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At least 109 records · Page 6Linked to original sources
PubMed1984

Cholecystokinin tetrapeptide, proglumide and open-field behavior in rats.

The effect of cholecystokinin tetrapeptide (CCK-4) was studied in an open field situation. CCK-4 increased locomotion and rearing and the effect was enhanced by proglumide, a selective antagonist of CCK-8. This is in sharp contrast to our earlier findings that CCK-8 decreased the open-field behavior and that proglumide completely blocked the effect. Thus, the effects of CCK-4 and CCK-8 appear to be opposite to each other in that one is excitatory and the other inhibitory to open-field responses.

Animals↗
PubMed1986

Does the cholecystokinin antagonist proglumide possess antipsychotic activity?

Cholecystokinin (CCK), a neuropeptide which fulfills almost all criteria for neurotransmitter status, has been co-localized with dopamine in midbrain mesolimbic and mesocortical neurons that have been implicated in the pathogenesis of schizophrenia. Preclinical research suggests that CCK may in part act to enhance central dopaminergic activity. In an attempt to evaluate the role of CCK relative to the dopamine hyperactivity hypothesis of schizophrenia, in the present investigation the putative CCK receptor antagonist, proglumide, was administered to four schizophrenic patients in a double-blind, placebo-controlled study. All patients were receiving concurrent neuroleptic medication, but were still significantly symptomatic. Proglumide was without effect on the patients' psychosis ratings. Potential reasons for this negative finding are discussed.

Adult↗
PubMed1984

The cholecystokinin antagonist, proglumide, increases food intake in the rat.

Cholecystokinin, secreted in response to ingested food entering the duodenum, may play a role in limiting food intake. Inhibition of cholecystokinin should therefore induce an increase in food intake. Proglumide, a specific antagonist of cholecystokinin was used to block the satiety effect of a food preload in rats. A significant increase in food intake was obtained following proglumide injection, thus supporting the hypothesis that cholecystokinin, released by food in the duodenum, acts as a short-term satiety factor.

Animals↗
PubMed1992

Inhibition of gastrin-stimulated growth of gastrointestinal tumour cells by octreotide and the gastrin/cholecystokinin receptor antagonists, proglumide and lorglumide.

The rat pancreatic cell line, AR42J possessed high-affinity gastrin and somatostatin receptors and its growth was stimulated by physiological gastrin-17 concentrations between 5 x 10(-11) mol/l and 10(-9) mol/l as measured by [75Se]selenomethionine uptake. The somatostatin analogue, octreotide (2 x 10(-7) to 2 x 10(-11) mol/l), reduced this stimulated growth. Gastrin-stimulated AR42J growth was also inhibited by proglumide (3 x 10(-4) mol/l) and lorglumide (3 x 10(-5) mol/l) at maximal G17 concentrations of 5 x 10(-11) and 10(-10) mol/l, respectively, and the analogues competed with [125I] gastrin-17 (5 x 10(-10) mol/l) for binding to gastrin receptors on AR42J (50% inhibitory concentrations, less than or equal to 10(-3) mol/l and 4 x 10(-6) mol/l, respectively. Octreotide reduced the basal growth of the human gastric cell line, MKN45G, (which is associated with intracellular gastrin immunoreactivity) in serum-free medium to 73% of control at a concentration of 2 x 10(-8) mol/l, which was reversed by gastrin-17 (10(-10) mol/l). Lorglumide (3 x 10(-5) mol/l) also reduced the basal growth to 30% of control, which was reversed to 78% by 10(-5) mol/l gastrin. Proglumide had no effect on the basal growth of MKN45G.

Animals↗
PubMed1985

Caerulein-induced acute necrotizing pancreatitis in mice: protective effects of proglumide, benzotript, and secretin.

