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)

A number of 5-HT3 receptor antagonists are currently in clinical development as antiemetics. In this paper we focus on two of these antagonists, granisetron and ondansetron, and compare their antimetic activity against cisplatin (10 mg/kg i.v.)- or whole body X-irradiation (200 rads)-induced emesis in the conscious ferret. The results presented here have been discussed in the light of the recently published literature. Our data suggest that in comparison to ondansetron, granisetron is a more potent, longer acting and pharmacologically "cleaner" compound with a more conventional dose-response profile. The possible impact of these features upon the performance of these compounds in the clinic is discussed particularly with respect to dosing regimens and clinical efficacy. Differences appear to be emerging between granisetron and ondansetron in both these respects, although a direct head-to-head clinical comparison has yet to be carried out. This would involve studies monitoring a sufficiently high number of patients receiving severely emetogenic regimes to allow real clinical differences to be detected with the appropriate statistical power.
Eur J Cancer 1992
PMID:Are all 5-HT3 receptor antagonists the same? 132 Sep 15

The study examined the budgetary implications of using 5-hydroxytryptamine3 receptor antagonists (5-HT3RA), granisetron or ondansetron, in the management of chemotherapy-induced emesis (CIE). A treatment model was constructed to represent a baseline of efficacy and costs for treating a cohort of patients with conventional antiemetics. Groups of patients who would be expected to receive the most benefit from 5-HT3RA were then identified and the effect upon costs of using these compounds in a consecutively larger proportion of selected patients was calculated. On the basis of illustrative costs from The Cookridge Hospital in the UK, it was concluded that the new antiemetics can be used in acute emesis with substantial clinical benefit for an increase of 3-10% to total treatment costs. However, for delayed emesis these compounds have not yet shown a clinical advantage, and the increase in total costs of 12-34% is not justified.
Eur J Cancer 1992
PMID:The budgetary impact of 5-HT3 receptor antagonists in the management of chemotherapy-induced emesis. 833 2

The availability of radiolabelled ligands selective for various putative neurotransmitter receptor sites and the development of quantitative autoradiography has led to a greater understanding of the neuronal pathway and receptor subtypes involved in the vomiting reflex induced by various mechanisms both within the central nervous system and the periphery. Receptors for acetylcholine, dopamine, histamine and serotonin have been detected in a number of brain regions associated with the vomiting reflex, and provide a rational basis for the antiemetic action of drugs that inhibit receptor subtypes for these neurotransmitters. The basis of the antiemetic action of other drugs such as dexamethasone and the cannabinoids is still obscure. Some drugs act on more than 1 receptor subtype. Metoclopramide may inhibit both dopamine D2- and 5-HT3 receptors in producing its antiemetic effect. Both metoclopramide and domperidone appear to have additional peripheral actions that contribute to their effectiveness. The cannabinoids are effective in cytotoxic-induced vomiting, perhaps acting via endorphin receptors or by inhibiting prostaglandin synthesis. The effectiveness of 5-HT3 receptor antagonists may depend on the block of both central and peripheral neuronal 5-HT3 receptors. Vomiting constitutes a major disadvantage to the use of many drugs; vomiting induced by aminoglycoside antibiotics appears to be due to ototoxicity and is relieved by histamine H1-receptor antagonists. The protracted vomiting associated with the use of some cytotoxics in cancer chemotherapy may involve psychic components, the chemoreceptor trigger zone and peripheral sensory neurons. Both 5-HT3 and dopamine D2-receptor antagonists exert some control, the former being more effective with cytotoxics of high emetogenic potential, such as cisplatin. Serotonin 5-HT3 receptor antagonists or high doses of metoclopramide in combination with anxiolytics and steroids as well as greater attention to pharmacokinetic profiles of the drugs involved would appear to offer improved control. The use of dopamine receptor antagonists in controlling emesis induced by dopamine agonists used in Parkinson's disease poses theoretical problems which can be overcome by using drugs with selectivity for the chemoreceptor trigger zone, such as domperidone or metoclopramide. However, higher doses of these drugs may produce some impairment of therapeutic responses to the agonists. Muscarinic and nicotinic agonists currently under investigation in Alzheimer's disease pose another therapeutic dilemma as emesis is due to a central action of these compounds. Several sites may be involved including the chemoreceptor trigger zone and frontal lobes. Opiates may act through dopamine receptors or mu-receptors on dopaminergic nerves, but serotonergic mechanisms may also be involved in the action of some opiates.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacological agents affecting emesis. A review (Part I). 137 16

