Cheon: Can postendoscopic retrograde cholangiopancreatography pancreatitis be prevented by a pharmacological approach?
Acute pancreatitis remains the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP), with reported incidence rates that have changed little over several decades. Patient- and procedure-related risk factors for post-ERCP pancreatitis (PEP) are well-defined. Effective measures to prevent PEP have been identified, including improvements in cannulation techniques and pancreatic stenting, as well as pharmacological intervention. Pharmacotherapy has been widely studied in the prevention of PEP, but the effect in averting PEP has been inconclusive. Although pharmacological prophylaxis is appealing, attempts to find an ideal drug are incomplete. Most available data on the efficacy of pharmacological agents for PEP prophylaxis have been obtained from patients at average risk for PEP. However, recently, a randomized prospective controlled trial of rectal nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent PEP in high-risk patients was published. The results revealed that rectal indomethacin reduced the incidence of PEP significantly. Thus, rectal administration of diclofenac or indomethacin immediately before or after ERCP is used routinely to prevent PEP. However, additional studies with NSAIDs using large numbers of subjects are necessary to confirm the prophylactic effect of these drugs and to establish whether they act synergistically with other prophylactic interventions, including pancreatic stenting.
Endoscopic retrograde cholangiopancreatography (ERCP) is now widely accepted as a therapeutic modality; its application, however, is limited because of the technical difficulty and unavoidable incidence of complications. Complications of ERCP include pancreatitis, bleeding, cholangitis, cholecystitis, and perforation; of these, post-ERCP pancreatitis (PEP) is the most frequent. Rates of pancreatitis of 2% to 9% are typical of most unselected prospective series [1
]. The risk of PEP varies greatly with indication, being < 5% for the management of common bile duct stones and reaching 20% or more in cases of suspected sphincter of Oddi dysfunction (SOD) [4
]. Despite attempts to address this problem, effective strategies to prevent this serious complication remain elusive.
Patient- and procedure-related risk factors for PEP are well-known. Recently, effective measures to prevent PEP have been identified, including improvements in cannulation techniques and pancreatic stenting, as well as pharmacological interventions.
Pharmacotherapy has been widely studied in the prevention of PEP, but the effects in averting PEP have been inconclusive. Although pharmacological prophylaxis is appealing, attempts to find an ideal drug are incomplete. Initial single-center randomized trials suggested efficacy, but were followed by conflicting results from larger multicenter studies [5
Recently, a randomized prospective controlled trial (RCT) of rectal nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent PEP in high-risk patients was published [6
]. The results revealed that rectal indomethacin reduced the incidence of PEP significantly. If prophylaxis with an inexpensive drug and peri-procedural administration could decrease the incidence of PEP, it would translate into major medical and economic benefits. This review assesses the mechanisms and various results of pharmacotherapy to minimize the incidence and severity of PEP.
A consensus classification was published in 1991 and defined this complication as a clinical syndrome, consistent with acute pancreatitis, with a serum amylase level at least three times normal at more than 24 hours after the procedure and requiring hospital admission or prolongation of a planned admission [7
]. The severity of PEP is based primarily on the length of hospitalization: mild PEP is defined as the need for hospital admission or prolongation of planned admission up to 3 days, moderate PEP is defined by the need for hospitalization from 3 up to 10 days, and severe PEP by hospitalization for more than 10 days, or significant complications. It should be noted, however, that transient hyperamylasemia without acute pancreatitis is common after ERCP. If after 24 hours there is doubt about the diagnosis of acute pancreatitis, a contrast-enhanced abdominal computed tomography scan is advisable.
MECHANISMS OF PEP
Understanding the pathogenesis of PEP is important in its prevention. Many mechanisms have been suggested for the induction of PEP, but they can be categorized as follows [8
1) Mechanical obstruction: If the flow of pancreatic juice is obstructed by trauma to the pancreatic sphincter or proximal pancreatic duct, edema of the pancreatic sphincter secondary to sphincterotomy or thermal injury, or prolonged spasm of the pancreatic sphincter in patients with sphincter hypertension may result.
