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At least 19 recordsLinked to original sources
PubMed1986

Structural features of various proglumide-related cholecystokinin receptor antagonists.

Thirteen proglumide derivatives that varied in the length of the di-n-alkyl group and in the substitutions on the benzoyl moiety were tested for their ability to interact with guinea pig pancreatic cholecystokinin (CCK) receptors. Each derivative was more potent than proglumide. There was a close correlation between their abilities to inhibit CCK-stimulated amylase release and to inhibit binding of 125I-CCK. For the di-n-alkyl derivatives the relative potency was n-pentyl greater than n-hexyl greater than n-butyl greater than n-propyl. For the benzoyl moiety, adding two electron-withdrawing groups increased potency more than adding a single electron-withdrawing group or adding electron-donating groups. The 3,4-dichloro-di-n-pentyl derivative of proglumide was 1,300 times more potent than proglumide, and its action was specific, competitive, and it functioned as a CCK receptor antagonist in rat, mouse, and guinea pig pancreas. For all proglumide derivatives there was a good correlation (r = 0.84, P less than 0.001) between their abilities to inhibit CCK-stimulated amylase release and that previously reported for their abilities to inhibit CCK-induced gallbladder contraction. However, certain proglumide derivatives had a much higher affinity for the pancreatic CCK receptor than for the CCK receptor mediating gallbladder contraction. For other proglumide derivatives the pattern was reversed. These results demonstrate that both the di-n-alkyl group and the substitution on the benzoyl moiety of proglumide are equally important determinants of affinity and that derivatives such as the di-n-pentyl 3,4-dichloro analogue can be produced that are 1,300 times more potent than proglumide.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1985

Differential antagonism by proglumide of various CCK-mediated effects in mice.

Proglumide has been reported to antagonize sulfated cholecystokinin octapeptide (CCK-8) in peripheral tissue and in neurophysiological single unit preparations. The present studies attempt to extend this reported antagonism to several actions of CCK-8 in mice in vivo. For comparison with proglumide, the antagonist activity of naloxone against CCK-8 has also been evaluated. Proglumide (150 mg/kg) antagonizes hot plate latency elevations produced by a moderate (0.17 mg/kg s.c.) dose of CCK-8, but not that by a higher (1.0 mg/kg) dose. The effects of intracerebroventricularly (i.c.v.) administered CCK-8 (0.3 micrograms) are also blocked by proglumide i.p. or i.c.v. Naloxone (0.5 mg/kg s.c.) significantly antagonizes the elevated hot plate latencies induced by CCK-8 i.c.v. (3.0 micrograms) and s.c. (3.0 mg/kg). Proglumide antagonizes the motor activity suppressant effects of CCK-8, but only at a high proglumide dose (150 mg/kg i.p.) and low CCK-8 doses. Naloxone (3.0 mg/kg) is not effective against CCK-8 in motor activity. The hypothermia induced by CCK-8 cannot be antagonized either by proglumide at doses up to 150 mg/kg i.p. or by naloxone at doses up to 3.0 mg/kg s.c. In vivo, proglumide may be considered as a weak antagonist of CCK-8 and the possibility exists that various actions of CCK-8 may be differentiated by their relative responsiveness to proglumide-induced antagonism.

Animals↗
PubMed1990

Proglumide selectively potentiates supraspinal mu 1 opioid analgesia in mice.

The cholecystokinin antagonist proglumide potentiates morphine analgesia. To understand more fully the opiate receptor subtypes involved with this effect, we investigated the effect of proglumide on spinal and supraspinal mu and spinal delta analgesia in mice. Proglumide alone had no effect on tailflick latencies, but increased, in a dose-dependent manner, tailflick latencies in morphine-tolerant mice. Proglumide also potentiated morphine analgesia in naive mice in a dose-dependent manner, with a maximal effect at 5-10 mg/kg. Proglumide both shifted the dose-response curve for morphine analgesia to the left and prolonged morphine's duration of action. Proglumide increased the sensitivity of supraspinal mu 1 receptor mechanisms of analgesia without influencing spinal mechanisms. Proglumide administered subcutaneously potentiated the analgesic actions of intracerebroventricular [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAGO; (mu 1), but not intrathecal DAGO (mu 2) or [D-Pen2,D-Pen5]enkephalin (DPDPE; delta). The selective mu 1 receptor antagonist naloxonazine blocked proglumide-enhanced morphine analgesia.

