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PubMed1994

Pharmacological profile of FK480, a novel cholecystokinin type-A receptor antagonist: comparison to loxiglumide.

The pharmacological profile of FK480[(S)-(+)-N-<1-(2)-fluorophenyl)-3,4,6,7-tetra hydro-4-oxo-pyrrolo(3,2,1-jk) (1,4)benzodiaze-pine-3-yl>-1H-indole-2- carboxamide], a novel cholecystokinin type-A (CCK-A) receptor antagonist, was compared with that of the CCK-A receptor antagonist, loxiglumide. Both FK480 and loxiglumide inhibited 125I-labeled CCK-8 (125I-CCK-8) binding to rat pancreatic and guinea-pig gallbladder membranes with IC50 values of 0.40 +/- 0.04 and 0.06 +/- 0.02 nM for FK480 and 330 +/- 66 and 66 +/- 10 nM for loxiglumide, respectively. These two agents also inhibited 125I-CCK-8 binding to guinea-pig brain (cerebral cortex) receptors with respective IC50 values of 72 +/- 11 nM and > 10 microM, indicating less affinity to central receptors. Intravenous administration of FK480 (ED50 = 18 micrograms/kg) was 2800 times more potent than that of loxiglumide (ED50 = 50 mg/kg) in inhibiting CCK-8-induced pancreatic amylase secretion in rats. Furthermore, FK480 had ED50 values of 10 and 8.4 micrograms/kg, respectively, in antagonizing CCK-8-induced inhibition of charcoal meal gastric emptying in mice when administered orally 1 or 5 hr before the CCK-8. Loxiglumide (ED50 = 23.5 mg/kg, when administered orally 1 hr before the CCK-8) also antagonized it, but its activity was 2400 times less than that of FK480. We conclude that FK480 is a potent, orally effective CCK-A receptor antagonist with long duration of action.

Amylases↗
PubMed1994

Cholecystokinin in the control of gastric acid and plasma gastrin and somatostatin secretion in healthy subjects and duodenal ulcer patients before and after eradication of Helicobacter pylori.

BACKGROUND: Exogenous cholecystokinin (CCK) is known to effect gastric secretory and motor functions but its physiological role in the control of these functions in healthy subjects and duodenal ulcer (DU) patients is unknown. METHODS AND SUBJECTS: In this study involving four series of young healthy normal and DU subjects, the gastric secretory tests were performed under basal conditions and following stimulation by modified sham-feeding (MSF), i.v. infusion of caerulein, gastrin releasing peptide (GRP) or pentagastrin (p-gastrin) (series A), after 500 ml of standard meal without or with addition of 15% soybean oil (series B) or acidification of meal to pH 2.5 (series C), and finally after eradication of Helicobacter pylori (HP) (series D). Studies were carried out without or with the pretreatment with placebo or loxiglumide, a specific antagonist of type A CCK receptors. In series A, the gastric secretion obtained by aspiration technique was measured after secretagogues (MSF, caerulein, GRP or p-gastrin), whereas in series B, C, and D intragastric pH was measured before and after test meal and plasma gastrin, CCK and somatostatin were assayed by specific radioimmunoassays. RESULTS: In healthy subjects, MSF increased gastric acid outputs to about 36% of p-gastrin maximum and treatment with loxiglumide failed to affect this secretion. Standard meal enhanced acid output to about 50% of p-gastrin maximum and raised plasma levels of gastrin, CCK but not somatostatin. The pretreatment with loxiglumide resulted in further increase both in gastric acid secretion and plasma gastrin and CCK, while somatostatin level was significantly reduced. Infusion of graded doses of caerulein or GRP resulted in dose-dependent stimulation of gastric acid secretion reaching, respectively, 35% and 25% of p-gastrin maximum. 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. Administration of loxiglumide resulted in a significant increase in plasma gastrin and CCK responses to GRP, whereas plasma somatostatin was not significantly altered. Addition of fat to standard meal prolonged gastric emptying of this meal by about 50% both in healthy subjects and DU patients (series B). Fat in healthy subjects significantly increased and prolonged intragastric pH after the meal while reducing the increments in plasma gastrin and enhancing plasma CCK without alteration of plasma somatostatin. Pretreatment with loxiglumide significantly reduced postprandial pH from control 4.8 to 2.5 and reversed the changes in pH caused by addition of fat. The increments in plasma gastrin and CCK were markedly augmented, whereas those of somatostatin were attenuated. DU patients showed lower postprandial pH (3.0) in tests with or without fat and higher increments in plasma gastrin. CCK antagonism failed to affect significantly the pH profile or the increments in plasma gastrin or CCK. CCK antagonism failed to affect significantly the pH profile or the increments in plasma gastrin. Intragastric application of standard meal of pH 3.0 in healthy subjects and DU patients (series C) resulted in significantly lower median 3 h intragastric pH as compared to that after meal of pH 6.5. After pretreatment with loxiglumide, the median pH after meals of both pHs was significantly lower in healthy subjects but not in DU patients. This reduction in pH was accompanied by more pronounced increase in plasma gastrin response to a meal of pH 6.5 only in healthy controls but not in DU subjects and by a significant increase in plasma CCK and decrease in plasma somatostatin.

