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)

A double-blind double-dummy, comparative study was carried out in 30 patients receiving highly emetogenic fast dose rate, single fraction total body irradiation prior to bone marrow transplantation. Patients were randomised into one of two groups, receiving either granisetron, a specific 5-HT3 antagonist or a combination of metoclopramide, dexamethasone phosphate and lorazepam to assess the comparative efficacy of the two regimens in the control of irradiation-induced nausea and vomiting. After 24 h eight patient (53%) treated with granisetron showed a complete response compared with two patients (13%) in the comparator group. The control of vomiting by granisetron, over both 24 h and 7-day periods (P = 0.001 and P = 0.004), was significantly better than that seen with the comparator and required significantly fewer rescue doses. The safety profiles in the two groups appeared similar, with the exception that granisetron produced less drowsiness than the comparator.
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PMID:Granisetron in the prevention of irradiation-induced emesis. 759 70

The role of serotonin as the possible trigger mechanism of vomiting associated with chemotherapeutic drugs was further investigated in cancer patients (n = 86). Increases in 5-hydroxyindoleacetic acid (5-HIAA) excretion rates (2.5-2.9 times baseline values) were observed 4 to 8 hours after high-dose cisplatinum (> or = 50 mg/m2). The daily excretion of 5-HIAA from 24-48, 48-72, and 72-96 hours after cisplatinum was not different from pre-cisplatinum levels. These results, together with the efficacy data for 5-HT3 antagonists, suggests that serotonin may trigger the early, intense period of emesis, but not the period of delayed emesis, following high-dose cisplatinum. Compared with the first cycle of chemotherapy, higher peak levels and more sustained elevations of 5-HIAA excretion were found after subsequent cycles, with high-dose cisplatinum. Further, no evidence of serotonin depletion was found after a single or after repeated cycles of treatment with high-dose cisplatinum. These data suggest that the more intense emetic response associated to repeated cycles of treatment may be triggered by greater changes in serotonin release. No significant differences in the rate and amount of 5-HIAA excreted induced by low-dose (30 +/- 2 mg/m2) and high-dose (84 +/- 3 mg/m2) cisplatinum were found between those patients who received dexamethasone (D) (20 mg i.v.) and those who received metoclopramide (M) (2 mg/kg, i.v.), irrespectively of the cycle of treatment. Interestingly, for M but not for D, best antiemetic protection was observed when lower amounts of serotonin were released (i.e., low-dose cisplatinum and initial cycles of treatment).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Participation of serotonin on early and delayed emesis induced by initial and subsequent cycles of cisplatinum-based chemotherapy: effects of antiemetics. 769 98

The purpose of this study was to evaluate and compare the antiemetic effectiveness and tolerability of Navoban (tropisetron) and Zofran (ondansetron) following high-dose (> or = 50 mg/m2) cisplatin chemotherapy. In a randomised, multi-centre, double-blind, double-dummy, parallel group study, 117 evaluable chemotherapy-naive patients who received Navoban were compared with 114 who received Zofran. Patient diary cards were used to assess both acute (Day 1) and delayed (Days 2-6) nausea and vomiting. Total control of acute vomiting was achieved in 54% of Navoban and 65% of Zofran patients (p = 0.052), and total control of acute nausea in 66% and 62% respectively (p = 0.655). Total control of delayed vomiting was achieved in 44% of Navoban patients and 46% of Zofran patients (p = 0.765), and of delayed nausea in 56% and 47% respectively (p = 0.207). Both reactions combined were totally prevented during the entire 6-day trial period in 22% of Navoban and 24% of Zofran patients (NS), while a further 42% of patients in both groups remained largely free from both nausea and emesis. The few adverse reactions (e.g. headache, constipation, diarrhoea) were mainly mild and typical of the 5-HT3-receptor antagonists. In conclusion, there were no significant differences in efficacy and tolerability between Navoban 5 mg once daily and the highest recommended dose of Zofran (32 mg on Day 1, followed by 8 mg three times a day).
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PMID:Is Navoban (tropisetron) as effective as Zofran (ondansetron) in cisplatin-induced emesis? The French Navoban Study Group. 774 65

One hundred and thirty-one children with a median age of 5 years were administered Navoban (tropisetron), a selective antagonist of the serotonin receptor (5-HT3), dosed once daily at 0.2 mg/kg (with a maximum of 5 mg daily) in a study aimed at evaluating the prevention of nausea and vomiting induced by anti-cancer chemotherapy. The most common malignancy (in 49% of patients) was acute lymphocytic leukaemia. Patients received Navoban during one or more courses of emetogenic chemotherapy for a total of 455 courses administered intravenously or intravenously and intrathecally (IV + IT). Most patients (89%) had already received cytotoxic chemotherapy before enrollment for the trial. On Day 1, Navoban was administered slowly and intravenously as a single dose before the start of chemotherapy, or by mouth as a single daily dose on subsequent days (median treatment duration = 5 days). On the first 5 days of each course of chemotherapy, response to Navoban per 24-hour period was graded as: complete (absence of both nausea and vomiting), partial (1-4 vomits and/or less than 5 hours of nausea), or failure (more than 4 vomits and/or at least 5 hours of nausea). Ninety-six per cent of the intravenous chemotherapy group and 97% of the IV + IT chemotherapy group had a complete (70% and 55% respectively) or partial (26% and 42% respectively) response during the first 24-hour period of the first course in which Navoban was used. The second and subsequent courses yielded similar percentages. Delayed emesis was observed mainly during those courses employing the most emetogenic chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Control of nausea and vomiting by Navoban (tropisetron) in 131 children receiving cytotoxic chemotherapy. 774 70

