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)

In order to elucidate the precise mechanism of ipecac syrup (TJN-119) on the occurrence of vomiting, we examined the effects of ipecac syrup on the abdominal afferent nerve activity as well as on the 5-HT levels of the ileum and area postrema in ferrets. Oral administration of TJN-119 (0.5 mg/kg) produced a significant increase in afferent abdominal vagus nerve activity which lasted approximately 1 hour. The maximum response induced by TJN-119 was estimated to be 219 +/- 18% of the pre-injection level. Cephaeline or emetine, the main alkaloids of ipecac syrup, also demonstrated similar effects on afferent vagus nerve activity. TJN-119 increased the 5-HT content in the ileum but not in the area postrema. These observations illustrate possible mechanisms that may act at peripheral sites. It was recently reported that TJN-119 has a high affinity to 5-HT4 receptors (Hasegawa et al., unpublished data). These results suggest that 5-HT4 receptors may be involved in the emetic action of TJN-119.
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PMID:Pharmacological aspects of ipecac syrup (TJN-119)-induced emesis in ferrets. 1191 11

Antidopaminergic gastrointestinal prokinetics (bromopride, clebopride, domperidone, levosulpiride and metoclopramide) have been exploited clinically for the management of motor disorders of the upper gastrointestinal tract, including functional dyspepsia, gastric stasis of various origins and emesis. The prokinetic effect of these drugs is mediated through the blockade of enteric (neuronal and muscular) inhibitory D2 receptors. The pharmacological profiles of the marketed compounds differ in terms of their molecular structure, affinity at D2 receptors, ability to interact with other receptor systems [5-hydroxytryptamine-3 (5-HT3) and 5-HT4 receptors for metoclopramide; 5-HT4 receptors for levosulpiride) and ability to permeate the blood-brain barrier (compared with the other compounds, domperidone does not easily cross the barrier). It has been suggested that the serotonergic (5-HT4) component of some antidopaminergic prokinetics may enhance their therapeutic efficacy in gastrointestinal disorders, such as functional dyspepsia and diabetic gastroparesis. The antagonism of central D2 receptors may lead to both therapeutic (e.g. anti-emetic effect due to D2 receptor blockade in the area postrema) and adverse (including hyperprolactinaemia and extrapyramidal dystonic reactions) effects. As the pituitary (as well as the area postrema) is outside the blood-brain barrier, hyperprolactinaemia is a side-effect occurring with all antidopaminergic prokinetics, although to different extents. Extrapyramidal reactions are most commonly observed with compounds crossing the blood-brain barrier, although with some differences amongst the various agents. Prokinetics with a high dissociation constant compared with that of dopamine at the D2 receptor (i.e. compounds that bind loosely to D2 receptors in the nigrostriatal pathway) elicit fewer extrapyramidal signs and symptoms. A knowledge of central and peripheral D2 receptor pharmacology can help the clinician to choose between the antidopaminergic prokinetics to obtain a more favourable risk/benefit ratio.
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PMID:Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. 1487 Dec 77

We investigated the effect of FK1052 [(+)-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one hydrochloride], a 5-HT3- and 5-HT4-receptor antagonist, on the emesis induced by motion stimuli, copper sulfate, or cisplatin in either Suncus murinus or ferrets and also clarified the role of the 5-HT3 and 5-HT4 receptors in these models. In Suncus murinus, oral administration of FK1052 (100 microg/kg) completely prevented emesis induced by cisplatin (18 mg/kg, i.p.). Intraperitoneal injection of scopolamine (10 mg/kg) and promethazine (32 mg/kg), but not FK1052 (1 mg/kg), significantly reduced the emetic responses by motion stimuli. In ferrets, copper sulfate (40 mg/kg, p.o.)-induced emesis was moderately prevented by FK1052 (3.2 mg/kg), but not by granisetron (3.2 mg/kg). Cisplatin-induced acute (10 mg/kg, i.v.) and delayed (5 mg/kg, i.p.) emesis were significantly reduced by single and multiple intravenous injection of both FK1052 (3.2 mg/kg) and granisetron (3.2 mg/kg), respectively. The present study suggests that FK1052 may be useful against both acute and delayed emesis induced by cancer chemotherapy. Moreover, it is suggested that blockades of 5-HT3 and 5-HT4 receptors are not relevant to the control of motion sickness; and furthermore, it suggested that blocking 5-HT4 receptors in addition to 5-HT3 receptors does not have an additional effect on the control of cisplatin-induced emesis, but that 5-HT4 receptors are at least partly involved in the mechanism of emesis induced by copper sulfate.
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PMID:Antiemetic activity of FK1052, a 5-HT3- and 5-HT4-receptor antagonist, in Suncus murinus and ferrets. 1607 68

We evaluated the antiemetic effect of zacopride, a potent 5-HT3-receptor antagonist with 5-HT4-receptor agonist properties, on delayed emesis caused by cisplatin (5 mg/kg, i.p.) in ferrets, compared with granisetron, a selective 5-HT3-receptor antagonist. Multiple intravenous injections of zacopride at 1 mg/kg, a dose that completely inhibited acute emesis caused bycisplatin (10 mg/kg, i.v.), significantly reduced delayed emesis. Granisetron (3.2 mg/kg) also reduced delayed emesis but this failed to reach statistical significance. The present study suggests that a combined 5-HT3-receptor antagonist/5-HT4-receptor agonist, like zacopride, may be useful against both acute and delayed emesis induced by cancer chemotherapy.
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PMID:Inhibitory effect of zacopride on Cisplatin-induced delayed emesis in ferrets. 1665 99

