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)

Dolasetron mesylate is a selective and potent 5-HT3 receptor antagonist. This drug is currently in development for the treatment of nausea and vomiting in chemotherapy. The metabolism of dolasetron mesylate was studied in six healthy male volunteers who were given a single 300 mg oral dose of [14C]dolasetron mesylate. An average of 59% of the total radioactivity was recovered in the urine and 25% in the feces. Metabolites were quantitated in urine samples taken up to 36 hr postdose. Reduced dolasetron (RD) accounted for 17-54% of the dose in urine. Hydroxylated metabolites of RD made up no more than 9% of the dose in urine. Most of the remaining urinary radioactivity consisted of conjugated metabolites of RD and hydroxy RD. Hydrolysis of selected urine samples showed that the glucuronide of RD was the most abundant conjugate in urine. A small percentage of the dose (< 1%) in urine was identified as the N-oxide of RD. Analysis of urine samples by chiral HPLC indicated that the R(+):S(-) ratio of RD was approximately 9:1.
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PMID:Human metabolism of dolasetron mesylate, a 5-HT3 receptor antagonist. 749 46

Loading therapy consisting of the ACNU regimen was instituted as postoperative anticancer chemotherapy for malignant gliomas. The efficacy rate of the regimen was 25% at a dose of 3 mg/kg. A high incidence of hematological changes, such as leukopenia (neutropenia) and thrombocytopenia, were observed after chemotherapy. The former could be prevented by the administration of G-CSF, but platelet infusions were necessary in some patients for amelioration of thrombocytopenia. Gastroenterological symptoms, such as nausea and vomiting, were also frequently noted. Granisetron (Kytril), which is a recently developed selective competitive inhibitor of the 5-HT3 receptor, was used for the treatment of these adverse effects, and was found to be clinically effective.
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PMID:[Effective measures against side effects by increasing ACNU dose for malignant glioma: effects on digestive organs]. 752 1

We have investigated the pharmacokinetics of a 5-day multiple oral dose of 5 mg tropisetron capsule in patients with malignant tumour who had received cisplatin single administration. Its anti-emetic effects on acute and delayed emesis and vomiting were also investigated. During the 5 days after this administration, changes in the release and metabolism of serotonin were investigated. The results may be summarized as follows: 1) The pharmacokinetic parameters of tropisetron revealed no significant change in the data between day 1 and day 5. Also, the parameters were almost similar to those observed in healthy adult males (clinical phase I study); Cmax. T1/2 and AUC 0-24 hrs on day 1 were 9.1 +/- 2.1 ng/ml, 12.5 +/- 4.2 hrs, 85.5 +/- 22.7 ng.hr/ml, respectively. The urinary excretion of the parent drug up until 24 hours after administration on day 1 was 3.8% of the dose administered and 2.9% of the total dose after the last administration; no difference in the urinary excretion rate was observed in healthy subjects. It was thus suggested that hydration accompanied by cisplatin administration did not affect the pharmacokinetics of tropisetron. 2) The changes in the amount of urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA) during 5 days after cisplatin administration were observed; urinary excretion of 5-HIAA increased 2.3 times (1.3-5.4 times) the baseline on the average during 6 to 12 hours on day 1. In 6 out of 10 patients, the increases in urinary excretion of 5-HIAA showed double or more the baseline during 2 to 5 days after cisplatin administration. Serotonin was thus deemed to be related to the development of delayed emesis. 3) The anti-emetic effects of tropisetron on acute and delayed emesis and vomiting were rated as "markedly effective" in 6 out of 11 patients (54.6%) and "effective" in 1 out of 11 patients (9.1%) on day 1; vomiting did not occur in any of these 7 patients. Tropisetron also controlled emesis and vomiting during days 2-5, and was rated as "almost favorable" in 6 out of 11 patients (54.5%). Further, in 4 out of 6 patients, in whom the urinary excretion of 5-HIAA was increased on day 2 onwards, vomiting did not occur during the time when the urinary excretion of 5-HIAA was increasing. On the basis of the above results, tropisetron is deemed to have certain antiemetic effects on delayed vomiting as well. Its 5-HT3 receptor mediated mechanism was similarly seen to inhibit acute nausea and vomiting.
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PMID:[Pharmacokinetic investigation of 5-day multiple dose of tropisetron capsule in patients who had received cisplatin and the usefulness of tropisetron capsule in the treatment of nausea and vomiting]. 754 65

