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)

The nausea and emesis associated with chemotherapy still constitute an important problem in anticancer treatment. The new specific 5-HT3 receptor antagonists appear to be effective against vomiting induced by chemotherapy and radiation. An overview is given of the current theories on the physiology of emesis and the available literature on ondansetron (GR38032F) as an antiemetic.
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PMID:Ondansetron, a new antiemetic therapy for oncology. An overview. 214 83

Emesis in chemotherapy containing Cisplatinum (DDP) is still a therapeutical dilemma. Emesis and nausea cause the cessation of a potential curative therapy in up to 10% of patients treated with DDP. We studied the antiemetic effectiveness of the selective Serotonin (5HT3)-receptor-antagonist Ondansetron (GR 38032F, Glaxo) in patients receiving high dose platinum chemotherapy. All patients suffered from severe emesis and were refractory to any standard antiemetic regimen (Metoclopramid). We studied the efficacy of the new drug against acute and delayed emesis following platinum chemotherapy. All adverse events are listed. Thirty four courses (n = 17 patients) of a platinum-containing regimen were analyzed so far. A sufficient antiemetic efficacy was observed in 56% of the courses. In 32 of 34 course (94%) the patients preferred the new drug compared with the standard antiemetic regime (Metoclopramid). In most cases only minor adverse events--which do not require any medical therapy--occurred. The most common adverse events were headache, constipation, dry mouth, abdominal discomfort and elevation of liver enzyme level without any clinical symptoms. One patient needed bowel surgery for severe constipation based on widespread intra-abdominal carcinosis.
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PMID:[Refractory vomiting with cisplatin therapy. Prospective study with the serotonin receptor antagonist GR 38032F]. 215 May 51

This article outlines the historical development of anti-emetic therapies and reviews the pathophysiology and clinical aspects of cytostatic drug-induced vomiting. The methodology and the factors affecting the results of clinical trials with anti-emetics are discussed. Advances in knowledge of the role of 5-hydroxytryptamine in cytostatic drug-induced vomiting have improved current anti-emetic therapy with the development of 5-HT3 receptor antagonists such as granisetron. Early trials show granisetron to be a very effective anti-emetic and suggest useful advantages over the regimens currently considered to be standard therapy for prophylaxis and treatment of cytostatic drug-induced emesis.
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PMID:The symptomatic control of cytostatic drug-induced emesis. A recent history and review. 216 81

Antagonists acting at the 5-hydroxytryptamine3 receptor are potent anti-emetic agents in cases of cytotoxic- and radiation-induced vomiting, and binding sites for these compounds have been described in brainstem areas known to be involved in mediation of nausea and vomiting. We have used autoradiography to examine the distribution of one of these antagonists, [3H]granisetron in the caudal brainstem of the ferret, a commonly used animal model for physiological investigations of emesis. The highest density of binding sites was found to be in the dorsomedial region of the nucleus of the solitary tract, the principal terminus for gastric vagal afferent fibres. Lower levels of binding were observed in the area postrema and the dorsal motor nucleus of the vagus. Following unilateral nodose ganglion excision, displaceable binding of [3H]granisetron in the nucleus of the solitary tract was attenuated on the ipsilateral side by 65%. Bilateral subdiaphragmatic vagotomy abolished binding of [3H]granisetron in the entire dorsal vagal complex. These results provide strong circumstantial evidence that 5-hydroxytryptamine3 receptors are located on vagal afferent terminals in the ferret brainstem.
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PMID:Evidence for presynaptic 5-hydroxytryptamine3 recognition sites on vagal afferent terminals in the brainstem of the ferret. 217 20