Adult↗
PubMed1994

The effects of loxiglumide on food intake in normal weight volunteers.

The aim of this paper was to investigate the effects of the CCK, a receptor antagonist loxiglumide on food intake, hunger and fullness in humans. A double blind, placebo controlled, cross-over test was carried out, with subjects taking one loxiglumide or one placebo tablet three times a day, 15 min before main meals or at comparable intervals. The work was carried out at the Centre for Human Nutrition, Northern General Hospital, University of Sheffield, on 11 healthy, normal weight, male and female volunteers. The following were measured: weighted-intake measurement of food intake during drug and placebo treatment; laboratory test of food intake on day three of each treatment; hunger and fullness ratings throughout this meal. A small, non-significant, increase in food intake as measured by the weighed intake diaries (8577 +/- 636 vs 7895 +/- 569 kJ (2049 +/- 152 vs 1886 +/- 136 kcal); P = 0.17) was seen during loxiglumide treatment, but no effect on food consumption from the evening test meal was observed and no effect on feelings of hunger and fullness before or after this meal was seen. These results do not support the hypothesis that, in the free feeding situation, endogenously released CCK is involved in the reduction of food intake or inhibition of hunger. However, a different dose of route of administration or a larger group of subjects may reveal an effect of loxiglumide on feeding in humans.

Adolescent↗
PubMed1993

[Effect of cholecystokinin and its antagonists lorglumide, devazepide, and L-365,260 on gastrointestinal motility in rats].

Cholecystokinin (CCK) plays an important role in gallbladder contraction and gut motility. Sincalide (CCK-8) evoked guinea pig isolated ileum contraction at 10(-5)-10(-1) mumol.L-1 in a concentration-dependent manner, EC50 being 207 pmol.L-1. It delayed the gastric emptying as well. The rate of inhibition of gastric emptying was 71 +/- 12% at 100 micrograms.kg-1 by ip. Sincalide antagonists: lorglumide, devazepide, and L-365,260 antagonized the ileal smooth muscle response to sincalide in a concentration-dependent manner. Their pA2 were 7.30, 10.02, and 7.77, respectively. Lorglumide, devazepide, and L-365,260 inhibited the delaying of gastric emptying evoked by sincalide. The IC50 were 0.11, 0.0064, and 0.66 mg.kg-1, respectively.

Animals↗
PubMed1993

The antagonistic effect of cholecystokinin octapeptide (CCK-8) on opioid effects in cardiovascular activities was mediated by CCK-B receptor.

Previous studies have shown that CCK-8 has distinct antiopioid effect in the central sites related with pain control and blood pressure control. The aim of this study was to explore the receptor mechanism by which CCK-8 antagonized the depressor effect of u- and k-opioid agonists, and to observe whether CCK-8 could antagonize the depressor effect induced by muscimol, a nonopioid substance. The results showed that (i) The antagonistic effect of CCK-8 on opioid-induced hypotension could be blocked by intrathecal (i. t.) administration of CCK-B antagonist L-365, 260 at nanogram doses, or by CCK-A antagonist devazepide at doses 20-40 times higher than L-365, 260, indicating that it was the CCK-B receptor which mediates the antiopioid effect. (ii) The depressor effect induced by intrathecal muscimol, a GABA agonist, was blocked neither by naloxone nor by CCK-8, supporting the notion that CCK-8 is an endogenous opioid antagonist rather than a universal anti-hypotension agent.

Animals↗
PubMedDate not supplied

CCK/gastrin antagonists--clinical perspectives.

