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PubMed2002

CCK1 central receptor antagonist prevented the intestinal stress symptoms in sheep.

The aim of this study was to determine the influence of mechanically induced duodenal distension (DD) and lorglumide (CCK1 receptor antagonist) premedication on electrical activity of various parts of gastrointestinal (GI) tract and the blood plasma cortisol level in sheep. The influence of lorglumide on the unfavourable effects of duodenal distension (performed with a balloon filled with water--40 and 80 ml; DD40 and DD80) was investigated in this study. These effects in sheep were as follows: the atony of forestomachs and abomasum and the transitory stimulation of myoelectrical activity of small intestine and distal parts of large intestine. The animals, under general anaesthesia, had electrodes inserted into the muscular layers of the organ, the duodenal fistula and (in another group of animals) also the ruminal fistula. Five minute duodenal distension (DD40 and DD80) caused an immediate and complete inhibition of the frequency of spike bursts as well as reticulo-ruminal and abomasal contractions, but also a transitory significant increase of spike bursts of the intestinal wall. The duodenal distension (DD40 and DD80) caused a significant increase of plasma cortisol concentration. Lorglumide did not significantly change the motility of gastrointestinal tract and cortisol concentration, but 10 min after the intracerebroventricular (i.c.v.) infusion in the doses of 1 and 2 mg in toto (i.e. 25 and 50 micrograms/kg B.W.) it decreased the cortisol concentration by 59.7%, as compared with the control values. Lorglumide administered in the above mentioned doses 10 min before the DD40 prevented all signs of intestinal stress and decreased the release of cortisol, but only for 10 min since the beginning of the duodenal distension. It is concluded, that lorglumide--an antagonist of the central CCK1 receptors can be an effective antistressoric agent in the stomach atony caused by the duodenal distension (mechanical-algetic-emotional stress) in sheep.

Animals↗
PubMedDate not supplied

The effect of a cholecystokinin receptor antagonist lorglumid on the proteinase-antiproteinase balance in taurocholate acute experimental pancreatitis (AEP) in rats.

The effect of new CCK receptor antagonist, lorglumid on taurocholate AEP in rats was studied. Lorglumid was applied intraperitoneally at a dose of 5.6 mg/kg BW immediately after taurocholate injection into choledochopancreatic duct. Activity of amylase, antithrombin III (AT III), alpha 1 protease inhibitor (alpha 1 PI), alpha 2 antiplasmin (alpha 2 AP) and alpha 2 M) in plasma, trypsin and chymotrypsin in pancreata were measured after 1, 3, 6 h of AEP. In AEP treated by lorglumid serum amylase activity and pancreatic wet weight was significantly reduced. The use of lorglumid prevented the increase of alpha 1 PI and alpha 2 AP compared to not treated animals. AT III and alpha 2 M in plasma and trypsin and chymotrypsin activity in pancreata did not change significantly in all groups. The mortality of the lorglumid treated rats was significantly lower in comparison with control group. It is concluded that lorglumid in taurocholate AEP moderates the changed plasma proteinase-antiproteinase balance. Our results indicate a protective effect of lorglumid in this model of acute experimental pancreatitis.

Acute Disease↗
PubMedDate not supplied

Receptor strategies in pancreatitis.

A variety of receptors on pancreatic acinar and duct cells regulate both pancreatic exocrine secretion and intracellular processes. These receptors are potential sites of action for therapeutic agents in the treatment of pancreatitis. Cholecystokinin (CCK) receptor antagonists, which may reduce the level of metabolic "stress" on acinar cells, have been shown to mitigate the severity of acute pancreatitis in a number of models. Not all studies have shown a benefit, however, and differences may exist between different structural classes of antagonists. Because increased pancreatic stimulation due to loss of feedback inhibition of CCK has been proposed to contribute to the pain of some patients with chronic pancreatitis, CCK receptor antagonists could also be of benefit in this setting. Somatostatin and its analogs diminish pancreatic secretion of water and electrolytes and have been effective in treating pancreatic fistulas and pseudocysts. These agents are also being evaluated for their ability to reduce pain in chronic pancreatitis (perhaps by reducing ductal pressure by diminishing secretory volume) and mitigating the severity of acute pancreatitis (possibly by reducing the metabolic load on acinar cells). Recently described secretin receptor antagonists may also have therapeutic value as a means of selectively inhibiting pancreatic secretion of water and electrolytes.