At cancer treatment, the use of antiemetics are often needed due to induction of nausea and vomiting. Some antiemetics have been shown to interact with the direct cytotoxic effects. The newly developed antiemetics have, as far as we know, not been studied in this respect. In the present study, the effects of the 5-HT3 receptor antagonists ondansetron and granisetron were evaluated on the cytotoxicity, induced by irradiation, bleomycin, epirubicin, estramustine, and cisplatin using fibroblasts (V79) and lung cancer cells (P31) in vitro. Ondansetron or granisetron (10(-5) mol/l) had no effect on the survival of irradiated cells. Granisetron (10(-5) mol/l) significantly potentiated cytotoxicity of 2.5 mg/l epirubicin on fibroblasts whereas the effect of granisetron (10(-7) mol/l) on the cytotoxic effect of 25 mg/l bleomycin, and estramustine (80 mg/l) seemed additive to lung cancer cells. Ondansetron was non-interactive with the cytotoxicity induced by any of the anti-cancer drugs. Although the encountered observation with an enhancing effect of granisetron on the epirubicin-induced cytotoxicity is seen in a specific experimental situation in vitro, the fact that 5-HT3 receptor antagonists are routinely used during cancer treatment indicate that attention should be given to a possible interaction with the antineoplastic action of cancer treatment.
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PMID:Interaction of the antiemetics ondansetron and granisetron with the cytotoxicity induced by irradiation, epirubicin, bleomycin, estramustine, and cisplatin in vitro. 757 57

A prospective trial was performed to better assess the risk of nausea and vomiting and the rescue value of tropisetron (TRO), a 5-HT3 receptor antagonist, in 88 patients undergoing fractionated radiotherapy to the abdomen or to large supradiaphragmatic fields and failing a first anti-emetic trial with metoclopramide (MET). Nausea was graded 0 (absent), 1 (mild), 2 (moderate) and 3 (severe). Nausea requiring anti-emetics (> or = grade 2) was present in 64% of the patients. MET was able to control nausea (< or = grade 1) in 26 of 58 patients (45%) who developed > or = grade 2 nausea during radiation treatment (2 patients vomiting without nausea included). 34 patients required TRO, and 31 experienced immediate relief. However, nausea (> or = grade 2) recurred in 7 patients from 1 to 3 weeks after starting TRO. Sex, age, field type and field size (cm2) did not influence the incidence and severity of nausea and vomiting. Only 24/88 patients vomited after starting radiotherapy. MET helped to eliminate emesis in one third of these patients. TRO helped to control vomiting in 73% of the salvaged patients. Constipation was observed in 8 patients on TRO and was a reason to stop the medication in 4 cases.
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PMID:Nausea and vomiting in fractionated radiotherapy: a prospective on-demand trial of tropisetron rescue for non-responders to metoclopramide. 757 72

