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)

Animal models of chemotherapy/radiotherapy-induced emesis successfully predicted the clinical efficacy of the 5-HT3 receptor antagonists for the control of acute emesis. Further studies in animals have provided valuable information relating to the pathophysiology of emesis and the mechanism of action of 5-HT3 receptor antagonists. These agents inhibit emesis by blocking the action of 5-HT at 5-HT3 receptors on the vagus nerve in the gastrointestinal tract and in the hindbrain vomiting system. 5-HT is hypothesized to be released from enterochromaffin cells following cytotoxic therapy or radiation. The mechanism by which 5-HT is released from enterochromaffin cells is unknown and, although various mechanisms have been proposed, none of these have provided convincing supportive evidence. In collaboration with scientists at Glaxo we have pioneered two models of cisplatin-induced acute and delayed emesis [Rudd et al., 1994]. In the first model, ferrets are given a low dose of cisplatin (5 mg/kg i.p.) and observed for 3 days. A pattern of emesis similar to that seen in the clinic has been observed with two distinct phases of emesis. Ondansetron, and particularly ondansetron plus high-dose dexamethasone, are effective in reducing the emetic response over days 1-3. The second model uses a higher dose of cisplatin (10 mg/kg i.p.) and an observation period of 24 h. Part of the emetic response over this time is resistant to 5-HT3 receptor antagonism. Studies into the mechanism of the emesis induced in both models may give an insight into cisplatin-induced emesis in man that is not controlled with 5-HT3 receptor antagonists.
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PMID:Mechanisms of chemotherapy/radiotherapy-induced emesis in animal models. 869 57

In the latter part of the 20th century, significant advances have been made in the understanding of the emetic reflex. As a result, there have been major improvements in the treatment of vomiting, particularly that associated with chemo- and radiotherapeutic treatments for neoplastic disease. The 5-HT3 receptor antagonists (ondansetron and granisetron) have been demonstrated to be of benefit in treating the profound emesis observed during cancer treatment. This observation, together with results from pharmacologic and physiologic investigations in both animals and humans, have identified 5-hydroxy-tryptamine (5-HT or serotonin) to be of fundamental importance in the pathogenesis of emesis. 5-HT appears to be released by radiation and chemotherapeutic agents from enterochromaffin cells within the wall of the intestine, and possibly from neurons within the brainstem. Stimulation of 5-HT3 receptors, located centrally in the dorsal medulla of the brainstem and peripherally on vagal afferent terminals in the gastrointestinal tract, appears to play a pivotal role in eliciting emesis. The interaction of 5-HT with non-5-HT3 receptors, particularly 5-HT1A and 5-HT4 receptors, may be important in the emetic reflex. The development of agents that interact with these receptors may offer alternative approaches to the treatment of nausea and vomiting.
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PMID:Serotonergic mediation of vomiting. 870 63

The pharmacological profile of five quinoxaline derivatives, a new class of 5HT3 receptor antagonists, is reported in the present study. All of the new compounds antagonized the effect of the selective 5-HT3 receptor agonist 2-methyl-5-HT in the isolated longitudinal muscle-myenteric plexus preparation (LMMP) of guinea-pig ileum. One of them, VC-605) was approximately three orders of magnitude more potent than ondansetron. In binding studies to 5-HT3 receptors from rat cerebral cortex membranes only VC-605 showed an affinity comparable to ondansetron. In the isolated rat oesophageal tunica muscularis mucosae preparation the new compounds, like 2-methyl-5-HT, only produced relaxation of the contraction induced by carbachol at high concentrations. In vivo, the quinoxaline derivatives were weak antagonists of the bradycardia response to 5-HT in the anesthetized rat. The quinoxaline derivatives, in particular VC-501 and VC-603, prevented retches and vomiting induced by 2-methyl-5-HT and cis-platinum in the ferret. The new compounds also enhanced the gastric emptying of solids in rats. The results obtained are probably indicative of the suggested species- and tissue-dependent differences in 5-HT3 receptor subtypes. The high potency and selectivity of one of the new quinoxaline derivatives, VC-605, at 5-HT3 receptors of guinea-pig ileum is remarkable. VC-605 may be a useful tool for further characterizing this possible 5-HT3 receptor subtype.
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PMID:Pharmacological properties of quinoxaline derivatives as a new class of 5-HT3 receptor antagonists. 874 88

