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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholecystokinin (CCK) receptor antagonists have been reported on have an inhibitory effect on acute experimental pancreatitis, but their long-term administration is also reported to block pancreatic regeneration. We examined whether the short-term administration of KSG-504 (KSG), a synthetic CCK-A receptor antagonist, inhibited the regeneration of pancreatic acinar cells after ethionine-induced acute pancreatitis in rats. KSG (50 mg/kg), given 12 times by subcutaneous injection at 6-h intervals, prevented the reduction of protein, amylase, and trypsinogen levels, and the DNA content of the pancreas and facilitated the recovery of these values. Ornithine decarboxylase activity in pancreatic tissue and a 5-bromo-2'-deoxyuridine labeling study indicated that DNA synthesis was accelerated in rats treated with KSG. These findings suggest that the short-term administration of KSG inhibits the development of ethionine-induced acute pancreatitis and facilitates the regeneration of acinar cells.
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PMID:Effects of short-term administration of the CCK receptor antagonist, KSG-504, on regeneration of pancreatic acinar cells in acute pancreatitis in rats. 755 Aug 60

This report reviews the effects of CCK on the pancreas and in particular analyzes recent studies in which CCK antagonists were used to evaluate the physiological role of CCK in modulating pancreatic function and morphology. CCK is released from endocrine cells of the small intestine in response to a meal. In various animal species there are CCK receptors on pancreatic acinar cells with two sites; occupation of the high affinity site is thought to mediate pancreatic secretion and growth, whereas occupation of the low affinity site by high CCK concentrations is thought to be responsible for supramaximal inhibition of secretion and pancreatitis. Recently, CCK receptors were also found on postganglionic cholinergic neurons in the gastrointestinal tract. Administration of CCK agonists stimulates pancreatic secretion and growth. Although in some previous studies CCK was given at doses that mimic its postprandial increase in plasma, these studies did not prove that the actions of exogenous CCK were physiologically important. In addition, it was unclear if CCK primarily acts as a true hormone or as a neurotransmitter. The development of specific CCK receptor antagonists made it possible to better evaluate the physiological role of CCK. In humans, CCK-A antagonists like loxiglumide or L-364,718 at doses that completely inhibited the action of supraphysiological doses of exogenous CCK reduced meal-stimulated pancreatic enzyme secretion only by approximately 50%. On the other hand, atropine abolished the postprandial increase in pancreatic secretion and in addition markedly reduced the increase in pancreatic secretion due to infusion of "physiological" doses of CCK (i.e., CCK doses that mimic its postprandial increase in plasma). The increase in pancreatic bicarbonate secretion was only slightly reduced by CCK blockade. CCK antagonists failed to reduce the postprandial increase in plasma insulin, but markedly reduced the postprandial PP release. CCK-A antagonists caused slight hypotrophy and hypoplasia of the exocrine pancreas. However, even after 9 months of effective blockade of the CCK-A-receptor, mice had normal body weight and an almost normal pancreas. CCK antagonists were unable to alter short-term changes in pancreatic growth due to feeding and fasting. In some species, CCK agonists induced development of pancreatic nodules and increased the growth of malignant tumors. Studies about the effects of CCK antagonists on induction and growth of pancreatic tumors showed controversial results. In conclusion, CCK may act on the pancreas by three pathways: (1) At low doses it serves as a neurotransmitter by acting on cholinergic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of CCK on pancreatic function and morphology. 818 59

KSG-504, a new synthetic cholecystokinin (CCK) receptor antagonist derived from proglumide, has superior selectivity and affinity to CCK-A receptors. We have investigated the effect of KSG-504 on ethionine-induced acute pancreatitis in rats and the influence of endogenous CCK on evolution of pancreatitis and regeneration of pancreatic acinar cells. Reduction of pancreatic proteins and digestive enzyme contents was dose-dependently prevented by subcutaneous administration of KSG-504. The inhibition of evolution of pancreatitis was demonstrated histologically in KSG-504 treated rats. The effect of KSG-504 on pancreatic regeneration was evaluated by bromodeoxyuridine labeling index (B.L.I.) of acinar cells. There was no significant difference of B.L.I. between KSG-504 treated and non-treated rats. These results suggest that KSG-504 has a beneficial effect on ethionine-induced acute pancreatitis by blockade of endogenous CCK.
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PMID:[Effect of KSG-504, a new synthetic cholecystokinin receptor antagonist on ethionine-induced acute pancreatitis in rats]. 828 14

