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1.
Int J Mol Sci ; 23(3)2022 Feb 08.
Article in English | MEDLINE | ID: mdl-35163821

ABSTRACT

Nonalcoholic steatohepatitis (NASH) is associated with obesity, metabolic syndrome, and dysbiosis of the gut microbiome. Cholecystokinin (CCK) is released by saturated fats and plays an important role in bile acid secretion. CCK receptors are expressed on cholangiocytes, and CCK-B receptor expression increases in the livers of mice with NASH. The farnesoid X receptor (FXR) is involved in bile acid transport and is a target for novel therapeutics for NASH. The aim of this study was to examine the role of proglumide, a CCK receptor inhibitor, in a murine model of NASH and its interaction at FXR. Mice were fed a choline deficient ethionine (CDE) diet to induce NASH. Some CDE-fed mice received proglumide-treated drinking water. Blood was collected and liver tissues were examined histologically. Proglumide's interaction at FXR was evaluated by computer modeling, a luciferase reporter assay, and tissue FXR expression. Stool microbiome was analyzed by RNA-Sequencing. CDE-fed mice developed NASH and the effect was prevented by proglumide. Computer modeling demonstrated specific binding of proglumide to FXR. Proglumide binding in the reporter assay was consistent with a partial agonist at the FXR with a mean binding affinity of 215 nM. FXR expression was significantly decreased in livers of CDE-fed mice compared to control livers, and proglumide restored FXR expression to normal levels. Proglumide therapy altered the microbiome signature by increasing beneficial and decreasing harmful bacteria. These data highlight the potential novel mechanisms by which proglumide therapy may improve NASH through interaction with the FXR and consequent alteration of the gut microbiome.


Subject(s)
Bacteria/classification , Non-alcoholic Fatty Liver Disease/drug therapy , Proglumide/administration & dosage , Receptors, Cytoplasmic and Nuclear/metabolism , Animals , Bacteria/genetics , Bacteria/isolation & purification , Disease Models, Animal , Gastrointestinal Microbiome/drug effects , Gene Expression Regulation/drug effects , Male , Mice , Mice, Inbred C57BL , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Non-alcoholic Fatty Liver Disease/chemically induced , Non-alcoholic Fatty Liver Disease/metabolism , Phylogeny , Proglumide/chemistry , Proglumide/pharmacology , Receptors, Cytoplasmic and Nuclear/chemistry
2.
J Neuroendocrinol ; 31(1): e12667, 2019 01.
Article in English | MEDLINE | ID: mdl-30521069

ABSTRACT

Sulphated cholecystokinin octapeptide (CCK-8s) is involved in feeding regulation as an anorexigenic neuropeptide in vertebrates. In rodents, i.c.v. administration of CCK-8s has been shown to affect not only feeding behaviour, but also psychomotor activity. However, there is still no information available concerning the psychophysiological effects of CCK-8s in goldfish. Therefore, in the present study, we examined the effect of synthetic goldfish (gf) CCK-8s on psychomotor activity in this species. Intracerebroventricular administration of gfCCK-8s at 0.1, 0.5 and 2.5 pmol g-1 body weight (BW) did not affect swimming distance (locomotor activity). Because goldfish prefer the lower to the upper area of a tank, we used this as a preference test (upper/lower test) to assess anxiety-like behaviour. Intracerebroventricular administration of gfCCK-8s at 2.5 pmol g-1 BW shortened the time spent in the upper area. The action of gfCCK-8s mimicked that of FG-7142 (the central-type benzodiazepine receptor inverse agonist, an anxiogenic agent) at 5 and 10 pmol g-1 BW. The anxiogenic-like effect of gfCCK-8s was abolished by treatment with the CCK receptor antagonist proglumide at 50 pmol g-1 BW. We also investigated the localisation of CCK/gastrin-like immunoreactivity in the goldfish brain. CCK/gastrin-like immunoreactivity was observed in the anxiety-related regions (the nucleus habenularis and the interpeduncular nucleus). These data indicate that gfCCK-8s potently affects psychomotor activity in goldfish, and exerts an anxiogenic-like effect via the CCK receptor-signalling pathway.


Subject(s)
Anxiety/physiopathology , Goldfish/physiology , Psychomotor Performance/physiology , Sincalide/physiology , Animals , Anxiety/chemically induced , Carbolines/administration & dosage , Female , Injections, Intraventricular , Locomotion/drug effects , Male , Proglumide/administration & dosage , Psychomotor Performance/drug effects , Sincalide/administration & dosage
3.
Drug Dev Res ; 78(2): 116-123, 2017 03.
Article in English | MEDLINE | ID: mdl-28370133

