Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013395 (dyspepsia)
 4,879 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dexloxiglumide, the (R)-isomer of loxiglumide, is a selective and highly potent CCK1 receptor antagonist. It is twice as potent as the racemic compound. because the anti-CCK activity is specific to the (R)-form, whereas the (S)-isomer is almost ineffective. It has been developed by Rotta Research Lab SpA for the treatment of diseases in which CCK1 receptor activity is potentially involved, including gastrointestinal motility, food intake and pancreatic disorders [218696]. Its receptor-mediated actions have been described in multiple in vitro and in vivo pharmacological systems. Results from both preclinical and clinical studies indicate that it is an effective inhibitor of gallbladder contraction, improves lower esophegal sphincter (LES) function, accelerates gastric emptying, accelerates colonic transit and significantly decreases symptoms in IBS and functional dyspepsia patients, and therefore has potential as an effective treatment for constipation-predominant IBS. functional dyspesia, constipation, LES function, gastric emptying disorders and biliary colics. Forest Laboratories has entered into an agreement with Rotta for the development and marketing of dexloxiglumide for the treatment of constipation-predominant IBS and phase III studies are currently ongoing in the US. In August 2000, Merrill Lynch expected that dexloxiglumide would not be launched until 2004 [379892], and in June 2001, predicted a US filing date in 2003 [413928].
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PMID:Dexloxiglumide Rotta Research Lab. 1209 Jul 34

Vagal afferents are extensively distributed in the digestive tract from the oesophagus to the colon. They are involved in the reflex control of normal gastrointestinal (GI) tract function (e.g. secretion and motility) as well as reflexes more characteristic of diseases such as functional dyspepsia and gastroesophageal reflux disease (e.g. vomiting, disordered lower esophageal sphincter relaxation and gastric accommodation). They are also implicated in signalling non-painful sensations (e.g. nausea and early satiety) associated with disease. A variety of receptors has been identified on vagal afferents, which can either enhance (e.g. 5-HT3, CCK1, VR1 and NK1 receptors) or reduce (e.g. ghrelin, leptin, k-opioid and GABAB receptors) activity, offering a range of potential therapeutic targets. Commonly used laboratory species (e.g. rat and mouse) lack an emetic reflex, and the implications of this for models of upper GI disorders have been explored in the light of expanding knowledge of the neuropharmacology of the emetic reflex implicating glutamate, prostanoids, cannabinoids and substance P. Additional pathophysiological roles for vagal afferents (e.g. in thermoregulation, arousal and fatigue) are being investigated, raising the intriguing possibility of the vagus as a target in non-GI disorders.
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PMID:Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. 1248 26

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