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)

Ondansetron, a potent and highly selective 5-HT3 receptor antagonist, prevents emesis following chemotherapy by antagonising the action of 5-hydroxytryptamine (5-HT) at 5-HT3 receptors on vagal afferent neurons that innervate the gastrointestinal tract and 5-HT3 receptors in the central vomiting system. Evidence suggests that chemotherapy induces the release of 5-HT from enterochromaffin cells in the small intestine. This stimulates vagal afferent nerves via 5-HT3 receptors. Information is then relayed, via the vagus nerve, to the central vomiting system. 5-HT3 receptors are also found in the hind-brain vomiting system including the area postrema (the site of the chemoreceptor trigger zone for emesis). Therefore, following chemotherapy, 5-HT activates 5-HT3 receptors at 2 sites to induce emesis. Clinical data showing that a single dose of ondansetron prevents acute emesis suggest that it is important to block the initiation of the emetic reflex. This may prevent the recruitment of central mechanisms involving 5-HT3 receptors.
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PMID:Mechanism of the anti-emetic activity of 5-HT3 receptor antagonists. 138 26

Forty-seven patients receiving non-cisplatin-containing chemotherapy were entered in a prospective study in which the efficacy of ondansetron plus dexamethasone and tropisetron plus dexamethasone in the prophylaxis of acute vomiting was evaluated. Thirty-nine patients were evaluable for cross-over analysis. During the 24 hours following the start of chemotherapy, 97% of patients on ondansetron plus dexamethasone reported total control of vomiting compared with 82% of those on tropisetron plus dexamethasone (p = 0.026). Thus, both 5-HT3- receptor antagonists combined with dexamethasone were highly effective in controlling acute vomiting induced by non-cisplatin-containing chemotherapy. The observed difference between the treatments may be caused by different dose schedules of ondansetron and tropisetron. A double-blind design with equal number of placebo-controlled administrations is needed to ascertain whether there is a significant pharmacological difference between ondansetron and tropisetron.
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PMID:Ondansetron and tropisetron with dexamethasone in the prophylaxis of acute vomiting induced by non-cisplatin-containing chemotherapy. 141 5

Nausea and vomiting are frequent and severe side-effects of cancer chemotherapy and radiotherapy, and are ranked by patients as one of the worst consequences of such therapy. Ondansetron prevents emesis by blocking the 5-HT3 receptors associated with the vomiting reflex. It has been studied in patients receiving highly emetogenic (cisplatin) chemotherapy, less emetogenic (non-cisplatin) chemotherapy, and radiotherapy. In all studies in these indications, ondansetron was found to be superior to metoclopramide in the control of nausea and emesis over the first 24 h following treatment, when these side-effects are normally most severe. Ondansetron has also been shown to be effective in children and the elderly in the control of cytotoxic-induced emesis. Additional studies have demonstrated that a single intravenous dose of ondansetron (8 mg or 32 mg) is as effective as a continuous infusion schedule, and an 8 mg twice-daily oral schedule is as effective as an 8 mg three times daily oral schedule.
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PMID:Experience with ondansetron in chemotherapy- and radiotherapy-induced emesis. 142 21

Ondansetron is a highly potent and selective antagonist at 5-HT3 receptors. Its anti-emetic actions were first revealed by its ability to antagonize retching and vomiting induced by chemotherapy and radiotherapy in animals and man. Subsequently, the availability of labelled 5-HT3 receptor ligands allowed identification of 5-HT3 receptors, located at highest densities in the area postrema, nucleus tractus solitarius (NTS), in other areas of the brain, and on afferent terminals of the vagus nerve. Postoperative nausea and vomiting may be caused by various factors: the anaesthetic, associated drugs, the surgical procedure, movement of the patient, sex, weight and pain. These factors mediate their effects via the higher brain circuits, the vestibular nuclei, the chemoreceptor trigger zone in the area postrema, or the upper gastrointestinal tract via the vagus nerve, influencing motor and visceral emetic outputs in the hind-brain. It is hypothesized that ondansetron blocks nausea and vomiting by 5-HT3 receptor antagonism at two specific sites: (i) centrally, in the area postrema/NTS; and (ii) peripherally on vagus nerve terminals. The absence of other pharmacological effects of ondansetron ensures an absence of side-effects.
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PMID:Pharmacology of ondansetron. 142 23

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

5-HT3 receptor antagonists such as ondansetron, granisetron, ICS205-930 and zacopride are highly effective in the ferret, cat or dog to prevent emesis caused by cisplatin and other chemotherapeutic agents, and radiation treatment. The anti-emetic effects may be mediated centrally in the area postrema and associated structures of the emetic reflex such as the nucleus tractus solitarius, which have a very high density of 5-HT3 receptors. Additional sites of action may be found on the 5-HT3 receptors located on the vagus nerve or enteric neuronal elements in the gastro-intestinal tract. The precise site(s) and mechanism(s) of action of different cytotoxic treatments to induce emesis remains to be determined, but appears to involve a common action on a 5-HT3 system. The 5-HT3 receptor antagonists do not impair normal behaviour and, in particular, fail to affect the extrapyramidal motor system and do not cause sedation. Of potential benefit, the 5-HT3 receptor antagonists have an anxiolytic profile of action in rodent and primate models. The 5-HT3 receptor antagonists are revealed as an important group of drugs to prevent emesis induced by a wide range of cytotoxic treatments.
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PMID:Neuropharmacology of emesis in relation to clinical response. 146 94

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


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