Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies of the mechanism of zacopride-induced emesis in ferrets have concluded that it is mediated predominantly by an antagonist effect on 5-HT3 receptors although the possibility of a contribution from an agonist effect at 5-HT4 receptors was not excluded. This study shows that zacopride (200 micrograms/kg p.o.)-induced emesis can be blocked by a 'high dose' (1000 micrograms/kg) of ICS205930 but not by a low dose (100 micrograms/kg) or by 'high doses' (1000 micrograms/kg) of another more selective 5-HT3 receptor antagonist granisetron. As ICS205930, at high doses, is reported to be a 5-HT4 receptor antagonist it appears likely that activation of 5HT4-receptors contributes to emesis induced by zacopride. 'High' doses of ICS205930, but not granisetron or ondansetron, can also block the vagally mediated emesis induced by oral CuSO4 suggesting that 5-HT4 receptors involved in emesis are closely associated with abdominal vagal afferents.
 ...
PMID:Preliminary evidence for the involvement of the putative 5-HT4 receptor in zacopride- and copper sulphate-induced vomiting in the ferret. 166 56

Drugs interacting with serotonin (5-hydroxytryptamine, 5-HT) receptors are of value in the treatment of several gastrointestinal disturbances. Selective 5-HT3 receptor antagonists (ondansetron, granisetron, tropisetron) are widely utilized to control emesis induced by chemotherapy and radiation, while agonists at 5-HT4 receptors (cisapride, renzapride, BIMU compounds) are endowed with gastrointestinal prokinetic action. Here we overview the therapeutic potential of drugs with potent mixed 5-HT4 agonist/5-HT3 antagonist properties (i.e. BIMU 1) in the management of anticancer therapy-induced emesis and of intestinal adynamic post-operative conditions associated with vomiting. In the former situation, the agonism at 5-HT4 receptors is expected to be of benefit via two possible mechanism: (i) inhibition of 5-HT release from enterochromaffin cells; (ii) restoration of anally driven peristaltic waves in the upper gastrointestinal tract. Moreover, 5-HT4 receptor-induced prokinetic activity may counteract colonic constipation, an unwanted effect which occurs in a number of patients treated with pure 5-HT3 receptor antagonists. Additionally, the above mentioned drugs might be of value in post-operative conditions associated with intestinal adynamia and emesis sensitive to 5-HT3 receptor blockade.
 ...
PMID:Therapeutic potential of drugs with mixed 5-HT4 agonist/5-HT3 antagonist action in the control of emesis. 747 21

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.
 ...
PMID:[Central serotonin receptors. Principal fundamental and functional aspects. Therapeutic applications]. 780 Oct 37

The involvement of visceral afferent fibers and 5-HT3 or 5-HT4 receptors in the vomiting induced by oral administration of copper sulfate was investigated in beagle dogs. Vomiting induced by copper sulfate (100 mg/kg) was inhibited markedly by bilateral abdominal vagotomy and bilateral greater splanchnic nerve section. The vomiting induced by copper sulfate was inhibited by blocking 5-HT4 receptors with high doses (1 and 3 mg/kg, i.v.) of ICS 205-930. On the other hand, blocking 5-HT3 receptors with MDL 72222 (0.5 and 5 mg/kg, i.v.) or low doses (0.01 mg/kg i.v.) of ICS 205-930 had no apparent effect on the vomiting induced by copper sulfate. Oral administration of a 5-HT4 receptor agonist, 5-methoxytryptamine (5-MT), caused vomiting at a dose of 100 mg/kg, and the vomiting was inhibited markedly by abdominal visceral nerve section or a high dose (1 mg/kg, i.v.), but not a low dose (0.01 mg/kg, i.v.), of ICS 205-930. Intravenous administration of 5-MT (10 mg/kg) failed to induce vomiting. These results suggest that the abdominal visceral afferent fibers and possibly peripheral 5-HT4 receptors play an important role in the vomiting induced by oral administration of copper sulfate in dogs.
 ...
PMID:Possible involvement of peripheral 5-HT4 receptors in copper sulfate-induced vomiting in dogs. 808 6

1. Erythromycin administration is associated with gastrointestinal problems, disturbed gastrointestinal motility and emesis. This study in the dog investigates the underlying mechanisms. 2. Intestinal myoelectrical activity and the occurrence and latency of emesis were recorded in eight conscious dogs. All drugs were administered intravenously. 3. Erythromycin (7 mg kg-1) increased contractions of the proximal small intestine, and caused emesis in all fasted dogs and in 5 dogs after food. Atropine (50 mg kg-1 min-1) and hexamethonium (10 mg kg-1 h-1) partially inhibited the GI motility effects but did not significantly reduce emesis. 4. Metoclopramide at a high dose (2 mg kg-1 h-1) reduced the incidence of emesis in the presence of increased intestinal motility, but a low dose (150 micrograms kg-1 h-1) was ineffective. 5. A 5-hydroxytryptamine3 (5-HT3) receptor antagonist, MDL 72222 (1 mg kg-1), reduced emesis when given alone and combined with metoclopramide (low dose). The 5-HT4 receptor agonist BRL24924 (Renzapride, 1 mg kg-1) had no effect on emesis either alone in combination with metoclopramide. 6. In conclusion, erythromycin-induced GI motility disturbances and emesis are not causally related. Whereas the increase in intestinal smooth muscle activity is possibly cholinergically mediated, emesis occurs at least in part via a 5-hydroxytryptaminergic mechanism, but does not involve the dopamine system.
 ...
PMID:Effects of cholinoceptor and 5-hydroxytryptamine3 receptor antagonism on erythromycin-induced canine intestinal motility disruption and emesis. 809 27

