Disease relevance of D01113

• Treatment of biliary colic with loxiglumide [1].
• However, loxiglumide did not inhibit the gastrocolonic response to a regular meal either in healthy volunteers or in patients with irritable bowel syndrome [2].
• Cholecystokinin receptor antagonist, loxiglumide, inhibits invasiveness of human pancreatic cancer cell lines [3].
• In contrast, the effects of L-364,718 and loxiglumide for caerulein-induced pancreatitis were 2-4-fold weaker than those for gallbladder emptying [4].
• The integrated increments of bile flow during a 3-h period after saline and 100 mg/kg body weight loxiglumide were -14 +/- 71 and 982 +/- 61 microliters/100 g body weight, respectively, and those of bile acids were 2.5 +/- 1.4 and 23.1 +/- 4.1 mumol/100 g body weight, respectively [5].

Psychiatry related information on D01113

• Loxiglumide also failed to alter the interdigestive colonic motor activity [2].
• To further explore the role of CCK in humans, the effect on satiety and eating behavior of a specific CCK-receptor antagonist, loxiglumide, that preferentially inhibits peripheral (CCK-A) receptors was investigated [6].
• From 1030 until the meal at 1200 there was a significant satiating effect of intraduodenal fat compared with the control and loxiglumide experiments according to the food selection lists, which was because of the satiating effect for the fat rich items (p<0.05) [7].
• This study was done to discover if a low dose of intraduodenal fat releasing physiological amounts of endogenous cholecystokinin exerts satiation or satiety effects, or both and if these effects could be inhibited by the CCK receptor antagonist loxiglumide [7].
• Rotta was developing loxiglumide, a competitive cholecystokinin (CCK) antagonist, for potential use in the treatment of cancer, gastrointestinal disease, eating disorders and pancreatitis [8].

High impact information on D01113

• The present study was designed (a) to characterize the activity of loxiglumide as a peripheral cholecystokinin (CCK) antagonist in healthy human subjects, and (b) to determine whether CCK is a physiologic regulator of the intestinal phase of meal-stimulated exocrine pancreatic and biliary secretions in man [9].
• Intravenous loxiglumide (22 mumol/kg per h) was highly potent in antagonizing CCK8-induced pancreatic enzyme and bile acid secretion as well as pancreatic polypeptide release [9].
• A 12-carbon but not a 10-carbon-long chain fatty acid reduced antral contractile amplitude, an effect that was abolished by loxiglumide (a specific CCK-A receptor antagonist) [10].
• Loxiglumide inhibited postprandial gallbladder emptying, reflux episodes, TLESRs, and time of pH of <4 and prevented the decrease in LES pressure induced by cholestyramine [11].
• In other groups of rats, the effect of 10 nmol/kg PACAP-27 was studied under the influence of either atropine; loxiglumide, an antisecretin serum; a combination of both loxiglumide and the antiserum; or a PACAP antagonist (PACAP 6-38) [12].

Chemical compound and disease context of D01113

• Intravenous infusion of loxiglumide (50 mg/kg body wt/hr), atropine (100 micrograms/kg body wt/hr), or anti-secretin serum did not modify the fluid hypersecretion observed at 24 hr after induction of acute pancreatitis [13].
• The CCK/gastrin receptor antagonists proglumide and loxiglumide dose-dependently inhibited spontaneous growth of AGS gastric cancer cells with half maximal inhibition at 8 mM and 200 microM, respectively [14].
• Both protection and accompanying hyperemia were completely abolished by blockade of CCK-A receptors with loxiglumide, whereas L-365,260, an antagonist of CCK-B receptors, had no effect [15].
• This study, however, shows that loxiglumide improves the survival rates in necrotizing acute pancreatitis induced by intraductal injection of taurocholate, followed by caerulein injection [16].
• We evaluated the effects of a new cholecystokinin (CCK) receptor antagonist, loxiglumide, in a model of mild pancreatitis induced by repeated injections of cerulein and in a severe necrotizing form of pancreatitis induced by retrograde ductal injection of sodium taurocholate (NaTc) in rats [17].

