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PubMed1979

[Effective out-patient treatment of gastric ulcer with proglumide: preliminary results (author's transl)].

In a double-blind trial 16 persons with gastric ulcer and 35 with duodenal ulcer were treated as out-patients with 1200 mg proglumide daily or 1320 mg magnesium tricilicate daily (as an "active placebo") for four weeks. The ulcers were assessed by endoscopy before and after treatment. The gastric ulcers disappeared in 75% of patients receiving proglumide (six of eight subjects) but in only 25% of those on the placebo (two of eight). There was no significant effect of proglumide on duodenal ulcers (17 in the proglumide and 18 in the placebo groups). Proglumide failed to affect either basal or maximally stimulated acid secretion, nor was there any change in the serum gastrin level. There were no side effects during proglumide administration. This underlines its therapeutic value in the treatment of gastric ulcer, in comparison with cimetidine or carbenoxolone.

Adult↗
PubMed1987

Proglumide, a cholecystokinin antagonist, increases gastric emptying in rats.

Injection of cholecystokinin (CCK) reduces food intake and delays gastric emptying. We have previously shown that endogenous CCK also reduces food intake. This may be achieved by a delay in gastric emptying. We investigated the role of CCK in gastric emptying by inhibiting the actions of CCK released by a meal, using a CCK antagonist, proglumide. We postulated that inhibition of CCK should induce an increase in gastric emptying. Gastric emptying was determined in rats by a marker dilution technique using direct gastric intubation. Proglumide (150 mg/kg) significantly accelerated emptying of liquid food by 12.8% (P less than 0.005, n = 12) when injected intraperitoneally following a food preload. Proglumide injected before feeding was ineffective. Oral proglumide, which inhibited gastrin-stimulated acid secretion, was also ineffective. We concluded that proglumide increased gastric emptying by acting on a factor released by the preload, and since proglumide is a specific antagonist, this factor was probably CCK. Therefore CCK may play a physiological role in the regulation of gastric emptying.

Administration, Oral↗
PubMed1987

Proglumide stimulates basal pancreatic secretion in the conscious rat.

The effect of proglumide, a glutaramic acid derivative, on pancreatic secretion was examined in vivo in the conscious rat with and without the return of bile-pancreatic juice (BPJ) to the intestine. Intravenous infusion of both 300 and 60 mg/kg proglumide significantly decreased protein output in a dose-related manner during BPJ diversion, but did not completely abolish the pancreatic hypersecretory response to BPJ diversion. Conversely, during basal secretion with BPJ being returned to the intestine, 300 mg/kg/h of proglumide increased the protein output. Dibutyryl cyclic GMP infused simultaneously with proglumide did not abolish the stimulatory effect of proglumide on basal secretion. It was concluded that proglumide inhibits pancreatic protein output during stimulated secretion by means of the luminal feedback mechanism but increases protein output during basal (BPJ returned) secretion in the conscious rat.

Animals↗
PubMed1985

Potentiation of systemic morphine analgesia in humans by proglumide, a cholecystokinin antagonist.

Proglumide, a cholecystokinin antagonist, potentiates analgesia produced in rats by morphine and endogenous opiates, and appears to reverse tolerance in rats to opiate analgesia. Therefore, proglumide and other cholecystokinin antagonists may be clinically valuable. We have tested proglumide's possible opiate analgesic potentiating effects by examining, in volunteers, the effects of morphine and proglumide on human pain visual analogue scale responses to 45-51 degrees C skin temperature stimuli. Proglumide (50-100 micrograms intravenously) potentiated both the magnitude and duration of analgesia produced by small doses of morphine. This study provides indirect evidence for a cholecystokinin-opiate interaction in humans. Therefore, cholecystokinin antagonists such as proglumide may serve to potentiate exogenous or endogenous opiate action.

Adult↗
PubMed1981

[Duodenal ulcer - multicenter double-blind study with proglumide].