Recently discovered serotonin3 (5-HT3) receptor antagonists are potent antiemetics in cytotoxic drug-induced vomiting. The specific site where 5-HT3 receptor antagonists act to abolish emesis is controversial. The major objective of this study was to determine whether the antiemetic effect of 5-HT3 receptor antagonists is exerted in the brain areas that reside inside or outside of the blood-brain barrier. Tropisetron, zatosetron (LY277359 maleate) and its quaternary analog zatosetron-QUAT were used in this study. Zatosetron and zatosetron-QUAT showed high affinity and selectivity for 5-HT3 receptors in radioligand binding studies. Both compounds antagonized 5-HT-induced bradycardia in rats with an approximate ID50 of 0.7 and 0.2 microgram/kg i.v., respectively. Zatosetron and tropisetron significantly inhibited cisplatin-evoked emesis in dogs (estimated ID50 values of 34.4 +/- 2.3 micrograms/kg and 108.3 +/- 4.8 micrograms/kg i.v., respectively). Zatosetron-QUAT (0.01-1.0 mg/kg i.v.) had no effect. [14C]-zatosetron-QUAT (100 micrograms/kg) was not detected in the brain after i.v. administration to rats, consistent with the inability of charged compounds to achieve significant brain concentrations. However, i.c.v. administration (100 ng/kg) of zatosetron-QUAT reduced emetic episodes significantly (11.6 +/- 1.6 vs. 2.8 +/- 1.2). These studies suggest that, in dogs, antagonism of 5-HT3 receptors located within the blood-brain barrier is important to block cisplatin-induced emesis.
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PMID:Antagonism of serotonin3 (5-HT3) receptors within the blood-brain barrier prevents cisplatin-induced emesis in dogs. 775 72

The use of high doses of cisplatin in treating cancers has been limited by two major adverse effects--emesis and peripheral neuropathies. The emesis has become largely controlled by the introduction of a new class of drugs--the 5-HT3 receptor antagonists. The current study was undertaken to determine if these drugs would also prevent cisplatin-induced neuropathy. We have used a developing rat as an animal model and determined the effects of cisplatin on morphology (loss of spinal cord calcitonin gene-related peptide (CGRP)-containing neurons) and behavior (gait abnormalities and pain perception). Rat pups from the age of 5 days were treated twice weekly for 4 weeks with cisplatin (1 mg/kg), the 5-HT3 antagonist MDL 72222 (3 mg/kg) or both. The animals were tested for pain perception (using tail-flick latencies) at 17 and 21 days of age and for a gait abnormality at 24 days of age. At 34 days of age, the animals were perfused and the lumbar region of the spinal cords stained immunocytochemically for CGRP. Our results show that cisplatin treatment resulted in a dramatic loss of CGRP neurons in the dorsal horn of the spinal cord and a corresponding increase in the animals' threshold for pain. In addition, the animals showed a pronounced gait abnormality, characterized by 'toeing-in'. Treatment with MDL 72222 not only failed to protect against the loss of CGRP neurons but also worsened the gait abnormalities seen after cisplatin treatment alone. These studies confirm and extend the list of morphological and functional adverse effects of cisplatin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A 5-HT3 receptor antagonist fails to prevent cisplatin-induced toxicity in immature rat spinal cord. 779 48

Serotonin (5-HT) is a central neurotransmitter and a neuromodulator. This amine is involved in many physiological functions and pathological disorders. Most of its effects are mediated by specific 5-HT receptors. In the first part of this paper, the present knowledge of 5-HT receptors is reviewed in terms of both pharmacology and molecular biology. In the second part, the functional properties of 5-HT receptors are analyzed and their involvement in pathophysiological processes is discussed. Most 5-HT receptors belong to the G-protein-coupled receptor family (5-HT1, 5-HT2 and 5-HT4 receptors), whereas one is a member of the ligand-gated ion-channel receptor family (5-HT3 receptor). 5-HT1 receptors are characterized by their high affinity for 5-HT and comprise several subclasses. Most are negatively coupled to adenylate cyclase but the 5-HT1C subtype is linked to phospholipase C activation and resembles the 5-HT2 receptor. By contrast, the newly identified 5-HT4 receptor is positively coupled to adenylate cyclase. Most 5-HT receptors have now been cloned, but their physiological roles are not completely understood. Better knowledge of 5-HT receptors has already led to the development of new drugs, such as buspirone, a 5-HT1A partial agonist devoid of benzodiazepine-like properties for the treatment of generalized anxiety. Anxiolytic properties have also been reported for 5-HT2 and 5-HT3 receptor antagonists. A new and potent anti-migrainous drug, sumatriptan, has recently been selected among compounds obtained by research on the 5-HT1D receptor. This key receptor controls the release of monoamines, amino acids and peptides, and new drugs are expected in the near future. The therapeutic potential of 5-HT3 antagonists is impressive, as these compounds have potent antiemetic, promnesic and antipsychotic properties in various animal models. Two such drugs have already been marketed for the prevention of radiation-induced emesis (ondansetron and granisetron) and are more potent than the antidopaminergic drugs. Many other data suggest that 5-HT receptors might be involved in other illnesses. Some drugs are in the development phase but identification of the relevant receptor is often difficult. Furthermore, the lak of specific ligands for some receptors clearly hinders functional correlations.
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PMID:[Central serotonin receptors. Principal fundamental and functional aspects. Therapeutic applications]. 780 Oct 37

