Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:CCK1 receptor antagonist, dexloxiglumide: effects on human isolated gallbladder. Potential clinical applications. 1648 60

Based on better recent knowledge of the factors involved in triggering visceral hyperalgesia, the therapeutic approach to irritable bowel syndrome (IBS) treatment is changing. The classical approach targeting first bowel movement alterations or motility disorders using spasmolytic agents has to be replaced by visceral antinociceptive drugs. Several mediators and receptors involved in gut hyperalgesia have already been identified. Serotonin (5-HT), tachykinins, CCK, NGF, and other mediators are involved in experimental models of gut hyperalgesia, and related receptor antagonists have already been introduced in clinical trials. However, IBS is associated with mucosal immune stimulation, considered a microinflammatory state associated with increased density of immunocytes and mast cells, offering new targets. Altered mucosal barrier permeability with increased entry of toxins and bacteria is considered to be responsible for the mucosal microinflammation. Endogenous but predominantly luminal factors have been identified as factors responsible for such altered permeability. These clinical data have opened the door to promising future drugs able to prevent or blunt such permeability alteration, which therefore may constitute a pathophysiological treatment for IBS.
 ...
PMID:[Therapeutic targets]. 1930 40

Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK2-selective ligands using radiolabelled binding assays. CCK antagonism was confirmed for the ligands in isolated tissue preparations. DSS (dextran sulfate sodium)-induced inflammation was analysed for derivative 7 and PNB-001 with L-365,260 as a standard. The IC50 of PNB-001 was determined to be 10 nM. Subsequent in vivo evaluation confirmed anti-inflammatory activity with respect to IBD assays. The best molecule, PNB-001, showed analgesic activity in the formalin test and in the hotplate assay, in which the analgesic effect of 1.5 mg kg-1 PNB-001 was equivalent to 40 mg kg-1 tramadol. The CCK2-selective antagonist PNB-001 protected rats against indomethacin-induced ulceration at similar doses. The GI protection activity was found to be more potent than that of the 10 mg kg-1 dose of prednisolone, which served as a standard.
 ...
PMID:Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease. 3010 86


<< Previous 1 2