Recent studies provide significant evidence that cholecystokinin (CCK) is involved in the induction and development of acute pancreatitis in experimental animals. However, the results obtained with specific CCK-A (peripheral) receptor antagonists are still controversial. The present studies were undertaken to evaluate the involvement of endogenous CCK and the CCK-A receptors in the development of severe acute pancreatitis induced in Otsuka Long-Evans Tokushima Fatty (OLETF) rats that have a selective defect in the CCK-A receptor. Three models of severe acute pancreatitis were induced by retrograde intraductal infusion of 4% sodium taurocholate, by the closed duodenal loop, or by a single intraperitoneal injection of 500 mg/100 g body weight of L-arginine in OLETF rats and control Long-Evans Tokushima Otsuka (LETO) rats. Plasma CCK levels rose up to 4- to 14-fold over the preloading values after the onset of acute pancreatitis in all three models in both groups of rats. However, histologic alterations as well as the magnitudes of increase in serum amylase and lipase activity and the pancreatic wet weight were significantly less in the OLETF rats than those in the LETO rats. In addition, 72 h after the onset of arginine pancreatitis, massive destruction of pancreatic parenchyma with a significant reduction in serum amylase and lipase activities and pancreatic wet weight was observed in the LETO rats, whereas these changes were not seen in OLETF rats. These results suggest that endogenous CCK and CCK-A receptors play a role in the development of severe acute pancreatitis in rats.
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PMID:Role of endogenous cholecystokinin and cholecystokinin-A receptors in the development of acute pancreatitis in rats. 905 82

We examined the role of the cholecystokinin-A (CCK-A) receptor in acute inflammatory and regenerative stages of experimental pancreatitis using a rat model lacking the CCK-A receptor [Otsuka Long-Evans Tokushima Fatty (OLETF) rats]. OLETF and control [Long-Evans Tokushima Otsuka (LETO)] rats were prepared with an internal bile fistula and with obstruction of pancreatic flow and were sacrificed 1-14 days later. Histological examination was performed, and changes in pancreatic wet weight, protein concentration, CCK-A and -B receptor mRNA levels, tyrosine kinase activities, and plasma amylase and CCK levels were determined. The plasma amylase level showed a transient increase on day 1, the CCK level remained at high levels throughout, and tyrosine kinase activity was increased significantly on day 3 but declined thereafter. These parameters were comparable for both strains during the acute inflammatory stage. However, no regenerative findings were observed by histological examination and the protein concentration in the pancreas was significantly lower in OLETF rats on days 7-14, during which time regeneration was completed in LETO rats. These observations indicate that the absence of the CCK-A receptor did not modify the acute phase of pancreatitis but significantly retarded regeneration of the pancreatic tissue.
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PMID:Role of cholecystokinin-A (CCK-A) receptor in pancreatic regeneration after pancreatic duct occlusion: a study in rats lacking CCK-A receptor gene expression. 951 Jan 32

The effect of FK480, a cholecystokinin-A (CCK-A) selective receptor antagonist, on spontaneously developed chronic pancreatitis was examined in WBN/Kob rats. Animals at age 18 weeks (18w-Control) already had the histologic appearance of chronic pancreatitis as indicated by inflammatory cell infiltration and fibrotic degeneration with interstitial edema. Rats treated with vehicle from 18 to 26 weeks of age (26w-Control) showed further development of pancreatitis as characterized by more extensive appearance of inflammatory cell infiltration and fibrotic changes, with the pancreatic weight significantly decreased. Serum amylase levels of 26w-Control animals were slightly decreased compared with those of 18w-Control animals, although the difference was not statistically significant. When rats were treated orally with 1, 10, and 100 microg/kg FK480 from 18 to 26 weeks of age, the decrease in serum amylase levels recovered dose dependently compared with 26w-Control, and the level in animals treated with 100 microg/kg FK480 was almost the same as that in 18w-Control rats. Histologic examinations revealed that the appearance of the pancreas of animals treated with FK480 was slightly improved with respect to inflammatory cell infiltration and edematous changes at the highest dose examined, although the difference was not statistically significant. Although blockade of the CCK-A receptor could be considered to exacerbate chronic pancreatitis due to possible inhibition of the trophic action of CCK, our results suggest that CCK-A receptor antagonists may not be detrimental to chronic pancreatitis.
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PMID:Effect of FK480, a CCK-A receptor antagonist, on spontaneously developed chronic pancreatitis in WBN/Kob rats. 978 45

