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 5-HT3 antagonist proposed for use in the treatment of chemotherapy-induced emesis, was first given to man in 1984 and in the 4 years subsequent to this, the drug was given to more than 220 different healthy volunteers. In pharmacodynamic studies, there was evidence to suggest that ondansetron was gastroprokinetic but reduced transit time through the small bowel. Ondansetron was of no benefit in a model of motion sickness. The pharmacokinetics of ondansetron have been defined in volunteers using intravenous and oral dosage regimens proposed for the clinic. Ondansetron had a terminal plasma half-life of 3.0-3.5 h and plasma clearance (principally metabolic) of the order of 600 ml/min, and there was no evidence of accumulation at steady state. The absolute oral bioavailability of ondansetron was 59%. Metabolic studies showed the drug to be excreted predominantly in urine and faeces, with a metabolite profile in urine similar to that seen in the animal species used for toxicological testing. Ondansetron is both safe and well tolerated at daily doses of up to 64 mg given to volunteers.
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PMID:The clinical pharmacology of ondansetron. 253 95

Although significant advances have been made in the treatment of malignant diseases, many agents cause nausea and vomiting severe enough to cause patients to be hospitalised or to refuse further treatment. Several classes of anti-emetics are currently used, but are only partially effective and are often associated with side effects such as extrapyramidal reactions. Ondansetron, a specific 5-HT3 antagonist, has been fully evaluated in the clinic, both as an intravenous and oral presentation, and in open studies in patients receiving non-cisplatin chemotherapy regimens it was highly effective in controlling acute and delayed emesis -- more than 90% of patients had a complete or major response to treatment. In three randomised, double-blind studies comparing ondansetron and metoclopramide, ondansetron was found to be superior in the control of both emesis and nausea. Ondansetron was also shown to be safe and well tolerated; in particular, no extrapyramidal reactions were reported.
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PMID:The role of ondansetron in the treatment of emesis induced by non-cisplatin-containing chemotherapy regimes. 253 97

Nausea and vomiting occur in all patients following high-dose cisplatin chemotherapy, unless an effective anti-emetic is administered. Early clinical studies therefore examined ondansetron treatment to establish an optimal dosing schedule for acute emesis. Pilot studies suggested that a daily dose of 32 mg ondansetron, given as a continuous intravenous infusion or intermittently on a mg/kg basis, gives optimum control of emesis, and was therefore selected for comparative studies. Efficacy was confirmed in two randomised, double-blind, crossover studies comparing ondansetron and metoclopramide. Ondansetron was superior to high-dose metoclopramide in controlling acute emesis and nausea, and there was a significant patient preference for ondansetron. These effects may be related to ondansetron's greater potency as a competitive 5-HT3 antagonist. In addition, ondansetron did not induce any extrapyramidal reactions, confirming the absence of any dopamine antagonist activity.
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PMID:Ondansetron in the prophylaxis of acute cisplatin-induced nausea and vomiting. 253 98

An open study of the new antiemetic BRL 43694A, a 5-hydroxytryptamine-3-receptor antagonist, was performed in 29 patients undergoing highly emetogenic cancer chemotherapy (25 patients received cisplatin in a dose greater than or equal to 50 mg/m2). Patients received BRL 43694A as a 30-minute infusion one hour after the administration of chemotherapy. 7 patients were treated with 40 micrograms/kg and 13 patients with 100 micrograms/kg BRL 43694A; the last 9 patients received an initial dose of 40 micrograms/kg with a provision for two additional interventional doses over 24 hours in the event of prolonged nausea or vomiting. 14 patients experienced no vomiting (48%) and 13 patients (45%) had 1-5 vomiting episodes over 24 hours following administration of the cytostatic agents. BRL 43694A did not cause major side effects. Based on our preliminary experience the new 5-HT3-receptor antagonist BRL 43694A is a potent antiemetic drug for the treatment of chemotherapy-induced nausea and vomiting.
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PMID:[BRL 43694A--a 5-hydroxytryptamine receptor blocker as an antiemetic in cytostatic therapy]. 254 16

