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PubMed1990

Proglumide analogues CR 1409 and CR 1392 inhibit cholecystokinin-stimulated insulin release more potently than exocrine secretion from the isolated perfused rat pancreas.

The effects of proglumide-related cholecystokinin (CCK) receptor antagonists CR 1409 and CR 1392 on CCK-octapeptide (CCK-8)-stimulated immunoreactive insulin (IRI) release and exocrine secretion were examined simultaneously in the isolated perfused rat pancreas. The CR 1409, at concentrations of 10-100 nM, significantly inhibited CCK-8 (100 pM) stimulation on IRI release but failed to inhibit the stimulatory effect of CCK-8 on both pancreatic juice flow and protein secretion. Increasing concentrations of CR 1409 inhibited both CCK-8-stimulated IRI release and exocrine secretion. Half-maximal inhibition was observed with approximately 2 nM for IRI release and 1 microM for protein secretion. When a higher dose (1 nM) of CCK-8 was used, the inhibitory effect of 10 nM CR 1409 on CCK-8-stimulated IRI release was abolished, whereas 10 microM CR 1409 retained significant inhibitory effect. Furthermore, 1 microM carbachol-induced IRI release was not altered by the addition of 10 microM CR 1409. The CR 1392 also had an inhibitory effect on both CCK-8-stimulated IRI release and exocrine secretion. The concentration of CR 1392 that caused half-maximal inhibition of CCK-8-stimulated IRI release was 300 times lower than that of exocrine secretion. In addition, 1 microM carbachol-stimulated IRI release was not altered by 100 microM CR 1392. Thus, the inhibitory effects of CR 1409 and CR 1392 on IRI release were mediated through the interaction at the CCK receptor and were more potent than those on juice and protein secretion. This study suggests, therefore, that CCK receptors on B cells might be different from those on acinar cells in terms of their relative affinities for antagonists.

Animals↗
PubMed1985

Mechanism of pancreatic growth induced by pancreatico-biliary diversion in the rat. Inhibition by proglumide, benzotript, and ranitidine.

Pancreatico-biliary diversion (PBD) stimulates pancreatic growth in the rat. The present experiment was designed to investigate the mechanism of this phenomenon. The potential roles of endogenous CCK, gastrin, and secretin were studied. Hormone measurements by specific RIA's show that PBD was associated with higher CCK plasma concentrations and, conversely, with lower gastrin circulating levels. Secretin and pancreatic polypeptide were unaffected by PBD. Seven days' subcutaneous administration of proglumide (1000 mg/kg/day), benzotript (100 mg/kg/day), two CCK and gastrin receptor antagonists, and Ranitidine (100 mg/kg/day) resulted in a significant inhibition of PBD-induced pancreatic growth, assessed by measurements of pancreatic weight, DNA, RNA and protein content. These results suggest, therefore, that CCK plays a central role in the development of the pancreatic adaptive response to PBD.

Adaptation, Physiological↗
PubMed1987

Influence of neural blockages and proglumide on rat pancreatic enzyme secretion in response to intraluminal fatty acid.

Effects of neural blockages on pancreatic enzyme secretion in response to infusing fatty acid into the lumen were investigated using anesthetized rats, equipped with bile-pancreatic and duodenal cannulae, to evaluate the relative contribution of the neural and the hormonal mediations in the pancreatic response. Oleate (0.2 ml) was injected as a bolus into the rat duodenum, and the trypsin output in bile-pancreatic juice was monitored to determine the pancreatic enzyme secretion response with continuous return of bile-pancreatic juice to the intestine. When anticholinergic agents such as atropine sulfate and scopolamine were administrated, although basal level in pancreatic enzyme secretion fell, the increase of pancreatic enzyme secretion from basal level after stimulation by oleate was not significantly different from that of the control (no blockage). However, the ganglion blocker, hexamethonium, inhibited the pancreatic enzyme secretion in response to oleate by 94%. An adrenergic blocker, guanethidine, also led to as much of a decrease as the ganglion blocker-induced decrease. Adrenergic alpha- and beta-blockers partially, but not completely, inhibited the enzyme secretion. Adrenergic blockage also suppressed the basal level in pancreatic enzyme secretion. On the other hand, a specific CCK antagonist, proglumide, significantly inhibited pancreatic enzyme secretion induced by oleate in the presence of scopolamine. These observations suggest that pancreatic enzyme secretion in response to oleate is primarily mediated by CCK and that adrenergic modulation may play an important role in the CCK-mediated pancreatic enzyme secretion in response to oleate, although interpretation of these results may have some restriction related to anesthesia.