ABSTRACT

Preclinical Research The aim of the present study was to analyze the antihyperalgesic and antiallodynic interaction between the non-selective cholecystokinin (CCK) antagonist receptor, proglumide, and the selective cyclooxygenase-2 inhibitor, celecoxib in streptozotocin (STZ)-induced diabetic rats. Hyperalgesia was evaluated in the formalin test and tactile allodynia using von Frey filaments. Isobolographic analyses were employed to define the nature of the compound interactions, using a fixed dose ratio (0.5:0.5). Proglumide (20-160 mg/kg) and celecoxib (0.3-30 mg/kg) in these fixed dose ratio combinations induced dose-dependent antihyperalgesia and an antiallodynic effect in diabetic rats. ED40 values were calculated for the treatments and an isobologram was constructed. Theoretical ED40 values for combination proglumide-celecoxib estimated from the isobolograms for antihyperalgesic and antiallodynic activity (30.50 ± 1.90 mg/kg and 45.81 ± 4.55 mg/kg, respectively) were obtained, while experimental ED40 values for this antihyperalgesic and antiallodynic combined effect (13.83 ± 0.65 mg/kg and 17.74 ± 3.57 mg/kg; respectively) were significantly different. Coadministration of proglumide-celecoxib showed an interaction index value of 0.45 ± 0.03 for the antihyperalgesic effect and 0.39 ± 0.08 for the antiallodynic activity, indicating a synergistic interaction. These data suggest that proglumide and celecoxib can interact synergistically to reduce hyperalgesic and allodynic behaviors in diabetic neuropathy. This combination could be useful to treat neuropathic pain in diabetic patients. Drug Dev Res 78 : 116-123, 2017. ©2017 Wiley Periodicals, Inc.


Subject(s)
Celecoxib/administration & dosage , Diabetes Mellitus, Experimental/complications , Diabetic Neuropathies/drug therapy , Hyperalgesia/drug therapy , Proglumide/administration & dosage , Animals , Celecoxib/therapeutic use , Diabetes Mellitus, Experimental/chemically induced , Diabetic Neuropathies/etiology , Dose-Response Relationship, Drug , Drug Combinations , Drug Synergism , Hyperalgesia/etiology , Male , Proglumide/therapeutic use , Rats , Rats, Wistar , Streptozocin , Treatment Outcome
4.
World J Gastroenterol ; 21(25): 7742-53, 2015 Jul 07.
Article in English | MEDLINE | ID: mdl-26167074

ABSTRACT

AIM: To examine the effects of pancreatic rest, stimulation and rest/stimulation on the natural course of recovery after acute pancreatitis. METHODS: Acute hemorrhagic pancreatitis (AP) was induced in male rats by intraductal infusion of 40 µL/100 g body weight of 3% sodium taurocholate. All rats took food ad libitum. At 24 h after induction of AP, rats were divided into four groups: control (AP-C), pancreas rest (AP-R), stimulation (AP-S), and rest/stimulation (AP-R/S). Rats in the AP-C, AP-R and AP-S groups received oral administration of 2 mL/kg body weight saline, cholecystokinin (CCK)-1 receptor antagonist, and endogenous CCK release stimulant, respectively, twice daily for 10 d, while those in the AP-R/S group received twice daily CCK-1 receptor antagonist for the first 5 d followed by twice daily CCK release stimulant for 5 d. Rats without any treatment were used as control group (Control). Biochemical and histological changes in the pancreas, and secretory function were evaluated on day 12 at 24 h after the last treatment. RESULTS: Feeding ad libitum (AP-C) delayed biochemical, histological and functional recovery from AP. In AP-C rats, bombesin-stimulated pancreatic secretory function and HOMA-ß-cell score were significantly lower than those in other groups of rats. In AP-R rats, protein per DNA ratio and pancreatic exocrine secretory function were significantly low compared with those in Control rats. In AP-S and AP-R/S rats, the above parameters recovered to the Control levels. Bombesin-stimulated pancreatic exocrine response in AP-R/S rats was higher than in AP-S rats and almost returned to control levels. In the pancreas of AP-C rats, destruction of pancreatic acini, marked infiltration of inflammatory cells, and strong expression of α-smooth muscle actin, tumor necrosis factor-α and interleukin-1ß were seen. Pancreatic rest reversed these histological alterations, but not atrophy of pancreatic acini and mild infiltration of inflammatory cells. In AP-S and AP-R/S rats, the pancreas showed almost normal architecture. CONCLUSION: The favorable treatment strategy for AP is to keep the pancreas at rest during an early stage followed by pancreatic stimulation by promoting endogenous CCK release.


Subject(s)
Cholecystokinin/metabolism , Pancreas/metabolism , Pancreatitis/metabolism , Administration, Oral , Animals , Biomarkers/blood , Bombesin/administration & dosage , Cell Proliferation , DNA Replication , Disease Models, Animal , Esters , Gabexate/administration & dosage , Gabexate/analogs & derivatives , Guanidines , Hormone Antagonists/administration & dosage , Insulin Resistance , Male , Pancreas/drug effects , Pancreas/pathology , Pancreas/physiopathology , Pancreatic Function Tests , Pancreatitis/chemically induced , Pancreatitis/diagnosis , Pancreatitis/drug therapy , Pancreatitis/pathology , Pancreatitis/physiopathology , Proglumide/administration & dosage , Proglumide/analogs & derivatives , Rats, Wistar , Receptor, Cholecystokinin A/antagonists & inhibitors , Receptor, Cholecystokinin A/metabolism , Recovery of Function , Taurocholic Acid , Time Factors
5.
Fiziol Zh (1994) ; 57(1): 66-71, 2011.
Article in Ukrainian | MEDLINE | ID: mdl-21516835

ABSTRACT

We investigated the influence of long-term diminishing of gastric acid secretion in rats by H(+)-K(+)-ATPase omeprasole on the gastrin blood level and the basal gastric acid secretion. We performed an experimental analysis of possible prophylactic drugs of structural and functional changes in gastric mucosa evoked by hypergastrinemia. It was shown that following 28 days of omeprazole injections the blood gastrin level and the output of basal acid secretion increased by 189.3% and 173.9-283.7%, respectively. It was concluded that an augmentation of the output of basal acid secretion results from the development of parietal cells hyperplasia evoked by trophic action of gastrin. We also show here that agonists of nuclear peroxisome proliferator activator receptors pioglytasone and melanin effectively prevent the changes in gastric acid secretion as an index of morphological changes.