In a randomised multicenter double blind study we investigated the healing-rate with proglumid and an antacid drug, studying 70 in- and outpatients with florid duodenal ulcer. We evaluated the size and depth of 59 chronic duodenal ulcers in 52 patients with endoscopic and x-ray-investigations before and after four-week-treatment. Inpatients of the proglumid-group had a significant higher healing-rate than inpatients in the antacid-group (95% against 70%, p less than 0.05). As found in endoscopy the outpatients in the proglumid-group had a higher healing-rate, but because of the smaller number of patients the difference was not significant. Summarized the in- and outpatients, the proglumid-group had a healing-rate of 83%, the antacid-group of 60% (p less than 0.05). Bigger ulcers with a size more than 120 mm2 at the beginning showed a significant better healing with proglumid than with the antacid-drug (t/2 = 14.6 resp. 24.6 days). With x-ray-examination we could not find differences of healing between the two groups, but younger patients often were not examined. The symptoms of patients did not show a significant difference during the healing-course. We could not find any side-effects. Proglumid is an effective drug for the healing of chronic duodenal ulcers.

Adult↗
PubMed1993

Effects of proglumide and enprostil on omeprazole-induced fundic endocrine cell hyperplasia in rats.

Long-term treatment with omeprazole induces hyperplasia of enterochromaffin-like cells, closely related to hypergastrinemia. We studied whether proglumide, an antagonist of gastrin/CCK receptor, and enprostil, a synthetic prostaglandin E2 derivative, might inhibit this hyperplasia. Six groups of 8 rats were treated for 10 weeks: a) untreated controls; b) omeprazole 10 mumol/kg; c) proglumide 500 mg/kg; d) enprostil 30 micrograms/kg; e) association of omeprazole and proglumide; f) association of omeprazole and enprostil. Serum gastrin levels were measured at different times during treatment. After sacrifice, fundic argyrophil cells were assessed by Grimelius' staining. Serum gastrin levels and argyrophil cell density were not modified in proglumide- and enprostil-treated groups, as compared with controls. Omeprazole increased significantly these two parameters. When given with omeprazole, proglumide decreased significantly serum gastrin levels and argyrophil cell density, as compared to omeprazole alone, while enprostil did not modify significantly these two parameters. These results indicate that proglumide, but not enprostil, can counteract the omeprazole-induced argyrophil cell hyperplasia in rats.

Animals↗
PubMed1998

The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain.

UNLABELLED: The analgesic efficacy of morphine is sometimes only partial in patients with chronic benign pain. Among the possible factors contributing to this limitation are increased levels of cholecystokinin (CCK). We performed this prospective, placebo-controlled, double-blind, cross-over study to examine the effect of proglumide, a nonspecific CCK agonist, on analgesia in patients taking morphine on a chronic basis. Forty patients with intractable pain who were taking sustained-release morphine were recruited, and we obtained results from 36 of these patients. Median visual analog scale scores before the study were 8 and 7 after the addition of placebo for 2 wk (P = 0.16), and 6 after proglumide for 2 wk (P = 0.002). Mobility was unchanged by proglumide or placebo. Of the 36 patients, 13 elected to continue receiving proglumide after the study. We conclude that proglumide enhances the analgesia produced by morphine in some, but not all, patients with chronic benign pain. IMPLICATIONS: The pain-killing effect of morphine is incomplete in some patients. Increasing doses may be needed to maintain the initial effect. The peptide cholecystokinin may be partially responsible for this. In this study, we demonstrated that the cholecystokinin antagonist proglumide increases the analgesic effect of morphine in some patients with chronic benign pain.

Adult↗
PubMed1987

Differential effects of proglumide on mesolimbic and nigrostriatal dopamine function.

Cholecystokinin octapeptide (CCK-8) is prevalent as a co-transmitter in the mesolimbic dopamine pathway. The effect of proglumide, a CCK-8 antagonist, on two acute and one chronic behavioral models of dopamine function was tested. First, haloperidol was used to inhibit stereotypies induced by apomorphine in rats. Pre-administration of proglumide significantly shifted the haloperidol dose response curve to the left. Second, rats were injected in the left caudate nucleus with kainic acid. Three weeks later, haloperidol was used to inhibit apomorphine-induced circling. Pre-administration of proglumide had no effect on this haloperidol dose response curve. Third, either proglumide, haloperidol, or combined treatment was administered to rats for 2 weeks. In proglumide-treated animals, a significant increase in 3H-spiperone binding sites in the nucleus accumbens was observed.