2) Hydrostatic pressure increase in the pancreatic duct: This may be related to the over injection of contrast medium, pancreatic manometry without aspiration, or an obstruction near the pancreatic sphincter (i.e., by compression from a distal bile duct stone).
3) Infection: The source of infection may be duodenal content, the endoscopic channel, or ERCP accessories.
Induction by whatever means leads to intrapancreatic digestive enzyme and cellular autodigestion. The patient's response to this insult is determined by the intensity of the inflammatory cascade and systemic response to this local event.
RESULTS OF PHARMACOLOGICAL APPROACHES TO PEP
A pharmacological agent that prevents PEP has been a goal of investigators for many years. The rationale for this effort centers on the interruption of one or more of the various postulated mechanisms of injury. Generally, chemopreventive studies have targeted five main areas:
1) The prevention of intra-acinar trypsinogen activation (gabexate and ulinastatin)
2) The reduction of pancreatic enzyme secretion (octreotide and somatostatin)
3) Relaxation of a sphincter of Oddi spasm (nitroglycerin [NG], phosphodiesterase [PDE] inhibitor type 5, and calcium channel blockers)
4) Interruption of the inflammatory cascade (NSAIDs, corticosteroids, interleukin-10 [IL-10], and heparin)
5) The prevention of infection (antibiotics)
Although pharmacological prophylaxis is appealing, most available data have been obtained from patients at average risk for PEP. In such circumstances, insufficient statistical power might account for the lack of demonstrated drug efficacy [9
]. Additionally, case mixes and/or the criteria used to define acute pancreatitis have varied [5
]. These variations in design may explain some of the contrasting results with respect to the effectiveness of drugs between different studies.
Prevention of intra-acinar trypsinogen activation
The protease inhibitor gabexate is a diffusible, synthetic inhibitor of trypsin, kallikrein, and plasmin. When administered by continuous intravenous infusion, gabexate reaches a steady state within 15 minutes, with a half-life of 55 seconds [10
], and is eliminated in its inactive form by the kidneys. In a RCT with 418 patients, an infusion of gabexate 30 to 90 minutes before ERCP and for 12 hours thereafter was associated with a significantly lower rate of pancreatitis (2.4%) compared with the control group (7.6%) [11
]. An initial meta-analysis suggested that gabexate significantly reduced the risk of pancreatitis (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.13 to 0.57); however, the number needed to prevent one episode of pancreatitis was relatively high, at 27 [12
]. A subsequent large multicenter study of gabexate in a single dose before ERCP and continued for 2 hours thereafter found no significant difference in the frequency of pancreatitis in the treatment group (8.1%) versus the placebo group (6.5%) [13
]. The schedule seemed unimportant, because neither a short duration of drug infusion (less than 6 hours) nor a long one (more than 12 hours) was beneficial [9
Ulinastatin has been studied in four RCTs as an agent to prevent PEP. In two, it was compared with a placebo, and in two it was compared with gabexate. The results of these studies are contradictory [14
]. In one RCT that included 406 patients [15
], the incidence of PEP was significantly lower with ulinastatin (150,000 U administered prior to ERCP) compared with the placebo (2.9% vs. 7.4%, p
= 0.041). However, this benefit was not confirmed in another RCT in which 227 patients were randomly allocated to receive either ulinastatin (100,000 U) or a placebo immediately after ERCP (PEP incidence of 6.7% and 5.6%, respectively; p
> 0.05) [17
Reduction of pancreatic enzyme secretion
The inhibition of exocrine pancreatic secretion can be obtained with somatostatin and its synthetic analog, octreotide. This hormone and its analog affect exocrine function directly by reducing the secretion of digestive enzymes, and indirectly by inhibiting secretin and cholecystokinin production. In addition to their antisecretory effects, somatostatin and octreotide have been demonstrated to modulate the cytokine cascade and may also have a cytoprotective effect on pancreatic cells, although the mechanisms of their cytoprotective effect remains unknown [18
]. In an initial meta-analysis, somatostatin was found to be effective (OR, 0.38; 95% CI, 0.22 to 0.65) [12
]. However, in a subsequent large-scale, multicenter, placebo-controlled trial with 382 patients, Andriulli et al. [13
] found that a single dose of somatostatin at 750 µg, started 30 minutes before the procedure and continued for 2 hours afterwards, was ineffective in preventing pancreatitis; pancreatitis occurred in 11.5% of patients who received somatostatin versus 6.5% of those given a placebo. A meta-analysis of somatostatin, in which data from short- and long-term infusion studies were pooled, found somatostatin to be ineffective (OR, 0.68; 95% CI, 0.44 to 1.04; p
= 0.075) [13
]. A recent study from Spain showed that a bolus dose of 250 µg of somatostatin administered immediately before introducing the catheter into the papilla of Vater, did not help prevent post-ERCP acute pancreatitis [20
]. Overall, the use of somatostatin did not reduce PEP.