Animals↗
PubMed1985

Effects of proglumide on ductal and basolateral secretion of pancreatic digestive enzymes.

Previous studies have shown that proglumide acts as a cholecystokinin (CCK) receptor antagonist in isolated pancreatic acini. To establish the effect of proglumide in the intact organ, its effects on both CCK-stimulated ductal and basolateral secretion of digestive enzymes were studied in the in vitro rabbit pancreas. CCK-stimulated ductal secretion of chymotrypsinogen, amylase, and total protein, as well as basolateral secretion of amylase, was inhibited by proglumide in a dose-dependent manner. Regression lines comparing ductal chymotrypsinogen and amylase outputs also were altered significantly by proglumide in a dose-dependent manner, with amylase secretion inhibited to a lesser degree. Similarly, the relative rates of amylase secretion across the ductal versus the basolateral cell surface were altered, with basolateral secretion inhibited to a lesser degree. The effects seen with increasing concentrations of proglumide at a given concentration of CCK mirrored the effects seen with decreasing the concentration of CCK in the absence of proglumide. Proglumide did not affect ductal or basolateral secretion stimulated by a cholinergic agonist and did not affect unstimulated pancreatic secretion. Thus, proglumide appears to act as a selective antagonist of CCK-stimulated secretion in the intact organ. The results further indicate that interactions of an agonist and an antagonist at the CCK receptor can alter not only the overall amount of enzymes secreted but their relative proportions as well.

Amylases↗
PubMed1990

Proglumide inhibits cholecystokinin and meal-stimulated pancreatic secretion and release of pancreatic polypeptide.

Exogenously administered cholecystokinin is a potent stimulant of pancreatic exocrine secretion and pancreatic polypeptide release. Release of cholecystokinin by amino acids and fats is strongly correlated with both pancreatic exocrine secretion and pancreatic polypeptide release. Despite this correlation, direct evidence that cholecystokinin is a physiologic mediator of these actions is not available. We have studied this problem in fasted dogs with chronic pancreatic fistulas by means of a specific cholecystokinin antagonist, proglumide, to inhibit the effect of cholecystokinin. Secretion, neurotensin (with secretin stimulation infusion), or cholecystokinin-octapeptide was infused intravenously, either with saline solution or with proglumide (300 mg/kg/hr). For endogenous release of cholecystokinin, intraduodenal infusions of phenylalanine and tryptophan or of sodium oleate were given with either intravenous saline solution or intravenous proglumide. Pancreatic secretion and release of cholecystokinin and pancreatic polypeptide were measured in plasma. Cholecystokinin-octapeptide stimulated pancreatic secretion of water and protein; both of these were significantly inhibited by proglumide. Intraduodenal amino acids and sodium oleate both caused significant release of cholecystokinin, which was not altered by proglumide; however, proglumide inhibited pancreatic secretion stimulated by intraduodenal amino acids and sodium oleate. Release of pancreatic polypeptide stimulated by amino acid and sodium oleate was also significantly inhibited by proglumide. Since proglumide appears to block actions of cholecystokinin, our results show that cholecystokinin is physiologically important for pancreatic secretion and for release of pancreatic polypeptide.

Amino Acids↗
PubMed1984

In vitro and in vivo effect of proglumide on cholecystokinin-stimulated amylase release in mouse pancreatic acini.