The pharmacological effects of the metabolites M1 and M2 of mosapride citrate ((+/-)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholi nyl] methyl]benzamide citrate, AS-4370, CAS 112885-42-4), a gastroprokinetic agent with serotonin 5-HT4 receptor agonist property, were compared with those of mosapride. In isolated guinea-pig ileum treated with phenoxybenzamine, the metabolites M1 and M2 enhanced electrically-evoked contractions with EC50 values of 1.2 x 10(-7) mol/l and 1.0 x 10(-6) mol/l, respectively. The metabolite M1 was twice less potent than that of mosapride. When administered intravenously, the metabolite M1 enhanced gastric emptying of a semisolid meal in mice and rats; the potency was 3 times less than that of mosapride in mice and almost equal to that of mosapride in rats. When administered orally, the metabolite M1 enhanced gastric emptying of a semisolid meal in mice and rats, and also enhanced gastric emptying of a resin pellet meal in rats. The potency of metabolite M1 was 10 times less than that of mosapride in rats, although it was equal to that of mosapride in mice. In these experiments, the metabolite M2 was far less active. In addition to these gastroprokinetic properties, the metabolite M1 possessed a potent 5-HT3 receptor antagonist property. The metabolite M1 antagonized the 2-methyl-5-HT-induced bradycardia in anesthetized rats with an ED50 value of 10.5 micrograms/kg, i.v., and inhibited the cisplatin-induced emesis in ferrets with a potency approximately 25 times that of mosapride. These results suggest that the metabolites M1 and M2 of mosapride do not play a crucial role in the gastroprokinetic effect of mosapride.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Pharmacological effects of the new gastroprokinetic agent mosapride citrate and its metabolites in experimental animals. 826 74

In species which vomit, elevated intestinal serotonin (5-hydroxytryptamine, 5-HT) may stimulate abdominal vagal afferent fibers, which in turn evoke the vomiting reflex. The release of 5-HT from intestinal enterochromaffin (EC) cells is regulated by polymodal mechanisms. The object of this study was to evaluate the involvement of 5-HT autoreceptors in the regulation of 5-HT release from the small intestine. Functional studies were carried out using 5-HT3 receptor agonist and antagonists, and 5-HT4 receptor agonist. Ferret and rat ileal tissue were isolated and 5-HT released into the bathing solution was determined using HPLC with an electrochemical detector (ECD). We previously reported that cisplatin produced a significant increase in cumulative 5-HT release and that ondansetron, a selective 5-HT3 receptor antagonist, did not alter the 5-HT release from the ferret ileum. In this study, a selective 5-HT3 agonist, 2-methyl-5-HT, induced a dose-dependent increase of 5-HT from the rat ileum. This release of 5-HT was significantly reduced by granisetron, a selective 5-HT3 receptor antagonist. Furthermore, a selective 5-HT4 receptor agonist, 5-methoxytryptamine induced a concentration-dependent increase of 5-HT in the rat ileum. These results suggest that both 5-HT3 and 5-HT4 receptors may be involved in intestinal 5-HT release.
 ...
PMID:Chemical modulation of 5-HT3 and 5-HT4 receptors affects the release of 5-hydroxytryptamine from the ferret and rat intestine. 855 68

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.
 ...
PMID:Recent advances in the pharmacology of gastrointestinal prokinetics. 893 12

The antiemetic activity of N-3389 (endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl-1 H-indazole-3-carboxamide dihydrochloride), a new 5-HT3 and 5-HT4 receptor antagonist, against cisplatin-, cyclophosphamide- and copper sulfate-induced emesis was investigated using ferrets. We also examined the effects of these agents on abdominal afferent vagus nerve activity in anesthetized ferrets. Both intraperitoneal (0.1-1.0 mg/kg) and oral (0.1-1.0 mg/kg) administration of N-3389 produced dose-dependent antiemetic effects. The time-course of cisplatin (10 mg/kg, i.p.)-induced emesis in another group of ferrets paralleled the increase in abdominal afferent vagus nerve activity induced by cisplatin (10 mg/kg, i.p.) and was inhibited by pretreatment with N-3389 (1.0 mg/kg, i.v.). Furthermore, the cisplatin (10 mg/kg, i.p.)-induced increase in abdominal afferent vagus nerve activity was markedly reduced by an additional injection of N-3389 (0.1-1.0 mg/kg, i.v.) in a dose-dependent manner. The antiemetic effects exhibited by N-3389 are probably due to the inhibition of 5-HT3 and 5-HT4 receptors on the abdominal afferent vagus nerves.
 ...
PMID:Antiemetic effects of N-3389, a newly synthesized 5-HT3 and 5-HT4 receptor antagonist, in ferrets. 908 45

This paper outlines the physiopharmacology of emesis and its gastrointestinal motor correlates in relation to the possible treatment strategies of a migraine attack. The gastrointestinal motor correlates of vomiting consist of a stereotyped motor response to diverse stimuli and basically include gastric relaxation and a series of events (intestinal motor inhibition and disruption of slow wave activity) in preparation for the occurrence of a retrograde giant contraction that propagates orally and empties intestinal contents into the stomach. These motor correlates always accompany vomiting, but may also appear as an independent phenomenon. Antidopaminergic agents, such as metoclopramide and domperidone, have antiemetic/prokinetic properties, block the gastrointestinal motor correlates of vomiting and may speed up absorption of antimigraine agents. The use of 5-HT4 receptor agonists may be an alternative strategy to achieve prokinesia during a migraine attack, although this issue still needs to be fully addressed by controlled studies. Sumatriptan was found to induce gastric relaxation and delay gastric emptying, but the impact of these effects during a migraine attack remains to be determined.
 ...
PMID:Pharmacology of emesis and gastrointestinal motility: implications for migraine. 1120 Aug


1 2 Next >>