Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated the effects of a new cholecystokinin (CCK) receptor antagonist, loxiglumide, in a model of mild pancreatitis induced by repeated injections of cerulein and in a severe necrotizing form of pancreatitis induced by retrograde ductal injection of sodium taurocholate (NaTc) in rats. A single subcutaneous injection or oral administration of 50 mg/kg of body weight of loxiglumide almost completely reduced the increases of serum amylase activity and pancreatic wet weight, and caused histologic improvements of the cerulein-induced acute pancreatitis when given 30 min before the first cerulein injection. Loxiglumide was also effective in reducing the elevated serum amylase activity, pancreatic wet weight, and histologic alterations even when administered after the induction of acute pancreatitis. However, loxiglumide offered no apparent beneficial effects when given 30 min before and 3 h after the induction of acute pancreatitis by NaTc as determined by changes in serum amylase activity, pancreatic wet weight, and histology. These results do not necessarily suggest that CCK is not important in the pathogenesis of pancreatitis, but do suggest that the sole blockade of peripheral CCK receptors is ineffective against NaTc-induced severe necrotizing pancreatitis.
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PMID:Effect of a new cholecystokinin receptor antagonist loxiglumide on acute pancreatitis in two experimental animal models. 234 42

Loxiglumide (D,L-4-(3,4-dichloro-benzoylamino)- 5-(N-3-methoxypropyl-pentylamino)-5-oxo-pentanoic acid, CR 1505) is a derivative of pentanoic acid and belongs to a newly discovered class of agents with cholecystokinin antagonistic activities. Loxiglumide has preventive effects on different types of experimental pancreatitis, induced e.g. by ceruletide (i.p. ED50 ca. 9 mumol/kg), by intrapancreatic taurocholate (i.p. ED50 ca. 80 mumol/kg) or by choline-deficient ethionine-supplemented diet (i.p. ED50 ca. 45 mumol/kg). Loxiglumide has a simple, non-polypeptidic chemical structure and may be a candidate for clinical investigations in man, e.g. for pancreatitis.
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PMID:Loxiglumide protects against experimental pancreatitis. 343 90

Recent studies have demonstrated that cholecystokinin (CCK) receptor antagonists not only reduce the severity of pancreatitis but also inhibit pancreatic regeneration after pancreatitis. This study was undertaken, therefore, to examine the effects of the CCK receptor antagonist loxiglumide on the exocrine pancreas when given after an episode of acute pancreatitis that was induced in rats by a 4-h subcutaneous infusion of 20 micrograms/kg body weight/h cerulein. Biochemical changes and secretory function in response to 100 ng/kg body weight cerulein were determined after a 6-day treatment with saline, loxiglumide (50 mg/kg body weight), or CCK-8 (2.5 micrograms/kg body weight), which was given three times a day starting 24 h after the induction of acute pancreatitis. In the saline-treated rats, pancreatic enzyme contents and pancreatic juice and protein output were significantly low, whereas the pancreatic weight and protein and DNA contents were comparable to those of the controls without pancreatitis. Loxiglumide treatment, although significantly decreasing protein output, had no influence on pancreatic weight, protein and DNA contents, or pancreatic juice flow but increased the amylase and lipase contents compared to those of the saline-treated postpancreatitic rats. CCK-8 treatment also had no influence on pancreatic weight or protein and DNA contents but significantly increased the pancreatic enzyme contents and pancreatic juice and protein output compared to those of the saline-treated postpancreatitic rats. These results suggest that loxiglumide does not significantly inhibit the recovery of exocrine function but appears to accelerate the increase in pancreatic amylase and lipase contents even when given after an attack of acute pancreatitis.
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PMID:Effect of the cholecystokinin receptor antagonist loxiglumide on pancreatic exocrine function in rats after acute pancreatitis. 754 70

Involvement of endogenous cholecystokinin (CCK) in the development of acute pancreatitis induced in rats by closed duodenal loop (CDL) was examined, and the effects of the potent and specific CCK receptor antagonist loxiglumide on this model of acute pancreatitis were evaluated. Plasma CCK bioactivity was markedly elevated 3 and 6 h after onset of acute pancreatitis. A single subcutaneous injection of 50 mg/kg body wt of loxiglumide 30 min before the induction of acute pancreatitis completely eliminated the hypercholecystokinemia. Loxiglumide given 3 h after the induction of acute pancreatitis suppressed plasma CCK bioactivity, which had risen up to 30-fold over basal value (0 h) at 3 h, to nearly the basal level. Loxiglumide pretreatment, in addition, significantly prevented the rise in serum amylase and lipase activity, as well as the increase in ascitic volume. It also ameliorated histological alterations of hemorrhagic and necrotizing pancreatitis. Reduction of plasma CCK bioactivity by loxiglumide after the onset of pancreatitis slowed the rate of progression of pancreatitis. However, pancreatic wet weight and cellular infiltration were not significantly influenced by loxiglumide treatment. These observations suggest that endogenous CCK is not involved in the initiation of acute hemorrhagic and necrotizing pancreatitis induced by CDL, but is involved in the development of pancreatitis in this model.
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PMID:Involvement of endogenous cholecystokinin in the development of acute pancreatitis induced by closed duodenal loop. 767 22