Subject(s)
Anti-Ulcer Agents/pharmacology , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/pathology , Gastrins/blood , Omeprazole/pharmacology , Animals , Anti-Ulcer Agents/administration & dosage , Anti-Ulcer Agents/adverse effects , Anti-Ulcer Agents/therapeutic use , Drug Therapy, Combination , Gastric Mucosa/metabolism , Hyperplasia/prevention & control , Male , Melanins/administration & dosage , Melanins/pharmacology , Melanins/therapeutic use , Omeprazole/administration & dosage , Omeprazole/adverse effects , Omeprazole/therapeutic use , Pioglitazone , Proglumide/administration & dosage , Proglumide/pharmacology , Proglumide/therapeutic use , Rats , Thiazolidinediones/administration & dosage , Thiazolidinediones/pharmacology , Thiazolidinediones/therapeutic use , Time Factors
6.
Pharmacol Biochem Behav ; 98(2): 220-6, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21163296

ABSTRACT

Cannabinoid CB1 receptor and cholecystokinin-1 (CCK(1)) receptors are located in peripheral nerve terminals of the gut, where they mediate satiety signals. Here we describe a detailed analysis of the interaction of both receptors in the control of feeding of food-deprived rats. Male Wistar rats were deprived for food 24h before testing. Rats were pre-treated with SR141716A (Rimonabant) or WIN 55,212-2 before CCK-8 sulphated administration and tested for food intake 60, 120 and 240 min after last drug injection. In parallel, the effect of Lorglumide--a CCK(1) receptor antagonist--pre-treatment was evaluated on feeding behaviour after SR141716A administration. Results show that SR141716A activates c-Fos expression in brainstem areas receiving vagal inputs. Blockade of CB1 receptors with SR141716A (1 mg/kg) reduces feeding and display additive satiety induction with the CCK(1) receptor agonist CCK-8 sulphated (5, 10, 25 µg/kg). The effect of SR141716A is not blocked by Lorglumide (10 mg/kg), indicating independent sites of action. Conversely, the administration of the CB1 agonist WIN 55,212-2 (2 mg/kg) reduced satiety induced by CCK-8. In conclusion, these results report additive anorectic actions for CCK1 activation and peripheral CB1 receptor blockade providing a framework for combined therapies in the treatment of eating disorders.


Subject(s)
Feeding Behavior/drug effects , Feeding Behavior/physiology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Sincalide/administration & dosage , Animals , Anorexia/etiology , Anorexia/physiopathology , Benzoxazines/administration & dosage , Brain/drug effects , Brain/physiology , Drug Synergism , Gene Expression/drug effects , Genes, fos/drug effects , Male , Morpholines/administration & dosage , Naphthalenes/administration & dosage , Piperidines/administration & dosage , Proglumide/administration & dosage , Proglumide/analogs & derivatives , Pyrazoles/administration & dosage , Rats , Rats, Wistar , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/physiology , Receptor, Cholecystokinin B/antagonists & inhibitors , Rimonabant
7.
Regul Pept ; 143(1-3): 56-63, 2007 Oct 04.
Article in English | MEDLINE | ID: mdl-17462749

ABSTRACT

Ghrelin, a 28-amino-acid peptide produced predominantly by oxyntic mucosa has been reported to affect the pancreatic exocrine function but the mechanism of its secretory action is not clear. The effects of intraduodenal (i.d.) infusion of ghrelin on pancreatic amylase outputs under basal conditions and following the stimulation of pancreatic secretion with diversion of pancreato-biliary juice (DPBJ) as well as the role of vagal nerve, sensory fibers and CCK in this process were determined. Ghrelin given into the duodenum of healthy rats at doses of 1.0 or 10.0 microg/kg increased pancreatic amylase outputs under basal conditions or following the stimulation of pancreatic secretion with DPBJ. Bilateral vagotomy as well as capsaicin deactivation of sensory fibers completely abolished all stimulatory effects of luminal ghrelin on pancreatic exocrine function. Pretreatment with lorglumide, a CCK(1) receptor blocker, reversed the stimulation of amylase release produced by intraduodenal application of ghrelin. Intraduodenal ghrelin at doses of 1.0 or 10.0 microg/kg increased plasma concentrations of CCK and ghrelin. In conclusion, ghrelin given into the duodenum stimulates pancreatic enzyme secretion. Activation of vagal reflexes and CCK release as well as central mechanisms could be implicated in the stimulatory effect of luminal ghrelin on the pancreatic exocrine functions.