The onset, course, and regression of the biochemical and structural alterations associated with pancreatitis induced by various doses of caerulein were studied in the mouse. In addition, the protective effect of secretin was compared with that of the cholecystokinin-receptor antagonists proglumide and benzotript. Subcutaneous or intraperitoneal injections of caerulein induced increases in serum amylase concentration and pancreatic weight and histologic evidence of acute pancreatitis, all effects being dose-related. Cytoplasmic vacuoles were the earliest histologic alterations. As the pancreatitis progressed these vacuoles increased to an enormous size. Interstitial inflammation and acinar cell necrosis were prominent after 6 h, reached a maximum after 12 h, and mostly disappeared after 4 days. During the course of pancreatitis approximately 40% of the acinar cells showed signs of severe degeneration or necrosis at the most effective doses of caerulein. Electron microscopy showed both intact and degenerating granules inside the vacuoles. Signs of basolateral exocytosis of zymogen granules were not observed. During the regression of pancreatitis, focal atrophy was a remarkable histologic finding. Repetitive initiation of pancreatitis (six courses of caerulein injections over 5 wk) produced marked focal atrophy and early fibrosis. High doses of proglumide or benzotript markedly ameliorated both the biochemical and structural alterations induced by caerulein. Secretin, even at very high doses, had only minor protective effects. This study presents a model of acute necrotizing pancreatitis in which the severity of the induced pancreatitis ranges dose-dependently from mild interstitial inflammation to severe necrosis. The ultrastructural alterations described herein support the hypothesis that the trigger mechanism of acute pancreatitis appears to be a primary intracellular event rather than an interstitial event that secondarily damages the acinar cells.

Acute Disease↗
PubMed1984

Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide.

Exogenous cholecystokinin selectively antagonizes opiate analgesia, which suggests that endogenous cholecystokinin may act physiologically as an opiate antagonist and may play a role in opiate tolerance. The use of the selective cholecystokinin antagonist proglumide provided a test of these hypotheses in rats that were either inexperienced with or tolerant to opiates. Proglumide potentiated analgesia produced by morphine and endogenous opiates and seemed to reverse tolerance. These results suggest that endogenous cholecystokinin systems oppose the action of opiates.

Analgesia↗
PubMed1985

Proglumide analogues: potent cholecystokinin receptor antagonists.

Proglumide [N-(benzoyl)-L-glutamic acid-1-di-n-propylamide] is a specific cholecystokinin receptor antagonist. In the present study we synthesized various analogues of proglumide and used pancreatic acini from guinea pig pancreas to examine the abilities of these analogues to function as cholecystokinin receptor antagonists. Each analogue inhibited cholecystokinin octapeptide-stimulated amylase secretion but did not stimulate amylase secretion when present alone. There was a close correlation between the ability of a particular analogue to inhibit the action of cholecystokinin on acinar cell function and its ability to inhibit binding of 125I-cholecystokinin. Structure-function studies demonstrated that neither the dipropylamide nor the benzoyl moieties are essential for inhibiting the action of cholecystokinin but that both groups are important in determining the inhibitory potency. Replacing the dipropylamide group with a hydroxyl group caused a 13-fold decrease in potency. Replacing the benzoyl moiety by an acetyl group caused a 30- to 40-fold decrease in inhibitory potency, whereas replacing the benzoyl moiety by a p-chlorophenoxyacetyl or phenoxyacetyl moiety caused a 75-fold increase in potency. Replacing both the dipropylamide moiety with a hydroxyl group and the benzoyl moiety with a phenoxyacetyl group resulted in a 5-fold decrease in inhibitory potency. Inhibition of cholecystokinin-stimulated amylase release by both the phenoxyacetyl and p-chlorophenoxyacetyl analogues was competitive in nature, fully reversible, and specific for those secretagogues that interact with the cholecystokinin receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1995

Proglumide, a cholecystokinin receptor antagonist, reduces neuroleptic action in Huntington's chorea.

In a pilot study, proglumide, a cholecystokinin receptor antagonist, was administered to 8 patients affected from Huntington's chorea under long-term haloperidol treatment. The effectiveness of haloperidol on chronic symptomatology was reduced by the concomitant administration of proglumide; the latter drug, when administered alone, did not modify the severity of chorea compared to placebo. Possible explanations of these results are discussed, stressing the modulatory role of CCK not only on the dopaminergic, but also on the GABAergic system.

Adolescent↗
PubMed1989

Effects of a new proglumide analogue CR 1392 on pancreatic exocrine secretion in the rat.

