Gabexate Mesylate-Poloxamer 407 Conjugate Alleviates Sodium Taurocholate-Induced Severe Acute Pancreatitis in an Optimized Rat Model.

BACKGROUND AND AIMS: We have previously shown that gabexate mesylate-poloxamer 407 conjugate (GMTI) alleviates traumatic pancreatitis in rats. In this study, we evaluated the therapeutic effect of GMTI on sodium taurocholate-induced severe acute pancreatitis (SAP) in an optimized rat model. METHODS: An SAP rat model was established via microinjection of 3.5% sodium taurocholate and retention in the bile duct for 1 min. SAP rats were administered GMTI via tail vein injection (i.v.) or tail vein injection + intraperitoneal injection (i.v. + i.p.). All rats were sacrificed at 12 h after treatment. Biochemical approach and enzyme-linked immunosorbent assay were performed to measure the serum levels of amylase (AMY), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). Hematoxylin and eosin staining and TUNEL assay were conducted to examine histopathology and acinar cell apoptosis in the rat pancreas. RESULTS: SAP was successfully induced in all model rats, as evidenced by progressively aggravating SAP symptoms and signs, pancreatic histopathological abnormalities, as well as elevated serum levels of TNF-α, IL-6, and AMY. The mortality rates at 1 h, 6 h, and 12 h were 0%, 0%, and 25%, respectively. GMTI therapy via i.v. or i.v. + i.p. significantly reduced pancreatic wet weights, ascites amounts, pathological scores, and circulating levels of TNF-α and IL-6 while promoting acinar cell apoptosis in SAP rats. GMTI therapy via i.v. + i.p. outperformed i.v. in improving pancreatic histology and reducing TNF-α and IL-6 serum levels in SAP rats. CONCLUSIONS: Our optimized SAP rat model is reliable and reproducible. GMTI therapy is a promising approach against SAP.

A phase 1/2 trial to evaluate the pharmacokinetics, safety, and efficacy of NI-03 in patients with chronic pancreatitis: study protocol for a randomized controlled trial on the assessment of camostat treatment in chronic pancreatitis (TACTIC).

BACKGROUND: Chronic pancreatitis (CP) is a progressive, fibro-inflammatory disease characterized by enzymatic autoactivation and subsequent fibrotic replacement of acinar cells. A significant proportion of patients develop pain, which may be due to many causes, including perineural inflammation, altered central processing of pain signals, parenchymal structural changes, and ductal obstruction. Currently there are no approved medical treatment options for CP-associated pain. NI-03 (camostat mesilate) is an orally administered serine protease inhibitor that reduces pancreatic enzyme activity and has been widely used for the treatment of CP-associated pain in Japan. The current study will assess the safety and efficacy of NI-03 for reduction of CP-associated pain in the USA. METHODS: The current study consists of two phases. First, a phase I study will be performed to establish the pharmacokinetics and safety profile over a 1-week period following a single dose (100, 200, or 300 mg). Subsequently, a phase II study will be performed consisting of a double-blind, randomized, controlled trial (RCT). This RCT will evaluate the efficacy of each of the three doses of NI-03 given three times daily compared to placebo over 28 days. A 7-day, single-blind, run-in period will precede the double-blind phase to assess baseline pain characteristics. The primary efficacy outcome is the average of worst daily pain scores (numeric rating scale of 0-10) over the terminal 7 days of the study period compared to baseline. Secondary efficacy outcomes include change in opioid dose and quality of life measures, and time to first rescue intravenous analgesic. Adverse events will be recorded. DISCUSSION: NI-03 has been used successfully and safely in Japan to treat CP-associated pain. The aim of the current study is to assess the safety and efficacy of NI-03 using a rigorous RCT in a population in the USA. This study may fill an important clinical gap to provide an effective medical treatment option for CP-associated pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02693093 . Registered through the National Institutes of Health on 26 February 2016.

Autoimmune hepatitis following drug-induced liver injury in an elderly patient.