Subject(s)
Amylases/metabolism , Pancreas/drug effects , Peptide Hormones/pharmacology , Animals , Capsaicin/administration & dosage , Capsaicin/pharmacology , Cholecystokinin/blood , Duodenum/drug effects , Duodenum/metabolism , Ghrelin , Humans , Male , Pancreas/enzymology , Pancreas/metabolism , Peptide Hormones/administration & dosage , Proglumide/administration & dosage , Proglumide/analogs & derivatives , Proglumide/pharmacology , Radioimmunoassay , Rats , Rats, Wistar , Receptor, Cholecystokinin A/antagonists & inhibitors , Vagotomy
8.
Vet Res Commun ; 31(8): 1021-36, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17279465

ABSTRACT

The effects of intravenous infusion of proglumide on regular ruminal contractions were examined in conscious sheep using doses that inhibit pancreatic exocrine secretion. After a control period of 20 min, proglumide was infused intravenously for 40 min at a dose of 15, 30 or 60 micromol/kg per min and venous blood was collected. The intravenous infusion of proglumide significantly increased the frequency of ruminal contractions at 15 micromol/kg per min without altering the amplitude, while it significantly decreased the frequency and amplitude of ruminal contractions at 30 and 60 micromol/kg per min in a dose-dependent manner. Proglumide did not increase contractile activity of the omasum, abomasum and duodenum or the plasma concentration of immunoreactive cholecystokinin (CCK). Application of proglumide at 1-30 mmol/L inhibited bethanechol-induced contraction in both longitudinal and circular muscle strips of the dorsal sac of the rumen. These results suggest that proglumide at a low dose acts indirectly on the rumen as a CCK receptor antagonist to increase the frequency of contractions, whereas at higher doses it inhibits cholinergic-induced contraction of the ruminal muscles or acts as an agonist to inhibit contractions in sheep. Hence, proglumide at high doses seems unsuitable for research or therapeutic use as a CCK receptor blockade in sheep.


Subject(s)
Gastrointestinal Motility/drug effects , Muscle Contraction/drug effects , Proglumide/pharmacology , Rumen/drug effects , Sheep/physiology , Abomasum/drug effects , Abomasum/physiology , Animals , Cholecystokinin/blood , Duodenum/drug effects , Duodenum/physiology , In Vitro Techniques , Infusions, Intravenous/veterinary , Male , Omasum/drug effects , Omasum/physiology , Proglumide/administration & dosage , Receptors, Cholecystokinin/antagonists & inhibitors , Rumen/physiology , Transducers, Pressure/veterinary
9.
Neuropharmacology ; 52(3): 788-95, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17157334

ABSTRACT

The effects of cholecystokinin (CCK-8) and the CCK receptor antagonist proglumide, on antinociception induced by local peripheral (subcutaneous) injected morphine in non-diabetic (ND) and streptozotocin-induced diabetic (D) rats, were examined by means of the formalin test. Morphine induced dose-dependent antinociception both in ND and D rats. However, in D rats, antinociceptive morphine potency was about twofold less than in ND rats. Pre-treatment with CCK-8 abolished the antinociceptive effect of morphine in a dose-dependent manner in both groups of rats. Additionally, proglumide enhanced the antinociceptive effect induced by all doses of morphine tested. Both CCK-8 and proglumide had no effect on flinching behaviour when given alone to ND rats. Unlike ND rats, in D rats proglumide produced dose-dependent antinociception and CCK-8 enhanced formalin-evoked flinches, as observed during the second phase of the test. In conclusion, our data show a decrease in peripheral antinociceptive potency of morphine when diabetes was present. Additionally, peripheral CCK plays an antagonic role to the peripheral antinociceptive effect of morphine, additional to the well known CCK/morphine interaction at spinal and supraspinal level.


Subject(s)
Cholecystokinin/metabolism , Morphine/therapeutic use , Narcotics/therapeutic use , Neuralgia/drug therapy , Animals , Area Under Curve , Cholecystokinin/administration & dosage , Cholecystokinin/antagonists & inhibitors , Diabetes Mellitus, Experimental/complications , Dose-Response Relationship, Drug , Drug Interactions , Formaldehyde/adverse effects , Male , Neuralgia/etiology , Pain Measurement , Pain Threshold/drug effects , Peptide Fragments/administration & dosage , Proglumide/administration & dosage , Rats , Rats, Wistar
10.
J Physiol Pharmacol ; 58 Suppl 6: 81-95, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18212402

ABSTRACT

UNLABELLED: Melatonin, known as a product of pineal gland is also produced in the digestive system. Melatonin receptors have been detected on pancreatic beta cells and this indoloamine influences the endocrine pancreatic function but the role of melatonin on pancreatic exocrine secretion is not known. AIM: To evaluate the effects of intraduodenal administration of melatonin or its precursor L-tryptophan on pancreatic protein output under basal conditions or following the stimulation of exocrine pancreas with diversion of pancreato-bliliary juice (DBPJ) and to assess the involvement of vagal nerves, and CCK in this process. METHODS: Under pentobarbiturate anesthesia the Wistar rats weighting 300g were surgically equipped with silicone catheters, one of them was inserted into pancreato-biliary duct, the other one--into duodenum. Melatonin (1, 5 or 25 mg/kg) or L-tryptophan (10, 50 or 250 mg/kg) were administered to the rats as intraduodenal (i.d.) bolus injection. Bilateral vagotomy was performed in the group of animals 7 days before the experiment. To assess the role of CCK in the melatonin or L-tryptophan-induced pancreatic secretory functions, lorglumide, the CCK(1) receptor antagonist was administered at dose of 1 mg/kg i.d. 15 minutes before the application of examine substances. During the study samples of pancreato-biliary juice were collected in 15 minutes aliquots to measure the protein outputs. RESULTS: Melatonin (1, 5, or 25 mg/kg ) or L-tryptophan (10, 50 or 250 mg/kg) produced significant and dose-dependent increases in pancreatic protein secretion under basal conditions or following the stimulation of this secretion by DBPJ. This was accompanied by a dose-dependent rise in CCK plasma level. Stimulation of pancreatic protein outputs caused by melatonin or L-tryptophan was completely abolished by vagotomy, or pretreatment with lorglumide. We conclude that melatonin as well as its precursor L-tryptophan, stimulates pancreatic exocrine function via mechanisms involving enteropancreatic reflexes and CCK.