Three major areas of medicine are identified in which there is a need for new antiemetic drugs. These are the nausea and vomiting arising from gastrointestinal motility disturbances (functional dyspepsia, diabetic neuropathy, classical migraine), the sickness evoked by abnormal motion, and the severe emesis experienced by cancer patients as a result of certain cytotoxic therapies. For gastrointestinal-related nausea, selective stimulants of gut motility are suggested to form the basis for a new type of antiemetic therapy. In motion sickness, there has been progress in the understanding of the illness, but little advance in the development of new drugs that selectively prevent this type of sickness. In cancer chemo- and radio-therapy, the discovery that selective 5-HT3 (5-HT, 5-hydroxytryptamine) receptor antagonists can prevent severe cytotoxic-evoked emesis now promises to radically change the type of antiemetic therapy given to these patients. This type of antiemetic compound and the pharmacology of the new 5-HT3 receptor antagonists are, therefore, discussed in detail.
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PMID:New antiemetic drugs. 217 55

In recent years the role of the area postrema in the emetic reflex has been predominant and the involvement of the abdominal visceral innervation has tended to be overlooked. This paper attempts to redress the balance reflex by reviewing aspects of the existing literature and complementing this with original studies from the ferret. In view of the widespread use of the ferret in studies of emesis and particularly in the characterization of the antiemetic actions of 5-HT3 receptor antagonist, the opportunity is taken to assess the suitability of this species for studies of emesis. It is concluded that the ferret is sensitive to a wide range of emetic stimuli including intragastric irritants, opiate and dopamine receptor agonists, many cytotoxic drugs, and radiation. For several stimuli it is more sensitive than other species and for radiation on the basis of its ED100 it appears to be the most sensitive of the laboratory animals studied. Using electrical stimulation of the central end of the dorsal vagal trunk in the abdomen in conscious and anaesthetized animals, the vagal afferents were shown to be capable of eliciting emesis. Using lesioning studies an involvement of the vagus in the emetic response to a number of cytotoxic drugs (e.g., cisplatinum, cyclophosphamide, mustine) and radiation was demonstrated, although the magnitude of the effect varied with the different stimuli. An attempt is made to reconcile these observations with previous studies of area postrema ablation. The problems of interpreting the effects of nerve lesions are critically discussed in light of preliminary evidence presented here that there may be a degree of plasticity in the emetic pathway following such lesions. The range of antiemetic effects of 5-HT3 receptor antagonists is reviewed and an attempt is made to identify the site(s) at which these agents act. Results are presented that suggest a link between the vagus and 5-HT3 receptor antagonism. These studies are discussed together with others and lead us to propose that (in the ferret) 5-HT3 receptor antagonists have their main antiemetic effect by acting on vagal afferent terminals in the wall of the upper gut with an additional minor site either in the nucleus tractus solitarius or presynaptically on the vagal afferent terminals in the medulla where binding sites for 5-HT3 receptor ligands have recently been demonstrated in this species.
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PMID:The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. 217 56

The results of an open study designed to evaluate the prevention of cisplatin-induced emesis by the specific 5-HT3 receptor antagonist ICS 205-930 are reported. Fifty-four cancer patients, treated with diverse chemotherapy regimens, all including cisplatin (greater than = 50 mg/m2), received ICS 205-930 for a total of 165 courses. ICS 205-930 (10 mg) was given i.v. immediately before the cisplatin infusion and a second 10-mg dose was given immediately after. In 109 courses (66%) the patients did not have any vomiting episodes. Nausea was absent in 44.8% of courses. More than 3 vomiting episodes occurred only in 17 (10.4%) courses, and severe nausea only in 11 (6.6%). ICS 205-930 was extremely well tolerated. Mild headache occurred during 7 courses (4.2%) in 4 patients, hypotension during 5 courses (3%) in 3 patients and lipothymia in 2 courses (1.2%) in 2 patients. These results suggest that ICS 205-930 is an effective and well tolerated antiemetic drug in patients receiving cisplatin chemotherapy.
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PMID:Prevention of nausea and vomiting in cisplatin-treated patients by a selective 5-hydroxytryptamine (5-HT3) receptor antagonist, ICS 205-930. 228 99

