ceruletide and Gallstones

Pancreatic acinar cells express proteinase-activated receptor-2 (PAR2) that is activated by trypsin-like serine proteases and has been shown to exert model-specific effects on the severity of experimental pancreatitis, i.e., PAR2(-/-) mice are protected from experimental acute biliary pancreatitis but develop more severe secretagogue-induced pancreatitis. P2pal-18S is a novel pepducin lipopeptide that targets and inhibits PAR2. In studies monitoring PAR2-stimulated intracellular Ca(2+) concentration changes, we show that P2pal-18S is a full PAR2 inhibitor in acinar cells. Our in vivo studies show that P2pal-18S significantly reduces the severity of experimental biliary pancreatitis induced by retrograde intraductal bile acid infusion, which mimics injury induced by endoscopic retrograde cholangiopancreatography (ERCP). This reduction in pancreatitis severity is observed when the pepducin is given before or 2 h after bile acid infusion but not when it is given 5 h after bile acid infusion. Conversely, P2pal-18S increases the severity of secretagogue-induced pancreatitis. In vitro studies indicate that P2pal-18S protects acinar cells against bile acid-induced injury/death, but it does not alter bile acid-induced intracellular zymogen activation. These studies are the first to report the effects of an effective PAR2 pharmacological inhibitor on pancreatic acinar cells and on the severity of experimental pancreatitis. They raise the possibility that a pepducin such as P2pal-18S might prove useful in the clinical management of patients at risk for developing severe biliary pancreatitis such as occurs following ERCP.

Topics: Acinar Cells; Animals; Bile Acids and Salts; Biliary Tract Diseases; Calcium; Calcium Signaling; Ceruletide; Cholangiopancreatography, Endoscopic Retrograde; Chymotrypsinogen; Coloring Agents; Enzyme Activation; Enzyme Precursors; Gallstones; Indicators and Reagents; Lipopeptides; Mice; Mice, Inbred C57BL; Mice, Knockout; Pancreatitis; Propidium; Receptor, PAR-2; Trypsinogen

In experimental animals, sphincterotomy facilitates passage of solids from the gallbladder and inhibits gallstone formation apparently by improvement in gallbladder emptying. In humans, however, gallbladder emptying has not been studied following endoscopic sphincterotomy (ES) in patients with gallstones. We therefore prospectively studied resting and cerulin-stimulated gallbladder volumes by real time ultrasonography in 15 patients of choledocholithiasis with gallbladder in situ (eight with and seven without gallbladder calculi) before and after (after bile duct clearance) ES. ES significantly lowered resting gallbladder volume (21.2 +/- 10.6 vs 11.1 +/- 5.0; P < 0.0001) and cerulin-stimulated residual gallbladder volume (10.8 +/- 5.6 vs 4.4 +/- 2.1; P < 0.0001). ES also significantly increased the gallbladder ejection fraction (47.3 +/- 12.1% vs 58.8 +/- 11.1%; P < 0.0001). The rate constant for gallbladder emptying after cerulin infusion also increased significantly after ES (-0.022/min vs -0.031/ min; P < 0.0001). Significant improvement in gallbladder motility was observed in both groups of patients with and without gallbladder calculi. ES significantly improves gallbladder motility in humans.

Topics: Adult; Case-Control Studies; Ceruletide; Cholelithiasis; Female; Gallbladder; Gallbladder Emptying; Gallstones; Gastrointestinal Agents; Humans; Male; Middle Aged; Prospective Studies; Sphincterotomy, Endoscopic; Ultrasonography