Most anticancer drugs are cytotoxic and produce various side-effects, among which nausea and vomiting are almost ubiquitous and usually extremely distressing to the patient. Cancer chemotherapy elicits two main phases of vomiting: an intense, acute phase of vomiting that occurs almost immediately following anti-cancer therapy and a milder, delayed phase of nausea and vomiting of longer duration. The mechanisms underlying the induction of nausea and vomiting after cancer chemotherapy are poorly understood but may be mediated by serotonin (5-hydroxytryptamine or 5-HT), particularly in the acute phase. Serotonin activates 5-HT3 receptors, which function as ligand-gated ion channels located either in the periphery and/or in the central nervous system to produce emesis, among other effects. The peripheral 5-HT3 receptors may be pharmacologically distinct from the central 5-HT3 receptors and may exhibit some association with GTP-binding proteins. In addition, different populations may exist as distinct subtypes of the same receptor. The 5-HT3 receptor antagonist ondansetron (GR 38032F) is effective in preventing the emesis induced by cytotoxic agents currently used in the treatment of many forms of cancer. Ondansetron has, comparatively, a much higher efficacy in the treatment of acute emesis following cancer chemotherapy than it does in the delayed phase, suggesting that the late phase of emesis may be mediated by other distinct mechanisms.
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PMID:Role of 5-hydroxytryptamine3 (5-HT3) antagonists in the prevention of emesis caused by anticancer therapy. 876 66

In Suncus murinus, various emetic responses and the anti-emetic activity of a new 5-hydroxytryptamine3 (5-HT3) receptor antagonist, GK-128 (2-[(2-methylimidazol-1-yl) methyl benzo[f]thiochromen-1-one monohydrochloride hemihydrate), were investigated. Cancer chemotherapeutic agents, cisplatin and cyclophosphamide, dose-dependently induced emesis of long-lasting duration. The 5-HT3 receptor agonist, 2-methyl-5-HT, and copper sulfate also induced emesis of short duration. However, another 5-HT3 receptor agonist, m-chlorophenylbiguanide, was not consistently emetic. GK-128 inhibited the emetic responses induced by chemotherapeutic agents and 2-methyl-5-HT with similar potency. The anti-emetic action of GK-128 was more potent than that of ondansetron, Y-25130, granisetron and metoclopramide. The order of potency of these drugs, except granisetron, was consistent with that of their 5-HT3 receptor binding affinity in rat cortex. GK-128 failed to inhibit copper sulfate-induced emesis. These data suggest that GK-128 has a potent inhibitory effect on emesis via the 5-HT3 receptor, and that the 5-HT3 receptor involved in emesis in Suncus murinus may be different from the classically defined 5-HT3 receptor in other animals such as rats, dogs and ferrets.
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PMID:The anti-emetic activity of GK-128 in Suncus murinus. 884 9

Emesis after the administration of cisplatin is a severe complication, and its treatment is an important problem clinically. Cisplatin forces the release of serotonin (5-HT) from enterochromaffin cells in the mucosa, and emesis occurs by the stimulation of 5-HT3 receptors. In this study, we established a simple and simultaneous method of determining 5-HT and its main metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), in plasma and urine by high performance liquid chromatography with electrochemical detection (HPLC-ECD), and determined the disposition of endogenous 5-HT and 5-HIAA after the administration of cisplatin in rats and dogs. In rats, we found no change in the plasma concentration of 5-HIAA after cisplatin administration, while a distinct increase was shown in the plasma concentration of 5-HT, but it was not significantly different from that of the control rats. The urinary excretion of 5-HIAA was also not different between the two groups. In dogs, we observed intense vomiting in all cisplatin treated dogs. However, we could not detect any change in the 5-HIAA or 5-HT level in the dog plasma. Furthermore, no significant difference in the urinary excretion of 5-HIAA was observed between the cisplatin group and the controls. From these results, the plasma concentration of 5-HT and the urinary excretion of 5-HIAA may not be suitable markers for the evaluation of emesis induced by anticancer drugs in dogs.
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PMID:Effect of cisplatin on the disposition of endogenous serotonin and its main metabolite, 5-hydroxyindole-3-acetic acid, in rats and dogs. 885 Mar 33

Gastrointestinal prokinetics promote or increase the coordination of the gut wall contractions leading to enhancement of propulsive motility and, consequently, caudal displacement of luminal contents. Currently, they are considered drugs of choice for the treatment of upper gastrointestinal tract functional motor disorders such as those associated with gastrooesophageal reflux disease, chronic dyspepsia, gastroparesis (idiopathic or secondary to other diseases) and acute or chronic idiopathic intestinal pseudo-obstruction. The aim of the present review is to give an outline of the pharmacology of currently available prokinetics and of novel drugs endowed with gastrointestinal prokinetic action that require further pharmacological and/or clinical testing. The novel drugs include recent generations of benzamide and non-benzamide 5-HT4 receptor agonists, motilin receptor agonists, and inhibitors of nitric oxide synthase. Furthermore, based on our improved knowledge of the role of 5-HT in emesis and gastrointestinal motility, the therapeutic potential of potent mixed 5-HT4 agonists--5-HT3 antagonists in the control of cytotoxic-drug-induced emesis and associated gut motor disturbances will be discussed. Lastly, a section of this review deals with the colon as a possible target for the action of prokinetics.
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PMID:Recent advances in the pharmacology of gastrointestinal prokinetics. 893 12