1. The current classification of receptors for 5-hydroxytryptamine (5-HT) is based on functional studies, and encompasses three main receptor types. 2. 5-HT1-like receptors mediate inhibition of release of various neurotransmitters from central and peripheral sites, smooth muscle contraction and relaxation (and release of endothelium-derived relaxing factor), tachycardia, a variety of behavioural actions (for example, forepaw treading, hypothermia, hyperphagia, drug discriminative stimulus properties, nociceptive pathway modulation, and anxiolytic, anti-aggressive and prosexual effects), and central neuronal excitatory and inhibitory activity. Selective antagonists for this receptor are not yet available, but the 5-HT2 receptor antagonists methysergide and methiothepin have appreciable affinity for 5-HT1-like receptors, and 5-carboxamidotryptamine is a selective agonist. 3. 5-HT2 receptors mediate smooth muscle contraction, platelet aggregation, increased capillary permeability, some behavioural syndromes (for example, head twitch and wet-dog shakes) and drug discriminative stimulus properties, central neuroexcitatory effects, and some neuroendocrine functions. Ketanserin and cyproheptadine are selective antagonists. 4. 5-HT3 receptors mediate peripheral afferent and efferent neuroexcitatory actions, anxiogenic effects, and modulation of cytotoxic drug-induced emesis, gastric emptying, and dopamine-related mesolimbic hyperactivity. Selective antagonists include cocaine, MDL 72222 and ICS 205-930; 2-methyl-5-HT is a selective agonist.
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PMID:The classification of 5-hydroxytryptamine receptors. 267 Mar 59

1. The purpose of the present study was to identify and investigate the role of 5-hydroxytryptamine3 (5-HT3) receptors in the area postrema in the control of cisplatin-induced emesis in the ferret. 2. Homogenate binding and autoradiography experiments using the high affinity 5-HT3 receptor ligand, [3H]-GR65630, identified the presence of a high concentration of 5-HT3 receptors in the area postrema of the ferret. 3. Intraperitoneal injection of the 5-HT3 receptor antagonists, GR38032F, GR65630A and MDL72222, at doses of 1, 0.1 and 1 mg kg-1 respectively, inhibited emesis induced by cisplatin, 9 mg kg-1 i.p. 4. Discrete injection of low doses of the 5-HT3 receptor antagonists directly into the area postrema region also inhibited cisplatin-induced (9 mg kg-1 i.p.) emesis. The dose ranges used were: GR38032F, 0.01-1 microgram; GR65630A, 0.001-0.1 microgram; MDL72222, 0.1-10 micrograms. 5. Cisplatin-induced emesis was not inhibited by discrete injection of ketanserin (30 micrograms) or methiothepin (30 micrograms) into the area postrema. Injection of the 5-HT3 receptor agonist, 2-methyl-5-HT, directly into the area postrema produced an incomplete emetic response. 6. These results confirm a role of 5-HT, and in particular 5-HT3 receptors, in the control of cisplatin-induced emesis, and show that at least one functional site for these receptors in modulating the emetic response is the area postrema, the locus of the chemoreceptor trigger zone.
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PMID:5-HT3 receptor antagonists injected into the area postrema inhibit cisplatin-induced emesis in the ferret. 272 Mar 10

In ferrets, the selective 5-hydroxytryptamine (5-HT) 5-HT3 receptor antagonist BRL 43694 given as a single injection (0.05-0.5 mg kg-1 i.v.) before cisplatin, or by divided dose (2 x 0.005-2 x 0.5 mg kg-1 i.v.) before and after cisplatin dramatically reduced or abolished the severe cisplatin-induced vomiting. BRL 43694 also substantially reduced the vomiting induced by cyclophosphamide:doxorubicin, and prevented the trimelamol-induced emesis. The severe emesis caused by whole body exposure to X-irradiation was prevented by intravenous or oral BRL 43694. A single i.v. dose of BRL 43694 given during an emetic episode or within the peak emetic period, abolished the vomiting induced by the cytotoxic drugs and by X-irradiation, usually within 30 s. Where the induction of emesis was prevented or subsequently abolished by BRL 43694, the associated behaviour (subjectively assessed as nausea) was also absent or greatly attenuated. BRL 43694 (0.1 mg kg-1 i.v.) did not affect the emesis evoked in dogs by the dopamine agonist apomorphine. The potent anti-emetic activity of BRL 43694 is discussed in terms of potential clinical use, and of the fundamental role that 5-HT3 receptors may play in the mechanisms of nausea and vomiting.
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PMID:The anti-emetic potential of the 5-hydroxytryptamine3 receptor antagonist BRL 43694. 285 11