Some of patients with an intact gall bladder develop acute cholecystitis or have gall bladder stone formation after endoscopic sphincterotomy. Endoscopic sphincterotomy may affect gall bladder motility.. To prospectively evaluate longterm effect of endoscopic sphincterotomy on gall bladder motility.. Thirty two patients with an intact gall bladder (15 with and 17 without gall bladder stones) who underwent endoscopic sphincterotomy for choledocholithiasis.. Gall bladder function was examined before and at from seven days to five years after sphincterotomy. Gall bladder volume, at fasting and after caerulein administration, was determined by ultrasonography.. After endoscopic sphincterotomy, the enlarged orifice remained patent during a five year follow up period. One patient with gall bladder stones subsequently developed acute cholecystitis, the remaining being asymptomatic. In the patients before sphincterotomy, particularly in those with gall bladder stones, the gall bladder showed larger fasting volume and lower caerulein stimulated maximum contraction than normal controls. Throughout five years after sphincterotomy, fasting volume of the gall bladder decreased and its maximum contraction increased, regardless of gall bladder stones; significantly different from the values before sphincterotomy (p < 0.05).. Endoscopic sphincterotomy decreases fasting volume of the gall bladder and increases its contraction ability for a long period. These changes may rather decrease the risk of future acute cholecystitis or gall stone formation.

Topics: Adult; Aged; Ceruletide; Female; Gallbladder; Gallbladder Emptying; Gallstones; Humans; Male; Middle Aged; Prospective Studies; Sphincterotomy, Endoscopic; Time Factors; Ultrasonography

Intraluminal pressure of sphincter of Oddi (SO) was measured in awake patients who had undergone cholecystectomy and T-tube drainage for cholecystocholedocholithiasis. Pressure measurement was carried out using microtransducer which was inserted through sinus tract under cholangioscopy after removing T-tube. Mean value of the basal pressure was 12.0 +/- 1.5 mmHg, the amplitude of the phasic contraction was 55.2 +/- 4.4 mmHg and the frequency of the phasic contraction was 4.2 +/- 0.3 cycle/min. Intravenous administration of caerulein or atropine caused marked decrease in the amplitude and the frequency of the phasic contraction of SO, whereas pentazocine caused marked increase in the basal pressure, the amplitude and the frequency of the phasic contraction of SO. Naloxone alone did not affect the phasic contraction of SO, but it reduced the increased amplitude and frequency of the phasic contraction of SO caused by pentazocine. In conclusion, cholinergic nerves, excitatory nerves mediated by opioid receptors and non-cholinergic non-adrenergic inhibitory nerves may modulate spontaneous motor activity of human sphincter of Oddi.

Topics: Adult; Aged; Aged, 80 and over; Atropine; Ceruletide; Cholelithiasis; Cholinergic Fibers; Female; Gallstones; Humans; Male; Middle Aged; Muscle Contraction; Postoperative Period; Receptors, Opioid; Sphincter of Oddi

Despite good results in gallbladder imaging, ultrasound (US) diagnosis of choledocholithiasis remains a challenge. The value of US before and after a provocative injection of the decapeptide ceruletide was examined in 25 patients with suspected common duct stones immediately prior to diagnostic retrograde cholangiography. An abnormal response (increase in US duct diameter) was seen in 4 of 6 patients with an obstructed duct, giving a sensitivity of 67% and predictive value of 80% for the procedure. There was a normal response (decrease in US diameter of a dilated duct or decrease/no change in a normal duct) in 14 of 19 with an unobstructed duct (specificity 79%, predictive value 93%) and an equivocal response (no change in diameter of a dilated duct) in 5 patients. In 1 patient a calculus not seen on the initial US became visible as the duct distended by ceruletide administration. Symptoms after ceruletide were few and not discriminatory. Although it added to the time and difficulty of performing biliary US, ceruletide administration proved a useful adjunct to the diagnosis of choledocholithiasis.