Adrenergic alpha-Antagonists↗
PubMed1976

[Stress ulcer and acute postoperative renal insufficiency. An attempt at preventive treatment with Solcoseryl and proglumide].

The study grouped 68 patients treated for severe post-operative or post-traumatic renal insufficiency, having survived over 7 days after being admitted into the Reanimation Department. A group of 32 patients were given systematic preventive treatment for nervous ulcers witch Solcoseryl and Proglumide. A control group of 36 patients received no specific treatment. Nervous ulcerations (showing up in gastrocopy) are found in three patients in the group receiving treatment, as compared with seven in the control group. This preventive treatment appears to be of interest, especially as other local or neuroleptic treatments are difficult to use in the group of patients concerned here.

Actihaemyl↗
PubMed2001

Effects of short term treatment with pentagastrin, proglumide, tamoxifen given separately or together with 5-fluorouracil on the growth in the murine transplantable Colon 38 cancer.

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.

Animals↗
PubMed1990

[The effect of proglumide on gallstone formation in guinea pigs].

In this study, the chronic effects of proglumide (PGM, a cholecystokinin/gastrin receptor antagonist) on gallstone formation and hepatic bile secretion were investigated as follows: Group 1: Fed with low protein (14%) lithogenic diet. Group 2: Fed with the same lithogenic diet and was given PGM (250 mg/kg, bid, p. o.). Group 3: Fed with commercial guinea pig chow (protein content 22%). Eight weeks later the animals were operated under urethane anesthesia, the gallbladders were removed and examined for gallstones. Meanwhile, by bile duct cannulation, the hepatic bile flow and bile contents were measured. It was found that: (1) the animal model was valid for the purpose specified; (2) the rate of gallstone formation was significantly lower in PGM group than in the controls (17.5% vs 56.8%, P less than 0.01); and (3) PGM significantly enhanced the flow rates and electrolyte contents and decreased the unconjugated bilirubin content of the hepatic bile. It is concluded that PGM may suppress gallstone formation in guinea pigs on lithogenic diet, and this may be related to its stimulatory effect on hepatic bile secretion and to its ability to induce a decrease in unconjugated bilirubin in the hepatic bile.

Animals↗
PubMed1990

[Effects of cholecystokinin, gastrin and proglumide on bile secretion in rats].

The aim of this study is to observe the effects of pentagastrin (P-Gas), CCK-8 and proglumide (PGM), which were used solely or in combination on choleresis in rats prepared with neck vein and hepatic-bile duct intubation. The results indicate that: 1) P-Gas does not provide cholecystic effect; 2) CCK-8 has a little stimulating effect on bile flow and output of bicarbonate; 3) PGM increases the bile flow and the outputs of biliary bicarbonate and chloride significantly, but it can not increase the bile acid output; 4) after administration of CCK-8 2.3 micrograms/(kg.h) iv infusion and PGM 200 mg ig in combination the outputs of bile flow, bicarbonates and chloride were greater than to PGM given alone, but after P-Gas 2 micrograms/(kg.h) was used together with PGM the outputs were less than to PGM given alone. The results suggest that PGM has a remarkable effect of choleresis and its mechanism may be attributed to bile acid independent fraction, while CCK-8 was only a weaker stimulant and P-Gas can not modify the bile flow and bile components. In addition, there may be a synergism effect between PGM and CCK-8 and an antagonist suppression between PGM and P-Gas on choleresis in the rat.

Animals↗
PubMed1989

[Inhibitory effect of a new proglumide derivative, loxiglumide, on CCK action in isolated rat pancreatic acini].

The effect of a new proglumide derivative, loxiglumide (DL-4-(3,4-dichloro-benzoyl-amino)-5-(N-3-methoxy-propyl-pentylamino+ ++)-5-oxo-pentanic acid; CR 1505), on binding of 125I-CCK-8 and amylase release stimulated by CCK-8 was investigated in isolated rat pancreatic acini. Loxiglumide inhibited CCK-8-stimulated amylase release and binding of 125I-CCK-8 to rat pancreatic acini in a dose-dependent manner. Loxiglumide caused a concentration-dependent rightward shift of the dose-response curve for CCK-8-stimulated amylase release without altering the maximal response. Schild plots showed a slope of 0.82 and pA2 value of 7.05. The inhibitory effect of loxiglumide on amylase release was reversible. Loxiglumide significantly inhibited amylase release in response to CCK-8, caerulein and gastrin-I. However, loxiglumide had no effect on amylase release stimulated by other receptor secretagogues (bombesin, carbamylcholine, secretion and vasoactive intestinal polypeptide) or by agents bypassing receptors (A23187 and TPA). These results indicate that loxiglumide acts as a potent, competitive and specific CCK antagonist on the pancreatic acini.