We describe a case of autoimmune hepatitis (AIH) that may have occurred following drug-induced liver injury with camostat mesilate and/or benzbromarone in an elderly patient. The patient's liver biopsy showed chronic active hepatitis and autoimmune hepatitis. Stopping the use of these drugs did not lead to complete remission, but the use of a low dose of corticosteroids completely cured his liver dysfunction. In the present case, liver dysfunction was caused by an autoimmune mechanism. Special attention should be paid to idiopathic AIH and drug-induced AIH in elderly patients.

Effect and cost of treatment for acute pancreatitis with or without gabexate mesylate: a propensity score analysis using a nationwide administrative database.

OBJECTIVES: Despite a lack of evidence, gabexate mesylate (GM) is routinely used for the treatment of acute pancreatitis (AP) in some countries. The present study examined the effect and cost of GM for AP treatment using the Japanese Diagnosis Procedure Combination database. METHODS: We performed a propensity score analysis to compare inhospital mortality, length of stay (LOS), and total costs between patients with AP treated with GM and those without GM in 2010. RESULTS: We identified 2483 patients treated with GM and 890 patients without GM. Overall, 77% of the patients treated with GM were nonsevere AP cases. The propensity-matched 707 pairs showed no significant difference between GM users and nonusers in inhospital mortality or median length of stay in nonsevere AP (1.0% vs 1.2%, P = 0.789; 10 vs 10 days, P = 0.160) and severe AP (8.4% vs 5.0%, P = 0.438; 12 vs 14 days, P = 0.487) cases. Total costs were significantly different between the GM users and the nonusers in nonsevere AP cases (US$4982 vs US$4373, P < 0.001), but not in severe AP cases ($6605 vs $6490, P = 0.764). CONCLUSIONS: Using GM for nonsevere AP cannot be justified because of higher costs without significant effects. Gabexate mesylate use is also not justifiable for severe AP because it does not reduce mortality or length of stay.

Effects of a synthetic protease inhibitor (gabexate mesilate) and a neutrophil elastase inhibitor (sivelestat sodium) on acid-induced lung injury in rats.

The present study was designed to examine the combined effects of a synthetic protease inhibitor, gabexate mesilate, with a specific neutrophil elastase inhibitor, sivelestat sodium, on acid-induced lung injury. Adult male Sprague-Dawley rats weighing 300-350 g were anaesthetised intraperitoneally with pentobarbitone sodium and the right jugular vein was cannulated. Following tracheostomy, rats were ventilated mechanically and underwent intratracheal instillation of hydrochloric acid (HCl, 0.1N 1.5 ml/kg) or normal saline. Gabexate mesilate (10mg/kg, i.p.) and/or sivelestat sodium (10mg/kg/h, i.v.) were administered 30 min before HCl instillation. Bronchoalveolar lavage fluid samples were obtained 5h after HCl instillation. In bronchoalveolar lavage fluid, the HCl-induced increases in total nucleated cell counts, neutrophil counts, optical density at 412 nm as an index of pulmonary haemorrhage, concentrations of albumin and cytokine-induced neutrophil chemoattractant (CINC) were significantly attenuated by either gabexate mesilate or sivelestat sodium treatment. Gabexate mesilate or sivelestat sodium treatment also significantly attenuated the wet to dry weight ratio induced by HCl. However, combined treatment with both gabexate mesilate and sivelestat sodium did not show additive effects on HCl-induced lung injury, compared with single treatments. These findings suggested that gabexate mesilate and sivelestat sodium each exhibited protective effects on acid-induced lung injury, but that synergistic effects of both agents are limited in this acid-induced lung injury model.

[Case of hyperkalemia possibly caused by gabexate mesilate].

We report a case of hyperkalemia in a recipient of living-related liver transplantation. The patient received a continuous infusion of gabexate mesilate at 60 mg x hr(-1) starting about 1 hr after the induction of anesthesia. The serum potassium concentration (K+) was increased from 4.53 mEq x l-(1) to 5.08 mEq x l(-1) within about 1 hr. Thereafter, a massive blood loss caused by an accidental damage of the portal vein necessitated rapid fluid therapy to maintain blood pressure. We observed an abnormal ECG recording including a wide QRS complex and a high T wave when about 30 units of leukocytes-reduced red cell concentrates had been transfused. Blood gas analysis showed high K+ (7.52 mEq x l(-1)) and metabolic acidosis (pH 7.167, base excess-12.5 mmol x l(-1)). We successfully controlled K+ with combination of therapies before causing any cardiac events to the patient. Gabexate mesilate is one possible cause of hyperkalemia in the present case because an increase in K+ was observed before transfusion, and transfusion might have augmented the effect. Gabexate mesilate is one of the protease inhibitors. Naphamostat mesilate, another protease inhibitor, is known to cause hyperkalemia by limiting potassium excretion from the kidney through an inhibition of Na/K-ATPase at the cortical collecting ducts. Although the mechanism by which gabexate mesilate causes hyperkalemia is unclear, it would be of benefit to use this drug cautiously, as it may cause hyperkalemia.