There are (at least) two types of receptor for cholecystokinin (CCK)/gastrin peptides. Highly potent specific antagonists are available for both types. The CCKA-receptor mediates classical CCK-like effects on the gut. Antagonists given to man inhibit pancreatic enzyme secretion and generally shorten gastrointestinal transit times. Potential clinical indications include anorexia, gastro-paresis, pseudo-paresis, pseudo-obstruction, severe constipation and chronic pancreatitis. However gallbladder contraction is markedly inhibited and this led to gallstone formation in baboons. This will obviously have to be avoided if CCKA antagonists are to be used in man. CCKB-receptors mediate the effects of gastrin on the gut and the effects of CCK in the brain. They inhibit gastrin-stimulated acid secretion. If used in acid-peptic disease they might inhibit the trophic effects of gastrin on enterochromaffin cells. CCKB-antagonists can also inhibit the growth of some gastrin-dependent tumours, including certain human colonic cancer cell lines which produce gastrin. CCKB-antagonists have a potent anxiolytic-like effect in animals, and this effect might become their main clinical application.

Animals↗
PubMed1993

Cholecystokinin does not delay gastric emptying of regular meals in healthy humans.

Exogenous CCK can delay gastric emptying of meals in the experimental animal and in humans. Studies using exogenous CCK, however, do not prove that the effects of exogenous peptide are of physiological importance. For this reason, the present study employed the specific CCK-antagonist loxiglumide (Rotta) to investigate the question as to whether CCK plays a physiological role in the regulation of gastric emptying. (1) Sonographic studies: Fourteen healthy subjects received a mixed solid-liquid 1,000 kcal meal made up of regular German food. Gastric emptying was calculated from antral volumes measured at 10-minute intervals. All subjects were studied twice on separate days, either with or without i.v. infusion of 1.0, 5.0 or 10.0 mg/kg h loxiglumide, each different dose being given to 4 or 5 subjects. (2) Scintigraphic studies: Eight subjects received an 800 kcal mixed solid-liquid meal consisting of regular food. Solid and liquid components were labeled with 99m-Tc and 113m-In, respectively. Gastric emptying was monitored using a computerized gamma-camera. All subjects were studied twice on separate days either with or without i.v. infusion of 5 mg/kg h loxiglumide. Both meals significantly increased plasma activity of CCK by 4-8 pM/ml (bioassay). However, loxiglumide did not significantly alter gastric emptying at any postprandial time when compared with the NaCl control. The failure of the CCK-antagonist to affect gastric emptying was seen with both type of meals and both the sonographic and scintigraphic techniques. In the scintigraphic studies, gastric emptying of both liquid and solid components were virtually identical in experiments with or without loxiglumide.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholecystokinin↗
PubMed1993

Inhibitory effect of intraduodenal infusion of loxiglumide on pancreatic exocrine secretion.

Inhibitory effect of loxiglumide (D,L-4-(3, 4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylamino)-5- oxo-pentanoic acid, CAS 107097-80-3) on exocrine pancreatic secretion was compared between intraduodenal and intravenous administration. Doubling doses of intravenous cholecystokinin octapeptide (CCK-8) resulted in a dose-dependent increase of pancreatic secretion from 50 to 400 ng/kg/h. Both intraduodenal and intravenous loxiglumide of 5 and 10 mg/kg/h produced a dose-dependent inhibition of the pancreatic protein secretion to all doses of CCK-8. Cumulative increment of pancreatic protein output was inhibited by 79% and 77% at 10 mg/kg/h of intraduodenal and intravenous loxiglumide, respectively. Extents of the inhibition were similar to each other between the two routes of loxiglumide infusion. However, plasma levels of loxiglumide after intraduodenal administration were about half of those observed after intravenous administration of the corresponding dose, although plasma CCK levels were not different. Intraduodenal loxiglumide is as effective as intravenous loxiglumide in inhibitory potency on pancreatic secretion. Therefore, possible therapeutic indications of oral loxiglumide could be expected.

Animals↗
PubMed1993

[Effect of combined use of CR1505 with UFT for the tumor growth of the subcutaneously transplanted pancreatic cancer in the Syrian golden hamsters].

We studied on the effect of combined use of CR1505 with UFT for the subcutaneously transplanted pancreatic cancer induced by BOP (N-nitrosobis (2-oxopropyl) amine) in the Syrian golden hamsters. The tumor growth in the group treated with both CR1505 and UFT was significantly inhibited compared with that in the group treated with only CR1505 or UFT. Labelling index judged by BrdU immunohistochemistry in the group with the combined use was significantly lower than that in the group with the single use. The differences of the body weights and blood analysis were not obscured in the both groups. Moreover, the concentrations of 5-FU and FT207 in tumors were not different between them. These results suggest that a new therapy of the combined use with CR1505 and UFT for the pancreatic cancer should be effective.