Animals↗
PubMed1992

[Treatment of recurrent ulcers after parietal cell vagotomy. Analysis of 18 cases].

One hundred and twenty seven patients had a follow-up of more than 4 years after parietal cell vagotomy for duodenal, pyloric or prepyloric ulcer. The recurrence rate is 15.8% (20 on 127). Eighteen patients who have recurred, had a follow-up of 2 years or more after treatment of the recurrent disease. Ten patients had a early recurrence (within 2 years); eight had a late one (more than 2 years). One patient had been operated as an emergency for perforation. Seventeen patients had first received a medical treatment. This treatment was sufficient for 10 out of 17. Seven patients were reoperated (3 partial gastrectomy), 4 partial gastrotomy associated with truncal vagotomy. Seven out of the 10 early recurrences was reoperated and only one of the 8 late recurrences was reoperated. The early recurrences seem to be more serious that the late ones. Medical treatment is always prescribed as first line therapy and a partial gastrectomy alone or with vagotomy is necessary in unsuccessful cases.

Adult↗
PubMed1992

Dose-response effects of oral loxiglumide on postprandial gall-bladder emptying in man.

The effect of two different single oral doses of loxiglumide (CR 1505, CAS 107097-80-3) on gall-bladder emptying induced by a 550-cal standard mixed meal in 6 healthy volunteers was studied. Following placebo, the maximal gall-bladder emptying occurred about 90 min after the meal (minimal residual gall-bladder volume 27.4% of basal volume). Loxiglumide 400 or 800 mg dose-dependently inhibited the physiologica gall-bladder emptying. Loxiglumide plasma levels dose-dependently increased. The inhibition of gall-bladder emptying and the kinetic of loxiglumide plasma levels were temporally related. The results of the present study confirm that oral loxiglumide is a potent orally active cholecystokinin (CCK) antagonist in man and that CCK is the major physiological mediator of gallbladder emptying in response to meal.

Adult↗
PubMed1992

[Effects of UFT and loxiglumide (CR1505) on liver metastasis of human pancreatic cancer cell line, KP-1 N in nude mice].

Effects of caerulein (CCK), 5-FU and CCK antagonist, loxiglumide (CR1505), were studied on the growth of human pancreatic cancer cell line, KP-1 N, in vitro. And effects of UFT and CR 1505 were also studied on liver metastasis in nude mice. The growth of KP-1 N was stimulated approximately 40% by addition of 10(-10) M of CCK in vitro. CR1505 antagonized the action of CCK, that is, the 40% growth rate increase was suppressed by addition of 25 microM of CR1505. Moreover, the growth rate of the cells dose-dependently decreased by the addition of CR1505. 5-FU also dose-dependently inhibited the growth of KP-1 N in culture. 5-FU additionally decreased the growth rate of KP-1 N in combination with CR1505. A number of metastatic nodules were found in the liver of nude mice a month after injections of KP-1 N cells into the spleen CR1505 suppressed the liver metastasis in nude mice which were administered with UFT. These results suggest that CR1505 would be useful for the treatment of human pancreatic cancer in combination with UFT.

Animals↗
PubMed2004

Effect of lipopolysaccharide on expression and characterization of cholecystokinin receptors in rat pulmonary interstitial macrophages.