The effect of proglumide on cholecystokinin (CCK)-stimulated amylase release was studied in vitro and in vivo in dispersed acini from mouse pancreas. In an in vitro study, proglumide at concentrations between 0.3-10 mM inhibited CCK-stimulated amylase release dose-dependently, while proglumide did not influence the basal amylase release at concentrations between 0-3 mM. Dose-response curves to CCK for amylase release shifted to the right with increase in proglumide concentration. This inhibition by proglumide was reversible. In addition, the effect of proglumide was selective for CCK and its related peptide, and this drug did not inhibit other secretagogues such as carbachol or gastrin releasing peptide in mouse acini. In contrast to its inhibitory effect in vitro, in vivo administration of proglumide (500 mg/kg/day, i.p., for 5 days) to mice did not cause the rightward shift of the dose-response curve to CCK for amylase release from dispersed acini.

Amylases↗
PubMed1986

The effects of the cholecystokinin antagonist, proglumide, on gonadotropin release in the rat.

Since cholecystokinin had manifest effects on anterior pituitary hormone 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 gonadotropin secretion. 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 the injection of the compound. In castrate female rats proglumide produced a small but significant increase in plasma LH whether administered by the intravenous or intraventricular route at the lower dose of 10 or 2 micrograms, respectively. The higher doses of 10 micrograms injected intraventricularly or 100 micrograms, injected intravenously failed to affect LH levels in these animals. In contrast there was a much larger increase in plasma LH in castrate males following intraventricular or intravenous injection of the lower doses of proglumide. Even after the higher doses, there was a slight increase in levels of LH by either route of injection. The results indicate that in the castrate animal proglumide can elevate LH levels by either route of injection but that the response is greater in castrate males than females. The reduction in response with the higher doses may reflect an agonist activity of proglumide. By contrast proglumide had no effect on plasma FSH except for a slight elevation observed following the intravenous or intraventricular injection of the lower doses of the compound in castrate males. The results favor a physiologically significant role of CCK in control of LH release in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Proglumide exhibits delta opioid agonist properties.

Recently, it was reported that proglumide, a cholecystokinin (CCK) antagonist, potentiates the analgetic effects of morphine and endogenous opioid peptides and reverses morphine tolerance by antagonizing the CCK system in the central nervous system of the rat. In order to provide additional insight into the mode of action of this agent, we assessed the effect of proglumide in the isolated guinea pig ileum and the mouse, rat and rabbit vas deferens. Furthermore, we studied the in vitro binding affinity of this substance to mouse brain synaptosomes. Our results show that proglumide inhibits, dose dependently, the electrically stimulated twitches in the mouse vas deferens and guinea pig ileum, but not in the rat or rabbit vas deferens. The inhibitory action of proglumide on the mouse vas deferens, but not on the guinea pig ileum, is antagonized by naloxone and by the selective delta-antagonist, ICI 174,864, in a competitive fashion. Other CCK antagonists were found to be devoid of such activity on the mouse vas deferens. In vitro binding studies showed that proglumide displaces D-ala-D-[leucine]5-enkephalin (DADLE), a delta agonist, but not ethylketocyclazocine (EKC), a preferentially selective kappa agonist. The effect of proglumide appeared to be elicited presynaptically since it did not alter the norepinephrine-induced contractions of the mouse vas deferens. Our results suggest that proglumide might exert its opiate-like effects by activation of delta-opioid receptors.

Animals↗
PubMed1988

Proglumide treatment in bile-induced acute experimental pancreatitis.

Rats with acute experimental pancreatitis were treated with the cholecystokinin (CCK)-receptor antagonist proglumide. S-amylase was not affected by proglumide during the initial 4 h but was reduced after 72 h as compared to pre-pancreatitis values. The amylase levels in peritoneal fluid were lower in proglumide treated animals at 1, 2, 4 and 72 h after the induction of the pancreatitis, and amylase in pancreatic tissue was increased by proglumide after six but not 72 h. In spite of these biochemical changes, suggesting beneficial therapeutic effects by proglumide, survival rate was not improved when using a dose of 100 mg/kg every 8 h for 48 h and significantly reduced at a dose of 500 mg/kg every 8 h for 48 h. The results do not support proglumide as the sole treatment in acute pancreatitis.