Cancer therapy with cytotoxic drugs such as cisplatin or cyclophosphamide is usually associated with violent crisis of vomiting. Recently, it was shown that 5-HT3 receptor antagonists block cisplatin-induced vomiting but the mechanisms and their sites of action remain unknown. We tested the hypothesis that these agents act on structures within the central nervous system by evaluating the effectiveness of vagal stimulation in eliciting fictive vomiting in decerebrate, paralyzed and ventilated cats before and after administration of such agents. Fictive vomiting was defined as a series of large bursts of synchronous activity in the phrenic and abdominal (expiratory) nerves (retching) followed by a burst in which the abdominal activity was prolonged (expulsion). The latency and number of these co-activations were measured before and after intravenous administration of three 5-HT3 receptor antagonists (GR 38032F (Ondansetron). Zacopride, and BRL 43694A (Granisetron]. All compounds, administered at doses of 1 and 2 mg/kg failed to block vomiting behaviour in 100% and 68% of trials, respectively. Nor did their administration affect the latency and number of co-activations. We conclude that intravenous administration of 5-HT3 receptor antagonists do not act centrally on either the brainstem neuronal network known as the "vomiting center" or related neuronal structures. Our results suggest that the anti-emetic effect of 5-HT3 receptor antagonists in cisplatin-induced vomiting is mediated peripherally rather than centrally.
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PMID:Vagal-induced vomiting in decerebrate cat is not suppressed by specific 5-HT3 receptor antagonists. 229 1

The present studies demonstrate the presence of specific [3H]GR65630 binding sites within the human brainstem using the techniques of in vitro receptor autoradiography and ligand binding to homogenates. Autoradiography revealed the greatest accumulation of specific binding in the area postrema and subpostrema (AP/ASP). A lower level of specific binding was identified in the nucleus tractus solitarius (excluding area subpostrema). No specific binding was evident in the remainder of the hindbrain at this level. Discrete dissection followed by ligand binding to homogenates revealed that the specific binding of [3H]GR65630 (defined by the presence of 30 microM metoclopramide) was differentially distributed with highest levels in the AP/ASP (112.1 fmol/mg protein) and lower levels in the dorsal vagal complex (nucleus tractus solitarius--excluding the area subpostrema--dorsal motor nucleus of the vagus and hypoglossal nucleus) (DVC) and olivary nucleus (ON) (22.9 and 3.9 fmol/mg, respectively). No specific binding was detectable in the reticular formation (RF) located ventral to the dorsal vagal complex. The specific [3H]GR65630 binding site was pharmacologically similar to the 5-HT3 receptor since the potent and selective 5-HT3 receptor antagonists ICS 205-930 and zacopride (100 nM) and the agonist 5-HT (10 microM) inhibited binding to the same extent as metoclopramide in each of the individual areas (90, 60 and 20% in the AP/ASP, DVC and ON, respectively). The 5-HT1-like and 5-HT2 receptor antagonist methysergide (10 microM) failed to compete for the binding site. 5-HT3 receptor recognition sites within the AP/ASP and the DVC may be functionally involved in the ability of 5-HT3 receptor antagonists to control emesis.
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PMID:Identification and distribution of 5-HT3 recognition sites within the human brainstem. 233 96

Metoclopramide (1) is a gastric motility stimulant and a weak dopamine and 5-HT3 receptor antagonist. Conformational restriction of the (diethylamino)ethyl side chain of 1 in the form of the azabicyclic tropane gave 3, a very potent gastric motility stimulant and 5-HT3 receptor antagonist but devoid of significant dopamine receptor antagonist properties. Subsequent alteration of the aromatic nucleus led to the identification of indazoles 6a-h, and 1- and 3-indolizines 7b-d and 8, and imidazo[1,5-alpha]pyridines 9 and 10, as potent 5-HT3 receptor antagonists devoid of either dopamine antagonist or gastric motility stimulatory properties. Further conformational restriction of the side chain identified quinuclidine 11 and isoquinuclidine 12 as potent 5-HT3 receptor antagonists which mimic the distorted chair conformation of the tropane with, in the case of 11, the N-methyl group axial. From these series, 6g (BRL 43694) was found to be both potent and selective and has been shown to be a very effective antiemetic agent against cytotoxic drug induced emesis both in the ferret and in man.
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PMID:5-Hydroxytryptamine (5-HT3) receptor antagonists. 1. Indazole and indolizine-3-carboxylic acid derivatives. 236 70


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