Animals↗
PubMedDate not supplied

Effect of hypergastrinemia and blockade of gastrin-receptors on pancreatic growth in the mouse.

BACKGROUND/AIM: The present study evaluates whether endogenous gastrin regulates pancreatic growth in the mouse. MATERIALS AND METHODS: Male NMRI mice weighing 12-15 g were assigned to six groups (10 mice/group) which were treated with different combinations of 0.9% NaCl, omeprazole, a CCK-A antagonist, a CCK-B antagonist, loxiglumide, and L365, 260 for 10 days each according to different protocols. RESULTS: Omeprazole caused a marked, 10-fold increase in serum gastrin which was not affected by the gastrin antagonist, but markedly reduced by the CCK-A antagonist. The marked increase in endogenous gastrin caused by omeprazole did not promote pancreatic growth in any way. Similarly, the gastrin antagonist did not inhibit pancreatic growth. In contrast, the CCK-A antagonist significantly decreased pancreatic weight and protein content. CONCLUSIONS: The present results strongly suggest that endogenous gastrin--in contrast to CCK--does not regulate pancreatic growth in the mouse. The inhibitory effect of loxiglumide on omeprazole-induced increase in serum gastrin might be explained by recent findings which showed that CCK-A antagonists can stimulate gastric acid secretion probably due to a reduction of the inhibitory effect of basal CCK on the D-cell and its somatostatin release. Probably such a slight stimulation of gastric acid secretion caused by the CCK-A antagonist might reduce the gastrin increase caused by omeprazole's abolishment of acid secretion.

Animals↗
PubMed1996

Eradication of Helicobacter pylori and gastrin-somatostatin link in duodenal ulcer patients.

Helicobacter pylori (Hp) infection may be associated with duodenal ulcer (DU) and accompanied by increased release of gastrin and deficiency of somatostatin (S-S) but the mechanisms of these changes in DU patients after eradication of Hp have been little studied. Cholecystokinin (CCK) has been implicated in the feedback control of gastric acid secretion in healthy subjects but its contribution to secretory disorders in DU patients has been little examined. This study, therefore, investigated whether CCK participates in the impairment of postprandial gastrin release and gastric acid secretion in active DU patients. Tests were undertaken in 10 DU patients without or with elimination of the action of endogenous CCK using loxiglumide (LOX), a selective CCK-A receptor antagonist, before and 4 wk. after eradication of Hp with triple therapy (omeprazole, amoxycillin and bismuth). In Hp positive DU patients, the postprandial acid secretion (measured by continuous intragastric pH monitoring) was accompanied by a pronounced increment in plasma gastrin with negligible increase of intraluminal release of S-S. The administration of LOX in these patients did not affect significantly the postprandial pH profile and the rise in plasma gastrin. After eradication of Hp the median postprandial intragastric pH increased to about 4.3 (compared to 3.5 before the Hp eradication); the postprandial gastrin concentration was reduced by about 40%, while luminal release of S-S was increased 2 folds. The administration of LOX resulted in significantly greater decrease in median pH (3.1) and higher rise in postprandial plasma gastrin in these patients. Also the postprandial plasma S-S showed a small, but significant decline (by about 25%) as compared to that in placebo treated patients. This study provides evidence that: (1) Hp infection in DU patients is accompanied by enhanced gastrin release and the reduction in luminal release of S-S; (2) The failure of LOX to affect gastric secretion and plasma gastrin DU Hp infected patients could be attributed, at least in part, to the failure of endogenous CCK to control gastric acid secretion via release of S-S; (3) Hp infected patients appear to exhibit a deficiency of S-S release that can be reversed by the eradication of Hp indicating that both peptides may contribute to the acceleration of the ulcer healing following Hp eradication in DU patients; (4) The test with LOX and gastric luminal S-S assay may be useful in identification of Hp positive DU patients with CCK-mediated impaired feedback control of gastric secretion and deficiency of S-S caused by Hp infection.

Adult↗
PubMed1996

Role of endogenous cholecystokinin in the regeneration of pancreatic tissue after acute hemorrhagic pancreatitis in rats.

