Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prokinetic effects of erythromycin, a macrolide antibiotic, on the gastrointestinal tract as a motilin receptor agonist and its potential value for the treatment of gastrointestinal motility disorders have recently attracted interest. The effects of erythromycin on the clinical symptoms and gastrointestinal motility of patients with chronic idiopathic pseudo-obstruction have not been investigated extensively. We presented a case of chronic idiopathic intestinal pseudo-obstruction, in a 67-year-old man in whom oral erythromycin (900 mg/day) dramatically improved postprandial abdominal distention, nausea, and vomiting. Other agents with prokinetic effects on intestinal motility, i.e., cisapride, domperidone, metoclopramide, and trimebutine maleate did not have a favorable effect. Gastric emptying, measured by the sulfamethizole method; and intestinal transit, evaluated using radio-opaque markers, were markedly improved by treatment with erythromycin. Our experience suggests that the prokinetic effects of erythromycin may be of therapeutic value in chronic idiopathic intestinal pseudo-obstruction.
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PMID:Effects of erythromycin in chronic idiopathic intestinal pseudo-obstruction. 902 52

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 Instead, the 5-HT4 agonist cisapride has been withdrawn due to side-effects.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 condition characterized by delayed gastric emptying and the most common known underlying cause is diabetes mellitus. Symptoms include nausea, vomiting, abdominal fullness, and early satiety, which impact to varying degrees on the patient's quality of life. Symptoms and deficits do not necessarily relate to each other, hence despite significant abnormalities in gastric emptying, some individuals have only minimal symptoms and, conversely, severe symptoms do not always relate to measures of gastric emptying. Prokinetic agents such as metoclopramide, domperidone, and erythromycin enhance gastric motility and have remained the mainstay of treatment for several decades, despite unwanted side effects and numerous drug interactions. Mechanical therapies such as endoscopic pyloric botulinum toxin injection, gastric electrical stimulation, and gastrostomy or jejunostomy are used in intractable diabetic gastroparesis (DG), refractory to prokinetic therapies. Mitemcinal and TZP-101 are novel investigational motilin receptor and ghrelin agonists, respectively, and show promise in the treatment of DG. The aim of this review is to provide an update on prokinetic and mechanical therapies in the treatment of DG.
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PMID:Diabetic gastroparesis: Therapeutic options. 2212 72

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

Ghrelin and motilin receptor agonists increase gastric motility and are attractive drug targets. However, 14 years after the receptors were described (18-24 years since ligands became available) the inactivity of the ghrelin agonist TZP-102 in patients with gastroparesis joins the list of unsuccessful motilin agonists. Fundamental questions must be asked. Pustovit et al., have now shown that the ghrelin agonist ulimorelin evokes prolonged increases in rat colorectal propulsion yet responses to other ghrelin agonists fade. Similarly, different motilin agonists induce short- or long-lasting effects in a cell-dependent manner. Together, these and other data create the hypothesis that the receptors can be induced to preferentially signal ('biased agonism') via particular pathways to evoke different responses with therapeutic advantages/disadvantages. Biased agonism has been demonstrated for ghrelin. Are motilin agonists which cause long-lasting facilitation of human stomach cholinergic function (compared with motilin) biased agonists (e.g., camicinal, under development for patients with gastric hypo-motility)? For ghrelin, additional complications exist because the therapeutic aims/mechanisms of action are uncertain, making it difficult to select the best (biased) agonist. Will ghrelin agonists be useful treatments of nausea and/or as suggested by Pustovit et al., chronic constipation? How does ghrelin increase gastric motility? As gastroparesis symptoms poorly correlate with delayed gastric emptying (yet gastro-prokinetic drugs can provide relief: e.g., low-dose erythromycin), would low doses of ghrelin and motilin agonists relieve symptoms simply by restoring neuromuscular rhythm? These questions on design and functions need addressing if ghrelin and motilin agonists are to reach patients as drugs.
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PMID:Ghrelin and motilin receptor agonists: time to introduce bias into drug design. 2443 86

The gastrointestinal tract is the major source of the related hormones ghrelin and motilin, which act on structurally similar G protein-coupled receptors. Nevertheless, selective receptor agonists are available. The primary roles of endogenous ghrelin and motilin in the digestive system are to increase appetite or hedonic eating (ghrelin) and initiate phase III of gastric migrating myoelectric complexes (motilin). Ghrelin and motilin also both inhibit nausea. In clinical trials, the motilin receptor agonist camicinal increased gastric emptying, but at lower doses reduced gastroparesis symptoms and improved appetite. Ghrelin receptor agonists have been trialled for the treatment of diabetic gastroparesis because of their ability to increase gastric emptying, but with mixed results; however, relamorelin, a ghrelin agonist, reduced nausea and vomiting in patients with this disorder. Treatment of postoperative ileus with a ghrelin receptor agonist proved unsuccessful. Centrally penetrant ghrelin receptor agonists stimulate defecation in animals and humans, although ghrelin itself does not seem to control colorectal function. Thus, the most promising uses of motilin receptor agonists are the treatment of gastroparesis or conditions with slow gastric emptying, and ghrelin receptor agonists hold potential for the reduction of nausea and vomiting, and the treatment of constipation. Therapeutic, gastrointestinal roles for receptor antagonists or inverse agonists have not been identified.
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PMID:Ghrelin and motilin receptors as drug targets for gastrointestinal disorders. 2639 67