Effects of a new cholecystokinin (CCK)A-receptor antagonist, T-0632 [sodium (S)-1-(2-fluorophenyl)-2, 3-dihydro-3-[(3-isoquinolinylcarbonyl) amino]-6-methoxy-2-oxo-1H-indole-3-propanoate], on caerulein-induced and pancreatic duct ligation-induced pancreatitis models were studied and compared with the CCKA-receptor antagonist loxiglumide and the orally active protease inhibitor camostate, respectively. In rats, orally administered T-0632 potently prevented the caerulein-induced increases in pancreatic digestive enzymes in plasma and suppressed the histological changes in the pancreas. The estimated ED50 values of T-0632 and loxiglumide were 0.0092 and 8.9 mg/kg, respectively. In dogs, T-0632 (0.1, 1 mg/kg, i.d.) prevented the caerulein-induced increase in plasma amylase activity in a dose-dependent manner. Loxiglumide (100 mg/kg, i.d.) did not show any preventive effects. In pancreatic duct ligation (6 hr)-induced pancreatitis of the rat, T-0632 (0.001-0.1 mg/kg, p.o.) partially prevented both the increase in plasma amylase activity and the histological changes in the pancreas, whereas camostate (10, 100 mg/kg, p.o.) did not show any preventive effects. In pancreatic duct ligation (3 hr)-induced pancreatitis, caerulein injection (1 microgram/kg, s.c.) caused a further increase in plasma amylase activity, and T-0632 (0.01, 0.1 mg/kg, p.o.) dose-dependently decreased the aggravation by caerulein. We conclude that T-0632 showed preventive effects on all of these pancreatitis models by oral or intraduodenal administration. These results suggest that CCK plays an important role in progression and aggravation of acute pancreatitis, and T-0632 may have a therapeutic value in these disease states.
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PMID:Effect of T-0632, a cholecystokininA receptor antagonist, on experimental acute pancreatitis. 907 44

Loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N- pentylglutaramic acid, CAS 107097-80-3, CR 1505) is a cholecystokinin-A (CCK-A) receptor antagonist. In this report, the effects of loxiglumide and gabexate mesilate were studied on three experimental acute pancreatitis models induced by caerulein, sodium taurocholate + caerulein and closed duodenal loop. The intravenous injection of loxiglumide at 3 and 10 mg/kg (6 times at hourly intervals) significantly inhibited an increase in serum amylase activity induced by the intraperitoneal injection of caerulein (50 micrograms/kg i.p., 6 times at hourly intervals) in mice. But gabexate mesilate at 10, 30 and 60 mg/kg did not. The intravenous infusion of loxiglumide at 18 and 60 mg/kg/h showed a life prolonging effect in the lethal necrotizing pancreatitis, induced by the subcutaneous injection of caerulein (50 micrograms/kg s.c., 4 times at 2 h intervals) after the injection of sodium taurocholate (10%, 0.1 ml/body) into the common bile duct, cumulative survival rates being 86 and 90%, respectively. Gabexate mesilate at 180 mg/kg/h showed the prolonging effect (cumulative survival rates 75%). The intravenous injection of loxiglumide at 6, 18 and 60 mg/kg/h significantly inhibited an increase in total ascitic lipase activity, and plasma amylase and lipase activity of rats with closed duodenal loop. These results suggest that CCK plays an important role in the progression of acute pancreatitis, and that loxiglumide may have a therapeutic potential for pancreatitis.
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PMID:Effects of loxiglumide on experimental acute pancreatitis in comparison with gabexate mesilate. 952 35

Rotta was developing loxiglumide, a competitive cholecystokinin (CCK) antagonist, for potential use in the treatment of cancer, gastrointestinal disease, eating disorders and pancreatitis. However, by April 2002 its development for indications other than acute and chronic pancreatitis had been discontinued in favor of the D-enantiomer, dexloxiglumide [449509], which is in clinical trials for gastrointestinal disorders [370620]. Loxiglumide is awaiting approval in Japan where it is being developed for acute and chronic pancreatitis by Mitsubishi Pharma and Kaken Pharmaceuticals, respectively [365460], [449509]. By September 1999, Kaken had submitted a Japanese NDA for the intravenous formulation for acute pancreatitis; approval was still pending in May 2001. At this time, the oral formulation was still 'pre-NDA' [411053]. By February 2000, loxiglumide had also been filed for approval in Japan for the treatment of acute pancreatitis by Mitsubishi-Tokyo [365460], [371091] and was still awaiting approval in October 2001 [422712], [430428]. In December 2001, analysts at Merrill Lynch predicted launch of loxiglumide in early 2002 for acute pancreatitis and late 2004 for chronic pancreatitis, with sales of Yen 1 billion in 2003 rising to Yen 6 billion in 2006 [450719].
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PMID:Loxiglumide Rotta research. 1557 Apr 66