Leukemia cutis originating in the extravasation site of i.v. gabexate mesilate infusion.

Leukemia cutis is a localized or disseminated skin infiltration by leukemic cells. A 64-year-old man was diagnosed with acute myeloid leukemia (AML) complicated by disseminated intravascular coagulation. During the course of treatment with gabexate mesilate, the substance accidentally leaked from the infusion site in his elbow. One month later, a dark red erythema and induration accompanied by severe pain appeared in the area proximal to the gabexate mesilate injection site. The biopsy specimen demonstrated not only inflammation but infiltration of leukemic cells as well. Immunohistochemical staining for intercellular adhesion molecule-1 and platelet/endothelial cell adhesion molecule-1 showed strong expression of endothelial cells and leukemic cells. We speculate that the gabexate mesilate might have played a role in the induction of leukemia cutis via adhesion molecules in our case.

Risk for post-ERCP pancreatitis after needle knife precut sphincterotomy following repeated cannulation attempts.

GOALS: The aim of this study was to determine the risk and identify the factors associated with post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis in patients who undergo needle knife precut sphincterotomy (NKS). In addition, we evaluated the effect of gabexate for the prevention of post-ERCP pancreatitis. BACKGROUND: NKS, after repeated cannulation attempts during ERCP, is known to increase the risk of post-ERCP pancreatitis. However, the specific risk factors for post-ERCP pancreatitis have not been identified, and the preventive role of protease inhibitors, such as gabexate, has not yet been established. STUDY: The medical records of 200 patients who underwent NKS, after repeated cannulation attempts during ERCP, were reviewed retrospectively. The potential risk factors for post-ERCP pancreatitis were investigated. The effect of gabexate infused after the ERCP procedure was also evaluated. RESULTS: Thirteen (6.5%) patients out of 200 developed post-ERCP pancreatitis. Sex, age, the presence of pancreatitis at procedure, underlying disease, direction of the sphincterotomy, success or failure of cannulation after NKS, diameter of common bile duct, pancreatic duct status, and the presence of acinar filling were not associated with the risk of pancreatitis. Gabexate infusion after ERCP increased the incidence of ERCP-associated pancreatitis. CONCLUSIONS: We could not identify any risk factors associated with the development of post-ERCP pancreatitis in patients who underwent NKS after repeated cannulation attempts during ERCP. However, gabexate administered after the ERCP procedure was found to increase the incidence of pancreatitis.

Gabexate in the prophylaxis of post-ERCP pancreatitis: a meta-analysis of randomized controlled trials.

BACKGROUND: Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography and the benefit of its pharmacological treatment is unclear. Although prophylactic use of gabexate for the reduction of pancreatic injury after ERCP has been evaluated, the discrepancy about gabexate's beneficial effect on pancreatic injury still exists. This study aimed to evaluate the effectiveness and safety of gabexate in the prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP). METHODS: We employed the method recommended by the Cochrane Collaboration to perform a meta-analysis of randomized controlled trials (RCTs) of gabexate in the prevention of post-ERCP pancreatitis (PEP) including three RCTs conducted in Italy and one in China. RESULTS: All of the four RCTs were of high quality. When the RCTs were analyzed, odds ratios (OR) for gabexate mesilate were 0.67 [95% CI (0.31 to approximately 1.47), p = 0.32] for PEP, 3.78 [95% CI (0.62 to approximately 22.98), p = 0.15] for severe PEP, 0.68 [95% CI (0.19 to approximately 2.43), p = 0.56] for the case-fatality of PEP, 0.88 [95% CI (0.72 to approximately 1.07), p = 0.20] for post-ERCP hyperamylasemia, 0.69 [95% CI (0.39 to approximately 1.21), p = 0.19] for post-ERCP abdominal pain, thus indicating no beneficial effects of gabexate on acute pancreatitis, the death rate of PEP, hyperamylasemia and abdominal pain. No evidence of publication bias was found. CONCLUSION: Gabexate mesilate can not prevent the pancreatic injury after ERCP. It is not recommended for the use of gabexate mesilate in the prophylaxis of PEP.