Acute Disease↗
PubMed1990

Differential effects of sulfated cholecystokinin octapeptide and proglumide injected intrathecally on antinociception induced by beta-endorphin and morphine administered intracerebroventricularly in mice.

The effects of sulfated cholecystokinin octapeptide (CCK-8s) and CCK-8s antagonist, proglumide, given intrathecally (i.t.) on inhibition of the tail-flick and hot-plate paw-licking responses induced by beta-endorphin and morphine given intracerebroventricularly (i.c.v.) were studied in male ICR mice. Both CCK-8s (up to 0.5 ng) and proglumide (up to 10 micrograms) injected alone did not affect significantly the control latencies of the tail-flick and paw-licking responses. I.t. injection of CCK-8s as doses from 0.125 to 0.5 ng dose dependently attenuated inhibition of the tail-flick response induced by i.c.v. administered beta-endorphin. The antagonistic effect of CCK-8s on beta-endorphin-induced inhibition was blocked by the co-i.t. injection of proglumide (0.1-1 micrograms) in a dose-dependent manner. High doses (2.5-10 micrograms) of proglumide given i.t. dose dependently enhanced inhibition of the tail-flick response induced by i.c.v. administered beta-endorphin. However, i.t. injection of CCK-8s and proglumide did not affect inhibition of the paw-licking response induced by i.c.v. administered beta-endorphin. The inhibitions of the tail-flick and paw-licking responses induced by i.c.v. administered morphine were not affected by i.t. injection of CCK-8s or proglumide. Our results suggest that CCK-8s in the spinal cord may play an important modulatory role in attenuating the descending pain inhibition induced by i.c.v. administered beta-endorphin but not morphine.

Analgesics↗
PubMed1985

Selective inhibition of pentagastrin- and cholecystokinin-stimulated exocrine secretion by proglumide.

The effectiveness and selectivity of proglumide, a putative cholecystokinin/gastrin receptor antagonist in vitro, were examined on gastric acid and pancreatic secretion in vivo. Gastric secretion was measured in conscious dogs in the basal state and during infusion of pentagastrin, histamine, or bethanechol, alone or in combination with proglumide (300 mg/kg . h). Pancreatic secretion was measured in anesthetized rats in response to cholecystokinin-octapeptide or secretin, alone or in combination with proglumide (100 mg/kg). Proglumide inhibited pentagastrin-stimulated secretion but had no effect on basal, histamine-stimulated, or bethanechol-stimulated gastric acid secretion. Inhibition of pentagastrin-stimulated secretion was of the competitive type. An apparent inhibitory constant was calculated to be 300 mg/kg . h; this dose is capable of eliciting plasma concentrations of approximately 1 mM. This estimate corresponds closely to that derived from measurements in isolated canine parietal cells. Proglumide also inhibited cholecystokinin-stimulated but not secretin-stimulated pancreatic secretion. The lack of effect of proglumide on basal, histamine-stimulated, or bethanechol-stimulated gastric acid secretion implies that background gastrin has no direct or synergistic influence on stimulation by other secretagogues. The selective effect of gastrin receptor antagonists contrasts with the effectiveness of muscarinic and histamine H2-receptor antagonists against secretion induced by all types of stimulants. Accordingly, the antisecretory potential of gastrin receptor antagonists is confined to digestive secretion when the effect of gastrin is optimal. Their potential as antitrophic agents in duodenal ulcer disease, however, has not been explored yet.

Animals↗
PubMed1983

Evidence that proglumide and benzotript antagonize secretagogue stimulation of isolated gastric parietal cells.