Ondansetron is a selective 5-HT3 receptor antagonist which has previously been reported in the Journal to be a promising new agent for use as prophylaxis against nausea and vomiting caused by chemotherapy and radiotherapy. Since the publication of this original review, further studies have been published that show ondansetron to be an effective antiemetic agent in patients receiving chemotherapy and radiotherapy. Several studies have shown ondansetron to be a more effective antiemetic agent than high-dose metoclopramide in patients with emesis induced by high- and low-dose cisplatin treatment, and noncisplatin chemotherapy-induced emesis. The drug as mono-therapy does not appear to offer any advantage over alternative therapies against delayed high-dose cisplatin-induced nausea and vomiting; however, extremely limited data suggest that ondansetron plus dexamethasone may be useful in this indication. Trials have shown combination therapy with ondansetron and dexamethasone to be significantly more effective than both ondansetron monotherapy and a standard antiemetic regimen comprising metoclopramide, dexamethasone and diphenhydramine against acute high-dose cisplatin-induced emesis. Results from a number of small scale trials suggest that ondansetron may be an effective treatment for chemotherapy-induced emesis refractory to conventional antiemetic therapy. Ondansetron also appears to be more effective against refractory emesis induced by noncisplatin chemotherapy than that induced by cisplatin chemotherapy. Several trials have shown ondansetron to be more effective than placebo as prophylaxis against postoperative nausea and vomiting; a further trial has shown single-dose ondansetron to be significantly more effective than single-dose droperidol or metoclopramide in this indication. In addition, several trials have shown ondansetron to be more effective than placebo as treatment for nausea and vomiting that has commenced postoperatively. The overall incidence of adverse events in ondansetron recipients during chemotherapy-induced emesis studies was 36%. Headache and constipation are the most common adverse events during ondansetron therapy. Thus, recent data affirms the efficacy of ondansetron in the treatment of acute chemotherapy-induced nausea and vomiting and shows it to be especially efficacious when combined with dexamethasone. It appears that the drug will also have a substantial role in the prophylaxis and treatment of postoperative nausea and vomiting.
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PMID:Ondansetron. An update of its therapeutic use in chemotherapy-induced and postoperative nausea and vomiting. 769

Selective 5-HT3 receptor antagonists such as ondansetron are potent antiemetics for chemotherapy-induced emesis. Ondansetron has been shown to be highly effective in preventing nausea and vomiting in children treated with chemotherapy and/or radiotherapy. However, its high cost may limit its application. A "physician profile" provided by the hospital pharmacy and a questionnaire survey conducted amongst the attending physicians of the hematology/oncology division of a children's hospital showed wide variation in ondansetron use. This variation was evident for both the indications of use and the schedule of administration. Moreover, 80% of the physicians were not aware of the actual cost of ondansetron. In order to reduce this variation, which may affect the quality of care and increase costs unnecessarily, guidelines have been developed for the use of antiemetic drugs in pediatric oncology patients at this institution.
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PMID:Variation in the use of ondansetron as an antiemetic drug in children treated with chemotherapy. 775

Neuroendocrine gut and pancreatic tumors are neoplasms that present distinct features from other malignant tumors. Firstly, in most patients, tumor growth is rather slow, and even in advanced metastatic disease, there is very little impairment of the general well-being of the individual, e.g. appetite and weight. Secondly, these tumors are known to produce specific peptide hormones which may be factors in some clinical conditions e.g. carcinoid, Zollinger-Ellison and hypoglycemic syndromes. These conditions can be critical to the patients and can occasionally be lethal. Therefore, the treatment of neuroendocrine tumors must control the clinical symptoms related to hormone over-production and prevent further tumor growth. These two features are not always in parallel. Systemic treatment of neuroendocrine tumors mainly consists of chemotherapy, interferon and somatostatin analog administration. Chemotherapy has been used for at least 30 years; the most effective combination has proved to be streptozotocin with 5-fluorouracil or adriamycin. This combination produces biochemical responses in up to 60% of patients with endocrine pancreatic tumors; the results in carcinoid patients are very poor and response rates are < or = 10%. Alpha-interferon (IFN-alpha) produces biochemical responses in approximately 50% of patients with malignant carcinoid tumors, significant reductions in tumor size in 15% and a further 39% of patients have disease stabilization with no further tumor growth. Somatostatin analogs have only been used clinically within the last 10 years, but produce symptomatic improvement in 70% of cases, biochemical responses in 40-60%, but rarely produce any significant reduction in tumor size. These analogs are particularly useful to control severe clinical symptoms and are the first-line therapy for the management of carcinoid patients both peri- and intra-operatively. Patients with endocrine pancreatic tumors, particularly those with glucagon and vasointestinal peptide-producing tumors, benefit most from this type of treatment. Recently, a combination of IFN-alpha and a somatostatin analog has showed an additive effect of these two drugs. The side effects of streptozotocin and 5-fluorouracil are mainly nausea and vomiting which can be controlled with 5-HT3 receptor blocker therapy. Another significant adverse reaction is impaired renal function. The adverse reactions to IFN-alpha are mainly flu-like symptoms, fatigue, mild impairment of liver and bone marrow function and autoimmune reactions in 15% cases. Somatostatin analog treatment causes a low frequency of adverse reactions, those which do occur include gall stone formation and steatorrhea. Future systemic treatment should be based on increased knowledge of the tumor biology, particularly growth-regulatory mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endocrine tumors of the gastrointestinal tract: systemic treatment. 785 82

