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Antiproteases in Preventing Post-ERCP Acute Pancreatitis

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Antiproteases in Preventing Post-ERCP Acute Pancreatitis JOP. J Pancreas (Online) 2007; 8(4 Suppl.):509-517. ROUND TABLE Antiproteases in Preventing Post-ERCP Acute Pancreatitis Takeshi Tsujino, Takao Kawabe, Masao Omata Department of Gastroenterology, Faculty of Medicine, University of Tokyo. Tokyo, Japan Summary there is no other randomized, placebo- controlled trial on ulinastatin under way. Pancreatitis remains the most common and Large scale randomized controlled trials potentially fatal complication following revealed that both the long-term infusion of ERCP. Various pharmacological agents have gabexate and the short-term administration of been used in an attempt to prevent post-ERCP ulinastatin may reduce pancreatic injury, but pancreatitis, but most randomized controlled these studies involve patients at average risk trials have failed to demonstrate their of developing post-ERCP pancreatitis. efficacy. Antiproteases, which have been Additional research is needed to confirm the clinically used to manage acute pancreatitis, preventive efficacy of these antiproteases in would theoretically reduce pancreatic injury patients at a high risk of developing post- after ERCP because activation of proteolytic ERCP pancreatitis. enzymes is considered to play an important role in the pathogenesis of post-ERCP pancreatitis. Gabexate and ulinastatin have Introduction recently been evaluated regarding their efficacy in preventing post-ERCP ERCP is widely performed for the diagnosis pancreatitis. Long-term (12 hours) infusion of and management of various pancreaticobiliary gabexate significantly decreased the incidence diseases. Early complications after ERCP of post-ERCP pancreatitis; however, no include acute pancreatitis, bleeding, prophylactic effect was observed for short- perforation, and infection (cholangitis and term infusion (2.5 and 6.5 hours). These cholecystitis) [1, 2]. Of these ERCP-related results may be due to the short-life of complications, pancreatitis remains the most gabexate (55 seconds). Since long-term common, with a reported incidence of 2 to infusion requires additional hospitalization, 15% in multicenter prospective studies [3, 4, the use of gabexate in all patients at average 5]. Most cases of post-ERCP pancreatitis are risk of developing post-ERCP pancreatitis is mild, showing complete recovery in a few an expensive strategy. Ulinastatin has a half- days. After severe ERCP-related pancreatitis, life of 35 minutes and can be given as a bolus however, secondary consequences (e.g. infusion. Short-term (10 minutes) pancreatic pseudocyst and abscess) and administration of ulinastatin showed a multiorgan failure frequently develop; significant reduction in the incidence of post- surgical intervention and prolonged hospital ERCP pancreatitis in one randomized stay are usually required, and eventually the controlled trial. Ulinastatin is superior to patient dies. In a reported series of 7,869 gabexate in terms of cost because it does not patients undergoing diagnostic or therapeutic require additional hospitalization. At present, ERCP, 3 patients (0.04%) died from severe JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 8, No. 4 Suppl. - July 2007. [ISSN 1590-8577] 509 JOP. J Pancreas (Online) 2007; 8(4 Suppl.):509-517. proteases, aprotinin, gabexate, and ulinastatin, have been evaluated for their prophylactic efficacy against post-ERCP pancreatitis in prospective randomized controlled trials (RCTs) (published in peer-review English journals) [9, 10, 11, 12, 13]. Since aprotinin was found to be ineffective in 1977 [9] and no further RCTs of aprotinin have been conducted, this review will focus on the efficacy of gabexate and ulinastatin regarding the prevention of post-ERCP pancreatitis. Efficacy of Gabexate Regarding the Figure 1. Postulated pathogenesis of the development Prevention of Post-ERCP Pancreatitis of post-ERCP pancreatitis and potential pharmacological prevention. Gabexate has had a long history regarding the prevention of pancreatic injury after ERCP. In post-ERCP pancreatitis [3, 4, 5]. The the late 1970’s, Japanese investigators had prevention of post-ERCP pancreatitis has already evaluated the efficacy and safety of been a never-ending challenge ever since gabexate in this regard [14, 15]. While the ERCP was introduced in clinical settings in results of these studies were encouraging, the the 1970s. number of patients enrolled was limited and The exact pathogenesis of post-ERCP study designs appeared to be inadequate. pancreatitis has remained unclear but diverse Nevertheless, these studies showed that factors, which include mechanical injury, prophylactic administration of gabexate was hydrostatic injury, chemical and allergic safe. injury, enzymatic