Ditolyguanidine (DTG) induced a dose-dependent emetic response in pigeons, with 100% of the birds vomiting after 5.6 mg/kg. Retching and vomiting originally induced by DTG could be conditioned to the test situation. Both the unconditioned and conditioned emetic responses were dose-dependently blocked by 8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT) and LY228729, agonists at the 5-HT1A subtype of serotonin receptor, but not by the 5-HT3, antagonist tropisetron. Higher doses (0.25-0.5 mg/kg) of tropisetron exhibited intrinsic emetic activity which could also be prevented by 8-OH-DPAT. NAN-190, a putative 5-HT1A partial agonist, produced both an antiemetic response when administered before DTG and also attenuated the antiemetic effects of 8-OH-DPAT. Pentobarbital blocked the conditioned, but not the unconditioned DTG-induced emesis. These results support the possibility that 5-HT1A agonists exhibit antiemetic activity against a broad range of emetic stimuli, including conditioned vomiting which is usually resistant to pharmacological attenuation.
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PMID:Antiemetic effects of 5-HT1A agonists in the pigeon. 782 54

Ondansetron in the prophylaxis of Cisplatin-induced emesis and nausea. The 5-HT3 antagonist ondansetron clearly offers a new approach to the control of Cisplatin-induced emesis and has been evaluated in Thailand. To evaluate anti-emetic efficacy of ondansetron in the prevention of nausea and vomiting induced by Cisplatin containing cancer chemotherapy regimen, we carried out an open multicentre study from January 1991 to December 1992. In this study, patients receiving Cisplatin based chemotherapy received ondansetron 32 mg as a single intravenous dose over 15 minutes prior to the administration of Cisplatin. This was followed by oral ondansetron 8 mg three times a day, preferably one hour before each meal for 5 days. All patients were chemotherapy naive in-patients and were at least 18 years or older with Karnofsky performance status of at least 60 per cent. The number of emetic episodes, nausea and food intake were recorded during the 24 hours following Cisplatin administration. A total of 103 patients were recruited with 84 (81.6%) evaluable patients (48 men and 36 women) scheduled to receive cisplatin chemotherapy at dose 60 mg/m2 or more (60-100 mg/m2), either as single agent or combination therapy. Complete response (complete control of emesis) was achieved in 60 per cent; major response (1-2 emetic episodes) was 13 per cent; minor response (3-5 emetic episodes) was 13 per cent; and failure (5+ emetic episodes) was 10 per cent. Side effects were very mild and not significant. We conclude that ondansetron is efficacious in protecting patients from Cisplatin induced emesis and nausea.
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PMID:Ondansetron: prevention of nausea & vomiting in cisplatin based chemotherapy. 784 94

1. Selective 5-HT3-receptor antagonists are highly effective in preventing nausea and vomiting associated with chemotherapy, radiotherapy and surgery. Their pharmacological activity may be determined in vitro and in animal models of emesis. However, these methods may not give an accurate indication of the antiemetic dose range of 5-HT3-receptor antagonists in patients. Two volunteer models have been used to predict more accurately clinically effective antiemetic doses of 5-HT3-receptor antagonists. 2. The flare response to intradermal 5-HT is thought to be mediated by excitation of 5-HT3-receptors on cutaneous afferents, with release of substance P and subsequent vasodilation. Antagonism of the flare response appears to provide an indication of the effective antiemetic dose of 5-HT3-receptor antagonists but data on duration of action are conflicting. 3. Ipecacuanha-induced emesis is thought to be mediated through both peripheral and central 5-HT3-receptors. Antagonism of this response has demonstrated a close correlation with clinically effective antiemetic doses of the specific 5-HT3-receptor antagonist, ondansetron, and has the advantage of being more conceptually relevant than the flare model. 4. Further work, with newer 5-HT3-receptor antagonists, will clarify the role of these models as predictive of the use of these drugs in clinical practice.
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PMID:Volunteer models for predicting antiemetic activity of 5-HT3-receptor antagonists. 791 68


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