Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nervous control of gastrointestinal motility is extremely complex, is regulated by the enteric system, the "brain of the gut", and modulated by extrinsic nerves. This system with its multiplicity of transmitters and receptors does not always allow a clear interpretation of experimental data, especially with compounds lacking specificity. In this review the complex situation is described particularly in relation to receptor populations (cholinergic, adrenergic, dopamine, histamine, 5-hydroxytryptamine, opioid, gamma-aminobutyric acid (GABA), prostanoid and dihydropyridine receptors), therapeutic aspects of drugs and their usefulness in children. Newer principles with known drugs and promising new compounds with a more appropriate kinetic or fewer side-effects, deriving from distinct pharmacological groups, as candidates for the treatment of gastrointestinal disorders are considered e.g. anticholinergics (prifinium or actilonium bromide), adrenergic alpha 2-agonists (clonidine, lidamidine) for diarrhoea in diabetic neuropathy, adrenergic beta-blockers for shortening postoperative ileus (propranolol), dopamine receptor antagonists (metoclopramide, domperidone, alizapride) and another prokinetic substance (cisapride) which may be useful for a number of applications as gastro-oesophageal reflux, gastro-paresis, intestinal pseudo-obstruction, cystic fibrosis and constipation, morphine derivatives (e.g. loperamide) for intractable diarrhoea and calcium antagonists (e.g. nifedipine) for achalasia. Increasing experience in digestive tract pharmacology and reliable clinical studies will furthermore be the basis for a more specific and better tolerated therapy of gastrointestinal motility disorders in adults and children.
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PMID:Rational pharmacotherapy of gastrointestinal motility disorders. 266 4

The past 20 years have seen notable advances in our understanding of the physiology and pharmacology of the emetic reflex leading to the identification of the anti-emetic effects of 5-hydroxytryptamine(3) (5-HT(3)) and neurokinin(1) receptor (NK(1)) antagonists. The introduction of 5-HT(3) and NK(1) receptor antagonists into the clinic has had a major impact in alleviating the nausea and vomiting associated with the treatment of cancer and the sequelae to anaesthesia and surgery (post-operative nausea and vomiting, PONV). Despite these advances there are major gaps in our understanding. Interestingly, one of these is the relatively poor ability to treat nausea. Additional gaps in our knowledge are highlighted to provide a framework within which directions for research can be proposed. Particular attention is drawn to: lacunae in knowledge of some currently used anti-emetics such as the source of dopamine required to initiate emesis; the theoretical assumptions and mechanisms underlying the concept of a "universal anti-emetic"; the variety of receptors at which agonists act to have anti-emetic effects (GABA (B), CB(1), 5-HT(1A), ghrelin, opioid); issues of translation from animals to humans and the relationship between the pathways involved in emesis and certain gastrointestinal disorders such as dyspepsia and gastroesophageal reflux, with the latter being of particular interest as some agents affecting reflux are also anti-emetic. Together, the unmet clinical need to adequately control nausea, possibly by new drugs acting within the brainstem, and the significant gaps in understanding key aspects of the emetic reflex, suggest an important need to focus and re-direct research into the distressing and sometimes life-threatening symptoms of nausea and vomiting.
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PMID:Treatment of nausea and vomiting: gaps in our knowledge. 1693 36

There is a large unmet need for effective drugs for the treatment of gastrointestinal disorders, notably irritable bowel syndrome, functional dyspepsia and gastroesophageal reflux disease. The market value for an effective irritable bowel syndrome therapeutic agent is estimated at over US10 billion dollars per annum. Each of these disorders seems to have a neural component, involving the intrinsic innervation of the gastrointestinal system, its extrinsic innervation or both. The substantially improved understanding of the transmitters, receptors and ion channels of enteric neurons that now exists has led to targeted therapy. The most promising targets so far have been 5-hydroxytryptamine receptors. Other targets include opioid, cholecystokinin, tachykinin, cannabinoid, corticotropin-releasing factor and protease-activated receptors. Ion channels are also potential targets. Although current knowledge has yet to be adequately translated into effective therapies, each of the targets holds promise for the future that might be realized as new compounds with appropriate receptor specificity and pharmacodynamic profiles are developed.
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PMID:Novel therapeutic targets for enteric nervous system disorders. 1776 56

Serotonin 5-hydroxytryptamine 4(5-HT4) receptor agonists have been widely prescribed as a prokinetics drug for patients with gastro-esophageal reflux disease and functional dyspepsia. QX100626, one of the 5-HT4 receptor agonists, has been studied as a promising agent for this clinical use. The objective of the present study was to identify possible target organs of toxicity and propose a non-toxic dose of QX100626 for clinical usage. After single lethal dose oral and intravenous testing in rodents, some signs indicative of adverse CNS effects were observed. The minimum toxic dose of QX100626 for a single oral administration for dogs was 90.0mg/kgb.w., and the severe toxic dose was more than 300mg/kgb.w. The No Observed Adverse Effect Level (NOAEL) of QX100626 by daily oral administration for rats and dogs was 20mg/kg and 10mg/kg, respectively, whereas the minimum toxic dosages were 67 and 30mg/kg, respectively. All of the adverse effects suggested that kidney, digestive tract, as well as nervous, hematological, and respiratory systems might be the target organs of toxicity for humans induced by QX100626. The compound could be a safe alternative to other existing prokinetic agents for the treatment of functional bowel disorders.
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PMID:Acute and subchronic toxicities of QX100626, a 5-HT4 receptor agonist, in rodents and Beagle dogs. 2510 57

Systemic sclerosis (SSc) is a multisystemic autoimmune connective tissue disorder; in the gastrointestinal tract, the esophagus is the most commonly affected organ. Symptoms of esophageal disease are due to gastroesophageal reflux disease (GERD) and esophageal motor dysfunction. Since the development of high-resolution manometry (HRM), this method has been preferred for the study of SSc patients with esophageal involvement. Using HRM, classic scleroderma esophagus, defined as absent or ineffective peristalsis of the distal esophagus in combination with a hypotensive lower esophageal sphincter, was found in as many as 55% of SSc patients. Endoscopy is the appropriate test for evaluating dysphagia and identifying evidence and possible complications of GERD. In the therapeutic area, treatment ranges from general supportive measures to the administration of drugs such as proton pump inhibitors and/or prokinetics. However, as many SSc patients do not respond to existing therapies, there is an urgent need for new therapeutic modalities. Buspirone, a 5-hydroxytryptamine 1A receptor agonist, could be a putative therapeutic option, as it was found to exert a significant beneficial effect in SSc patients with esophageal involvement. This review summarizes our knowledge concerning the evaluation and management of esophageal manifestations in SSc patients, including emerging therapeutic modalities.
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PMID:Evaluation and management of esophageal manifestations in systemic sclerosis. 2950 63