Biological context of D01113

• Gastric emptying of radio-opaque markers ingested with the test meal was significantly accelerated by loxiglumide (area under the curve [markers x h] 33.3 [SEM 3.8] vs 17.9 [2.7] after placebo) [18].
• This study evaluates the effects of the specific cholecystokinin receptor antagonist loxiglumide on gall-bladder emptying after a meal or after intravenous infusion of caerulein in humans [19].
• By means of loxiglumide, a potent and highly specific antagonist for cholecystokinin (CCK), the effects of blocking CCK receptors on gastrointestinal motility were investigated in a placebo-controlled study in healthy young men (aged 21-39, mean 24 years) [18].
• Loxiglumide largely prevented the inhibitory effect of intraduodenal fat on food intake (245(30)g) [7].
• The infusion of loxiglumide markedly accelerated the gastric emptying of the mixed meal (area under curve, 5576 +/- 352 min vs 3498 +/- 109 min; p less than 0.001) and the pure glucose meal (area under curve 5662 +/- 537 min vs 3551 +/- 534 min; p less than 0.05) [20].

Anatomical context of D01113

• Opposite effects of cholestyramine and loxiglumide on gallbladder dynamics in humans [21].
• Loxiglumide (10 mg.kg-1.h-1) significantly augmented basal gastric acid output from 1.8 +/- 0.3 to 3.9 +/- 0.6 mmol H+/h (P less than 0.005) but did not significantly influence integrated basal serum gastrin concentrations (2 +/- 21 vs. 32 +/- 21 pmol L-1.h-1) [22].
• Loxiglumide at this dose abolishes the actions of CCK at various target organs including gallbladder and pancreas, when given at doses that mimic postprandial plasma concentrations of CCK [23].
• Lorglumide and loxiglumide inhibit gastrin-stimulated DNA synthesis in a rat tumoral acinar pancreatic cell line (AR42J) [24].
• Administration of loxiglumide failed to change insulin secretion in response to perfusion of the same meal or perfusion of a 10-amino acid solution into the duodenum [25].

Associations of D01113 with other chemical compounds

• The experiments were repeated under cholinergic (atropine) and cholecystokinin (loxiglumide) blockade [26].
• Tests were undertaken with and without elimination of endogenous CCK by loxiglumide, a selective CCK-A receptors antagonist, before and after eradication of H pylori with triple therapy (omeprazole, amoxicyllin, bismuth) [27].
• Cephalic phase stimulated by modified sham feeding in group A subjects increased gastric acid secretion to about 50% of pentagastrin maximum and the treatment with loxiglumide in a standard dose (20 mumol/kg iv loading dose plus infusion of 20 mumol/kg/h afterwards) failed to affect this secretion [28].
• More speculative new drugs for IBS include cholecystokinin antagonists such as loxiglumide and the gonadotrophin-releasing hormone analogue, leuprorelin (leuprolide) [29].
• 2. TP-680 showed approximately 2 and 22 times greater selectivity for peripheral CCKA receptors relative to brain CCK (CCKB) receptors than MK-329 and loxiglumide, respectively, when IC50 values for inhibition of [125I]-CCK-8 binding in isolated acini and cerebral cortex were compared [30].

Gene context of D01113

• In 7 additional volunteers, the effect of cholestyramine was studied during intravenous perfusion of saline or the CCK-A receptor antagonist loxiglumide [11].
• Meal-stimulated integrated incremental plasma PP concentrations were significantly suppressed (55-65% inhibition, P less than 0.01) by loxiglumide [31].
• Loxiglumide inhibits cholecystokinin stimulated somatostatin secretion and simultaneously enhances gastric acid secretion in humans [32].
• Administration of loxiglumide (1200 mg orally) caused a reduction in the postprandial intragastric pH and the two- to three-fold increase in plasma gastrin [33].
• When loxiglumide was added, the acid responses to caerulein and GRP were further increased by 2-3 folds, attaining a peak similar to the p-gastrin maximum [34].

Analytical, diagnostic and therapeutic context of D01113

• Gallbladder contraction stimulated by ingestion of a liquid test meal was completely abolished by oral administration of loxiglumide 30 min before the test meal [18].
• Additional experiments using gamma camera scintigraphy confirmed the accelerating effect of loxiglumide on gastric emptying of the mixed meal (P less than 0.01) [35].
• In a double-blind, placebo-controlled study, we investigated the effect of the specific CCK-A receptor antagonist loxiglumide on food intake (carbohydrate-rich meal) and on subjective hunger feelings scored with visual analogue scales and food selection lists in seven healthy obese women and in seven healthy lean women [36].
• 1. Interactions between cholecystokinin octapeptide (CCK-8) and CCKA-receptor antagonists derived from benzodiazepines (devazepide) and glutamic acid (lorglumide and loxiglumide) have been examined in an improved bioassay using the guinea-pig, isolated, gall bladder preparation [37].
• METHODS: Eight healthy subjects underwent esophageal manometry using a 10-lumen sleeve assembly during placebo or loxiglumide (10 mg/kg/h) in a randomized double-blind order [38].

References