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

This review illustrates, through a series of case histories, how oral medicine insights aid the diagnosis and management of patients with excessive tooth wear. The cases reviewed are drawn from the records of 500 southeast Queensland patients referred to the author over a 12 year period. Patients most at risk of dental erosion have work and sports dehydration, caffeine addiction, gastro-oesophageal reflux, asthma, diabetes mellitus, hypertension or other systemic diseases or syndromes that predispose to xerostomia. Saliva protects the teeth from the extrinsic and intrinsic acids which cause dental erosion. Erosion, exacerbated by attrition and abrasion, is the main cause of tooth wear. These cases illustrate that teeth, oral mucosa, salivary glands, skin and eyes should be examined for evidence of salivary hypofunction and attendant medical conditions. Based on comprehensive oral medicine, dietary analyses and advice, it would seem patients need self-management plans to deal with incipient chronic tooth wear. The alternative is the expensive treatment of pain, occlusal damage and pulp death required to repair the effects of acute severe tooth wear.
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PMID:The oral medicine of tooth wear. 1183 70

Gastro-oesophageal reflux disease (GORD) is a chronic disorder characterised by an increased exposure of the oesophagus to intragastric contents. Currently, GORD symptoms are maintained under control with antisecretory agents, mainly gastric proton pump inhibitors (PPIs). Although impaired oesophageal motility may partly underlie the pathophysiology of GORD, the use of prokinetic agents has been found to be unsatisfactory. To date, novel pharmacological approaches for GORD are mainly related to the control of transient lower oesophageal sphincter (LOS) relaxations (TLOSRs). The majority of patients with GORD have reflux episodes during TLOSRs, which are evoked by gastric distension, mainly occurring after ingestion of a meal. Patients with reflux disease with normal peristalsis and without or with mild erosive disease could potentially benefit from anti-TLOSR therapy. This therapy might also be of value to treat some severe forms of esophagitis in combination with PPIs. GABA-B-receptor agonists are the most promising class of agents identified so far for TLOSR control. The GABA-B-receptor agonist, baclofen, is the most effective compound in inhibiting TLOSRs in humans. Since baclofen has several CNS adverse effects, novel orally available GABA-B agonists are needed for effective and well tolerated treatment of GORD. Endogenous or exogenous cholecystokinin (CCK) causes a reduction in LOS pressure, an increase in TLOSR frequency and a reduction in gastric emptying. In healthy volunteers and patients with GORD, loxiglumide, a selective CCK1-receptor antagonist, was found to reduce the rate of TLOSRs, although its effect on postprandial acid reflux may be modest. Orally effective CCK antagonists are not marketed to date. The anticholinergic agent atropine, given to healthy volunteers and patients with GORD, markedly reduced the rate of TLOSRs. Because of severe gastrointestinal (and other) adverse effects of anticholinergics, including worsening of supine acid clearance and constipation, it is unlikely that this class of drugs will have a future as anti-TLOSR agents on a routine basis. In spite of their effectiveness in reducing TLOSR rate, untoward adverse effects, such as addiction and severe constipation, currently limit the use of morphine and other opioid mu-receptor agonists. The same applies to nitric oxide synthase inhibitors, which are associated with marked gastrointestinal, cardiovascular, urinary and respiratory adverse effects. Animal studies provide promising evidence for the use of cannabinoid receptor 1 agonists, by showing potent inhibition of TLOSRs in the dog, thus opening a new route for clinical investigation in humans. A better understanding of TLOSR pathophysiology is a necessary step for the further development of novel drugs effective for anti-reflux therapy.
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PMID:Progress with novel pharmacological strategies for gastro-oesophageal reflux disease. 1496 71

Diet analysis and advice for patients with tooth wear is potentially the most logical intervention to arrest attrition, erosion and abrasion. It is saliva that protects the teeth against corrosion by the acids which soften enamel and make it susceptible to wear. Thus the lifestyles and diet of patients at risk need to be analysed for sources of acid and reasons for lost salivary protection. Medical conditions which put patients at risk of tooth wear are principally: asthma, bulimia nervosa, caffeine addiction, diabetes mellitus, exercise dehydration, functional depression, gastroesophageal reflux in alcoholism, hypertension and syndromes with salivary hypofunction. The sources of acid are various, but loss of salivary protection is the common theme. In healthy young Australians, soft drinks are the main source of acid, and exercise dehydration the main reason for loss of salivary protection. In the medically compromised, diet acids and gastroesophageal reflux are the sources, but medications are the main reasons for lost salivary protection. Diet advice for patients with tooth wear must: promote a healthy lifestyle and diet strategy that conserves the teeth by natural means of salivary stimulation; and address the specific needs of the patients' oral and medical conditions. Individualised, patient-empowering erosion WATCH strategies; on Water, Acid, Taste, Calcium and Health, are urgently required to combat the emerging epidemic of tooth wear currently being experienced in westernised societies.
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PMID:Tooth wear: diet analysis and advice. 1588 Sep 60

