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)

To reduce weight, some morbidly obese patients are treated with an intragastric balloon, often resulting in increased reflux symptoms. As transient lower esophageal sphincter relaxations (TLESRs) are the major mechanism underlying reflux and can be reduced by cholecystokinin-A (CCK(A)) blockade, we hypothesized that the CCK(A)-receptor antagonist loxiglumide could reduce gastroesophageal reflux in these subjects. Postprandial manometric studies were performed in 12 obese subjects during infusion of placebo or loxiglumide. Before balloon placement, loxiglumide did not significantly reduce the rate of TLESRs but attenuated the postprandial decrease in LES pressure. After 10 weeks of balloon treatment, loxiglumide significantly reduced the rate of TLESRs. Postprandial LES pressure was significantly increased, whereas the meal-induced decrease in LES pressure was absent. Neither loxiglumide nor balloon placement affected gastroesophageal reflux. In conclusion, CCK(A) receptors play an important role in post-prandial LES pressure decrease and are involved in the reflex pathway underlying the triggering of TLESRs, at least after balloon placement.
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PMID:Role of CCK(A) receptors in postprandial lower esophageal sphincter function in morbidly obese subjects. 1245 91

No study has reported an association between gastroesophageal reflux disease (GERD) or its therapies and gallbladder function. We compared pre- and postoperative gallbladder function in patients undergoing fundoplication to determine the following: (1) whether patients with chronic GERD have preexisting gallbladder motor dysfunction; (2) whether medical or surgical therapy alters gallbladder function; and (3) whether division of the hepatic branch of the anterior vagus nerve is detrimental to gallbladder motility. Nineteen patients with documented GERD consented to a preoperative cholecystokinin-stimulated technetium hepatobiliary (CCK-HIDA) scan to quantify the gallbladder ejection fraction (GBEF). All patients underwent laparoscopic Nissen fundoplication. One month after fundoplication, 12 patients completed a repeat CCK-HIDA scan for determination of GBEF, with comparison to the preoperative GBEF. Among patients with preoperative GERD, 11 (58%) of 19 met the scintigraphic criteria for gallbladder dysfunction (GBEF <35%), which is a ratio comparable to that in patients undergoing a CCK-HIDA scan for presumed biliary dyskinesia during the same time period (31 [60%] of 53; P = NS, chi-square test) and exceeds the rate of abnormal GBEF reported in healthy volunteers (3%). Six of seven patients with a low preoperative GBEF who underwent repeat evaluation postoperatively had normalization of the GBEF (P < 0.05, paired t-test). In the 12 patients who underwent postoperative CCK-HIDA scanning, there was no association between preservation or division of the hepatic branch of the anterior vagus nerve and postoperative gallbladder dysfunction (P = NS, chi-square test). Unexpectedly, 58% of patients with GERD demonstrated gallbladder motor dysfunction prior to fundoplication, with improvement to normal occurring in most of those studied postoperatively. These data support controlled trials to determine the effect of chronic GERD and antisecretory therapy on gallbladder and global gastrointestinal smooth muscle function. Preservation of the hepatic branch of the anterior vagus nerve during fundoplication offered no clear benefit with regard to early postoperative gallbladder function.
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PMID:Gallbladder function before and after fundoplication. 1250 18

Cholecystokinin (CCK) is a regulatory peptide hormone, predominantly found in the gastrointestinal tract, and a neurotransmitter present throughout the nervous system. In the gastrointestinal system CCK regulates motility, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion. In the nervous system CCK is involved in anxiogenesis, satiety, nociception, and memory and learning processes. Moreover, CCK interacts with other neurotransmitters in some areas of the CNS. The biological effects of CCK are mediated by two specific G protein coupled receptor subtypes, termed CCK(1) and CCK(2). Over the past fifteen years the search of CCK receptor ligands has evolved from the initial CCK structure derived peptides towards peptidomimetic or non-peptide agonists and antagonists with improved pharmacokinetic profile. This research has provided a broad assortment of potent and selective CCK(1) and CCK(2) antagonists of diverse chemical structure. These antagonists have been discovered through optimization programs of lead compounds which were designed based on the structures of the C-terminal tetrapeptide, CCK-4, or the non-peptide natural compound, asperlicin, or derived from random screening programs. This review covers the main pharmacological and therapeutic aspects of these CCK(1) and CCK(2) antagonist. CCK(1) antagonists might have therapeutic potential for the treatment of pancreatic disorders and as prokinetics for the treatment of gastroesophageal reflux disease, bowel disorders, and gastroparesis. On the other hand, CCK(2) antagonists might have application for the treatment of gastric acid secretion and anxiety disorders.
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PMID:Cholecystokinin antagonists: pharmacological and therapeutic potential. 1278 87

