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

This paper described an outline of pharmacological studies of 5-HT3 receptor antagonists, mainly on ondansetron, which control nausea and vomiting associated with cancer chemotherapy. Administration of cytotoxic drugs is known to increase serotonin (5-HT) concentrations, and when released, 5-HT provokes the emetic responses via two routes; 1) 5-HT acts as an intrinsic transmitter substance and stimulates the emetic response via 5-HT3 receptors on vagal afferent terminals; 2) 5-HT transmits impulses to the vomiting center via 5-HT3 receptors on the chemoreceptor trigger zone in the area postrema of the central nervous system. 5-HT3 receptor antagonists are thought to exert an antiemetic action by specifically and competitively blocking 5-HT3 receptors.
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PMID:[An outline of 5-HT3 receptor antagonists (1)--In pharmacological actions]. 823 73

This paper described an outline of clinically applications of 5-HT3 receptor antagonists, mainly on ondansetron, which control nausea and vomiting associated with cancer chemotherapy. Clinically, 5-HT3 receptor antagonists demonstrated significantly superior antiemetic effects to metoclopramide which has been prescribed for relatively long time. The response rates for granisetron and those for ondansetron were different due to the different categorical scales. However, when the same scale was applied, similar efficacies have been observed. Introduction of the tablet form may well broaden the clinical applications. Considering the highly evaluated safety, 5-HT3 receptor antagonists, from the viewpoints of clinical usefulness and safety, seems to be useful drugs for controlling nausea and vomiting associated with cancer chemotherapy.
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PMID:[An outline of 5-HT3 receptor antagonists (2)--In clinical applications]. 825 39

The interactions of the antiemetic metopimazine (MPZ) and of the chemotherapeutic agents, cisplatin, carboplatin, doxorubicin, etoposide and vincristine were investigated at five neurotransmitter receptor binding sites. MPZ had nanomolar affinity for alpha 1, dopamine D2 and histamine H1 receptors, weak affinity for muscarinic cholinergic receptors, but no affinity for 5-hydroxytryptamine3 (5-HT3) receptors. Except for vincristine, which showed nanomolar affinity of muscarinic cholinergic receptors, none of the chemotherapeutic agents showed affinity for any of the receptors investigated at concentrations ranging between 10(-5) and 10(-7) M. Accordingly, chemotherapy-induced nausea and vomiting seems to be mediated by mechanisms other than the direct interaction of cytostatics with the neurotransmitter receptors investigated. Our finding that MPZ is without affinity for 5-HT3 receptors and therefore seems to mediate its antiemetic effect predominantly by dopamine D2 receptor blockade makes it an interesting drug for use in combinations with the new class of antiemetics, the 5-HT3 receptor antagonists. Data obtained in a recent clinical trial support this observation.
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PMID:Interaction of the antiemetic metopimazine and anticancer agents with brain dopamine D2, 5-hydroxytryptamine3, histamine H1, muscarine cholinergic and alpha 1-adrenergic receptors. 826 89

Tropisetron is a novel, potent and highly selective 5-HT3 receptor antagonist, which is active in the treatment of nausea and vomiting induced by highly emetogenic chemotherapeutic drugs such as cisplatin. Tropisetron selectively blocks the excitation of the presynaptic 5-HT receptors of the peripheral neurones involved in the emetic reflex, and may have other direct actions in the CNS on 5-HT3 receptors, mediating the actions of vagal inputs to the area postrema. Toxicological studies show that tropisetron is generally well tolerated by all animal species investigated and no specific organ toxicity was observed, other than slight loss of body weight development. In man, tropisetron metabolism is linked to the cytochrome P-450 2D6 isoenzyme system, which determines the polymorphism of debrisoquine/sparteine metabolism. As a result, there are phenotypical populations of extensive and poor metabolizers. The two main adverse events in human volunteer tolerability studies with tropisetron were headache and constipation. These adverse events tended to be slightly more intense and to last longer in poor metabolizers, compared with extensive metabolizers. Tropisetron had similar pharmacokinetic characteristics in elderly patients and renal patients, compared with healthy subjects. From a toxicological and pharmacokinetic point of view, therefore, daily doses of 5 mg tropisetron can be administered to both poor and extensive metabolizers, as well as to special populations, without any particular precautions.
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PMID:Pharmacology, toxicology and human pharmacokinetics of tropisetron. 836 93