AIM: To investigate the effect of lipopolysaccharide (LPS) on the expression and the binding characteristics of cholecystokinin receptors (CCK-R) in rat pulmonary interstitial macrophages (PIMs). METHODS: The PIMs isolated from rat lung tissues were purified by the collagenase digestion method combined with alveolar lavage and pulmonary vessel perfusion. The expression of CCK-R mRNA was detected by RT-PCR and Southern blot analysis and the binding experiments were performed by radioligand binding assay (RBA). RESULTS: CCK-A receptor (CCK-AR) and CCK-B receptor (CCK-BR) mRNA were detected in rat PIMs and their RT-PCR amplified products had a size of approximately 1.37 kb and 480 bp, respectively. The relative expression of CCK-BR mRNA was higher than that of CCK-AR mRNA after incubation with LPS for 0.5, 2, and 6 h. The expression of CCK-R mRNA could be upregulated obviously by LPS. Southern blot analysis of RT-PCR amplified CCK-AR and CCK-BR mRNA products using [gamma-32P]ATP 5'-end-labelled probe showed specific hybridization bands. The specific binding of [3H]CCK-8S to rat PIM membranes was detected in the rats administered with LPS for 48 h, but not in normal rats. Scatchard analysis of the saturation curves suggested the presence of CCK-R with a high affinity (Kd = 0.68 +/- 0.28 nmol/L) and a low binding capacity (Bmax = 32.5 +/- 2.7 fmol/g protein) in rat PIMs. The specific binding of [3H]CCK-8S to rat PIM membranes was inhibited by unlabelled CCK-8S (IC50 = 2.3 +/- 0.8 nmol/L), CCK-AR specific antagonist CR1409 (IC50 = 0.19 +/- 0.06 micromol/L) and CCK-BR specific antagonist CR2945 (IC50 = 3.2 +/- 0.1 nmol/L). CONCLUSION: Two types of functional CCK-AR and CCK-BR existed in rat PIMs and their expression could be upregulated by LPS.

Animals↗
PubMed2004

Use of a hepta-Tyr antibiotic modified silica stationary phase for the enantiomeric resolution of D,L-loxiglumide by electrochromatography and nano-liquid chromatography.

Hepta-Tyr antibiotic modified silica stationary phase was used for the chiral resolution of D,L-loxiglumide, a new drug under investigation proposed for the treatment of gastrointestinal diseases. The chiral stationary phase was packed into fused silica capillaries of 75 microm i.d. for a length of only 7 cm and used for both capillary electrochromatography (CEC) and nano-liquid chromatography (nano-LC) running the experiments with the same instrumentation; in order to increase the electroosmotic flow (EOF) the antibiotic stationary phase was mixed with amino-silica particles (3:1, w/w) generating a relatively high reversed EOF. The enantiomeric resolution of loxiglumide by CEC was strongly influenced by several experimental parameters such as applied electric field, mobile phase composition, capillary temperature, etc. Optimum experimental conditions were found applying 15 kV at 20 degrees C and eluting with acetonitrile-sodium phosphate buffer at pH 6 (1:1, v/v). The same capillary was tested for nano-LC experiments. Good chiral separation of loxiglumide was achieved selecting the appropriate mobile phase considering the type and concentration of organic modifier. The nano-LC optimised method was therefore validated and applied to the analysis of a pharmaceutical formulation declared to contain only D-loxiglumide.

Anti-Bacterial Agents↗
PubMed2004

[New aspects of pharmaco-therapy for acute pancreatitis].

Despite improvement in intensive medical care management, the mortality rate from severe acute pancreatitis is still high. Attempt to reduce the mortality rate, some new drugs were investigated on experimental pancreatitis and clinical cases. There have been several clinical trials of somatostatin, somatostatin analogue octreotide, and a cholecystokinin A(CCK-A) receptor antagonist, loxiglumide, for the inhibition of pancreatic secretion. On the other hand, for the inhibition of the systemic inflammatory response, many studies in the use of the platelet-activating factor(PAF) antagonist, lexipafant, were reported in clinical trials. IS-741, a new synthetic anti-inflammatory agent, has been studied on various models of experimental pancreatitis. In this paper, it is introduced the results of these new drugs on experimental pancreatitis or clinical trials.

Acute Disease↗
PubMed2004

Effects of juice from Morinda citrifolia (Noni) on gastric emptying in male rats.

The effects of juice from Morinda citrifolia (noni) on gastric emptying, gastrointestinal transit, and plasma level of cholecystokinin (CCK) in rats were studied. Male rats were given noni by gavage at levels of 0.25, 1, or 4 ml/kg once per day for one or 7 days. The rats in the control group were given water, while the rats in the experimental group were fasted overnight before measurement of gastrointestinal motility. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal (10%) and Na251CrO4 (0.5 microCi/ml). Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Then, gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Finally, blood samples were collected for measurement of CCK by radioimmunoassay. The administration of noni at 0.25 ml/kg, but not at 1 ml/kg and 4 ml/kg, for 1 day significantly inhibited gastric emptying. In contrast, gastric emptying was significantly inhibited by oral noni (0.25, 1, or 4 ml/kg) for 7 days. Intraperitoneal injection of lorglumide (5 or 10 mg/kg), a selective CCK1 receptor antagonist, effectively attenuated the noni-induced inhibition of gastric emptying. The intestinal transit and body weight, food intake, water intake, urine volume as well as feces weight were not altered by the administration of noni either acutely or chronically, but the administration of oral noni (1 ml/kg) for 7 days increased the level of plasma CCK in male rats. These results suggest that oral noni inhibits gastric emptying in male rats via a mechanism involving stimulation of CCK secretion and CCK1 receptor activation.