We examined the anti-emetic effect, safety and usefulness of ondansetron hydrochloride, a selective 5-HT3 receptor antagonist, given orally once daily at the dosage of 4 mg, for 3 to 5 consecutive days to patients with nausea and emesis induced by non-platinum anti-cancer drugs such as cyclophosphamide, doxorubicin and carboplatin. Out of 84 cases where anti-emetic effects were evaluated, numbers of cases assessed as excellent and good were 36 (83.3%) and 34 (40.5%), respectively, the efficacy rate being 83.3% (70/84). Side effects, such as moderate constipation (3 cases) and mild headache (3 cases), were observed in 8/85 cases (9.4%). Abnormalities in clinical laboratory findings including elevation of hepatic function and uricacid values and increase in eosinocyte counts, were observed in 3/85 cases (3.5%). As to overall safety, 78/85 cases (91.8%) were evaluated as having no problem in safety, and 7/85 cases (8.2%), as having minor problem in safety. As to clinical usefulness based on anti-emetic effect and overall safety, out of 79 cases the drug was assessed as very useful in 29 cases (36.7%) and useful in 35 cases (44.3%), the rate of "useful" or above being 81.0% (64/79). Furthermore, when ondansetron was administered in 3 courses of chemotherapy, though the number of patients was small, it was shown that anti-emetic effect of ondansetron did not decline and no problem in safety was observed. From the above, ondansetron which exerted adequate anti-emetic effect in 4 mg once daily doses was considered as a useful and safe anti-emetic in treatment of nausea and emesis associated with cancer chemotherapy.
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PMID:[Examination of inhibitory effect, safety and usefulness of SN-307 (ondansetron) administered orally once daily for 3-5 consecutive days on nausea and emesis associated with non-platinum anti-cancer drugs]. 138 75

Ondansetron, a selective 5-HT3 receptor antagonist, has already been reported to have a marked effect to alleviate or prevent nausea and vomiting associated with cancer chemotherapy, after its intravenous administration. The present study was planned to examine the usefulness of its tablet form, which was prepared for the convenient use in outpatients receiving chemotherapy. In order to make an objective evaluation of anti-emetic effect and safety of ondansetron 4 mg tablet, this study was conducted in double-blind comparison versus placebo in patients receiving cisplatin at a single dose of 50mg/m2 or higher. Either 4 mg of ondansetron or placebo (lactose tablet) was administered orally once at 2 hrs prior to administration of cisplatin. If any satisfactory anti-emetic effects were not obtained, 4 mg of ondansetron injection was given once intravenously as a rescue medication. The inhibitory effect on nausea and vomiting was assessed in 4 grades as "excellent", "good", "fair" and "poor" based on severity of nausea and number of vomiting that occurred during the first 24hrs after administration of cisplatin. When rescue medication was conducted, the case was assessed as "poor". Ondansetron was significantly superior to placebo in inhibition of nausea and vomiting, in which efficacy rates (excellent+good) of ondansetron and placebo groups were 58.1% (25/43 cases) and 16.7% (7/42 cases), respectively. Number of cases requiring rescue medication with ondansetron injection was obviously greater in placebo group (31 cases) than that in ondansetron group (12 cases). In those patients given ondansetron injection as the rescue medication, satisfactory effects were obtained in 5 cases in ondansetron group and in 18 cases in placebo group. Although side effects including chest itching (ondansetron group), headache and dull headache (placebo group) were observed after the rescue medication with ondansetron injection, these symptoms were not severe and disappeared after 1-2 days. As mentioned above, ondansetron tablet was shown to possess excellent anti-emetic effect on nausea and emesis induced by high dose of cisplatin and to have no problem in safety. Hence ondansetron was proven to be clinically very useful anti-emetic.
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PMID:[Anti-emetic effect and safety of ondansetron tablet in double-blind comparison with placebo]. 141 14

Ondansetron is a 5-HT3 receptor antagonist which is effective and well tolerated as an antiemetic for emesis induced by cancer chemotherapy and radiation therapy, and in the prevention and treatment of postoperative nausea and vomiting. Ondansetron is rapidly absorbed after oral administration (tmax 1.9 h) with an absolute bioavailability of around 60%. Its terminal elimination half-life is 3.5 h and it is extensively hepatically metabolized. Plasma clearance is 0.38 litre h-1 kg-1 and volume of distribution is 1.8 litre kg-1. Plasma clearance is reduced by age (31% reduction) and hepatic failure (80% reduction in severe failure). In patients undergoing general anaesthesia there is a slight prolongation of terminal half-life, which is not of clinical significance. Ondansetron is very well tolerated in volunteer studies. Headache, mild abdominal pain, and constipation occur infrequently. There is no evidence for effects of ondansetron on cardiac function (electrocardiogram, cardiac output, blood pressure and heart rate), and haemostatic function in volunteers and patients. Respiratory depression induced during general anaesthesia is not potentiated by ondansetron. No drug interactions have been noted with temazepam, atracurium, alfentanil and alcohol in man. There are also no interactions seen in animal studies using pentobarbitone, morphine, neostigmine, prednisolone and diazepam.
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PMID:Clinical pharmacology of ondansetron in postoperative nausea and vomiting. 142 20