Octreotide, a synthetic analog of somatostatin, has a much longer half-life [21
]. It decreases the secretion of pancreatic enzymes and reduces intraductal pressure, and, possibly, proteolysis. However, octreotide increases the basal pressure and frequency of phasic contractions of the sphincter of Oddi and might contribute to pancreatic outflow obstruction and, hence, pancreatitis [22
]. Serum levels peak at 4 minutes after intravenous infusion and within 30 minutes after a subcutaneous dose [21
]. Of the published studies of octreotide, most have shown no significant reduction in the frequency of PEP compared with a placebo [21
Relaxation of a sphincter of Oddi spasm
NG is a nitric oxide donor with potent relaxant effects on smooth muscle, including the sphincter of Oddi [25
]. The use of a low-cost drug such as NG to reduce the incidence of PEP is interesting in view of the potentially fatal cases that could be prevented. The influence of NG on the incidence of PEP was evaluated in two meta-analyses that pooled data from five RCTs involving 1,662 patients [26
]. The studies were homogeneous, and both meta-analyses showed an overall significant reduction in PEP. In most patients, NG was administered transdermally. When the subanalysis was restricted to these patients, transdermal NG failed to show a significant reduction in PEP [9
]. The use of NG was associated with a significant risk of transient hypotension and headache.
PDE type 5 (PDE-5) inhibitor
PDE-5 inhibitor is a smooth muscle relaxant. Beyond its original indication for erectile dysfunction [28
] and other vascular diseases, including pulmonary artery hypertension [29
] and Raynaud's phenomenon [30
], clinical investigations have been expanded to include hypercontractile esophageal motility disorders [31
] and biliary SOD [32
]. PDE-5 inhibitor reduces basal sphincter of Oddi pressure [32
]. The administration of PDE-5 inhibitor before ERCP may decrease sphincter of Oddi tone, allow easier cannulation, and ultimately reduce the occurrence of PEP. An RCT that included 278 patients undergoing ERCP showed no significant decrease in the rate of pancreatitis in the treatment group compared with the placebo group (8.0% vs. 7.8%, p
= 0.94) [33
Calcium channel blocker
Nifedipine, a calcium channel antagonist, was ineffective in two RCTs [34
Interruption of the inflammatory cascade
NSAIDs have anti-inflammatory mechanisms of action beyond the inhibition of prostaglandin synthesis. NSAIDs have been shown to be potent inhibitors of phospholipase-A2 (PLA2) activity in the serum of patients with acute pancreatitis when tested in vitro
]. PLA2 catalyzes the hydrolysis of cell membrane phospholipids, leading to the production of numerous inflammatory mediators, and is believed to play a critical role in the initial inflammatory cascade in acute pancreatitis by generating prostaglandins, leukotrienes, kinins, and platelet-activating factor, which, in turn, lead to tissue damage and autodigestion of the pancreas [37
]. PLA2 inhibition leads to the suppression of several important classes of proinflammatory lipids; thus, the use of PLA2 inhibitors has been considered an attractive therapeutic strategy in the treatment of inflammation-related diseases and tissue injury. Diclofenac is second only to indomethacin in its PLA2 inhibitory activity [36
]. In patients undergoing high-risk ERCP, Murray et al. [38
] reported a statistically significant protective effect for 100 mg of diclofenac, administered rectally upon arrival in the recovery area. However, that study showed no benefit in patients with SOD. A study by Cheon et al. [39
] demonstrated no difference in PEP incidence between those given oral diclofenac (50 mg before and after ERCP) and a placebo in 207 predominantly high-risk patients (72% of patients had suspected SOD or underwent pancreatic therapy). Recently, a prospective RCT evaluating the protective effect of rectally administered indomethacin on PEP yielded a statistically conclusive result [6