There are now abundant evidence to confirm the role of serotonin (5-HT) and in particular, 5-HT3 receptors in the control of cisplatin-induced emesis. Emesis caused by cisplatin is associated with an increase in the concentration of 5-HT in the intestinal mucosa and in the area postrema. The intestinal mucosa contains enterochromaffin (EC) cells that synthesize and secrete approximately 80% of all 5-HT produced in the body. A selective 5-HT3 agonist, 2-methyl-5-HT, induced a dose-dependent increase in 5-HT level from the ileum. Furthermore, a selective 5-HT4-receptor agonist, 5-methoxytryptamine also induced a concentration-dependent increase of 5-HT level. Both 5-HT3 and 5-HT4 receptors may be involved in intestinal 5-HT release. It is proposed that anticancer drugs cause 5-HT release from the EC cells and that the released 5-HT stimulates the 5-HT3 receptors on the afferent vagal fibers, resulting in their deporalization. Electrical stimulation of the abdominal vagal afferents is capable of inducing emesis, and abdominal vagotomy suppresses cisplatin-induced emesis. These results indicate that the vagus is the major afferent pathway involved in the detection of emetic stimuli.
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PMID:[Role of serotonin in emesis]. 897 84

The interaction of S 21007 [5-(4-benzyl piperazin-1-yl)4H pyrrolo [1,2-a]thieno[3,2-e]pyrazine] with serotonin 5-HT3 receptors was investigated using biochemical, electrophysiological and functional assays. Binding studies using membranes from N1E-115 neuroblastoma cells showed that S 21007 is a selective high affinity (IC50 = 2.8 nM) 5-HT3 receptor ligand. As expected of an agonist, S 21007 stimulated the uptake of [14C]guanidinium (EC50 approximately 10 nM) in NG 108-15 cells exposed to substance P, and this effect could be prevented by the potent 5-HT3 receptor antagonist ondansetron. In addition, like 5-HT and other 5-HT3 receptor agonists (phenylbiguanide and 3-chloro-phenylbiguanide), S 21007 (EC50 = 27 microM) produced a rapid inward current in N1E-115 cells. The 5-HT3 receptor agonist action of S 21007 was also demonstrated in urethane-anaesthetized rats as this drug (120 micrograms/kg i.v.) triggered the Bezold-Jarisch reflex (rapid fall in heart rate), and this action could be prevented by pretreatment with the potent 5-HT3 receptor antagonist zacopride. Finally, in line with its 5-HT3 receptor agonist properties, S 21007 also triggered emesis in the ferret. Evidence for 5-HT3 receptor antagonist-like properties of S 21007 was also obtained in some of these experiments since previous exposure to this compound prevented both the 5-HT-induced current in N1E-115 cells and the Bezold-Jarisch reflex elicited by an i.v. bolus of 5-HT (30 micrograms/kg) in urethane-anaesthetized rats. These data suggest that S 21007 is a selective 5-HT3 receptor agonist which can exhibit antagonist-like properties either by triggering a long lasting receptor desensitization or by a partial agonist activity at 5-HT3 receptors in some tissues.
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PMID:Interaction of S 21007 with 5-HT3 receptors. In vitro and in vivo characterization. 898 86

A series of 2-piperazinylbenzimidazole derivatives were prepared and evaluated as 5-HT3 receptor antagonists. Their 5-HT3 receptor affinities were evaluated by radioligand binding assays, and their abilities to inhibit the 5-HT-induced Bezold-Jarisch reflex in anesthetized rats were determined. Compound 7e (lerisetron, pKi = 9.2) exhibited higher affinity for the 5-HT3 receptor than did tropisetron and granisetron, while compound 7q (pKi = 7.5) had very low affinity for this receptor, showing that substitution on the N1 atom of the benzimidazole ring is essential for affinity and activity. The effect of substitution on the aromatic ring of benzimidazole by several substituents in different positions is also discussed. A strong correlation between the 5-HT3 antagonistic activity of the studied compounds and the position of substitution on the aromatic ring was established. Thus, while the 4-methoxy derivative 7m showed weak affinity for the 5-HT3 receptor (pKi = 6.7), the 7-methoxy derivative 7n exhibited the highest affinity (pKi = 9.4). Compounds 7e and 7n are now under further investigation as drugs for the treatment of nausea and emesis evoked by cancer chemotherapy and radiation.
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PMID:New 2-piperazinylbenzimidazole derivatives as 5-HT3 antagonists. Synthesis and pharmacological evaluation. 904 49


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