The effects of proglumide analogue. CR 1392, on pancreatic exocrine secretion were studied in the isolated pancreatic acini and the isolated perfused pancreata of rats. In the isolated acini, CR 1392 caused a parallel rightward shift of the dose-response curve for amylase secretion stimulated by cholecystokinin octapeptide (CCK-8). CR 1392 inhibited maximally stimulated amylase release by CCK-8 (100 pM) in a concentration-dependent manner, with a half maximal inhibition (ID50) at 8.0 +/- 0.6 microM. CR 1409, another proglumide analogue, also caused a concentration-dependent inhibition (ID50: 3.2 +/- 0.4 microM). Although CR 1409 was about 2.5-fold more potent than CR 1392 in inhibiting the stimulated amylase release, 1 mM CR 1409 caused 107.4 +/- 0.9% increase in amylase release, suggesting acinar cell damage. CR 1392 (1 mM) also caused 19.9 +/- 2.3% increase in amylase release, but was less toxic than CR 1409. The antagonism produced by CR 1392 was selective for CCK and had no effect on amylase release stimulated by other receptor secretagogues or by agents bypassing receptors. CR 1392 added 20 min after the CCK-8 stimulation rapidly abolished pancreatic exocrine secretion in both isolated acini and isolated perfused pancreas. Although the inhibitory effect of CR 1392 was fully reversible in the isolated acini, the pancreata perfused with 100 microM CR 1392 for 20 min did not respond to the subsequent stimulation with CCK-8 for more than 20 min. These results indicate that CR 1392 is a potent, competitive, specific and long acting antagonist of CCK in rat pancreas.

Amylases↗
PubMed1990

A pilot randomized control trial of proglumide (a gastrin receptor antagonist) in advanced colorectal cancer.

Forty-one patients with advanced colorectal cancer were entered into a randomized controlled trial of treatment with proglumide--a gastrin receptor antagonist. There was no difference in survival between the treated and the untreated groups of patients, although there was a trend towards increased survival in those treated patients with hepatic metastases alone. Proglumide does not cause regression in advanced colorectal cancer but larger studies would be required to detect an effect on tumour growth.

Adenocarcinoma↗
PubMed1989

A preliminary dose-ranging trial of proglumide for the treatment of refractory schizophrenics.

A dose-finding study of proglumide added to neuroleptics for the treatment of schizophrenic patients who were relatively refractory to their ongoing neuroleptic regimen was performed. Initially, four patients were open-label treated using a regimen of progressively increasing doses (proglumide 0.5-1024 mg/day) for 4 weeks. Afterwards, seven patients were given low doses (0.5 mg/day) followed by higher doses (500 mg/day) for a total period of 8 weeks. Overall, no improvement was seen in these refractory patients as a group at any dose. In individual patients, modest improvement or worsening of psychotic symptoms was observed. The results suggest that more potent cholecystokinin (CCK) antagonists and a greater knowledge of CCK pharmacology are needed before novel treatments exploiting the interaction of CCK and dopamine in the brain can be developed.

Antipsychotic Agents↗
PubMed1989

Effects of atropine, proglumide, and somatostatin analogue (SMS 201-995) on bombesin-induced gallbladder contraction and CCK secretion in humans.

The effects of atropine, proglumide, and somatostatin analogue (SMS 201-995) on bombesin-induced gallbladder contraction and plasma cholecystokinin (CCK) secretion were investigated in healthy volunteers. The gallbladder size was measured by real-time ultrasonography and the plasma CCK levels by radioimmunoassay. Bombesin (5 micrograms/30 min infusion) induced gallbladder contractions that reduced the gallbladder area to 36.6 +/- 2.1% of the original area 45 min after bombesin infusion, and caused a significant increase of plasma CCK from a basal level of 10.3 +/- 1.8 pg/ml to a peak level of 42.9 +/- 8.9 pg/ml (p less than 0.01) at 20 min. Atropine (500 micrograms, im) inhibited significantly (p less than 0.01) the gallbladder contraction (maximum contractile rate, 78.7 +/- 6.4%) in response to bombesin without any change of plasma CCK secretion, whereas proglumide (800 mg/day for 3 days, per os) decreased slightly but not significantly the gallbladder contraction, and had no effect on plasma CCK secretion. On the other hand, SMS 201-995 (50 micrograms, sc) almost completely inhibited both bombesin-induced CCK secretion and gallbladder contraction (maximum contractile rate, 93.6 +/- 6.2%). These findings suggest that atropine inhibits bombesin-induced gallbladder contraction, not via suppression of CCK release, but probably by inhibiting cholinergic mechanisms, whereas somatostatin inhibits gallbladder contraction, at least in part, by the suppression of bombesin-stimulated CCK secretion.