]. Of the 602 patients enrolled, the majority (82%) were suspected of having SOD. Overall, PEP occurred in 27/295 (9.2%) patients in the indomethacin group versus 52/307 patients in the placebo group (p
= 0.005). This RCT showed that prophylactic rectal indomethacin significantly reduced the incidence and severity of PEP in patients at elevated risk for this complication. Whether the route of delivery of prophylactic NSAIDs affects the clinical efficacy is still an area of uncertainty. Suppository medications have reduced relative bioavailability compared with oral formulations for most drugs [40
], attributable to erratic absorption and loss through the anal sphincter. However, by the oral route, drugs may be destroyed by gastric acidity. Delayed-release diclofenac (enteric-coated), as used in this study, resists dissolution at the low pH of gastric fluids but is rapidly released in the higher pH environment of the duodenum. It is completely absorbed from the gastrointestinal tract after oral administration, but the bioavailability is only about 50% to 60% because of extensive first-pass metabolism, possibly as a result of intestinal cytochrome P450 (CYP2C9, 3A4, and 3A5) [41
]. After the oral ingestion of diclofenac, peak plasma levels are reached in about 2 hours (range, 1 to 4) in fasting healthy volunteers; on the other hand, peak plasma levels with rectal administration are reached within 30 minutes [39
]. These time differences are probably significant clinically.
In summary, the prophylactic rectal administration of NSAIDs (indomethacin and diclofenac) may result in a substantial reduction in the incidence of PEP, translating into major medical and economic benefits.
OTHER ANTI-INFLAMMATORY DRUGS
Recombinant IL-10 has been evaluated for prophylactic immunomodulation of the proinflammatory cascade [42
]. An initial RCT that included 144 higher-risk patients undergoing ERCP found lower rates of pancreatitis in each of two treatment groups (3% at 4 µg/kg and 5% at 20 µg/kg) versus the control group (11%, p
]. Two subsequent trials did not confirm this benefit [43
Xanthine oxidase inhibitors, such as allopurinol, might prevent PEP by inhibiting the generation of oxygen-derived free radicals. However, an RCT found no difference in the frequency of PEP in patients given allopurinol (12.1%) compared with those given a placebo (7.9%) [45
A role for corticosteroids of various forms (methylprednisolone, prednisone, and hydrocortisone) has been investigated. Several RCTs with large numbers of patients demonstrated no benefit, or trend towards a benefit, for various corticosteroid formulations [45
Heparin has a direct inhibitory effect on pancreatic proteases in both plasma and pancreatic tissue and improves pancreatic microcirculation during experimental pancreatitis [48
]. The potential of subcutaneous heparin as a prophylactic agent for PEP has been evaluated in two RCTs that included 564 patients [49
]. One of these, a prospective RCT that included 438 patients, found that low-molecular weight heparin did not result in even a trend towards a protective effect against PEP (8.8% vs. 8.1%, p
= 0.87) [50
There are many drugs that theoretically could have a role in the prevention of PEP and which may have shown promise in animal studies or even a single, randomized clinical study. When clinical studies are repeated elsewhere, however, the results are frequently disappointing. The most promising agents, NSAIDs (indomethacin and diclofenac) can reduce the incidence of PEP. Effective PEP prophylaxis has only been demonstrated using diclofenac or indomethacin administered rectally. NSAIDs are inexpensive and simple to administer, and encouraging results have been obtained with these agents. Indeed, today, routine rectal administration of diclofenac or indomethacin immediately before or after ERCP is recommended for the prevention of PEP. However, additional studies of NSAIDs with larger numbers of subjects are necessary to confirm the prophylactic effect and to establish whether these medications act synergistically with other prophylactic interventions, including pancreatic stenting.