Dopamine antagonists, such as metoclopramide and domperidone, and the motilin receptor agonist erythromycin have been the cornerstones in drug treatment of severe gastroparesis for more than a decade. No new drugs have been approved for treatment of this disorder in this period. Instead, the 5-HT4 agonist cisapride has been withdrawn due to side-effects. The effectiveness of intrapyloric botulinum toxin for gastroparesis remains to be shown. In the last decade, gastric electrical stimulation (GES) with a fully implantable device has evolved as a promising treatment, with significant effects on nausea and vomiting in most patients with severe, drug-refractory diabetic gastroparesis and postsurgical gastroparesis. A proportion of patients with severe idiopathic gastroparesis and patients with idiopathic nausea and vomiting also respond. More research is needed to achieve precise selection of responders/non-responders to GES, and to study the potential benefit of GES in other patient groups suffering from severe nausea or vomiting.
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PMID:Severe gastroparesis: new treatment alternatives. 1764 6

Gastroparesis is a disorder of gastric emptying that occurs in the absence of mechanical obstruction. Its cardinal features include nausea, vomiting, bloating, early satiety and discomfort. Weight loss, dehydration, electrolyte disturbances and malnutrition may develop in severe cases. The majority of cases is idiopathic, long standing diabetes mellitus is responsible for about 25-30% of cases. Diabetic gastroparesis may render glucose control extremely difficult, its treatment represents a major challenge. Besides frequent, small meals and psychological support, several drug options are available, however, their efficacy is limited and only a few randomized studies have been performed to date. Prokinetic agents (erythromycin, domperidone, metoclopramide) and antiemetics (phenothiazines, serotonin antagonists, butyrophenones) are the most wide-spread medicaments. Among the novel, recently developed agents, 5-HT4 serotonin receptor agonists and dopamine D2 receptor antagonists are the most promising. Injection of botulinum toxin into the pyloric sphincter resulted in faster gastric emptying and symptom alleviation in some studies. Gastric electric stimulation appears to be one of the most effective options, both low and high-frequency stimulation may alleviate symptoms. Gastrostomy/jejunostomy and other surgical interventions are considered as "last resort".
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PMID:[Gastroparesis and its treatment options]. 1829 33

Within the last 50 years, diabetic gastroparesis has become a well recognized complication of type 1 and type 2 diabetes. It is a syndrome characterized by abnormal gastric function, resulting in delayed emptying of the stomach in the absence of any evident mechanical obstruction, predominantly manifested by early satiety, postprandial fullness, nausea, vomiting, and weight loss. The past five years have shown significant advances in its pathophysiology and in new diagnostic tests. Prokinetic medications remain the therapeutic focus for improving clinical symptoms of gastroparesis through enhanced gastric emptying. This article summarizes the present knowledge of prokinetics, with emphasis on medications currently available, as well as drugs under clinical investigation, including some agents in advanced clinical trials that are likely to be used in the treatment of diabetic gastroparesis in the future. These include the ghrelin agonists and newer 5-HT4 agonists devoid of cardiac side effects.
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PMID:Prokinetics in diabetic gastroparesis. 2268 94

Nausea is one of a cluster of symptoms described subjectively by patients with delayed gastric emptying. The mechanisms and treatments are unclear (anti-emetic drugs are not fully effective against nausea). Can nausea be relieved by stimulating gastric emptying? Physostigmine (together with atropine) has been shown experimentally to stimulate gastric motility, relieve nausea and restore normal gastric motility. Is this mimicked by gastric prokinetic drugs? The answer is complicated by mixed pharmacology. Metoclopramide increases gastric motility by activating myenteric 5-HT4 receptors but also directly inhibits vomiting via D2 and 5-HT3 receptor antagonism; relationships between increased gastric motility and relief from nausea are therefore unclear. Similarly, the D2 receptor antagonist domperidone has direct anti-emetic activity. Nevertheless, more selective 5-HT4 and motilin receptor agonists (erythromycin, directly stimulating gastric motility) inhibit vomiting in animals; low doses of erythromycin can also relieve symptoms in patients with gastroparesis. Ghrelin stimulates gastric motility and appetite mostly via vagus-dependent pathways, and inhibits vomiting in animals. To date, ghrelin receptor activation has failed to consistently improve gastric emptying or symptoms in patients with gastroparesis. We conclude that nausea can be relieved by gastric prokinetic drugs, but more clinical studies are needed using drugs with selective activity. Other mechanisms (e.g. ghrelin, vagal and central pathways, influencing a mechanistic continuum between appetite and nausea) also require exploration. These and other issues will be further explored in a forthcoming special issue of the European Journal of Pharmacology, which focusses on mechanisms of nausea and vomiting.
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PMID:The relationship between gastric motility and nausea: gastric prokinetic agents as treatments. 2383 91


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