Adult↗
PubMedDate not supplied

Effects of gastrin, proglumide, loxiglumide and L-365,260 on growth of human colon carcinoma cells.

Gastrin-17 stimulated growth of the human colon carcinoma cell line HT29 but not of the human colon carcinoma cell lines T84, HCT116 and the mouse fibroblast cell line 3T3-L1. Correspondingly, specific gastrin binding sites were only found on HT29-cells. Proglumide, loxiglumide and L-365,260 inhibited gastrin-17 stimulated growth of HT29-cells at doses which did not influence cell growth when given without gastrin. At higher concentrations proglumide and loxiglumide reduced cell proliferation in all cell lines investigated. Gastrin-17 could not reverse these effects. This growth inhibition was therefore considered as not gastrin receptor mediated. The results demonstrate that only some human colon carcinoma cell lines are stimulated by gastrin. This stimulation can be inhibited by gastrin/CCK-antagonists.

3T3 Cells↗
PubMed1987

Electrophysiological studies on the specificity of the cholecystokinin antagonist proglumide.

Recent evidence suggests that the glutaramic acid derivative proglumide (PROG) is a selective antagonist of cholecystokinin (CCK) in the rat CNS. The extent of this selectivity has now been characterized in more detail. Iontophoretic or intravenous (i.v.) administration of PROG was ineffective against the excitatory effect of iontophoretically applied neurotensin on midbrain dopamine (DA) cells, the excitatory effect of substance P and the inhibitory effect of Met-enkephalin on prefrontal cortical neurons, and the inhibitory effect of histamine on neurons of the sensorimotor cortex. In contrast, PROG blocked the excitatory effect of the C-terminal octapeptide of CCK in all 3 areas. Furthermore, iontophoretic PROG diminished, whereas CCK enhanced the inhibitory effect of similarly applied DA and GABA on DA cells. PROG pretreatment (1 mg/kg, i.v.) reduced the inhibitory potency and maximum effect of i.v. apomorphine (APO) on A9 DA neurons, while the inhibitory potency of APO was enhanced by i.v. CCK. Pretreatment with PROG plus CCK resulted in APO effects which were no different from those after PROG alone. Chronic treatment with PROG (1 mg/kg, p.o., 21 days) resulted in a return to normal of DA cell APO sensitivity. Combined, these findings suggest that PROG may be a relatively selective CCK antagonist, that the functional effect of dendritically released DA may be influenced by endogenously released CCK, and that tolerance may develop to the effects of chronic CCK receptor blockade.

Action Potentials↗
PubMed1987

Cholecystokinin facilitates ejaculation in male rats: blockade with proglumide and apomorphine.

Systemic administration of the active, sulfated form of cholecystokinin-octapeptide (CCK-8S), at a dose known to inhibit dopamine (DA) release, significantly reduced the latency to ejaculate and number of intromissions preceding ejaculation in sexually active male rats. This effect was identical to that reported for low doses of the DA receptor agonist apomorphine, which bind preferentially to presynaptic DA autoreceptors. The facilitatory effect of CCK-8S on ejaculation was blocked by the putative CCK receptor antagonist proglumide and by a presynaptic dose of apomorphine. Blockade of the effect of CCK-8S with a presynaptic dose of apomorphine is consistent with CCK induction of depolarization block in DA neurons. These data suggest that CCK-8S and apomorphine may reduce the ejaculation threshold in sexually active male rats by inhibition of DA release via two different mechanisms of action.

Animals↗
PubMed1987

Cholecystokinin octapeptide, proglumide, and conditioned taste avoidance in rats.