Conflict of interest
No potential conflict of interest relevant to this article is reported.
1. Freeman ML, Nelson DB, Sherman S, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996;335:909–918. PMID : 8782497.
2. Masci E, Mariani A, Curioni S, Testoni PA. Risk factors for pancreatitis following endoscopic retrograde cholangiopancreatography: a meta-analysis. Endoscopy 2003;35:830–834. PMID : 14551860.
3. Cheon YK, Cho KB, Watkins JL, et al. Frequency and severity of post-ERCP pancreatitis correlated with extent of pancreatic ductal opacification. Gastrointest Endosc 2007;65:385–393. PMID : 17321236.
4. Chen YK, Foliente RL, Santoro MJ, Walter MH, Collen MJ. Endoscopic sphincterotomy-induced pancreatitis: increased risk associated with nondilated bile ducts and sphincter of Oddi dysfunction. Am J Gastroenterol 1994;89:327–333. PMID : 8122639.
5. Freeman ML, Guda NM. Prevention of post-ERCP pancreatitis: a comprehensive review. Gastrointest Endosc 2004;59:845–864. PMID : 15173799.
7. Cotton PB, Lehman G, Vennes J, et al. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointest Endosc 1991;37:383–393. PMID : 2070995.
8. Murray WR. Reducing the incidence and severity of post ERCP pancreatitis. Scand J Surg 2005;94:112–116. PMID : 16111092.
9. Dumonceau JM, Andriulli A, Deviere J, et al. European Society of Gastrointestinal Endoscopy (ESGE) Guideline: prophylaxis of post-ERCP pancreatitis. Endoscopy 2010;42:503–515. PMID : 20506068.
10. Nishijima MK, Takezawa J, Taenaka N, Shimada Y, Yoshiya I. Application of HPLC measurement of plasma concentration of gabexate mesilate. Thromb Res 1983;31:279–284. PMID : 6415853.
11. Cavallini G, Tittobello A, Frulloni L, Masci E, Mariana A, Di Francesco V. Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography: gabexate in digestive endoscopy: Italian Group. N Engl J Med 1996;335:919–923. PMID : 8786777.
12. Andriulli A, Leandro G, Niro G, et al. Pharmacologic treatment can prevent pancreatic injury after ERCP: a meta-analysis. Gastrointest Endosc 2000;51:1–7. PMID : 10625786.
13. Andriulli A, Clemente R, Solmi L, et al. Gabexate or somatostatin administration before ERCP in patients at high risk for post-ERCP pancreatitis: a multicenter, placebo-controlled, randomized clinical trial. Gastrointest Endosc 2002;56:488–495. PMID : 12297762.
14. Fujishiro H, Adachi K, Imaoka T, et al. Ulinastatin shows preventive effect on post-endoscopic retrograde cholangiopancreatography pancreatitis in a multicenter prospective randomized study. J Gastroenterol Hepatol 2006;21:1065–1069. PMID : 16724996.
15. Tsujino T, Komatsu Y, Isayama H, et al. Ulinastatin for pancreatitis after endoscopic retrograde cholangiopancreatography: a randomized, controlled trial. Clin Gastroenterol Hepatol 2005;3:376–383. PMID : 15822043.