Subject(s)
Melatonin/pharmacology , Pancreas, Exocrine/drug effects , Tryptophan/pharmacology , Vagus Nerve/drug effects , Animals , Cholecystokinin/blood , Dose-Response Relationship, Drug , Duodenum/metabolism , Male , Melatonin/administration & dosage , Melatonin/blood , Pancreas, Exocrine/metabolism , Pancreatic Juice/metabolism , Proglumide/administration & dosage , Proglumide/analogs & derivatives , Proglumide/pharmacology , Rats , Rats, Wistar , Receptor, Cholecystokinin A/antagonists & inhibitors , Receptor, Cholecystokinin A/physiology , Tryptophan/blood , Vagotomy , Vagus Nerve/physiology
11.
World J Gastroenterol ; 11(17): 2549-51, 2005 May 07.
Article in English | MEDLINE | ID: mdl-15849809

ABSTRACT

AIM: Patients with advanced stage cardiac adenocarcinoma have a very poor prognosis. Surgery is the first choice of treatment for this kind of patients. Peptide hormone gastrin is a recognized growth factor for gastric cancer, and gastrin receptor antagonist proglumide can block the effects of gastrin. The aim of this study was to investigate the actions of proglumide as an adjuvant treatment to improve the postoperative long-term survival rate of patients with cardiac adenocarcinoma. METHODS: We performed a randomized, controlled study of gastrin receptor antagonist proglumide in 301 patients with cardiac adenocarcinoma after proximal subtotal gastrectomy. The oral dose of 0.4 g proglumide thrice daily preprandially was maintained for more than 5 years in 153 cases (proglumide treatment group). In the control group, 148 patients underwent operation only. In clinicopathologic features, there was no significant difference between the two groups (P>0.05). All patients were followed up during their lifetime, and the survival rates were analyzed combined with clinicopathologic factors by SPSS 11.5 statistical software. RESULTS: The 1, 3, 5 and 10-year survival rate of the patients was 88.4%, 48.8%, 22.6% and 13.4%, respectively. The 1, 3, 5 and 10-year survival rate of the proglumide treatment group was 90.2%, 49.7%, 26.8% and 17.6% compared to 86.5%, 48.0%, 18.2% and 8.9% of the control group. There was a significant difference between the two groups (P = 0.0460). The patients in proglumide treatment group had no obvious side effects after administration of the drug, and no definite hepatic and renal function damage was found. According to single factor log-rank analysis, the long-term survival rate was correlated with the primary tumor position (P = 0.0205), length of the tumor (P = 0.0000), property of the operation (P = 0.0000), histopathologic grading (P = 0.0003), infiltrating degree of the tumor (P = 0.0000), influence of lymph node metastasis (P = 0.0000), clinicopathologic staging (P = 0.0000) and administration of proglumide (P = 0.0460). Cox regression analysis demonstrated the infiltrating degree of tumor (P = 0.000), influence of lymph node metastasis (P = 0.039) and the clinicopathologic staging (P = 0.003) were independent prognostic factors. Administration of proglumide (P = 0.081), length of the tumor (P = 0.304), radical status of the resection (P = 0.224) and histopathologic types (P = 0.072) were not the independent prognostic factors. CONCLUSION: Proglumide is convenient to use with no obvious toxic side effects, and prolonged postoperative administration of proglumide as a postoperative adjuvant treatment can increase the survival rate of patients after resection of cardiac adenocarcinoma. Proglumide may provide a new effective approach of endocrinotherapy for patients with gastric cardiac cancer.


Subject(s)
Adenocarcinoma/drug therapy , Anti-Ulcer Agents/administration & dosage , Heart Neoplasms/drug therapy , Proglumide/administration & dosage , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Combined Modality Therapy , Female , Heart Neoplasms/mortality , Heart Neoplasms/surgery , Humans , Male , Middle Aged , Prospective Studies
12.
Endokrynol Pol ; 56(6): 933-8, 2005.
Article in English | MEDLINE | ID: mdl-16821214