We investigated the therapeutic effects of a cholecystokinin A (CCK-A) receptor antagonist, loxiglumide, on various models of experimental pancreatitis. This study shows that loxiglumide ameliorated caerulein-induced acute pancreatitis in mice as previously reported. The effects of loxiglumide on hemorrhagic and necrotizing acute pancreatitis is controversial. This study, however, shows that loxiglumide improves the survival rates in necrotizing acute pancreatitis induced by intraductal injection of taurocholate, followed by caerulein injection. In addition, the administration of loxiglumide improved both the biochemical and pathological changes of edematous acute pancreatitis induced by a closed duodenal loop in rats. It is concluded that the CCK-A receptor antagonist, loxiglumide, has therapeutic and/or prophylactic effects on acute pancreatitis in various models of experimental acute pancreatitis.
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PMID:Therapeutic effects of loxiglumide on experimental acute pancreatitis using various models. 1002 35

In our continuing research for dual CCK-A and -B antagonists, according to our hypothesis that dual CCK-A and -B antagonists should be more efficacious than selective CCK-A antagonists for the treatment of pancreatitis, we have prepared various 5-alkyl-9-methyl-1,4-benzodiazepines. From the compounds prepared, 1-cyclohexyl-carbonylmethyl-5-ethyl-9-methyl-3- (m-tolylureido)-2-oxo-1,4-benzodiazepine, (40) was selected as a candidate for development due to its well-balanced high affinity for both receptors. The R-enantiomer of 40, (R)-40 (FR 208419), had 27-fold higher affinity for the CCK-A receptor and 8-fold more potent CCK-B receptor binding activity than (S)-40. The biological activity after p.o. administration of (R)-40, estimated from the ID50 value (0.23 mg/kg p.o.) obtained by preliminary evaluation by gastric emptying effects, is considered to be high enough for further development. This compound is now undergoing further biological evaluations with a view to clinical development.
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PMID:Dual CCK-A and CCK-B receptor antagonists (II). Preparation and structure activity relationships of 5-alkyl-9-methyl-1,4-benzodiazepines and discovery of FR208419. 1070 68

Cholecystokinin (CCK) is a major gastrointestinal hormone that plays an important role in stimulation of pancreatic secretion and gall-bladder contraction, regulation of gastrointestinal motility and induction of satiety. Ingestion of fat and protein induces significant increases in plasma CCK. Intraluminal mediators of CCK secretion, luminal CCK releasing factor and diazepam-binding inhibitor, were purified from rat intestinal secretion. These CCK-releasing factors (RF) are secreted tonically by the small intestine and stimulate CCK release. Another kind of CCK-RF named 'monitor peptide' was purified from the rat pancreatic juice that stimulates CCK secretion when introduced into rat intestine. Bile exclusion from the duodenum causes an increase in basal CCK and enhances stimulated plasma CCK release, and bile salt replacement reverses these effects. Thus, the CCK-RF are spontaneously secreted into the intestinal lumen in humans, while the CCK-producing cells are under constant suppression by intraduodenal bile acids. In acute pancreatitis, plasma CCK levels are high in patients with gallstone pancreatitis, but not in patients with pancreatitis from other causes, such as alcoholic and idiopathic pancreatitis. A transient disturbance of bile flow into the duodenum by stones or oedema of the pancreas together with impairment of pancreatic exocrine function might cause the increase in plasma CCK release in gallstone pancreatitis. Patients with chronic pancreatitis with mild to moderate impairment of exocrine function and abdominal pain, had significantly higher plasma CCK concentrations, whereas patients with pancreatic insufficiency had a significantly lower plasma CCK response to a test meal than the healthy subjects. The increased CCK may further aggravate pancreatitis and worsen the prognosis of pancreatitis by stimulating the injured pancreas, resulting in the vicious circle via endogenous CCK release. The CCK-A receptor antagonist might be therapeutically useful in acute pancreatitis by stopping the vicious circle.
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PMID:Pathophysiological role of cholecystokinin in humans. 1075 24

Despite improvement in intensive medical care management, the mortality rate from severe acute pancreatitis is still high. Attempt to reduce the mortality rate, some new drugs were investigated on experimental pancreatitis and clinical cases. There have been several clinical trials of somatostatin, somatostatin analogue octreotide, and a cholecystokinin A(CCK-A) receptor antagonist, loxiglumide, for the inhibition of pancreatic secretion. On the other hand, for the inhibition of the systemic inflammatory response, many studies in the use of the platelet-activating factor(PAF) antagonist, lexipafant, were reported in clinical trials. IS-741, a new synthetic anti-inflammatory agent, has been studied on various models of experimental pancreatitis. In this paper, it is introduced the results of these new drugs on experimental pancreatitis or clinical trials.
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PMID:[New aspects of pharmaco-therapy for acute pancreatitis]. 1555 91


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