16. Ueki T, Otani K, Kawamoto K, et al. Comparison between ulinastatin and gabexate mesylate for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a prospective, randomized trial. J Gastroenterol 2007;42:161–167. PMID : 17351806.
17. Yoo JW, Ryu JK, Lee SH, et al. Preventive effects of ulinastatin on post-endoscopic retrograde cholangiopancreatography pancreatitis in high-risk patients: a prospective, randomized, placebo-controlled trial. Pancreas 2008;37:366–370. PMID : 18953247.
18. Abdel Aziz AM, Lehman GA. Pancreatitis after endoscopic retrograde cholangio-pancreatography. World J Gastroenterol 2007;13:2655–2668. PMID : 17569133.
19. Andriulli A, Caruso N, Quitadamo M, et al. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis: the evidence-based medicine derived from a meta-analysis study. JOP 2003;4:41–48. PMID : 12555015.
20. Vila JJ, Jimenez FJ, Prieto C, Borobio E, Juanmartinena JF, Borda F. Utility of bolus somatostatin administration in preventing pancreatitis after endoscopic retrograde cholangiopancreatography: a controlled, non-randomized study. Gastroenterol Hepatol 2006;29:231–236. PMID : 16584693.
21. Sternlieb JM, Aronchick CA, Retig JN, et al. A multicenter, randomized, controlled trial to evaluate the effect of prophylactic octreotide on ERCP-induced pancreatitis. Am J Gastroenterol 1992;87:1561–1566. PMID : 1279967.
22. Binmoeller KF, Dumas R, Harris AG, Delmont JP. Effect of somatostatin analog octreotide on human sphincter of Oddi. Dig Dis Sci 1992;37:773–777. PMID : 1563323.
23. Arcidiacono R, Gambitta P, Rossi A, Grosso C, Bini M, Zanasi G. The use of a long-acting somatostatin analogue (octreotide) for prophylaxis of acute pancreatitis after endoscopic sphincterotomy. Endoscopy 1994;26:715–718. PMID : 7536155.
24. Tulassay Z, Dobronte Z, Pronai L, Zagoni T, Juhasz L. Octreotide in the prevention of pancreatic injury associated with endoscopic cholangiopancreatography. Aliment Pharmacol Ther 1998;12:1109–1112. PMID : 9845400.
26. Bang UC, Nojgaard C, Andersen PK, Matzen P. Meta-analysis: nitroglycerin for prevention of post-ERCP pancreatitis. Aliment Pharmacol Ther 2009;29:1078–1085. PMID : 19236312.
27. Shao LM, Chen QY, Chen MY, Cai JT. Nitroglycerin in the prevention of post-ERCP pancreatitis: a meta-analysis. Dig Dis Sci 2010;55:1–7. PMID : 19160042.
28. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction: Sildenafil Study Group. N Engl J Med 1998;338:1397–1404. PMID : 9580646.
29. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148–2157. PMID : 16291984.
30. Fries R, Shariat K, von Wilmowsky H, Bohm M. Sildenafil in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy. Circulation 2005;112:2980–2985. PMID : 16275885.
32. Cheon YK, Cho YD, Moon JH, et al. Effects of vardenafil, a phosphodiesterase type-5 inhibitor, on sphincter of Oddi motility in patients with suspected biliary sphincter of Oddi dysfunction. Gastrointest Endosc 2009;69:1111–1116. PMID : 19243765.
33. Oh HC, Cheon YK, Cho YD, Do JH. Use of udenafil is not associated with a reduction in post-ERCP pancreatitis: results of a randomized, placebo-controlled, multicenter trial. Gastrointest Endosc 2011;74:556–562. PMID : 21802079.
34. Prat F, Amaris J, Ducot B, et al. Nifedipine for prevention of post-ERCP pancreatitis: a prospective, double-blind randomized study. Gastrointest Endosc 2002;56:202–208. PMID : 12145597.