ABSTRACT

The role of gastrins and their receptors in the pathogenesis of colon cancer has been discussed for many years but it still remains unresolved. Although fluorouracil (FU) remains to be reference chemotherapy for colon cancer, its efficacy is unsatisfactory. Recently, we have shown a synergistic effect of proglumide (a non-selective blocker of cholecystokinin-gastrin receptors) applied together with FU, on the proliferation and apoptosis of transplantable Colon 38 cancer cells in vivo. The aim of this study was to examine direct effects of proglumide (10(-5)-10(-10) M) applied either alone or together with FU (0.25, 2.5 and 25 microg/ml) on the proliferation of murine Colon 38 cancer cells in vitro. Cell proliferation was assessed by the modified colorimetric Mosmann method. Proglumide inhibited the proliferation of Colon 38 cells at the concentrations of 10(-6), 10(-8) and 10(-10) M. FU inhibited the proliferation of cancer cells in all studied concentrations, exerting the most profound antiproliferative effect at the concentrations of 2.5 and 25 microg/ml. Thus, the former concentration was chosen to study its interactions with proglumide. Proglumide applied together with FU exerted a synergistic effect on the inhibition of proliferation of Colon 38 cells at 10(-8), 10(-9), 10(-10) M concentrations. The most profound inhibitory effect was observed in the group incubated with FU and 10(-10) M of proglumide. The obtained results indicate a possibility of new therapeutic options for colon cancer, but further studies are needed to elucidate, if the synergistic effect of FU and proglumide occurs also in the colon cancer in humans.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cell Proliferation/drug effects , Colonic Neoplasms/drug therapy , Fluorouracil/administration & dosage , Proglumide/administration & dosage , Analysis of Variance , Animals , Apoptosis/drug effects , Cell Division/drug effects , Colonic Neoplasms/pathology , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , In Vitro Techniques , Mice , Tumor Cells, Cultured
13.
Pancreas ; 27(4): e90-5, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14576503

ABSTRACT

The purpose of this study was to test the hypothesis that circulating ethanol at concentrations of approximately 0.1 mg% stimulates pancreatic secretion. Awake rats recovered from surgery were used in these experiments. Intravenous infusion protocols were established that produced blood ethanol concentrations 0.1 mg% for over an hour. Maintenance of 0.1 mg% blood ethanol concentration or transient concentrations as high as 0.17 mg% did not cause significant increases in pancreatic protein or fluid secretion. To test whether elevated blood ethanol would augment stimulated pancreatic secretion, the trypsin inhibitor camostat was infused intraduodenally at doses of 0.05, 0.2, and 0.5 mg/hr, each dose level infused for 2 hours. Elevated blood ethanol concentrations (0.1 mg%) did not significantly affect camostat-stimulated pancreatic protein or fluid secretion. In contrast to intravenous infusion, intraduodenal infusion of ethanol significantly stimulated pancreatic protein and fluid secretion, which was associated with blood ethanol concentrations of > or =0.19 mg%. The increases in pancreatic secretion were completely blocked by intravenous infusion of the cholecystokinin (CCK) receptor antagonist CR1409. We conclude that circulating ethanol does not stimulate pancreatic secretion in awake, recovered rats and that intraduodenal ethanol-stimulated pancreatic secretion is mediated by CCK.


Subject(s)
Ethanol/blood , Gabexate/analogs & derivatives , Pancreas/metabolism , Proglumide/analogs & derivatives , Animals , Consciousness , Dose-Response Relationship, Drug , Duodenum , Esters , Ethanol/administration & dosage , Gabexate/administration & dosage , Guanidines , Infusions, Intravenous/methods , Infusions, Parenteral , Male , Pancreas/drug effects , Proglumide/administration & dosage , Rats , Rats, Wistar , Receptors, Cholecystokinin/antagonists & inhibitors , Time Factors
14.
Clin J Pain ; 19(3): 200-1, 2003.
Article in English | MEDLINE | ID: mdl-12792559

ABSTRACT

AIM: To investigate the potential pro-analgesic effect of the non-specific CCK antagonist proglumide on the analgesia produced by dihydrocodeine. METHOD: A double-blind, placebo-controlled crossover study of 30 adult subjects. RESULTS: Mean pain scores fell from a baseline of 8.12-7.89 during the placebo phase (N.S.) and to 6.82 during the proglumide phase (P < 0.05). Side effects were minor. CONCLUSION: The CCK antagonist proglumide enhances the analgesic effect of dihydrocodeine.


Subject(s)
Codeine/analogs & derivatives , Codeine/administration & dosage , Pain/drug therapy , Proglumide/administration & dosage , Adult , Aged , Analgesics/administration & dosage , Cholecystokinin/antagonists & inhibitors , Chronic Disease , Cross-Over Studies , Double-Blind Method , Drug Synergism , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Placebo Effect , Treatment Outcome
15.
Pancreas ; 26(1): 87-91, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12499923

ABSTRACT

INTRODUCTION AND AIM: To examine the involvement of cholecystokinin (CCK) in the basal pancreatic exocrine, we investigated the effect of loxiglumide (CR1505), a CCK1 receptor antagonist, on basal pancreatic exocrine secretion in conscious rats. METHODOLOGY: After the basal collection of pancreatic juice for 1 hour, loxiglumide (10 mg/kg/h) or saline was infused via the femoral vein continuously for 2 hours. RESULTS: Loxiglumide significantly suppressed the basal pancreatic protein and amylase outputs. However, loxiglumide did not alter the basal pancreatic juice volume. CONCLUSIONS: These results demonstrate that loxiglumide suppresses basal pancreatic exocrine secretion in normal rats. They also suggest that CCK is involved in basal pancreatic exocrine in conscious rats and that loxiglumide may be useful as a therapeutic agent for pancreatitis, even during fasting, by attenuating the basal pancreatic exocrine burden on the pancreas.


