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)

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 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.
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PMID:Antiemetic effects of N-3389, a newly synthesized 5-HT3 and 5-HT4 receptor antagonist, in ferrets. 908 45

The classification of receptors involved in the emetic reflex has completely changed during the past 10 years. Today investigational agents acting as combined 5-HT3 antagonists/5-HT4 agonists, dopamine D2/D3 antagonists and the neurokinin1 antagonists are in focus. Positron emission tomography (PET) is rapidly advancing as an investigational tool in the detection and staging of cancer and in the evaluation of response to treatment. It is emphasized that PET could also be useful in further investigations of the pathophysiology of emesis. Though antiemetic treatment has been optimized, delayed emesis, emesis during multiple cycles and, especially, refractory emesis after chemotherapy continue to present significant challenges requiring further clinical investigations, as does the syndrome of chronic nausea and vomiting in patients with advanced cancer.
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PMID:Antiemetic research: a look to the future. 945 30

This review will focus on the mechanisms of emesis initiated or inhibited from receptors located in the periphery or activated by a peripherally released humoral factor. Excitatory and inhibitory receptors have been found in the thorax. Nausea and vomiting sometimes occur after coronary artery occlusion or with vasovagal syncope, and the receptors of this emetic response are probably tension receptors of the left ventricle. The thorax is also source of antiemetic receptors. Vagal section above the level of the heart causes an intractable vomiting syndrome and central cervical vagal stimulation inhibits vomiting. In addition, respiratory maneuvers that decrease activation of pulmonary afferents enhance the sensitivity to motion sickness. Therefore, pulmonary vagal afferent fibers may tonically inhibit retching and vomiting. Abdominal stimulation by irritants or toxins can activate nausea and vomiting through mechano- or chemoreceptors. Mechanoreceptors have been found in the stomach, jejunum and ileum, but the location of these receptors in the gut wall or the type of mechanical stimuli most effective in exciting these receptors is unknown. The chemoreceptors have a similar distribution and are probably located in the mucosa and respond to a variety of noxious agents, eg, CuSO4. CuSO4-induced vomiting is mediated by peripheral 5-HT4 receptors. Two clinically relevant toxic stimuli, x-irradiation and chemotherapeutic agents, have been found to activate vomiting through 5-HT3 receptors in the digestive tract. Regardless of the stimulus, the afferent neural pathways mediating emesis from the abdomen may be the same. The noxious stimulus may cause release of serotonin from enterochromaffin cells of the digestive tract, which activates visceral afferents. The vagus nerves mediate responses from the stomach and proximal small intestine and the splanchnic nerves and spinal cord mediate responses from the entire small intestine. Emesis-related afferents from the periphery terminate primarily in the nucleus tractus solitarius and area postrema. The area postrema contains the chemoreceptive trigger zone that can be activated by endogenous agents released into the circulation from the periphery. The role of peripheral receptors or peripherally released agents in the etiology of cyclic vomiting is unknown, but multiple pathways have been identified that can form a brain-gut interaction to provide a possible mechanism of cyclic vomiting.
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PMID:Noxious stimulation of emesis. 1049 41

Several serotonin (5-HT) receptor subtypes have been defined by pharmacological responses to selective agonists and antagonists and by pathways of receptor-effector coupling. Using molecular techniques, additional receptor subtypes have been described. 5-HT receptors are prevalent in the central nervous system and gut and participate in induction of emesis. 5-HT3 antagonists are used to prevent emesis from cancer chemotherapy and also demonstrate efficacy in radiation-induced nausea, postoperative nausea, hyperemesis gravidarum, and nausea and vomiting with the acquired immunodeficiency syndrome. 5-HT4 agonists exhibit prokinetic properties in nauseated patients with gastroparesis and functional dyspepsia. Conversely, 5-HT4 antagonists have antiemetic activity in some experimental models. The 5-HT1D receptor agonist sumatriptan reduces emesis with migraine headaches and in cyclic vomiting syndrome, most likely via action on central nervous system sites. In other models, 5-HT1A and 5-HT2A/5-HT2C agonists exhibit antiemetic properties. The utility of 5-HT receptor ligands in treating emesis is the subject of active investigation.
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PMID:Serotonin receptor physiology: relation to emesis. 1049 49

Tropisetron is used as an anti-emetic agent against chemotherapy-induced nausea and vomiting. Tropisetron shows strong 5-HT3 antagonist and weak 5-HT4 antagonist activities in vitro. In the various animal models of vomiting including chemotherapy- or radiotherapy-induced emesis in the dog and ferret, tropisetron is reported to inhibit the emetic episodes. The potent anti-emetic activity of oral tropisetron rather than the i.p. administered drug suggests that it can act directly from the intestinal lumen as well as from the blood stream after its absorption. Moreover, the anti-emetic activity of tropisetron may involve the 5-HT4-receptor mechanism in addition to the 5-HT3-receptor mechanism. Tropisetron has several pharmacological activities other than anti-emesis such as the stimulation of the gastric emptying and the inhibition of the diarrhea, visceral pain and anxiety. These effects of tropisetron may contribute to the high clinical efficacy of tropisetron against chemotherapy-induced emesis.
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PMID:[Pharmacological review of tropisetron]. 1058 35