Proglumide has been shown to be an in vivo inhibitor of secretagogue-stimulated gastric acid secretion. In the present study, we have examined the ability of proglumide and benzotript, a new tryptophan derivative, to inhibit acid output from isolated gastric fundic parietal cells from rabbit. As measured with the [14C]aminopyrine (AP) accumulation method as an index of acid secretion, the two drugs inhibited basal AP with IC-50 values of 1 X 10(-2) M for proglumide and 1 X 10(-3) M for benzotript. In the case of secretagogue stimulation (1) benzotript slightly affected histamine-induced AP (15% inhibition at 5 X 10(-3) M), proglumide did not; (2) both proglumide and benzotript inhibited in a non-competitive manner acetylcholine-induced AP; (3) these isolated cells were sensitive to gastrin and the dose-response curve for the stimulant was biphasic (maximum for 1 X 10(-9) M), suggesting a desensitization mechanism. Proglumide and benzotript competitively inhibited both [125I]gastrin binding to its receptor sites and gastrin-induced AP, suggesting they are members of a class of gastrin-receptor antagonists. But, this suggestion cannot exclude other post-receptorial mechanisms involved in the acid output from parietal cells.

Aminopyrine↗
PubMedDate not supplied

The influence of proglumide, a putative CCK antagonist, on cerebral ischemia in gerbil.

Studies were conducted to clarify the possible role of CCK in cerebral ischemia and to evaluate the effects of proglumide, a competitive and reversible CCK antagonist, as a potential therapeutic or prophylactic tool in the treatment of cerebral ischemia. Proglumide at the doses of 10, 50 and 150 mg/kg was administered to gerbils before unilateral carotid ligation, and its effect on stroke index score, incidence and mortality rate was observed. Our results show that proglumide injected prior to carotid ligation at the dose of 150 mg/kg significantly reduces both incidence and mortality rate and changes the distribution of the stroke index score in gerbils. There was a significant inverse relationship between the dose of proglumide and both incidence and mortality: the greater the injection dose of proglumide, the lower the incidence and mortality. These results suggest that CCK may be involved in the pathological processes of cerebral ischemia and proglumide or related compounds prove to be effective in the pharmacological prophylaxis of ischemic brain damage.

Animals↗
PubMed1996

The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia.

Discovery of the involvement of endogenous opiates in placebo analgesia represents an important step in understanding the mechanisms underlying placebo response. In the present study, we investigated the effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia in a human model of experimentally induced ischemic pain. First, we found that part of the placebo response was reversed by naloxone, confirming previous studies on the role of opioids in the placebo phenomenon. Second, since it was demonstrated that the action of exogenous and endogenous opiates is potentiated by proglumide, we analysed the effects of this cholecystokinin antagonist on placebo response and found that it enhanced placebo analgesia. The placebo effect can thus be modulated in two opposite directions: it can be partially abolished by naloxone and potentiated by proglumide. The fact that placebo potentiation by proglumide occurred only in placebo responders, but not in non-responders, suggests that activation of an endogenous opiate system is a necessary condition for the action of proglumide. These results suggest an inhibitory role for cholecystokinin in placebo response, although the low affinity of proglumide for cholecystokinin receptors does not rule out the possibility of other mechanisms.

Adult↗
PubMed1989

Proglumide potentiates morphine analgesia for acute postsurgical pain.

Proglumide, an antagonist of cholecystokinin, has been shown to potentiate morphine analgesia in animal and human experimental pain models. This study was undertaken to determine whether proglumide enhances morphine analgesia for patients experiencing postoperative pain. At onset of pain after the removal of impacted third molars, patients (n = 60) received intravenously either 4 mg morphine, 8 mg morphine, or 4 mg morphine plus proglumide (0.05, 0.5, or 5 mg). The administration of 8 mg morphine significantly reduced pain, in comparison with baseline and 4 mg morphine, for the first 30 minutes. The addition of 0.05 mg proglumide resulted in a significant increase in the magnitude and duration of the analgesic activity of 4 mg morphine; 0.5 and 5.0 mg proglumide did not produce this effect. No difference was seen in respiratory rate or in the frequency of side effects among the various forms of treatment. These data indicate that a low dose of proglumide potentiates both the magnitude and the duration of morphine analgesia in a clinical model of acute pain, without any detectable increase in side effects.

Adolescent↗
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↗