Animals↗
PubMed1991

Effect of lorglumide (CR-1409) on pancreatic secretory and trophic response to caerulein in newborn rats.

The authors investigated whether lorglumide a specific CCK-receptor antagonist affects the pancreatic actions of caerulein in female newborn Wistar rats. Pancreatic secretory response (expressed as the decrease in specific trypsin activity in the pancreas) was studied in 11-day-old rats following acute administration of saline (control), caerulein (0.3, 1, or 3 micrograms/kg s.c.) either without or with lorglumide (10 mg/kg s.c.). Lorglumide was given 15 min before caerulein. In chronic studies rats were treated 3x/day for 10 days from the day of birth (Day 1) with caerulein and lorglumide as above. On Day 11 the rats were decapitated and exsanguinated, their pancreas removed and analyzed. Acute administration of caerulein induced a dose-dependent depletion of specific trypsin activity from the pancreas and this was antagonized by lorglumide. Chronic treatment with each dose of the peptide increased total pancreatic trypsin content. Besides, the 3 micrograms/kg dose caused to increase pancreatic protein, DNA, and amylase content and to increase plasma corticosterone level. Chronic administration of lorglumide did not influence normal pancreatic growth, while it strongly inhibited the increase in trypsin content evoked by caerulein. However, lorglumide, given alone or in combination with caerulein, induced a significant increase in pancreatic amylase content without affecting plasma corticosterone level.

Amylases↗
PubMed1991

[Conformational-functional relationships of tetragastrin analogs].

Sets of low-energy backbone conformations of the active tetragastrin analogue Boc-Trp-Leu-Asp-Phe-NH2 and two competitive antagonists Boc-Trp-Leu psi (CH2NH)-Asp-Phe-NH2 and Boc-Trp-Leu-Asp-O-CH2-CH2-C6H5 were obtained using theoretical conformational analysis methods. Groups of the conformations were selected for the three analogues, allowing a spatial matching of Trp, Asp and Phe residues responsible for the gastrin receptor binding. Three conformations possessing the lowest energies among the geometrically similar structures of these three peptides are suggested as a model for the "receptor-bound" conformations of these analogues. Backbone spatial folding resembling an alpha-helix turn is characteristic of these conformations. The correspondence of the proposed model to the available data on structure--activity relationships for tetragastrin analogues is discussed. Orientations of the putative receptor-bound conformations in a "water--lypophylic medium" two-phase system were investigated.

Amino Acid Sequence↗
PubMed1991

[Effects of CR1505, a CCK antagonist, on pancreatic growth in hamsters].

The effects of CR1505, a CCK antagonist, on CCK-stimulated and normal pancreas were studied in Syrian golden hamsters. The CCK-stimulated trophic effect was inhibited by CR1505 in a dose-dependent manner, in which CR1505 100 mg/kg bw resulted in a complete inhibition of the weight of pancreas, the total pancreatic protein and DNA contents, compared to the control. Otherwise, CR1505 administration in doses of 25, 50, 100 mg/kg bw alone, didn't induce any significant changes among CR1505-treated groups and the control one. However, in the dose of 200 mg/kg bw, the weight of pancreas, the total pancreatic protein and DNA contents were significantly lower than control levels, suggesting pancreatic atrophy in the hamster. It's concluded that CR1505 is an effective CCK receptor antagonist that could inhibit the CCK-induced pancreatic trophic effect. Furthermore, CR1505 administration to normal pancreas brought out pancreatic atrophy, indicating that CCK seems to play an important role in the maintenance of normal pancreatic growth in hamsters.

Animals↗