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

Research into new methods of controlling acid secretion is driven by existing medical needs in gastro-oesophageal reflux disease treatment. Histamine receptor subtype 3 agonists offer one approach for acid inhibition but no agent is yet undergoing clinical testing. Other, as yet unrealized strategies include preventing the fusion of the tubulovesicular elements that contain H+/K+-ATPase with the parietal cell membrane, or blocking channels that recycle K+ in the parietal cell. Of more promise are gastrin (cholecystokinin) receptor antagonists and potassium-competitive acid blockers; examples of both are in clinical development. It is probable that gastrin receptor antagonists would be used adjunctively with proton pump inhibitors, possibly for meal-induced reflux. The potassium-competitive acid blockers have attributes that may facilitate use as monotherapy for the treatment of gastro-oesophageal reflux disease. The early promise of gastrin receptor antagonists and potassium-competitive acid blockers remains to be defined in large-scale trials.
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PMID:Novel approaches to the pharmacological blockade of gastric acid secretion. 1588 17

Cholecystokinin is the main hormonal regulator of gallbladder motility. Dexloxiglumide, the active enantiomer of loxiglumide, interacts competitively with CCK1 receptors as determined in preclinical studies, such as specific radioligand binding assays or functional studies on isolated guinea pig gallbladder, where it inhibited smooth muscle cell contractions induced by cholecystokinin-octapeptide (CCK-8), the most prominent active forms of cholecystokinin. Dexloxiglumide has a potent antagonistic effect, of a competitive nature, on human gallbladder cholecystokinin type 1 receptors. In isolated human gallbladder, dexloxiglumide produced a concentration-dependent rightward shift of the cholecystokinin-octapeptide curve, without affecting its maximal response. Gallbladder motility was evaluated in clinical studies. Dexloxiglumide, orally administered to healthy volunteers at putative therapeutic doses, did not interfere with post-prandial gallbladder kinetics, despite an increase of fasting gallbladder volume. At present, dexloxiglumide is in an advanced stage of clinical research in gastroenterology. Overall, clinical observations suggest that dexloxiglumide may become an effective treatment in several gastrointestinal disorders. Moreover, the beneficial effects can be obtained without increasing the risk of gallstones formation, a potential hazard subsequent to the inhibition of gallbladder contractions and the resulting bile stasis. The potent and selective antagonist dexloxiglumide may offer a possible therapeutic tool for use not only in functional gastrointestinal disorders, such as irritable bowel syndrome, constipation, gastroesophageal reflux disease and functional dyspepsia, but also in other pathologies, such as biliary colics, pancreatic diseases and gastrointestinal tumors.
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PMID:CCK1 receptor antagonist, dexloxiglumide: effects on human isolated gallbladder. Potential clinical applications. 1648 60

Proton pump inhibitors (PPIs) have revolutionized the treatment of gastro-oesophageal reflux disease (GERD). However, nearly 30% of all GERD patients are still symptomatic despite standard dose PPI treatment. Consequently, better treatment options are needed particularly in nonerosive reflux disease (NERD), which provides the largest number of patients that fail PPI. Transient lower esophageal relaxation (TLESR) is the underlying mechanism for most acid reflux events. Therefore, reducing the rate of TLESRs pharmacologically is an attractive therapeutic approach. Some compounds that were evaluated include: anticholinergics, opioids, cholecystokinin antagonists, nitric oxide antagonists, somatostatin, and GABA-B agonists. Currently, the GABA-B agonist baclofen generated the most promising results. Although data regarding GERD is lacking, visceral pain modulation, either pharmacologically or via mind-body interventions, was found to be efficacious in a variety of functional bowel disorders, including functional chest pain of presumed esophageal origin. Finally, intensive research is currently undergoing to develop newer acid suppressive agents. The acid pump inhibitors are reversible competitive inhibitors of the proton pump. These agents are potent suppressors of gastric acid secretion, and their effect is unrelated to food intake. Moreover, they demonstrate a faster onset of action and a predictable dose response effect as compared to the current PPIs. Although some of the preliminary clinical data is promising, thus far none of these agents is commercially available.
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PMID:New horizons in the medical treatment of gastro-oesophageal reflux disease. 1648 67

Cholecystokinin (CCK) is a peptide hormone which is found both in the gastrointestinal tract throughout the human small intestine and nerves in the myenteric plexus of the enteric nervous system and in the central nervous system. This dual location constitutes the anatomical basis for this in functions as a hormone and a neurotransmitter implicated in the regulation of both systems. CCK regulates not only motor functions in the gastrointestinal tract like lower oesophageal sphincter relaxation, gastric secretion and emptying, gall bladder contractility and bile secretion into the duodenum, intestinal and colonic motility, but also sensory functions and plays a role in the regulation of food intake. These effects are mediated through selective receptors CCK1 and CCK2. Over the last few years, research has focused on understanding the role of CCK, its receptors with antagonists at the biological, pharmacological, clinical and therapeutic level. As far as the CCK1 antagonists is concerned, important inroads have been made in the potential role of these antagonists in the treatment of GERD, IBS and pancreatitis. They have also shown encouraging results in sphincter of Oddi dysfunction and some gastrointestinal cancers. This review focuses on the recent ad vances of the biological role of CCK and their CCK1 antagonists: their current basic and clinical status in gastroenterology, with particular emphasis on the potential therapeutic role of the CCK1 antagonists and future research directions.
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PMID:CCK1 antagonists: are they ready for clinical use? 1669 65