This state-of-the-art review describes the development, over the past 12 years, of new agents for the control of chemotherapy- and radiotherapy-induced emesis. While the mechanism of chemotherapy-induced nausea and vomiting is still not fully understood, significant progress in prevention of the symptoms has been achieved. The discovery that high-dose metoclopramide was very effective in antiemetic control ultimately led to the development of a new class of antiemetics, the 5-HT3 receptor antagonists, of which tropisetron is the most recent to be introduced. The emphasis of the review is on acute chemotherapy-induced emesis and includes current thinking on the influence of patient characteristics on the emetic outcome. The new 5-HT3 receptor antagonists do not demonstrate any of the distressing extrapyramidal reactions so frequently encountered with conventional antiemetics acting at dopamine receptor sites. Mild headache is the most characteristic side effect of this class of agents. The major advantages of the newer 5-HT3 receptor antagonists, such as tropisetron, over the conventional antiemetic regimens are convenience, flexibility and, above all, single-dose usage.
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PMID:Current issues in the management of nausea and vomiting. 836 96

An open, two-armed, multicentre trial was conducted in 231 patients with malignant disease who had previously failed to respond to conventional antiemetic treatment for the prevention of chemotherapy-induced nausea and vomiting. Patients were randomized to receive either tropisetron (5 mg/day; n = 115) or a standard antiemetic therapy, which was considered optimal for each individual but did not include a 5-HT3 receptor antagonist (n = 116). Acute vomiting on Day 1 was controlled in 60 (52%) tropisetron patients, compared with only 29 (25%) patients receiving optimal standard therapy (p < 0.001). Acute nausea was completely inhibited in 37 (32%) tropisetron patients, compared with 22 (19%) patients on optimal standard therapy (p < 0.05). On Day 1, delayed vomiting was also significantly better prevented by tropisetron (p < 0.001). Side effects from tropisetron (headache and constipation) were mild, and no extrapyramidal symptoms were observed in any tropisetron patients, in contrast, to 14 (13%) patients in the 'optimal standard' group. In conclusion, in cases of acute nausea and vomiting it is more effective to switch refractory patients to tropisetron rather than attempt to optimize the dose of standard antiemetic therapy. For delayed nausea and vomiting, combination antiemetic therapy, with differing types of receptor antagonism and corticosteroids may provide the best way forward. Such studies are in progress.
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PMID:Tropisetron in the prevention of chemotherapy-induced nausea and vomiting in patients responding poorly to previous conventional antiemetic therapy. 836 95

The efficacy of tropisetron, a new 5-HT3 receptor antagonist, was evaluated in a group of 15 children with a variety of malignant tumours. The majority of children (14/15) received fractionated chemotherapy and on day one complete control of acute nausea and vomiting was observed in 68.7% of all patients with a single, 15-minute, i.v. infusion of tropisetron. Partial control of vomiting was observed in 25% of patients and of nausea in 31.3% of patients on Day 1. Complete control of delayed nausea and vomiting was more variable, with an observed range between 50%-81% of patients over Days 2-6. There was no loss of appetite in 75% of patients treated with tropisetron on Day 1 and, more variably, in 62%-87% of patients on Days 2-6. Side effects were recorded in 18.8% of chemotherapy cycles, the most significant being insomnia in 12.5% of cycles and slight fever in 6.3% of cycles. It was concluded that tropisetron was well suited for children and could be recommended for those receiving a high burden of fractionated chemotherapy.
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PMID:Tropisetron in the control of nausea and vomiting induced by combined cancer chemotherapy in children. 836 98