Subject(s)
Hormone Antagonists/pharmacology , Islets of Langerhans/metabolism , Proglumide/analogs & derivatives , Proglumide/pharmacology , Receptors, Cholecystokinin/antagonists & inhibitors , Amylases/metabolism , Animals , Hormone Antagonists/administration & dosage , Infusions, Intravenous , Islets of Langerhans/drug effects , Kinetics , Male , Pancreatic Juice/metabolism , Proglumide/administration & dosage , Proteins/metabolism , Rats , Rats, Sprague-Dawley , Receptor, Cholecystokinin A , Receptors, Cholecystokinin/physiology , Wakefulness
16.
Pancreas ; 25(1): e1-5, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12131781

ABSTRACT

INTRODUCTION: Cholecystokinin (CCK)-receptor antagonists have been found to markedly reduce the severity of pancreatitis and improve survival in experimental animal models of acute pancreatitis. CCK appears to play an important role in the development and progression of acute pancreatitis, and the recent development of CCK antagonists has provided a new approach to the treatment of acute pancreatitis in humans. AIMS: The therapeutic efficacy of a CCK-A receptor antagonist, loxiglumide, in patients with painful acute attacks of chronic pancreatitis was evaluated. METHODOLOGY: A multicenter dose-response controlled trial was conducted at 110 institutions in Japan from June 1993 to December 1994. Chronic pancreatitis was diagnosed for all patients on the basis of the Japanese criteria for chronic pancreatitis. Two-hundred seven patients were randomized to oral treatment with loxiglumide (300, 600, and 1,200 mg/d) or placebo for 4 weeks. The efficacy of treatment was evaluated on the basis of clinical symptoms, physical signs, and serum pancreatic enzyme levels. The groups were comparable with respect to age, sex, etiology, complications, and previous treatment. RESULTS: The improvement rate of the abdominal and/or back pain was 46% in the loxiglumide 300-mg group, 59% in the 600-mg group, and 52% in the 1,200-mg group, and it was 36% in the placebo group (600 mg versus placebo: p < 0.05). The physical signs evaluated--abdominal tenderness and resistance--improved in all three loxiglumide groups, and the serum pancreatic amylase and trypsin levels decreased significantly in the 600-mg group (p < 0.05). The overall clinical improvement rate was 46% in the 300-mg loxiglumide group, 58% in the 600-mg group, and 52% in the 1,200-mg group, and it was 34% in the placebo group. CONCLUSION: These results indicate that oral administration of loxiglumide may be useful in the treatment of patients with acute, painful attacks of chronic pancreatitis, and 600 mg/d is recommended as a beneficial dosage.


Subject(s)
Hormone Antagonists/administration & dosage , Pancreatitis/drug therapy , Proglumide/analogs & derivatives , Proglumide/administration & dosage , Acute Disease , Administration, Oral , Adult , Amylases/blood , Chronic Disease , Female , Humans , Lipase/blood , Male , Middle Aged , Pain/etiology , Pancreatitis/blood , Pancreatitis/complications , Receptor, Cholecystokinin A , Receptors, Cholecystokinin/antagonists & inhibitors , Treatment Outcome , Trypsin/blood
17.
Pol J Vet Sci ; 5(1): 35-42, 2002.
Article in English | MEDLINE | ID: mdl-11944584

ABSTRACT

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.


Subject(s)
Duodenum/physiology , Gastrointestinal Motility/drug effects , Hormone Antagonists/pharmacology , Hydrocortisone/blood , Proglumide/analogs & derivatives , Proglumide/pharmacology , Sheep/physiology , Animals , Catheterization/veterinary , Cerebral Ventricles , Electromyography/veterinary , Hormone Antagonists/administration & dosage , Proglumide/administration & dosage
18.
Neoplasma ; 48(2): 133-8, 2001.
Article in English | MEDLINE | ID: mdl-11478694

ABSTRACT

It is well known that 5-fluorouracil (5-FU) is the most effective drug in the treatment of colon cancer, however the positive response is small, only about 20%. On the other hand, it has been postulated that the growth of colon cancer depends on many growth factors, such as gastrin and estrogens. The search for new substances increasing the antitumor effect of 5-FU has lasted for many years. The aim of the present study was to examine the effects of pentagastrin (PEN, syntetic gastrin analogue), proglumide (PRO, a blocker of gastrin receptor) and tamoxifen (TAM, a partial estrogen antagonist) given separately or together with 5-FU on proliferation, apoptosis, necrosis and proliferation/apoptosis (P/A) ratio in the murine transplantable Colon 38 cancer. The male mice were implanted with a suspension of Colon 38 cells. After 7 days, the animals were treated with PEN (250 microg/kg b.w., twice daily), PRO (100 mg/kg. b.w., twice daily), TAM (10 microg/animal) separately or together with 5-FU (60 mg/kg b.w., once) for 2 days. The incorporation of bromodeoxyuridine (BrdU) into cell nuclei was used as an index of cell proliferation (labeling index--LI). The in situ labeling of nuclear DNA fragmentation according to TUNEL method was considered as an apoptotic index (AI). It was found that 5-FU increased the apoptosis, unexpectedly increased the LI and decreased the P/A ratio when compared to control. Both PEN and PRO increased the apoptosis and in the case of PRO decreased P/A ratio when compared to control. TAM did not affect any of the examined parameters. All of the investigated substances modify the 5-FU action: PEN and PRO on AI and LI and TAM on AI and P/A ratio. Necrosis was observed in 3 tumors treated with PEN + 5-FU, in 2 tumors of PRO + 5-FU group and in 1 tumor of group with 5-FU and with PEN. Further studies are needed to elucidate if those modification of 5-FU action by the examined substances will be useful in the inhibition of the growth of Colon 38 cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/drug therapy , Fluorouracil/therapeutic use , Pentagastrin/therapeutic use , Proglumide/therapeutic use , Tamoxifen/therapeutic use , Animals , Apoptosis/drug effects , Bromodeoxyuridine , Cell Division/drug effects , Colonic Neoplasms/pathology , Fluorouracil/administration & dosage , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Pentagastrin/administration & dosage , Proglumide/administration & dosage , Tamoxifen/administration & dosage
19.
Scand J Gastroenterol ; 36(3): 241-6, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11305509