35. Sand J, Nordback I. Prospective randomized trial of the effect of nifedipine on pancreatic irritation after endoscopic retrograde cholangiopancreatography. Digestion 1993;54:105–111. PMID : 8319838.
36. Makela A, Kuusi T, Schroder T. Inhibition of serum phospholipase-A2 in acute pancreatitis by pharmacological agents in vitro. Scand J Clin Lab Invest 1997;57:401–407. PMID : 9279965.
37. Niederau C, Schulz HU. Current conservative treatment of acute pancreatitis: evidence from animal and human studies. Hepatogastroenterology 1993;40:538–549. PMID : 8119638.
38. Murray B, Carter R, Imrie C, Evans S, O'Suilleabhain C. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography. Gastroenterology 2003;124:1786–1791. PMID : 12806612.
39. Cheon YK, Cho KB, Watkins JL, et al. Efficacy of diclofenac in the prevention of post-ERCP pancreatitis in predominantly high-risk patients: a randomized double-blind prospective trial. Gastrointest Endosc 2007;66:1126–1132. PMID : 18061712.
40. van Hoogdalem EJ, de Boer AG, Breimer DD. Pharmacokinetics of rectal drug administration, part II: clinical applications of peripherally acting drugs, and conclusions. Clin Pharmacokinet 1991;21:110–128. PMID : 1884566.
41. van der Marel CD, Anderson BJ, Romsing J, Jacqz-Aigrain E, Tibboel D. Diclofenac and metabolite pharmacokinetics in children. Paediatr Anaesth 2004;14:443–451. PMID : 15153204.
42. Deviere J, Le Moine O, Van Laethem JL, et al. Interleukin 10 reduces the incidence of pancreatitis after therapeutic endoscopic retrograde cholangiopancreatography. Gastroenterology 2001;120:498–505. PMID : 11159890.
43. Morrow JB, Zuccaro G Jr, Conwell DL, et al. Sedation for colonoscopy using a single bolus is safe, effective, and efficient: a prospective, randomized, double-blind trial. Am J Gastroenterol 2000;95:2242–2247. PMID : 11007224.
44. Sherman S, Cheng CL, Costamagna G, et al. Efficacy of recombinant human interleukin-10 in prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis in subjects with increased risk. Pancreas 2009;38:267–274. PMID : 19214137.
45. Budzynska A, Marek T, Nowak A, Kaczor R, Nowakowska-Dulawa E. A prospective, randomized, placebo-controlled trial of prednisone and allopurinol in the prevention of ERCP-induced pancreatitis. Endoscopy 2001;33:766–772. PMID : 11558030.
46. De Palma GD, Catanzano C. Use of corticosteriods in the prevention of post-ERCP pancreatitis: results of a controlled prospective study. Am J Gastroenterol 1999;94:982–985. PMID : 10201469.
47. Sherman S, Blaut U, Watkins JL, et al. Does prophylactic administration of corticosteroid reduce the risk and severity of post-ERCP pancreatitis: a randomized, prospective, multicenter study. Gastrointest Endosc 2003;58:23–29. PMID : 12838216.
48. Toulon P, Chadeuf G, Bouillot JL, et al. Involvement of heparin cofactor II in chymotrypsin neutralization and in the pancreatic proteinase-antiproteinase interaction during acute pancreatitis in man. Eur J Clin Invest 1991;21:303–309. PMID : 1909634.
49. Barkay O, Niv E, Santo E, Bruck R, Hallak A, Konikoff FM. Low-dose heparin for the prevention of post-ERCP pancreatitis: a randomized placebo-controlled trial. Surg Endosc 2008;22:1971–1976. PMID : 18214607.
50. Rabenstein T, Fischer B, Wiessner V, et al. Low-molecular-weight heparin does not prevent acute post-ERCP pancreatitis. Gastrointest Endosc 2004;59:606–613. PMID : 15114301.