Animals↗
PubMed1986

Proglumide (gastrin and cholecystokinin receptor antagonist) inhibits insulin secretion in vitro.

CCK-8 and its desulfated analog (des-CCK-8) increase insulin secretion from isolated rat pancreatic islets in the presence of 8.3 mM glucose in a concentration-dependent manner. Proglumide (DL-4-benzamido-N,N-dipropylglutaramic acid), a gastrin and cholecystokinin (CCK) receptor antagonist, inhibits the synergistic effect of CCK on insulin release in the presence of 8.3 mM glucose; its EC50 (half-maximal effective concentration) was 1.2 +/- 0.4 mM. Its effect is specific in that it does not inhibit the glucose- or GIP (glucose dependent insulinotropic peptide) induced insulin secretion to a major degree. CCK-8, des-CCK-8 and proglumide compete for binding of 125I-CCK-33 to rat pancreatic islets; the IC50 of proglumide was 0.8 mM. The affinity of proglumide is in the range of both its EC50 for inhibition of insulin secretion and its IC50 in other in vitro systems tested so far (exocrine pancreas, gall bladder, cortex). Its inhibitory effect presumably is not a gastrin antagonizing effect since gastrin does not stimulate insulin secretion. The data therefore indicate that proglumide should be monitored for diabetic effects in vivo.

Animals↗
PubMed1994

CCK-receptor antagonists proglumide and loxiglumide stimulate bile flow and biliary glutathione excretion.

The mechanism for the choleresis induced by CCK-receptor antagonists, proglumide, loxiglumide, and CR 1409, was examined in anesthetized rats and compared to the effects of CCK itself. These agents were infused intravenously over a 2-hr period, and bile flow, and biliary excretion of bicarbonate, total bile acids, and glutathione were measured in 30-min intervals. All three antagonists produced a dose-dependent choleresis, but a significant decrease in bile acid excretion, indicating that they stimulate bile flow via a bile acid-independent mechanism. The increase in bile flow was associated with a parallel increase in biliary glutathione and bicarbonate output in rats treated with proglumide and loxiglumide. In animals pretreated with acivicin to inhibit gamma-glutamyltransferase activity, proglumide was shown to stimulate biliary excretion of reduced glutathione (GSH), but not glutathione disulfide (GSSG), indicating the absence of oxidative stress in the liver. GSH output was increased by only 0.5-0.9 mumol/30 min after infusion of proglumide at a dose of 75 mg/kg/hr, whereas bile volume was increased 0.2-0.4 ml/30 min, indicating that this increased biliary GSH excretion can account for only a small fraction of the increased bile volume, given an osmotic efficiency for GSH of 34 microliters/mumol. In contrast to CCK receptor antagonists, CCK itself had no effect on bile flow and outputs of bicarbonate, GSH, and bile acids, suggesting that the effects of the antagonists are not related to their interaction with CCK receptors. These findings demonstrate that proglumide and loxiglumide stimulate a bile acid-independent bile flow that is only partially explained by an increase in GSH excretion.

Animals↗
PubMed1988

Proglumide antagonizes cholecystokinin effects on plasma glucose and insulin in rats in vivo.

Proglumide was shown to possess a low affinity for cholecystokinin (CCK) receptors and to inhibit the synergistic action of CCK8 on glucose-mediated insulin release in vitro. Proglumide (400 mg/kg i.p., given 15 min before an i.v. combination of CCK8 and glucose) reversed the CCK8 (0.5 nmol/kg)-induced increase of plasma insulin levels and decrease of glucose levels. It had no effect on plasma insulin and glucose levels when the glucose bolus was administered alone. Camostate (400 mg/kg p.o.; Foy-305; a trypsin inhibitor acting via endogenously released CCK) increased plasma insulin levels by 10 microU/ml during an oral glucose (500 mg/kg) tolerance test. Pretreatment with proglumide (400 mg/kg i.p.) antagonized this effect. The data indicate that proglumide has an antagonistic effect on either exogenously added or endogenously released CCK with respect to plasma insulin and glucose levels and that it has no effect on plasma insulin and glucose levels when glucose is given alone. Therefore, proglumide and the newly developed, more potent CCK receptor antagonists are able to disturb insulin and glucose homoeostasis.

