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)

Tropiestron is a potent and selective antagonist of 5-hydroxytryptamine receptors. Tropisetron was developed for the indication of cancer chemotherapy-induced emesis. The pharmacokinetic and metabolic dispositions of tropisetron were studied in 12 healthy male volunteers receiving a single oral dose of 62 or 312 mumol (20 or 100 mg) of [14C]tropisetron. Serial plasma samples and complete urine and feces were collected for 120 hr postdose. Whereas the absorption of oral doses of 62-312 mumol tropisetron was rapid and complete, bioavailability was estimated to be only 66% for the 312 mumol dose and 52% for the 62 mumol dose, apparently because of saturable first-pass metabolism. Maximal concentrations of tropisetron averaged 87 and 608 nM after doses of 62 and 312 mumol, respectively, and the parent drug accounted for 21 and 36% of the radioactivity in AUC0-24 hr pools. Approximately 90% of the drug was metabolized before excretion, and approximately 70% of the dose was recovered in the urine. Following both the 62 and 312 mumol doses, the terminal half-life of tropisetron averaged 6-7 hr and that of total radioactivity was 10-11 hr. Tropisetron and its metabolites in plasma and urine were separated by gradient elution reversed-phase HPLC. Structures of eight metabolites were assigned on the bases of NMR and MS data. Tropisetron was metabolized by oxidative hydroxylation of the indole ring at positions 5, 6, and 7. The hydroxylated derivatives are further conjugated with glucuronic acid and sulfate. N-Oxygenation and oxidative N-demethylation at the tropinyl nitrogen also occur in trace amounts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacokinetics and metabolism of the 5-hydroxytryptamine antagonist tropisetron after single oral doses in humans. 135 42

We investigated the role of adrenergic receptors in the mechanisms of initiation of vomiting and its gastrointestinal (GI) motor correlates. The effects of clonidine, UK-14304, St-91, naphazoline, phenylephrine and isoproterenol were examined for their ability to initiate vomiting and its GI motor correlates. Only the alpha-2 adrenoceptor agonists UK-14304, clonidine, St-91 and naphazoline activated vomiting and its GI motor correlates. Tolerance of vomiting, but not its GI motor correlates, readily developed to all alpha-2 adrenergic receptor agonists but St-91. The responses to UK-14304 or clonidine were blocked by idazoxan, yohimbine, clonidine tolerance or high doses of phenoxybenzamine, but not by propranolol or prazosin. The responses to UK-14304 or clonidine were also blocked by fentanyl, 1-(1-naphthyl) piperazine, methysergide, SCH 22390 or scopolamine, but not by haloperidol, sulpiride, domperidone or naloxone. Adrenoceptor antagonists, clonidine tolerance or sympathetic blockade did not block vomiting or its GI motor correlates activated by apomorphine, CuSO4 or cholecystokinin-octapeptide. We concluded that alpha-2 adrenergic receptors of the chemoreceptive trigger zone can initiate vomiting and its GI motor correlates, but these receptors do not mediate vomiting induced by another chemoreceptive trigger zone stimulant, apomorphine, or stimulation of the GI tract using CuSO4. However, 5-hydroxytryptamine-2 serotonergic, muscarinic cholinergic and opiate receptors within the central nervous system participate in controlling emesis activated by alpha-2 adrenergic agonists. Peripheral adrenergic receptors do not mediate the GI motor correlates of vomiting.
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PMID:The role of adrenergic receptors in the initiation of vomiting and its gastrointestinal motor correlates. 135 60

The intracerebroventricular (i.c.v.) injection of clonidine, xylazine, adrenaline and methoxamine elicited dose-dependent vomiting in cats in that order of potency. The vomiting induced by clonidine, xylazine and adrenaline was antagonized by i.c.v. yohimbine and phentolamine possessing alpha 2-adrenoceptor-blocking activity, but not by prazosin showing alpha 1-adrenoceptor-blocking activity. In contrast, methoxamine-induced vomiting was antagonized by prazosin, but not by yohimbine. The vomiting induced by xylazine and adrenaline was not prevented by i.c.v. 6-hydroxydopamine treatment, but was prevented by i.c.v. reserpine treatment. Ablation of the area postrema with some damage to extremely adjacent areas abolished the vomiting induced by each alpha-adrenoceptor agonist. These results indicate that both central alpha 1- and alpha 2-adrenoceptors are involved in the emetic pathway in cats, although alpha 2-adrenoceptors seem to have the main role. It is also suggested that monoamines, and in particular 5-hydroxytryptamine in the brain, are involved in the regulation of alpha-adrenoceptor-mediated vomiting.
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PMID:Central alpha-adrenoceptor subtypes involved in the emetic pathway in cats. 136 6

