Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a phase I study of BRL43694A, a 5HT3-receptor antagonist, a single dose of 40 micrograms/kg was given to 24 patients. All patients received cytostatic treatment expected to cause nausea and vomiting. During the first 24 h, 12 patients were completely protected from nausea and vomiting, 4 experienced nausea and 8 had moderate vomiting; mild headache occurred in 10 patients. No cardiovascular (including ECG) changes took place. Apart from headache, no neurological side effects occurred.
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PMID:A phase I study of a new 5HT3-receptor antagonist, BRL43694A, an agent for the prevention of chemotherapy-induced nausea and vomiting. 254 9

Binding of the 5-HT3 receptor ligand [3H]BRL 43694 was investigated in the human medulla oblongata using in vitro autoradiography. High levels of saturable, displaceable binding (Bmax 1.88 pmol/mg protein, Kd 1.21 nM) were seen in the dorsal vagal complex but in no other medullary region. The results provide evidence for the existence of 5-HT3 receptor binding sites in a brain region involved in the control of vomiting in man.
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PMID:Localization of 5-HT3 receptor binding sites in human dorsal vagal complex. 261 76

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

The distribution of 5-hydroxytryptamine receptors of the 5-hydroxytryptamine3 type was examined in human brain post mortem tissue, using quantitative in vitro autoradiography. The selective and potent 5-hydroxytryptamine3 receptor antagonist [3H]ICS 205-930 [(3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester] was used as ligand. Highest levels of labelling were found in discrete nuclei of the lower brainstem. At all levels of the spinal cord the substantia gelatinosa was also densely labelled. In contrast, specific binding in the forebrain was very low and concentrated in some regions of the limbic system. The enrichment of [3H]ICS 205-930 binding sites in nuclei of the dorsal medulla and spinal cord is in good agreement with the proposed role for 5-hydroxytryptamine in sensory processing. High densities of 5-hydroxytryptamine3 binding sites in the area postrema support a central site of action for 5-hydroxytryptamine in emesis. Finally, the presence of [3H]ICS 205-930 binding sites in the limbic system provides an anatomical substrate for the behavioural effects of 5-hydroxytryptamine3 receptor antagonists.
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PMID:5-hydroxytryptamine3 receptors in the human brain: autoradiographic visualization using [3H]ICS 205-930. 279 43

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

15 patients receiving cytotoxic drugs (other than cisplatin) that had previously produced nausea and vomiting refractory to first-line antiemetics were given a selective 5-HT3 receptor antagonist (GR38032F), 4 mg intravenously and 4 mg orally, immediately before chemotherapy, the oral dose being repeated 5 and 10 h later. Nausea, vomiting, and side-effects were recorded for the ensuing 24 h. The 15 patients received a total of thirty-one courses of chemotherapy. Only 1 patient vomited. The only adverse events were dryness of the mouth in 1 patient, mild sedation in 1, and diarrhoea in 1, and these were not clearly drug related.
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PMID:Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5-HT3 receptor antagonist. 288 54

GR38032F is a highly selective 5HT3-receptor antagonist which inhibits vomiting induced by cisplatin, cyclophosphamide or X-radiation in the ferret. Since cisplatin selectively increased the levels of 5HT and 5HIAA in the intestinal mucosa, a possible site of the antiemetic action of GR38032F may be on 5HT3-receptors on vagal afferents in the small intestine. The potent antiemetic action of GR38032F should be of clinical value in reducing the nausea and vomiting associated with radiotherapy or chemotherapy of cancer.
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PMID:Antiemetic properties of the 5HT3-receptor antagonist, GR38032F. 296 67

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

Recent studies have implicated 5-HT3(5-HT-M) receptors in the genesis of retching and vomiting evoked by antineoplastic agents. Such receptors have so far only been located peripherally, notably on the vagus. Therefore, the effects of bilateral abdominal vagotomy and antagonism of 5-HT3 receptors have been investigated on retching and vomiting induced by radiation. The gastrokinetic substituted benzamide BRL24924, (Beecham Pharmaceuticals) which has 5-HT3 receptor antagonist properties, was used. Using the ferret, it was shown that whole body x-radiation produced retching and vomiting, which was most severe during the 30 min following irradiation, and continued for at least 90 min. Abdominal vagotomy almost totally abolished the retching and vomiting, occurring during the 30 min immediately after irradiation. The following 60 min period was similar to that of control animals. This would suggest that the emetic events can be divided into a vagally-dependent and independent phase. In a small dose, BRL 24924 mimicked abdominal vagtotomy, in a larger dose, it almost totally abolished the retching and vomiting throughout the entire 90 min period. These results suggest that 5-HT3 receptor antagonists are capable of ameliorating radiation-induced retching and vomiting and that, while an important site of their action could be the abdominal vagi, other areas are probably also involved.
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PMID:Evidence for an extra-abdominal site of action for the 5-HT3 receptor antagonist BRL24924 in the inhibition of radiation-evoked emesis in the ferret. 367 May 59

Drugs interacting with serotonin (5-hydroxytryptamine, 5-HT) receptors are of value in the treatment of several gastrointestinal disturbances. Selective 5-HT3 receptor antagonists (ondansetron, granisetron, tropisetron) are widely utilized to control emesis induced by chemotherapy and radiation, while agonists at 5-HT4 receptors (cisapride, renzapride, BIMU compounds) are endowed with gastrointestinal prokinetic action. Here we overview the therapeutic potential of drugs with potent mixed 5-HT4 agonist/5-HT3 antagonist properties (i.e. BIMU 1) in the management of anticancer therapy-induced emesis and of intestinal adynamic post-operative conditions associated with vomiting. In the former situation, the agonism at 5-HT4 receptors is expected to be of benefit via two possible mechanism: (i) inhibition of 5-HT release from enterochromaffin cells; (ii) restoration of anally driven peristaltic waves in the upper gastrointestinal tract. Moreover, 5-HT4 receptor-induced prokinetic activity may counteract colonic constipation, an unwanted effect which occurs in a number of patients treated with pure 5-HT3 receptor antagonists. Additionally, the above mentioned drugs might be of value in post-operative conditions associated with intestinal adynamia and emesis sensitive to 5-HT3 receptor blockade.
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PMID:Therapeutic potential of drugs with mixed 5-HT4 agonist/5-HT3 antagonist action in the control of emesis. 747 21


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