Animals↗
PubMed1987

The effects of the cholecystokinin antagonist, proglumide, on prolactin secretion in the rat.

Since cholecystokinin produced important effects on prolactin secretion following its intraventricular injection in ovariectomized rats, we have evaluated the effects of the cholecystokinin antagonist, proglumide, to assess the physiologic significance of CCK in the control of prolactin release. Conscious rats of either sex were used following implantation of third ventricular and/or intravenous cannulae for the administration of proglumide. Blood samples were drawn from conscious animals at various times after injection of the compound. Intraventricular injection of 1 or 10 micrograms of proglumide produced a dramatic decline in plasma prolactin levels in either castrate or intact male rats. Similar results were found following the intravenous injection of 10 or 100 micrograms of the drug. These results contrasted sharply with the findings in ovariectomized females in which the intraventricular injection of the same two doses of proglumide used in males produced a dose-related elevation of prolactin which was opposite to the delayed lowering of prolactin following the intravenous injection of the same doses of the compound used in males. These results indicate that proglumide can lower prolactin in male rats and suggests a physiologically significant role of CCK in the control of prolactin secretion in the male. There appears to be a sex difference in the response since the results contrasted sharply in ovariectomized female rats. The results in the females are puzzling and it is apparent that further studies are needed to determine whether or not CCK has a physiologically significant role to play in prolactin secretion in the female. Since previous results have shown that CCK has no effect on the release of prolactin by the pituitary directly these interactions are presumably taking place in the hypothalamus.

Animals↗
PubMed1984

Effect of proglumide, a cholecystokinin receptor antagonist, on caerulein-stimulated pancreatic enzyme secretion and pancreatic polypeptide release in the dog.

In five conscious dogs we studied the effect of proglumide, a cholecystokinin (CCK) antagonist, on caerulein-stimulated pancreatic secretion and release of pancreatic polypeptide (PP). Graded doses of caerulein (15-240 ng/kg per h) were infused intravenously. Experiments were repeated with a fixed infusion of proglumide (40 mg/kg per h). Release of PP following increasing doses of caerulein was significantly inhibited by proglumide (P less than 0.01). However, proglumide did not significantly affect caerulein-stimulated pancreatic protein secretion. Proglumide might be useful in defining the physiological role of CCK.

Animals↗
PubMed1985

The effect of vagotomy on the increase in food intake induced by the cholecystokinin antagonist, proglumide.

Cholecystokinin, secreted when ingested food enters the duodenum, may act as a satiety factor. Injection of proglumide, a specific antagonist of cholecystokinin, induced an increase in food intake. The satiety effect of administered cholecystokinin is abolished by bilateral subdiaphragmatic vagotomy. If endogenous and exogenous cholecystokinin act via the same mechanism, then vagotomy should abolish the proglumide-induced increase in food intake. Proglumide was used to block the satiety effect of a food preload in sham-operated and vagotomized rats. Proglumide induced an increase in food intake in sham-operated rats confirming earlier results. No change in meal size was observed in vagotomized rats following proglumide injection. These results suggest that vagotomy abolishes the effect of endogenous cholecystokinin on food intake. However, evidence of dumping in vagotomized rats prevents the interpretation of the data as a direct vagal involvement in endogenous CCK-induced satiety.

Animals↗
PubMedDate not supplied

Blocking of cholecystokinin octapeptide behavioral effects by proglumide.