The effect of deoxynivalenol (DON, vomitoxin) on brain amine levels was investigated in swine. DON, a trichothecene mycotoxin, causes suppression of feed intake (anorexia) in susceptible species. Following acute administration of DON to pigs (0.25 mg/kg, IV), concentrations of endogenous catecholamines norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenyl-acetic acid (DOPAC), and homovanillic acid (HVA), and the indoleamines, 5-hydroxytryptamine (5HT, serotonin) and 5-hydroxyindoleacetic acid (5HIAA) were determined in five brain regions, periodically during the 24 h post-dosing. Analysis was carried out by high performance liquid chromatography, using electrochemical detection. Effects of DON in the swine brain were transmitter, time and region-specific. It was observed that levels of the major transmitters (NE, DA and 5HT) were statistically different from controls in the hypothalamus (Hypo), frontal cortex (FCX) and cerebellum (Cb) up to 8 h post-dosing. Overall, DON administration elevated NE and depressed DA concentrations in these regions, and levels of 5HT which increased initially in Hypo (1 h), had dropped significantly below controls in both Hypo and FCX at 8 h. These alterations, however, were not indicative of known neurochemical changes associated with chemical-induced anorexia. Instead, this data suggested that the neurochemical effects of acute DON exposure might be due to peripheral toxicological events (i.e., vomiting), which overwhelmed its more subtle feed refusal activity.
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PMID:Effect of deoxynivalenol on neurotransmitters in discrete regions of swine brain. 137 99

This review describes clinical experience with tropisetron, a new 5-hydroxytryptamine type 3 (serotonin 3)-receptor antagonist, which was found to possess antiemetic properties in animal studies and pilot studies in chemotherapy-treated patients. Tropisetron 5mg once daily is an effective and well tolerated antiemetic treatment for chemotherapy-induced emesis. Tropisetron can be administered without special precautions to all patients who undergo aggressive chemotherapy, and remains effective during multiple chemotherapy courses. The efficacy of tropisetron compares well with that of the best available complicated antiemetic cocktails, but tropisetron is better tolerated. The simple dosage schedule of either 1 injection or 1 capsule per day makes tropisetron ideal for both inpatient and outpatient treatment.
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PMID:Tropisetron. A review of the clinical experience. 138 Apr 28

Oral tropisetron, a 5-hydroxytryptamine type 3 (serotonin3) [5-HT3]-receptor antagonist, at a dose of 5mg daily was evaluated as antiemetic prophylaxis during postoperative abdominal irradiation. 20 women with International Federation of Gynecology and Obstetrics (FIGO) stage I to III ovarian carcinoma were included. 12 women received irradiation of whole abdominal fields and 8 of lower abdominal/pelvic fields. Efficacy and adverse events were recorded by the patients in diary-form booklets. The cumulative weekly incidence of patients with nausea, which was generally mild and of short duration, increased from 30% at the start of radiotherapy to 54% at the end of treatment. Episodes of vomiting occurred in less than 10% of the patients. Diarrhoea was common towards the end of the radiotherapy courses, and the proportion of patients needing extra antidiarrhoeal medication (loperamide) increased from 38% during the first week to 100% at the end of the radiotherapy course. Mean weight loss was 1.2kg during the 5- to 6-week course. Overall ratings for quality of life were excellent or good in 75 to 85% of patients. Tropisetron seems to be a promising and well tolerated drug in conjunction with extended radiotherapy of abdominal fields. This was an open study, establishing the methodology for long term follow-up of patients during fractionated radiotherapy.
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PMID:Tropisetron, a new 5-HT3-receptor antagonist, in the prevention of radiation-induced nausea, vomiting and diarrhoea. 138 Apr 31

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 emetogenic properties of chemotherapeutic agents differ in terms of the frequency, intensity, time of onset, and duration of vomiting and nausea. As the effects of antiemetic agents in the control of emesis induced by different chemotherapeutic agents could differ, new antiemetics must be tested against a variety of chemotherapy challenges. In many non-cisplatin chemotherapy situations, a partly or totally oral schedule of antiemetic administration may be preferable. The selective 5-hydroxytryptamine (5-HT3)-receptor antagonist, ondansetron, has been shown to be a safe, effective, and well-tolerated antiemetic in the prevention of nausea and vomiting from several non-cisplatin chemotherapies. In randomized studies, ondansetron has compared favorably with metoclopramide in patients receiving cyclophosphamide-containing chemotherapy regimens.
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PMID:Antiemetic activity of ondansetron in cancer patients receiving non-cisplatin chemotherapy. 138 49

Hepatic oxidative metabolism accounts for more than 95% of ondansetron clearance from the body. The major excreted metabolites are conjugates of 7-hydroxy or 8-hydroxyondansetron, which appear to contribute little to the activity of the parent drug. Ondansetron plasma clearance averages approximately 0.45 L/h/kg, is similar in young male volunteers and cancer patients undergoing cisplatin-based chemotherapy, and does not change significantly with repeated dosing. Clearance decreases with increasing age, whereas volume of distribution remains unchanged. The result is an increase in mean plasma half-life from 3.5 hours in young volunteers (18-40 years) to 5.5 hours in volunteers over 75 years of age. Clearance and volume of distribution are higher in young (7-12 years) cancer patients, resulting in a mean plasma half-life of 2.5 hours. Plasma clearance is slightly slower in females. Ondansetron clearance decreases and half-life increases in patients with severe hepatic insufficiency. Clearance may be enhanced in patients receiving known hepatic enzyme inducers. Because of large intersubject variability in clearance and the relative safety of ondansetron, adjustments in ondansetron dosing based on age or gender alone are not recommended. Ondansetron is rapidly and completely absorbed when administered as a tablet. A relationship exists between control of emesis and the area under the plasma concentration-time curve for ondansetron. All data collected to date support the thesis that ondansetron is a competitive antagonist of the 5-hydroxytryptamine (5-HT3) receptor in humans.
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PMID:Ondansetron metabolism and pharmacokinetics. 138 54

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


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