compared with affinities for other receptors. Other 5-HT3 receptor antagonists, largely those having a benzamide structure, are non-selective. These include metoclopramide, renzapride and zacopride which stimulate gastric motility via activation of 5-HT4 receptors; metoclopramide is also a potent dopamine receptor antagonist. Selective 5-HT3 receptor antagonists are a major advance in the treatment of chemotherapy- and radiotherapy-induced emesis in cancer patients. These agents inhibit emesis by blocking 5-HT3 receptors on vagal afferent nerve terminals in the gastrointestinal mucosa and on terminals on the same vagal nerves in the vomiting system. Inhibition of acute emesis appears to be produced by blocking the initiation of the emetic reflex induced via 5-HT3 receptors and by 5-HT released from enterochromaffin cells in the small intestine, as well as by blocking 5-HT3 receptors in the hindbrain vomiting system.
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PMID:Selectivity of 5-HT3 receptor antagonists and anti-emetic mechanisms of action. 152 96


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