Topics: Bile Ducts; Ceruletide; Gallstones; Humans; Ultrasonography

The combination of ceruletide-induced relaxation of the sphincter of Oddi plus flushing with saline has recently been proposed as a novel procedure for the treatment of residual common bile duct (CBD) stones. In this study we have administered intravenous ceruletide (2 ng kg-1 body weight min-1 for 1 h) plus intraductal saline (800-3000 ml, infused at a rate that kept biliary pressure below 30 cmH2O) to a group of 14 patients. The treatment induced the passage of residual stones in 11 subjects (79 per cent) with complete clearance in 7 (50 per cent). The majority of the cleared concretions (11/15) had a diameter less than 10 mm. No severe side-effects were recorded during the treatment. Four of the seven subjects who exhibited incomplete CBD clearance underwent a short cycle of mono-octanoin administration in order to reduce the size of residual radiolucent stones. This course of treatment was followed by another attempt with intravenous ceruletide and saline washout which gave a successful response in an additional three cases. These data indicate that the combination of ceruletide and flushing is a safe and inexpensive method for treatment of residual stones. The procedure is feasible for both radiolucent and radio-opaque stones and is mainly eligible for small concretions of diameter less than 10 mm. Larger (greater than 10 mm) radiolucent stones may be partially dissolved with mono-octanoin and then eliminated by the washout technique.

Topics: Adult; Aged; Caprylates; Ceruletide; Female; Gallstones; Glycerides; Humans; Injections, Intravenous; Intubation; Male; Middle Aged; Sodium Chloride; Solvents; Sphincter of Oddi; Therapeutic Irrigation

The synthetic peptide ceruletide induces maximal relaxation of the sphincter of Oddi. In a preliminary communication, ceruletide controlled saline infusion of the common bile duct (CBD) was found to be effective in promoting the passage of retained ductal calculi after cholecystectomy and exploration of the common bile duct. This paper reports on the further experience with this simple treatment which was administered to 27 patients with retained ductal calculi in 16 different hospitals within the U.K. The success of the procedure was documented by repeat T-tube cholangiography. Passage of stones into the duodenum was documented in 13 patients (48%) with complete clearance in 9 (33%) following one saline infusion/ceruletide treatment. The radiological stone size ranged from 3 to 15 mm. Within this range, there was no correlation between a successful outcome and size of retained stones. The duration of the saline T-tube infusion during ceruletide treatment averaged 54.7/min (SD 14.3). There was no correlation between flow rate of saline through the T-tube and a successful outcome. A significant inverse correlation was observed between the CBD pressure during ceruletide controlled saline T-tube infusion and successful stone passage (chi 2 = 9.9, P less than 0.01). Ampullary impaction by a stone was encountered in one patient. These results are encouraging and indicate that pharmacological dilatation of the sphincter of Oddi together with saline infusion is effective in the management of retained stones after exploration of the common bile duct. This treatment, which does not require any special expertise, should be tried in the first instance before more invasive procedures are used.

Topics: Adult; Aged; Aged, 80 and over; Ceruletide; Cholecystectomy; Female; Gallstones; Humans; Infusions, Intravenous; Male; Middle Aged; Sodium Chloride; Solutions; Sphincter of Oddi

Topics: Ampulla of Vater; Ceruletide; Cholelithiasis; Cystic Duct; Gallstones; Humans; Sodium Chloride; Sphincter of Oddi; Therapeutic Irrigation

This long-term follow-up of 27 patients treated with conservative surgery for necrohemorrhagic pancreatitis (NHP) showed that an almost complete recovery of the exocrine function is achieved within 4 years after discharge, while about half of the patients presented still abnormal endocrine function. The morphological sequelae, pointed out by endoscopic retrograde pancreatography in almost 50% of the cases, remained unchanged during the follow-up period. Therefore, these data seem to exclude an evolution of NHP towards chronic pancreatitis.

Topics: Acute Disease; Alcoholism; Ceruletide; Female; Follow-Up Studies; Gallstones; Glucose Tolerance Test; Hemorrhage; Humans; Male; Necrosis; Pancreas; Pancreatic Function Tests; Pancreatitis; Postoperative Period; Radiography; Secretin