Significant progress has been made in recent years in developing more effective means of preventing nausea and vomiting induced by cancer chemotherapy. With appropriate application of currently available antiemetic regimens, the majority of patients with cancer who are receiving chemotherapy can anticipate experiencing no emesis during their treatment. Nevertheless, incompletely controlled emesis remains a problem for a significant percentage of patients. Persistent challenges include delayed emesis and emesis following high-dose chemotherapy regimens. The goal of complete prevention of emesis in all patients remains elusive. Therefore, there is a strong rationale for investigating new antiemetic approaches. New antiemetic agents currently under development target the neurotransmitters serotonin (5-hydroxytryptamine; 5-HT) and substance P. A number of new selective antagonists of serotonin 5-HT3 receptors are in clinical trials. Given the lack of clinically significant differences between the available 5-HT3 receptor antagonists, it appears unlikely that any of these new agents will have substantial advantages over currently approved agents. Several other serotonin receptors have been targeted including the 5-HT4, 5-HT1A and 5-HT2A receptors. Of these approaches, only agonism of the 5-HT1A receptor has produced an agent that has proceeded into clinical testing. The most exciting new class of antiemetics currently under development focuses on antagonism of the effects of the neurotransmitter substance P. Results of early clinical trials with tachykinin neurokinin NK1 receptor antagonists demonstrate enhanced control of acute emesis with their addition to currently available agents and promising activity in controlling delayed emesis. Available evidence would strongly suggest that this class of agents will represent the next important advance in efforts to control nausea and vomiting induced by chemotherapy.
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PMID:Antiemetics for cancer chemotherapy-induced nausea and vomiting. A review of agents in development. 1065 96

Nausea and vomiting are debilitating symptoms complicating many clinical conditions. Conventional antiemetic agents act as muscarinic, histamine, and dopamine receptor antagonists in the central nervous system. In a retrospective analysis, tricyclic antidepressant drugs demonstrated efficacy in long-term treatment of functional nausea. Some cases of vomiting result from impaired gastrointestinal motor activity. Agents which act on gastric serotonin (5-HT4), dopamine, and motilin receptors accelerate gastric emptying and relieve symptoms in gastroparesis. Recent investigations suggest that some patients with refractory gastroparesis may benefit from gastric electrical pacing. The treatment of acute chemotherapy-induced emesis was revolutionized by 5-HT3 receptor antagonists; however, these agents are less efficacious in delayed vomiting. Neurokinin (NK-1) receptor antagonists show promise in treating delayed chemotherapy-evoked emesis. Furthermore, animal studies indicate a broad spectrum of action for NK-1 antagonists in treating diverse causes of nausea and vomiting. The cyclic vomiting syndrome is characterized by discrete episodes of relentless vomiting separated by asymptomatic intervals and is associated with migraine headaches. Antimigraine therapies including the 5-HT1D receptor agonists sumatriptan reduce the severity of cyclic vomiting attacks. Investigations into these and other novel treatments may provide important advances in the care of difficult cases of nausea and vomiting resulting from disparate illnesses.
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PMID:Novel approaches to the treatment of nausea and vomiting. 1069 61

To clarify the mechanism for the severe emesis concomitant with intensive chemotherapy, we investigated the effects of 5-HT3- and 5-HT4-receptor antagonists on the emesis induced by the high-dose of cisplatin in Suncus murinus. The emesis induced by 50 mg/kg of cisplatin was reduced by the oral pretreatment with tropisetron, which is known as a 5-HT3- and 5-HT4-receptor dual antagonist in vitro, with the ID50 value of 0.52 mg/kg. On the contrary, granisetron, a selective 5-HT3-receptor antagonist, did not markedly inhibit the emesis at up to 30 mg/kg. Moreover, GR125487, a selective 5-HT4-receptor antagonist, did not inhibit the emesis. However, co-administration of GR125487 and granisetron significantly reduced the number of emetic episodes. The study of the co-administration of GR125487 with tropisetron showed that GR125487 did not further enhance the inhibitory effect of tropisetron alone, suggesting that the anti-emetic effect of tropisetron is mediated via the blockade of both 5-HT3 and 5-HT4 receptors. These results suggest that both the 5-HT3 and 5-HT4 receptors are involved in the emesis induced by the high-dose of cisplatin in Suncus murinus.
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PMID:Possible involvement of 5-HT4 receptors, in addition to 5-HT3 receptors, in the emesis induced by high-dose cisplatin in Suncus murinus. 1124 77


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