Past research has shown that large (pharmacological) doses of cholecystokinin octapeptide (CCK-8) can influence conditioned behavior in rats. In the present study rats were allowed to locate and drink from a drinking tube that contained a sucrose solution. Following 30 sec exposure to the sucrose, intraperitoneal injections of NaCl or CCK-8 were given, with several variables measured 24 hr later. CCK-8 (100 micrograms/kg) was found to increase the latency to begin drinking the sucrose. It was also found that CCK-8 (10 micrograms/kg and 100 micrograms/kg) reduced the amount of sucrose consumption following the pairing of sucrose exposure and CCK-8. In addition, CCK-8 (100 micrograms/kg) reduced the amount of time rats spent in the area of the conditioning apparatus where the sucrose was located. These results are consistent with past research which found that CCK-8 can produce conditioned taste avoidance in rats. These results suggest that pharmacological doses of CCK-8 can act as an aversive stimulus during conditioning. Proglumide was found to block all of the effects produced by CCK-8 while producing little effect by itself.

Animals↗
PubMedDate not supplied

Unsulfated CCK-8 not blocked by proglumide or CR 1409 in the mouse abdominal irritant-induced stretching assay: possible central site of action.

Previous studies have shown that unsulfated cholecystokinin octapeptide (CCK-8-U) shares with the sulfated octapeptide (CCK-8-S) and the carboxyl-terminal tetrapeptide (CCK-4) the ability to block abdominal irritant-induced stretching when administered intracerebroventricularly. The effects of CCK-8-U, however, are not naloxone-reversible and do not appear upon systemic administration. To assess the hypothesis that the antistretching effects of CCK-8-U are mediated by central-type (CCK-B), rather than peripheral-type (CCK-A) receptors, the present experiments examined the reversal of these effects by CR 1409, a CCK receptor antagonist with in vitro selectivity for CCK-A receptors, and by proglumide. Both antagonists, when administered ICV, blocked the antistretching effects of CCK-8-S and CCK-4 (ICV), but not those of CCK-8-U. CR 1409 was approximately 40 times more potent against CCK-8-S by the ICV route than subcutaneously, indicating a likely action on CCK-A receptors in the brain. The effects of morphine, bombesin and neurotensin (ICV) were not blocked by CR 1409, indicating specificity for CCK receptor-mediated effects. The antistretching effects of CCK-8-U do not appear to be mediated by CCK-A receptors, and the possibility of a CCK-B receptor site of action must be considered.

Abdomen↗
PubMed1985

Proglumide, a gastrin receptor antagonist, inhibits growth of colon cancer and enhances survival in mice.

Some tumors are responsive to hormone manipulation. Some gastric and colonic adenocarcinomas from both humans and animals have specific gastrin receptors. A transplantable mouse colon adenocarcinoma cell line (MC-26) contains gastrin receptors; growth of MC-26 colon cancer in vivo is stimulated by pentagastrin (PG). The purpose of this study was to determine whether a gastrin-receptor antagonist, proglumide (PGL), would inhibit growth of MC-26 colon cancer and prolong survival in tumor-bearing mice. Subcutaneous tumors were induced by injecting single-cell suspensions of MC-26 cells into 50 mice divided into 10/group. In Experiment 1, all mice received 1 X 10(5) tumor cells and treatment groups were divided as follows: Group A received intraperitoneal (IP) saline (0.2 ml tid beginning on day 1); B, IP, PGL (250 mg/kg tid) from day of tumor cell inoculation; and C, IP PGL (250 mg/kg tid) from day 7 after tumor implantation. In Experiment 2, mice were inoculated with half the number of tumor cells. Group I mice received saline and Group II received PGL in the same manner starting on day 1. Tumors were measured and all mice were sacrificed on day 23. In Experiment 1, mean tumor area in Group B (PGL-treated) was significantly smaller than Group A on days 11, 14, 17, and 21. Tumors of Group C were significantly smaller than controls on day 21. Survival of PGL-treated mice was significantly prolonged. In Experiment 2, mean tumor area, mean tumor weight, and tumor DNA and RNA content were significantly less in the PGL-treated group than control. It was concluded that growth of a gastrin-responsive colon cancer was inhibited and host survival was enhanced by treatment with a gastrin-receptor antagonist. Hormone manipulation may be a useful treatment for gastrointestinal cancers.

Adenocarcinoma↗