An open field apparatus was used to assess the effect of proglumide, a selective antagonist of cholecystokinin octapeptide (CCK-8), to block the behavioral effect of CCK-8 in rats. Intracerebroventricular (ICV) injection of CCK-8 (0.5 to 2 micrograms) was effective in suppressing general exploratory activities and this effect was blocked by proglumide at doses of 2 to 5 micrograms administered ICV or 1 mg/kg administered subcutaneously. The effect of peripherally administered CCK-8 (10 micrograms/kg) was blocked by peripherally administered proglumide at a dose of 2 mg/kg but not by centrally administered proglumide at a dose of 5 micrograms/rat. The behavioral effect of CCK-8 was thus clearly blocked by proglumide.

Animals↗
PubMedDate not supplied

Proglumide fails to increase food intake after an ingested preload.

Proglumide, a selective antagonist of exogenous cholecystokinin in vitro, also inhibits the reduction of food intake induced by the systemic administration of cholecystokinin octapeptide (CCK-8) in food deprived rats. On the basis of an increase in the size of a brief test meal which followed an oral preload and treatment with a single dose of proglumide, it was suggested that a role for endogenous cholecystokinin in satiety had been demonstrated. We attempted to replicate this finding and could not under very similar experimental conditions. Subsequently, we tested whether other proglumide doses would antagonize the satiating effect of a larger oral preload on test meal intake. When these results were also found to be negative, we confirmed that proglumide (at several doses) significantly antagonized the reduction in food intake induced by exogenous CCK-8 under our conditions. Since proglumide antagonized the satiating effect of exogenous CCK-8, but did not increase food intake after oral preloads that were presumed to release endogenous CCK, we conclude that a reliable satiating effect of endogenous CCK remains to be demonstrated.

Animals↗
PubMed1988

Two proglumide analogues are equipotent antagonists of the inhibition of food intake by CCK-8.

The reduction in food intake produced by exogenous CCK-8 (8 micrograms.kg-1, IP) in 18 hr food-deprived rats was significantly reversed by either of two proglumide analogues at doses of 0.44 and 4.4 microM.kg-1. The two glutamic acid derivatives tested were CR-1409 [N-(3,4-dichlorobenzoyl)-L-glutamic acid-1-di-n-pentylamide], effective at doses of 0.2 and 2.0 mg.kg-1, IP, and PGDPA [N-(phenoxyacetyl)-L-glutamic acid-1-di-n-propylamide], effective at the equimolar doses of 0.16 and 1.6 mg.kg-1, IP, as well as at 16 mg.kg-1 (44 microM.kg-1). By comparison, proglumide reversed the inhibition of food intake by CCK-8 at 160 mg.kg-1 (470 microM.kg-1), but not at 16 mg.kg-1 (47 microM.kg-1). At the 0.44 microM.kg-1 dose which antagonized CCK-8-induced satiety, neither PGDPA nor CR-1409 reduced the inhibition of food intake induced by bombesin, supporting the behavioral specificity of these CCK antagonists. Previous in vitro studies have shown that CR-1409 was approximately 4000-fold more potent than proglumide and PGDPA was 100-fold more potent than proglumide as antagonists of CCK-8-induced amylase secretion and binding in pancreatic acinar cells. Here, we found no potency difference between PGDPA and CR-1409; each was more than 1000-fold more potent than proglumide as an antagonist of the inhibition of food intake produced by CCK-8. This nonparallelism between the potencies of these antagonists at CCK receptors located upon pancreatic acinar cells and at CCK receptors involved in CCK-8-induced satiety suggests that the two receptor populations differ pharmacologically.

Animals↗
PubMed1991

Hypnotic action of flunitrazepam is reversed by proglumide in rats.

1. Caerulein, an analogue of cholecystokinin (CCK-8), like CCK-8, has been shown to produce hypnotic effects similar to those of benzodiazepine (flunitrazepam). 2. Proglumide antagonizes the action of CCK-8 and of its analogue. 3. The aim of the present study was to demonstrate whether proglumide would affect the potent hypnotic action of flunitrazepam in rats. 4. The association of proglumide with flunitrazepam suppress the increase of total sleep time and slow wave sleep seen after flunitrazepam alone. Proglumide alone has no effect on sleep stages. The authors report here for the first time that the hypnotic action of flunitrazepam is antagonized by proglumide in rat.

Animals↗