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.
Br J Cancer Suppl 1992 Dec
PMID:Neuropharmacology of emesis in relation to clinical response. 146 94

The incidence, severity, and onset of radiation-induced emesis (RIE) are related to field size, site, and dose per fraction. Radiation-induced emesis can occur (1) within 2 to 3 weeks in approximately 50% of patients after conventional fractionated radiotherapy (200 cGy/fraction) to the upper abdomen, (2) acutely in more than 90% of patients receiving fractionated total body irradiation (TBI) for bone marrow transplantation, and (3) within 30 to 60 minutes in more than 80% of patients following single high-dose (> 500 cGy)/large field hemibody irradiation (HBI). The increased frequency of emesis associated with TBI and HBI has renewed the interest in the mechanism and treatment of RIE. A number of studies have reported a significant difference in the incidence of emesis following doses of > or = 500 cGy to the upper-mid (> 80%) and lower (20% to 40%) hemibody. The data suggested that the organ responsible for emetic response was in the upper abdomen. However, the mechanism of RIE is not well understood, although degradation products from normal tissues and tumor have been suggested. The introduction and effectiveness of the 5-hydroxytryptamine3 receptor antagonists in chemotherapy-induced emesis and the location of these receptors in the upper abdomen (possible site of the radiation-associated emetic response) suggested that this group of compounds may have a role in RIE. Lucraft and Palmer (Clin Radiol 33:621-622, 1982) reported no differences between levonantradol and chlorpromazine in preventing RIE in patients treated with single doses of more than 10 Gy to a small upper abdominal field. Priestman (Eur J Cancer Clin Oncol 25:529-533, 1989 [Suppl]) reported on a pilot and randomized study with ondansetron after single doses of 8 to 10 Gy to the upper abdomen. In the pilot study, ondansetron achieved major or complete control of vomiting in 77% to 90% of patients; subsequently, he reported a significant difference between ondansetron (97%) and metoclopramide (45%) in controlling RIE on the day of radiotherapy. Hewitt et al (Bone Marrow Transpl 7:431-433, 1991) reported a complete or major response on 93% of the days of ondansetron therapy during pretreatment therapy with cyclophosphamide and TBI for bone marrow transplantation. A preliminary analysis of 41 patients treated with HBI at the Rex Cancer Center confirms the role of ondansetron in RIE. Twenty-eight patients (upper-mid 16 patients/lower HBI 12 patients) did not receive pretreatment antiemetics (group A); seven received non-ondansetron pre-HBI (group B); and six received ondansetron (group C).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Radiation-induced emesis: effects of ondansetron. 148 81

5-HT3 receptor antagonists, ondansetron, granisetron and tropisetron are highly specific for the 5-HT3 receptor and have a selectivity ratio of approximately 1000:1 compared with affinities for other receptors. Other 5-HT3 receptor antagonists, largely those having a benzamide structure, are non-selective. These include metoclopramide, renzapride and zacopride which stimulate gastric motility via activation of 5-HT4 receptors; metoclopramide is also a potent dopamine receptor antagonist. Selective 5-HT3 receptor antagonists are a major advance in the treatment of chemotherapy- and radiotherapy-induced emesis in cancer patients. These agents inhibit emesis by blocking 5-HT3 receptors on vagal afferent nerve terminals in the gastrointestinal mucosa and on terminals on the same vagal nerves in the vomiting system. Inhibition of acute emesis appears to be produced by blocking the initiation of the emetic reflex induced via 5-HT3 receptors and by 5-HT released from enterochromaffin cells in the small intestine, as well as by blocking 5-HT3 receptors in the hindbrain vomiting system.
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PMID:Selectivity of 5-HT3 receptor antagonists and anti-emetic mechanisms of action. 152 96

Trials of selective 5-hydroxytryptamine3 receptor antagonists have shown excellent antiemetic activity for chemotherapy containing cisplatin when compared with high-dose metoclopramide. There is little information about the efficacy of these new agents for chemotherapy other than for high-dose cisplatin. We performed a double-blind, randomized trial comparing a single dose of the 5-hydroxytryptamine3 receptor antagonist granisetron (BRL 43694A) as a single intravenous dose with dexamethasone plus prochlorperazine in 152 patients receiving their first course of moderately emetogenic chemotherapy (mainly doxorubicin- and cyclophosphamide-containing combinations). During the first 24 hours, there was a statistically significant advantage for the granisetron group in terms of the prevention of both nausea and emesis. There was no difference in the frequency of reported adverse events. We conclude that granisetron is more effective than dexamethasone plus prochlorperazine in patients who are receiving moderately emetogenic cytotoxic agents.
J Natl Cancer Inst 1991 Aug 21
PMID:Superiority of granisetron to dexamethasone plus prochlorperazine in the prevention of chemotherapy-induced emesis. 165 63


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