An open, non-comparative, Nordic multicenter study was performed during 1991-1992 to evaluate the new 5-HT3 receptor antagonist tropisetron, as an antiemetic agent in various types of cancer chemotherapy. More than 600 patients were recruited from 16 cancer centers in Sweden, Finland and Denmark. In this report an interim analysis on 231 patients is presented. Gynecological cancers (61%), lung cancer (14%) and breast cancer (7%), were the main diagnoses. In 118 of 231 patients (51%) prior experience of chemotherapy was documented. In 91 patients (39%) cisplatin was part of the cytostatic regimen. Carboplatin (27%), doxorubicin (32%), epidoxorubicin (18%) were also frequently included. In all, 18 cytostatic agents were studied. The median number of courses studied was 3.3 (range 1-15). Overall 153 of 231 patients (67%) were completely protected from acute nausea and vomiting during the first course of chemotherapy. Delayed nausea and vomiting (Days 2-6) were completely controlled in 45%-72%. Treatment efficacy remained stable (57%-89%) over 10 consecutive courses of chemotherapy. For non-cisplatin regimens complete protection was achieved in 78% compared with 51% for cisplatin-regimens (p < 0.0001). Patients with no prior experience of chemotherapy had greater control of acute nausea and vomiting (73%) than patients treated before (61%) in the first course, but not in subsequent courses. There were no such differences in control of delayed nausea and vomiting between chemotherapy-naive and previously treated patients. Sex and age were significant prognostic factors with regard to antiemetic response. Adverse events were recorded in 19%-36% of the cases during long-term follow-up. Headache (16%) and constipation (5%) were most frequent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tropisetron in the prevention of chemotherapy-induced nausea and vomiting: the Nordic experience. 836 99

Tropisetron is a 5-HT3 receptor antagonist which suppresses nausea and vomiting induced by cancer chemotherapeutic agents. In this study, tropisetron was evaluated on a compassionate-need basis in 545 cancer patients who had either proved refractory to antiemetic treatment during previous chemotherapy or who were at high risk of emesis as a result of current therapy. Tropisetron (5 mg or 10 mg) was administered as a 15-minute infusion prior to chemotherapy, with the further possibility of an additional dose, either orally or parenterally, on one or more subsequent days. In some patients the drug was administered orally on the day before treatment. On Day 1 of Course 1, 64.7% of patients had a complete response to tropisetron, i.e. no nausea or vomiting, and 26.9% of patients had a partial response. More than 80% of patients with a complete response in Course 1 had a complete response in Course 2 and of the partial responders in Course 1, 37% achieved a complete response in Course 2. Of the 7.6% failures in Course 1, a further 26% achieved a complete response in Course 2. Tropisetron was well tolerated, with adverse effects recorded in only 45 (8%) patients.
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PMID:Compassionate use of tropisetron in patients at high risk of severe emesis. 836

The selective 5HT uptake inhibitor, litoxetine (SL 81.0385), currently under development as an antidepressant was shown to have antiemetic properties in the ferret. Litoxetine (at 1 and 10 mg/kg i.v.) dose dependently reduced the number of retches and vomiting as well as the number of emetic episodes induced by cisplatin (10 mg/kg i.v.) and delayed the onset of emesis. Fluoxetine (at 1 or 10 mg/kg i.v.) failed to inhibit cisplatin-induced emetic responses and, in contrast, significantly increased the number of retches and vomiting and accelerated the onset of emesis. The possibility that the antiemetic effects of litoxetine may be mediated through an interaction with 5HT3 receptors was studied using [3H]quipazine or [3H]BRL 43694 to label the 5HT3 receptor. Litoxetine has moderate affinity for cerebral 5HT3 receptors (Ki = 85 nM), while fluoxetine, similar to other 5HT uptake inhibitors, has only negligible affinity for this receptor (Ki = 6.5 microM). It is proposed that litoxetine inhibits cisplatin-induced emetic responses due to its moderate 5HT3 antagonist properties. The clinical use of the majority of serotonergic antidepressants (e.g. fluoxetine, fluvoxamine etc.) is associated with gastrointestinal discomfort (particularly nausea and vomiting) as a major side-effect. If nausea and vomiting associated with the use of 5 HT uptake inhibitors are due to stimulation of 5HT3 receptors, the concomitant 5HT3 antagonism of litoxetine may limit the gastrointestinal side-effects of this novel antidepressant and thus offer an important advantage.
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PMID:Litoxetine: a selective 5-HT uptake inhibitor with concomitant 5-HT3 receptor antagonist and antiemetic properties. 838 15


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