injury, infection and In 1996, Cavallini et al. reported the results of thermal injury, have been postulated as causes a well-designed multicenter RCT of gabexate of post-ERCP pancreatitis [6, 7, 8]. Many for preventing post-ERCP pancreatitis [10]. pharmacologic agents of different types have They administered 1g of gabexate or a been used to prevent post-ERCP pancreatitis placebo intravenously from 30-90 minutes on the assumption that they pharmacological- before ERCP and for 12 hours afterwards. ly inhibit one or more of the aforementioned Although no significant difference was seen factors associated with pancreatic damage in the incidence of hyperenzymemia between (Figure 1). Irrespective of the etiology of the 2 groups, the rate of post-ERCP acute pancreatitis, the activation of proteolytic pancreatitis was significantly lower in the enzymes, starting with trypsinogen activation gabexate group than in the placebo group to trypsin in pancreatic acinar cells, has been (5/208, 2.4% vs. 16/210, 7.6%; P=0.003). In considered to play an initial role in the addition, all 5 patients with pancreatitis in the pathogenesis of pancreatitis. Trypsin would gabexate group were graded as mild whereas subsequently trigger the activation of other one-third of the patients in the placebo group enzymes and the inflammatory cascade. On developed necrotizing pancreatitis. At that the basis of this pathogenesis, antiproteases, time, gabexate was the first drug to have which have been used to manage acute shown a preventive effect against post-ERCP pancreatitis in routine clinical settings in pancreatitis in a multicenter RCT; the results some countries, may be theoretically useful were impressive, but some drawbacks of for preventing pancreatitis after ERCP. Since gabexate in this study were pointed out [16]. we know the timing for the development of The main drawback was its long-term pancreatitis after ERCP, adequate doses of administration. The continuous 12-hour antiproteases could be administered infusion regimen is inconvenient and requires prophylactically. Currently, three anti- an overnight hospital stay after ERCP. Since JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 8, No. 4 Suppl. - July 2007. [ISSN 1590-8577] 510 JOP. J Pancreas (Online) 2007; 8(4 Suppl.):509-517. diagnostic ERCPs as well as therapeutic continuously for a long period of time (greater procedures are routinely performed on an than 12 hours)in order to prevent pancreatitis. outpatient basis in the United States [17, 18] Efficacy of Ulinastatin Regarding the and some other countries [19, 20], the cost of Prevention of Post-ERCP Pancreatitis this regimen was expensive. Responding to these criticisms, the same Ulinastatin is an intrinsic trypsin inhibitor authors conducted another RCT comparing a extracted and purified from human urine 6.5-hour infusion of 0.5 g gabexate to a 13- which inhibits various enzymes such as alpha- hour infusion of 1 g gabexate and found that chymotrypsin, lipase, amylase, elastase, and the frequency of post-ERCP pancreatitis was carboxylase. Ulinastatin has been used similar between the 2 regimens [21]. They clinically to treat acute pancreatitis, mainly in concluded that the preventive effect of the Japan and China [25, 26, 27]. Furthermore, short-time (6.5 hours) infusion was equivalent this agent has been given routinely in many to the long-term (13 hours) one. Japanese institutions as a prophylactic to Unfortunately, there was no placebo group in prevent post-ERCP pancreatitis. The main this comparative study presumably for ethical advantages of ulinastatin over gabexate are as reasons and, therefore, their conclusion was follows: a) the inhibitory effect of ulinastatin not convincing. In addition, a year after this on pancreatic enzymes is stronger than that of report, Andriulli et al. found, in a large scale gabexate [28, 29, 30]; b) in various multicenter randomized placebo-controlled experimental models of pancreatitis, trial, that the 6.5-hour infusion of 0.5 g suppression of the development and gabexate did not prevent post-ERCP progression of pancreatitis is more potent in pancreatitis [12]. The same authors also the ulinastatin group than in the gabexate reported three meta-analyses of the group [28, 29]; and c), since its serum half- prophylactic effect of gabexate on post-ERCP life is relatively long (35 minutes), ulinastatin pancreatitis in 2000 [22], 2002 [11] and 2007 can be administered by bolus injection [31] in [23]. The first and second meta-analyses contrast to gabexate. showed that gabexate significantly reduced Ulinastatin would be superior to gabexate the incidence of pancreatitis, but the with regard to clinical use if a short-term preventive effect was lost when gabexate was administration of ulinastatin reduced the given for a short-term (less than 4 hours) [11,
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