An open, noncomparative, Nordic multicenter study was carried out during 1991-1992 to evaluate the 5-HT3 receptor antagonist tropisetron (Navoban) as an antiemetic agent for various types of cancer chemotherapy. A total of 630 patients were recruited from 15 centers in Sweden, Denmark, and Finland. Gynecological cancers (60%), breast cancer (15%), and lung cancer (10%) were the main diagnoses. Prior experience of chemotherapy was documented in 338 patients (54%). In 260 patients (41%), cisplatin was part of the cytostatic regimen. Carboplatin (23%), doxorubicin (27%), and epidoxorubicin (24%) were also frequently included. In all, 23 cytostatic agents were used in various combinations. The mean number of courses studied was 4.6 (range 1-19). Altogether, 394 of 619 evaluable patients (64%) were completely protected from acute nausea and vomiting during the first course of chemotherapy. Delayed nausea and vomiting were completely prevented in 45%-73% (days 2-6) in the complete series. Treatment efficacy remained stable (60%-79%) during ten consecutive courses of chemotherapy. With noncisplatin regimens, complete protection from acute nausea and vomiting was achieved in 72% compared with 52% for cisplatin regimens (P < 0.0001). Patients without prior experience of chemotherapy had higher control rates of acute nausea and vomiting (72%) compared to patients treated before (57%) during the first course, but not later on. There were no differences in delayed nausea and vomiting.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tropisetron (Navoban) in the prevention of chemotherapy-induced nausea and vomiting--the Nordic experience. 785 34

The pharmacology of 5-HT and the classification of 5-HT receptors have become increasingly complex. However, recent advances have produced a new nomenclature system for 5-HT receptors. 5-HT3 receptors are neuronal receptors coupled directly to cation channels. Recently, many selective 5-HT3-receptor antagonists including tropisetron, zacopride, ondansetron, granisetron, zatosetron, nazasetron, YM060 and YM114 (KAE-393) have been developed. Many actions attributable to the 5-HT3-receptor have been described in both the peripheral and central nervous systems, and clinical trials are already showing the potential use of these 5-HT3 receptor antagonists in a number of disorders of the gastrointestinal tract and central nervous system, such as nausea and vomiting induced by cancer chemotherapy, anxiety, depression, schizophrenia and migraine. In addition, endogenous 5-HT is suggested to be one of the substances that mediate stress-induced responses in gastrointestinal function, i.e., increase in fecal pellet output and diarrhea. Moreover, YM060, YM114 (KAE-393) and granisetron have been reported to inhibit restraint stress- and 5-HT-induced increases in fecal pellet output and diarrhea in rats and mice, indicating that endogenous 5-HT may mediate stress-induced changes in bowel function through the 5-HT3 receptor. Therefore, 5-HT3-receptor antagonists are new therapeutic drugs for stress-induced gastrointestinal dysfunctions like irritable bowel syndrome (IBS).
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PMID:[Serotonin (5-HT)3 receptors: antagonists and their pharmacological profiles]. 795 7


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