Amylases↗
PubMed1989

[Effect of proglumide (PGM) on bile flow and contents in humans and animals].

UNLABELLED: Proglumide (PGM) is a CCK/gastrin receptor antagonist. The purpose of this study was to observe the effect of PGM on bile flow and the outputs of bile contents in humans and animals. METHODS: 1) In patients who had undergone cholecystectomy, bile was collected through T tubes during fasting at 15 min intervals before (control) and after PGM 1.2 ingestion. Drinking water test was done under the same conditions. 2) Dogs and rats were fasted overnight, and the common bile duct was cannulated for bile collection. PGM was given intravenously in bolus. Bile flow, electrolytes, cholesterol, bilirubin, total bile acid, protein and lecithin (content) were measured in humans and dogs. The values were expressed as value per 15 min and compared with control using the Student's t-test. The results show: bile flow, outputs of HCO-3, K+, Na+, CI-, Ca++, cholesterol, bilirubin, total bile acid and protein levels all increased remarkably after PGM administration. In rats, the bile flow increased in a dose response manner between PGM dosages of 100, 200, 400 mg/kg (r = 0.795, P less than 0.001 at 15-30 min). We conclude that PGM has a choleretic effect in human as well as in animals of different species.

Adult↗
PubMed1989

[Treatment of peptic ulcer using proglumide (Milid)].

20 patients with peptic gastric ulcer and 30 patients with peptic duodenal ulcer were treated with Milid (Proglumid). The following results were achieved: in 85% of the patients with peptic gastric ulcer and in 93% of the patients with duodenal ulcer the pain was relieved on the 4th day on the average. In 95-96% of the patients treated the dyspeptic complaints disappeared on the 2-3 day. The endoscopic examination performed on the 20th day revealed full epithelization of the ulcer in 30% of the patients with gastric ulcer and in 43.3% of the patients with duodenal ulcer. Following the treatment course the basic secretion and acid production fell statistically significantly in the patients with gastric ulcer while in the patients with duodenal ulcer the basic and stimulated secretion and acid production were suppressed. The drug Milid does not change the serum gastrin level but suppresses the gastrin secretion in the gastric juice. The Milid treatment leads to an increase of the quantity of the N-acetylneuraminic acid in the gastric juice which partly reflects the cytoprotective action of Milid. The drug can be used in the everyday practice for the treatment of peptic ulcer.

Adult↗
PubMed1989

[Effect of proglumide on choleresis in rats].

We are the first to report that proglumide (PGM) has a marked effect on promoting choleresis in rats. After iv infusion PGM 50, 100, 200, 400 mg/(kg.h), the bile quantities of 120-150 min were 0.4 +/- 0.14, 0.46 +/- 0.11, 0.75 +/- 0.25, 0.87 +/- 0.21 ml/30 min, respectively. They were significantly higher values than either basic bile flow (0.24 +/- 0.06 ml/30 min) or the solvent control of 5% NaHCO3 (0.22 +/- 0.13 ml/30 min, P less than 0.01) and obviously dose-dependent. After ig PGM 200 mg, bile flow observed at the peak of secretion between 60-90 min was 0.67 +/- 0.22 ml/30 min. Compared to that observed before PGM administration, the bile fluid collected was found to have increased 1.7-3.2 times, up to even 7 times. The choleretic effect continued 8-12 h after the infusion was terminated. The secretions of HCO3- and chlorides in the bile also increased during PGM infusion as compared with the control (P less than 0.05-0.01). On the contrary, the concentrations of cholic acids decreased remarkably (P less than 0.05-0.01). It is suggested that the mechanism of choleresis promoted by the infusion of PGM may be cholic acid-independent, but that it is related to the secretion of inorganic salts in cholangiole. Compared with three other choleretics commonly used clinically, phenylpropanol, dehydrocholic acid and sodium taurocholate, the effect of PGM is significantly superior (P less than 0.01).