ABSTRACT

BACKGROUND: Increased gastric emptying and defective action of endogenous cholecystokinin (CCK), that is known to inhibit this emptying, have been implicated in the pathogenesis of duodenal ulcer (DU). The aim of this double blind study was to assess whether CCK and somatostatin participate in the impairment of gastric motility in active DU patients before and after Helicobacter pylori eradication. METHODS: Tests were undertaken in 10 DU patients without or with elimination of the action of endogenous CCK using loxiglumide, a selective CCK-A receptor antagonist, before and 4 weeks after eradication of H. pylori with 1 week triple therapy that resulted in healing of all DUs tested. The gastric emptying rate after feeding was determined using the 13C-acetate breath test. Before each test, samples of gastric juice were obtained by aspiration using a nasogastric tube for determination of somatostatin using specific radioimmunoassay. RESULTS: Prior to H. pylori eradication gastric emptying half-time was 31 +/- 6 min in placebo-treated DU patients and this emptying rate was not significantly affected in tests after pretreatment with loxiglumide (10 mg/kg i.v.). Following eradication of H. pylori, in tests with placebo gastric emptying half-time was significantly longer (48 +/- 9 min) compared to that prior to H. pylori eradication. Pretreatment with loxiglumide in H. pylori eradicated DU patients significantly enhanced the gastric emptying rate with an emptying half-time of only 33 +/- 4 min. Eradication of H. pylori resulted in a significant increase in somatostatin concentration in gastric juice and loxiglumide significantly reduced this luminal somatostatin in H. pylori-eradicated subjects compared to values before anti-H. pylori therapy. CONCLUSIONS: 1) H. pylori infection in DU patients is accompanied by enhanced gastric emptying and reduction in luminal release of somatostatin; 2) the failure of loxiglumide to affect gastric emptying in H. pylori-infected DU patients might be attributed, at least in part, to the failure of endogenous CCK to control gastric motility due to deficient release of somatostatin; and 3) H. pylori-infected patients appear to exhibit a deficient somatostatin release by endogenous CCK that can be reversed by the eradication of H. pylori indicating that both CCK and somatostatin may contribute to normalization of gastric emptying following H. pylori eradication in DU patients.


Subject(s)
Cholecystokinin/metabolism , Duodenal Ulcer/drug therapy , Gastric Emptying/physiology , Helicobacter Infections/drug therapy , Helicobacter pylori/drug effects , Proglumide/administration & dosage , Adolescent , Adult , Analysis of Variance , Cholecystokinin/drug effects , Duodenal Ulcer/microbiology , Follow-Up Studies , Gastric Emptying/drug effects , Gastric Mucosa , Gastrins/blood , Gastroscopy , Helicobacter Infections/diagnosis , Helicobacter pylori/isolation & purification , Hormone Antagonists/administration & dosage , Humans , Injections, Intravenous , Male , Postprandial Period , Probability , Proglumide/analogs & derivatives , Reference Values , Sensitivity and Specificity , Somatostatin/analysis , Somatostatin/drug effects , Sucralfate/administration & dosage , Treatment Outcome
20.
Am J Physiol Regul Integr Comp Physiol ; 279(1): R189-95, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10896881

ABSTRACT

Cholecystokinin (CCK) interacts with neural signals to induce satiety in several species, but the mechanisms are unclear. We therefore tested the hypothesis that alimentary CCK (CCK-A) receptors mediate the interaction of CCK with an appetizer on food intake in humans. CCK octapeptide (CCK-8, 0.75 microgram infused over 10 min) or saline (placebo) with concomitant infusions of saline (placebo) or loxiglumide, a specific CCK-A antagonist, was infused into 16 healthy men with use of a double-blind, four-period design. All subjects received a standard 400-ml appetizer (amounting to 154 kcal) but were free to eat and drink thereafter as much as they wished. The effect of these infusions on feelings of hunger and satiety and on food intake was quantified. CCK-8 induced a reduction in calorie intake (P < 0.05) compared with saline. Furthermore, a decrease in hunger feelings (P < 0.05, saline-CCK-8 vs. all other treatments) and an increase in fullness were observed. These effects were antagonized for hunger and fullness by loxiglumide. We conclude that CCK-8 interacts with an appetizer to modulate satiety in humans. These effects are mediated by CCK-A receptors.


Subject(s)
Cholecystokinin/blood , Eating/physiology , Proglumide/analogs & derivatives , Receptors, Cholecystokinin/metabolism , Satiety Response/physiology , Adult , Cross-Over Studies , Double-Blind Method , Eating/drug effects , Energy Intake/drug effects , Energy Intake/physiology , Humans , Hunger/drug effects , Hunger/physiology , Infusions, Intravenous , Male , Proglumide/administration & dosage , Receptor, Cholecystokinin A , Receptors, Cholecystokinin/antagonists & inhibitors , Satiety Response/drug effects , Sincalide/administration & dosage
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