The aim of this study was to investigate the effect of endogenous cholecystokinin (CCK) on pancreatic regeneration after acute hemorrhagic pancreatitis. Acute hemorrhagic pancreatitis was induced in rats by two intraperitoneal cerulein injection (20 micrograms/kg BW) with 5h water-immersion stress once a day for successive 3 days. After the cessation of repetition of acute pancreatitis the rats were treated with successive feeding with 0.1% camostat-containing diet or SC injection of CR-1505 (CCK receptor antagonist, 50 mg/kg BW x 2/day) for 7 days. Zymogen enzymes and protein contents per DNA in pancreatic tissue were significantly higher in rats treated with camostat compared with control rats, and plasma CCK level was elevated. To the contrary, pancreatic regeneration was retarded in the rats treated with CR 1505. It is concluded that endogenous CCK has a trophic effect during regeneration after acute hemorrhagic pancreatitis.

Acute Disease↗
PubMedDate not supplied

Early development of experimental biliary pancreatitis and its amelioration by CCK-receptor blockade.

BACKGROUND/AIMS: Development of pancreatitis has extensively been studied in models using CDE-diet and cerulein. This study analyzes early alterations and effects of CCK-receptor blockade in a model of biliary pancreatitis which better reflects the pathogenesis of human pancreatitis. MATERIAL AND METHODS: The common part of the bile and pancreatic duct was surgically ligated in fed rats which were allowed to recover. The CCK-antagonist CR1409 at 10 mg/kg or 0.9% NaCl was s.c. given every 6 hours. Morphological alterations were quantified by histological grading. Biochemical evidence of pancreatitis was assessed by determination of amylase concentrations in serum and ascites. A bioassay was used to determine plasma cholecystokinin. RESULTS: Ligation of the common bile and pancreatic duct caused an increase in serum amylase, development of ascites with high amylase concentrations, and morphological evidence of pancreatitis without major mortality. Electron microscopy showed early loss of microvilli and defects in basal lamina representing initial stages of duct ruptures. Early ultrastructural damage to acini included multiple vacuoles, peripheral loss of density of ("targetoid") zymogen granules and dilatation of RER. Acinar vacuolization, edema, hemorrhage and necrosis mainly occurred in areas neighboring the ducts. Duct ligation was associated with a significant increase in plasma CCK. The CCK-antagonist significantly reduced the biochemical and morphological severity of obstructive pancreatitis. CONCLUSIONS: Obstruction of the common channel of the bile and pancreatic ducts results in transient mild to moderate acute pancreatitis and in an increase in plasma CCK. Since CCK-receptor blockade ameliorated the severity of pancreatitis it is likely that increased plasma CCK plays a contributory or permissive role in pancreatitis caused by duct obstruction.

Animals↗
PubMed1997

[Newly-developing therapies of pancreatic cancer--immunotherapy, gene therapy, differentiation therapy, endocrine therapy and others].

Pancreatic cancer is extremely resistant to various cancer therapies, however, variety of new therapies for pancreatic cancer have been investigated: (1) immunotherapy including cytokines like TNF, adoptive immunotherapy with lymphokine-activated killer cells or cytotoxic T-lymphocytes, and tumor vaccines using mutated Ki-ras oncoprotein or irradiated tumor cells which were transfected by cytokine genes; (2) gene therapy including transfer of cytokine genes or antisense Ki-ras oncogene, and a combination of gene transfer of herpes simplex virus thymidine kinase and subsequent administration of ganciclovir; (3) differentiation therapy including a quinolinone derivative, vesnarinone; (4) endocrine therapy including cholecystokinin-receptor antagonist, CR1505 or L364,718; (5) heavy water, and etc. All of these therapies will be applied for the treatment of pancreatic cancer in the near future.

Animals↗
PubMed1997

Cholecystokinin antagonistic activities of loxiglumide.

Cholecystokinin (CCK) antagonistic activities of loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N-pentylgl utaramic acid, CR1505, CAS 107097-80-3) were investigated in the gastrointestine and gallbladder in vivo. Intravenous administration of loxiglumide antagonized the CCK-induced reduction of gastric emptying in rats, acceleration of intestinal transport in mice, increase in ileal motility in rabbits, gallbladder contraction in guinea pigs and acceleration of gallbladder emptying in mice. Orally administered loxiglumide also antagonized the CCK-induced gallbladder emptying in mice. Furthermore, egg yolk-stimulated gallbladder emptying in mice was also inhibited by loxiglumide, indicating that this agent antagonizes not only exogenous but also endogenous CCK. These results demonstrate that loxiglumide is an intravenously and orally effective, potent CCK antagonist.

Animals↗