Animals↗
PubMed1987

Inhibition of pentagastrin-stimulated up-regulation of gastrin receptors and growth of mouse colon tumor in vivo by proglumide, a gastrin receptor antagonist.

We have recently demonstrated that gastrin stimulates growth of mouse colon cancer (MC-26) in vivo by regulation of gastrin receptors (GR). In the present study, we have tested the effect of proglumide (PGL), a GR antagonist, on the trophic and GR-regulatory effects of gastrin on MC-26 tumors. Four groups of 12 mice each were inoculated with 5 X 10(4) MC-26 cells and given injections of either normal saline (control), pentagastrin (PG), PGL, or both PG + PGL for 21 days. At the end of the treatment period, body, tumor, fundic, and colon weights were noted and GR measured. Two types of specific gastrin-binding sites were found on tumor cell membranes of control mice, one with high binding affinity (Kd = less than 1.0 nM) and low capacity (GR), and the other with a very high capacity and a low affinity (Kd = greater than 0.1 microM) (type 2 gastrin-binding sites). Only the type 1 GR were observed on the fundic mucosal and colon membranes. PG treatment resulted in a significant weight increase of the tumors with an up-regulation of only type 1 GR. On the other hand, PG had no significant effect on fundic mucosal and colonic GR levels, but caused a significant increase in fundic mucosal weights. PGL completely inhibited both the trophic and GR up-regulatory effects of PG on tumors, but incompletely reduced the PG-stimulated fundic mucosal weight gain, indicating differential sensitivity of tumor and normal tissues to PGL. PGL, in the absence of PG, was slightly trophic for normal fundic mucosa, but had no effect on MC-26 tumors and normal colon. The one striking effect of PGL, in the presence of PG, was the significant lowering of the binding affinity of type 1 GR for gastrin on both the tumor and normal gastrointestinal tissues. This effect may be another mechanism by which PGL interferes with the actions of PG on MC-26 tumors and fundic mucosa of mice.

Animals↗
PubMed1979

Pharmacokinetic approach to proglumide long-term activity.

In order to explain the long-term therapeutic activity of (+/-)-4-benzamide-N,-di-n-propylglutaramic acid (proglumide, Milid) a pharmacokinetic study was carried out in rats by three administration routes. As a result, experimental data could have been fitted to a tri- or tetra-exponential equation, with terminal half-life of about 24 h. Since human pharmacokinetics was found to be rather similar to that in rats, it can be extrapolated that steady state plasma level of drug during therapeutic dosage regimen should range around 60% of peak level of single administration.

Animals↗
PubMed1993

[A study on the mechanism of the choleretic effect of proglumide].

It has been found in this laboratory that proglumide (PGM) can increase hepatic bile flow in humans and in several species of animals, and lower gallstone formation in experimental animals. In order to further investigate the mechanisms of this choleretic effect of PGM, studies with isolated rat liver cells and plasma membranes were performed. The results indicated that PGM could increase the activity of membrane Na+, K(+)-ATPase significantly. On the other hand, PGM decreased the net uptake of 14C-glycocholic acid by rat liver cells. These data suggest that the choleretic effect of PGM is likely to be mediated through the enhancement of membrane Na+, K(+)-ATPase activity (which would in turn increase water and electrolyte output), rather than by affecting bile acid uptake by liver cells. It was also observed that PGM could reverse the inhibitory effect of somatostatin on the activity of membrane Na+, K(+)-ATPase. These results provide some clues for the elucidation of the mechanisms of the inhibitory effect of PGM on gallstone formation in experimental animals.

Animals↗
PubMed1987

Biological effects of a proglumide derivative as cholecystokinin antagonist in conscious dogs.

In conscious dogs we studied the effects of a new cholecystokinin (CCK) antagonist (coded CR 1505) on CCK8-stimulated exocrine pancreatic secretion and release of pancreatic polypeptide (PP). Graded doses of CCK8 (25-400 ng kg-1h-1) were infused i.v. Experiments were repeated against a background infusion of CR 1505 at different doses (0.1, 1 and 10 mg kg-1h-1). The lowest dose of CR 1505 had no biological effects. However, at the upper two doses the compound significantly inhibited the CCK8-stimulated PP release. Furthermore, a significant inhibition of exocrine pancreatic protein secretion was observed with 10 mg kg-1h-1 of CR 1505 (P less than 0.05). The results suggest that CR 1505 could be a useful tool in defining the physiological role of CCK in vivo.

Animals↗