GR-C507/75 (GR38032F) antagonizes the 5-HT3 (serotonin) receptor and prevents cisplatin-induced emesis in animals. In this dose-ranging trial, 44 patients with cancer receiving chemotherapy known to produce nausea and vomiting (including cisplatin, cyclophosphamide, and doxorubicin) received three intravenous (IV) infusions of GR-C507/75 every two hours beginning 30 minutes before chemotherapy. Ten dosage levels were explored, ranging from 0.04 mg/kg to 0.35 mg/kg in each of the three infusions. Toxicities were mild and included sedation, dizziness, headache, transient elevations of SGOT or alanine aminotransferase (ALT), and dry mouth. No akathisia or acute dystonic reactions were observed. Antiemetic effects were seen in patients receiving cisplatin at 120 mg/m2. GR-C507/75 can be safely administered on this schedule at IV dosages up to 0.35 mg/kg in patients receiving chemotherapy. Further studies of this agent at higher dosages and by different schedules are appropriate.
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PMID:Dose-ranging evaluation of the serotonin antagonist GR-C507/75 (GR38032F) when used as an antiemetic in patients receiving anticancer chemotherapy. 296 55

BMY-25801, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]2-(1-methyl-2-oxopropoxy ) benzamide, a new antiemetic agent free of D2-dopamine receptor antagonist properties, was effective against emesis induced by cytostatic agents (cisplatin, cyclophosphamide and doxorubicin) and total body radiation in the ferret. It also was effective against cisplatin-induced emesis in the dog; however, it was inactive against emesis caused by apomorphine and hydergine in the same species. In terms of activity profile, BMY-25801 could be differentiated both from metoclopramide and domperidone. Metoclopramide was nonselectively active against emesis induced by cytostatic agents, radiation and D2-dopamine receptor agonists, whereas domperidone was selectively effective against emesis induced by apomorphine and hydergine only. BMY-25801 failed to reveal any D2-dopamine receptor antagonist properties in several pharmacological tests (catalepsy, apomorphine stereotypy, serum prolactin, striatal dihydroxyphenylacetic acid and [3H]spiperone displacement) whereas metoclopramide was uniformly active in these tests. The activity profile of domperidone was compatible with its classification as a peripherally acting D2-dopamine receptor antagonist. BMY-25801 and metoclopramide antagonized serotonin-induced bradycardia (Bezold-Jarisch reflex) in the anesthetized rat, a response involving peripheral neuronal 5-HT3 receptors. Thus, BMY-25801 represents a novel antiemetic acting independently of D2-dopamine receptor mechanisms; however, its exact mode of action remains unknown.
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PMID:BMY-25801, an antiemetic agent free of D2-dopamine receptor antagonist properties. 297 41

The involvement of 5-hydroxytryptamine (5-HT) 5-HT3 receptors in the mechanisms of severe emesis evoked by cytotoxic drugs or by total body irradiation have been studied in ferrets. Anti-emetic compounds tested were domperidone (a dopamine antagonist), metoclopramide (a gastric motility stimulant and dopamine antagonist at conventional doses, a 5-HT3 receptor antagonist at higher doses) and BRL 24924 (a potent gastric motility stimulant and a 5-HT3 receptor antagonist). Domperidone or metoclopramide prevented apomorphine-evoked emesis, whereas BRL 24924 did not. Similar doses of domperidone did not prevent emesis evoked by cis-platin or by total body irradiation, whereas metoclopramide or BRL 24924 greatly reduced or prevented these types of emesis. Metoclopramide and BRL 24924 also prevented emesis evoked by a combination of doxorubicin and cyclophosphamide. These results are discussed in terms of a fundamental role for 5-HT3 receptors in the mechanisms mediating severely emetogenic cancer treatment therapies.
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PMID:Evidence that 5-hydroxytryptamine3 receptors mediate cytotoxic drug and radiation-evoked emesis. 331 Nov 9


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