This chapter presents new clinical applications of the prototypic GABA(B) receptor agonist baclofen for the treatment of addiction by drugs of abuse, such as alcohol, cocaine, nicotine, morphine, and heroin, a novel baclofen prodrug Arbaclofen placarbil, the GABA(B) receptor agonist AZD3355 (Lesogabaran) currently in Phase 2 clinical trials for the treatment of gastroesophageal reflux disease, and four positive allosteric modulators of GABA(B) receptors (CGP7930, GS39783, NVP-BHF177, and BHFF), which have less propensity for the development of tolerance due to receptor desensitization than classical GABA(B) receptor agonists. All four compounds showed anxiolytic affects. In the presence of positive allosteric modulators the "classical" GABA(B) receptor antagonists CGP35348 and 2-hydroxy-saclofen showed properties of partial GABA(B) receptor agonists. Seven micromolar affinity GABA(B) receptor antagonists, phaclofen; 2-hydroxy-saclofen; CGP's 35348, 36742, 46381, 51176; and SCH50911, are discussed. CGP36742 (SGS742) showed statistically significant improvements of working memory and attention in a Phase 2 clinical trial in mild, but not in moderate Alzheimer patients. Eight nanomolar affinity GABA(B) receptor antagonists are presented (CGP's 52432, 54626, 55845, 56433, 56999, 61334, 62349, and 63360) that were used by pharmacologists for numerous in vitro and in vivo investigations. CGP's 36742, 51176, 55845, and 56433 showed antidepressant effects. Several compounds are also available as radioligands, such as [(3)H]CGP27492, [(3)H]CGP54626, [(3)H]CGP5699, and [(3)H]CGP62349. Three novel fluorescent and three GABA(B) receptor antagonists with very high specific radioactivity (>2,000 Ci/mmol) are presented. [(125)I]CGP64213 and the photoaffinity ligand [(125)I]CGP71872 allowed the identification of GABA(B1a) and GABA(B1b) receptors in the expression cloning work.
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PMID:Chemistry and pharmacology of GABAB receptor ligands. 2065 77

Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu(5)) have remained attractive to researchers as potential therapies for a number of central nervous system related diseases, including anxiety, pain, gastroesophageal reflux disease (GERD), addiction, Parkinson's disease (PD), and fragile X syndrome (FXS). In addition to the many publications with supportive preclinical data with key tool molecules, recent positive reports from the clinic have bolstered the confidence in this approach. During the two year time span from 2009 through 2010, a number of new mGlu(5) NAM chemotypes have been disclosed and discussed in the primary and patent literature. A summary of several efforts representing many diverse chemotypes are presented here, along with a discussion of representative structure activity relationships (SAR) and synthetic approaches to the templates where possible.
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PMID:Recent advances in the design and development of novel negative allosteric modulators of mGlu(5). 2192 49

Glutamate is the major excitatory transmitter in the mammalian CNS, exerting its effects through both ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGlus) belong to family C of the G-protein-coupled receptors (GPCRs). The eight mGlus identified to date are classified into three groups based on their structure, preferred signal transduction mechanisms, and pharmacology (Group I: mGlu(1) and mGlu(5); Group II: mGlu(2) and mGlu(3); Group III: mGlu(4), mGlu(6), mGlu(7), and mGlu(8)). Non-competitive antagonists, also known as negative allosteric modulators (NAMs), of mGlu(5) offer potential therapeutic applications in diseases such as pain, anxiety, gastroesophageal reflux disease (GERD), Parkinson's disease (PD), fragile X syndrome, and addiction. The development of SAR in a (3-cyano-5-fluorophenyl)biaryl series using our functional cell-based assay is described in this communication. Further characterization of a selected compound, 3-fluoro-5-(2-methylbenzo[d]thiazol-5-yl)benzonitrile, in additional cell based assays as well as in vitro assays designed to measure its metabolic stability and protein binding indicated its potential utility as an in vivo tool. Subsequent evaluation of the same compound in a pharmacokinetic study using intraperitoneal dosing in mice showed good exposure in both plasma and brain samples. The compound was efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu(5) antagonists. A new operant model of addiction termed operant sensation seeking (OSS) was chosen as a second behavioral assay. The compound also proved efficacious in the OSS model and constitutes the first reported example of efficacy with a small molecule mGlu(5) NAM in this novel assay.
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PMID:(3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu(5): Discovery of a new tool compound with activity in the OSS mouse model of addiction. 2192 50

Opioids are the most commonly prescribed medications to treat severe pain in the Western world. It has been estimated that up to 90% of American patients presenting to specialized pain centres are treated with opioids. Along with their analgesic properties, opioids have the potential to produce substantial side effects, such as nausea, cognitive impairment, addiction and urinary retention. In the gut, opioids exert their action on the enteric nervous system, where they bind to the myenteric and submucosal plexuses, causing dysmotility, decreased fluid secretion and sphincter dysfunction, which all leads to opioid-induced bowel dysfunction (OIBD). In the clinic, this is reported as nausea, vomiting, gastro-oesophageal reflux-related symptoms, constipation, etc. One of the most severe symptoms is constipation, which can be assessed using different scales for subjective assessment. Objective methods such as radiography and colonic transit time can also be used, together with manometry and evaluation of anorectal function to explore the pathophysiology. Dose-limiting adverse symptoms of OIBD can lead to insufficient pain treatment. Even though several treatment strategies are available, the side effects are still a major challenge. Traditional laxatives are normally prescribed but they are often insufficient to alleviate symptoms, especially those from the upper gastrointestinal tract. Newer prokinetics, such as prucalopride and lubiprostone, may be more effective in alleviating OIBD. Another treatment approach is co-administration of opioid antagonists, which either cannot cross the blood-brain barrier or selectively target opioid receptors in the gastrointestinal tract. However, although these new agents have proved to be more efficacious than placebo, clinical trials still need to prove their superiority to standard co-prescribed laxative regimes.
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PMID:Opioid-induced bowel dysfunction: pathophysiology and management. 2295 May 33