This article summarizes data published during the past year that improve our understanding of the mechanisms by which various neurotransmitters, paracrine agents, and hormones regulate gastric acid secretion and are themselves regulated. The main stimulants of acid secretion are histamine, gastrin, and acetylcholine. The main inhibitor is somatostatin, which exerts a tonic restraint on parietal, enterochromaffin-like (ECL), and gastrin cells. Histamine, released from ECL cells, stimulates the parietal cell directly via H(2) receptors and indirectly via H(3) receptors coupled to inhibition of somatostatin secretion. Gastrin, acting via gastrin/cholecystokinin-B (CCK-B), now termed CCK(2), receptors on ECL cells activates histidine decarboxylase, releases histamine, and induces ECL hypertrophy and hyperplasia. The latter might be responsible for the rebound hyperacidity observed after withdrawal of long-term antisecretory therapy. The neurotransmitter pituitary adenylate cyclase-activating polypeptide stimulates histamine secretion from isolated ECL cells, but its physiologic role, if any, is not known. Acetylcholine, released from gastric postganglionic intramural neurons, stimulates the parietal cell directly via muscarinic M(3) receptors and indirectly by inhibiting somatostatin secretion. Although infection with H. pylori is associated with increased basal and stimulated acid outputs in patients with duodenal ulcer, most people infected with the organism are asymptomatic and have pangastritis with decreased acid output. In the latter, eradication of the bacterium leads to an increase in gastric acidity and is associated with a two-to threefold increase in gastroesophageal reflux.
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PMID:Gastric secretion. 1703 Nov 23

Dexloxiglumide is a potent and selective cholecystokinin type 1 (CCK1) receptor antagonist currently under development in a variety of diseases affecting the gastrointestinal tract such as gastro-oesophageal reflux disease, irritable bowel syndrome (IBS), functional dyspepsia, constipation and gastric emptying disorders. In female patients with constipation-predominant IBS, clinical efficacy has been demonstrated following administration of dexloxiglumide 200 mg three times daily. Dexloxiglumide is rapidly and extensively absorbed after single oral administration in humans with an absolute bioavailability of 48%. The incomplete bioavailability is due to both incomplete absorption and hepatic first-pass effect. Following multiple-dose administration of 200 mg three times daily, the accumulation is predictable, indicating time-independent pharmacokinetics. In addition, dexloxiglumide pharmacokinetics are dose-independent after both single and repeated oral three-times-daily doses in the dose range 100-400 mg. Dexloxiglumide absorption window extends from the jejunum to the colon and the drug is a substrate and a weak inhibitor of P-glycoprotein and multidrug resistance protein 1. Plasma protein binding of dexloxiglumide is 94-98% and the drug has a moderate to low volume of distribution in humans. Systemic clearance of dexloxiglumide is moderate and cytochrome P450 (CYP) 3A4/5 and CYP2C9 have been implicated in the metabolism of dexloxiglumide to produce O-demethyl dexloxi-glumide. This metabolite is further oxidised to dexloxiglumide carboxylic acid. These two major metabolites (accounting for up to 50% of dexloxiglumide elimination) have been identified. However, in human plasma the unchanged drug represents the major (up to 91%) component of the metabolic profile. The parent drug is believed to be the major contributor to the efficacy of the compound, since its major metabolites are pharmacologically inactive. In addition, the drug is a single isomer chiral drug (eutomer) that does not undergo chiral inversion into its pharmacologically inactive enantiomer (distomer). After oral administration of (14)C-dexloxiglumide, radioactivity is mainly excreted in bile and in faeces (74% of dose) with much lower excretion in urine (20% of dose). Renal excretion of unchanged dexloxiglumide is low (7% of dose in urine and faeces, 1% of dose in urine) and is dose-independent in the dose range 100-400 mg. As the kidney is a minor contributor to the elimination of dexloxiglumide and/or its metabolites in humans, the pharmacokinetics of the drug should not be affected in patients with renal insufficiency. The pharmacokinetics of dexloxiglumide are also not affected by age, sex and administration with a high-fat breakfast. Mild and moderate liver impairment do not affect the pharmacokinetics of dexloxiglumide but severe liver impairment causes increases in systemic exposure to dexloxiglumide and O-demethyl dexloxiglumide. Thus, the drug should be prescribed with caution in patients with severe hepatic impairment even though no dose adjustment is warranted. The results of different drug interaction studies have indicated that no clinically relevant metabolic and concomitant drug-drug interactions are expected during the clinical use of dexloxiglumide.
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PMID:Pharmacokinetic profile of dexloxiglumide. 1711 94


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