Does gabexate mesilate affect serum concentrations of acute phase proteins after endoscopic retrograde cholangiopancreatography examination?

BACKGROUND/AIMS: To explore the possibility that the preventive effect of gabexate mesilate on endoscopic retrograde cholangiopancreatography-related acute pancreatitis may be mediated by its modulation of acute phase proteins. METHODOLOGY: Thirty consecutive patients who underwent endoscopic retrograde cholangiopancreatography were randomly assigned to receive 1g of gabexate mesilate (13 patients) or a placebo (17 patients) by continuous i.v. infusion starting 30 minutes before the endoscopy session and continuing for 12 hours afterward. In all patients, C-reactive protein, serum amyloid A and interleukin 6 serum concentrations were determined before endoscopy and 4, 8, 12 and 24 hours afterward. RESULTS: Interleukin 6 basal serum concentrations were not statistically different between patients who had been treated with gabexate mesilate and those who had received the placebo (P = 0.279), whereas C-reactive protein (P = 0.033) and serum amyloid A (P = 0.022) basal values were significantly lower in the gabexate mesilate group than in the placebo group. Compared to basal values, serum interleukin 6 concentrations significantly increased at 4 (P = 0.048) and at 8 (P = 0.025) hours; the increase of serum interleukin 6 concentrations was not significant at 12 (P = 0.092), but became significant at 24 (P = 0.025) hours. C-reactive protein and serum amyloid A serum concentrations increased significantly only at 12 (P = 0.001, P = 0.012, respectively) and 24 (P < 0.001, P = 0.013, respectively) hours. The modifications of serum concentrations of interleukin 6, C-reactive protein and serum amyloid A were not significantly different between the gabexate mesilate and the placebo groups. CONCLUSIONS: Gabexate mesilate does not affect serum concentrations of acute phase proteins after endoscopic retrograde cholangiopancreatography examination and it is able to prevent acute pancreatitis related to endoscopic retrograde cholangiopancreatography via a different mechanism than that explored in this study.

Fatal cases of gabexate mesilate-induced anaphylaxis.

Gabexate mesilate, ethyl-4-(6-guanidinohexanoyloxy) benzoate monomethanesulfonate (C16H23N3 O4CH4O3S: M.W. 417.48), is a synthetic protease inhibitor and was introduced for clinical use in 1978. It rarely induces anaphylaxis, and patients with gabexate mesilate-induced shock had been reported to survive with appropriate treatments including respiratory support. However, there were increasing reports on fatal cases in recent years: 6 cases have been reported to develop fatal anaphylaxis following dripping infusions of gabexate mesilate. All the fatal cases rapidly developed anaphylaxis (within 5 minutes), whereas 7 out of 11 in recovered cases developed it 5 or more minutes after the injection. Venous access should be kept for at least 30 minutes to prepare for and to treat this fatal reaction in patients receiving gabexate mesilate repeatedly.

Multicentre comparative study of two schedules of gabexate mesilate in the treatment of acute pancreatitis. Italian Acute Pancreatitis Study Group.

AIM: To compare the efficacy of two different schedules of gabexate mesilate (900 mg/day, or 1,500 mg/day) in the treatment of severe acute pancreatitis. SETTING: Forty-two Italian medical and surgical centres took part in the study. STUDY DESIGN: A multicentre, prospective, open label, comparative, parallel-group, randomized study. METHODS: The patients enrolled in the study had acute pancreatitis as demonstrated by typical abdominal pain and baseline serum amylase concentrations more than twice the upper normal limit, findings compatible with acute pancreatitis at imaging techniques, and a Glasgow criteria score of > or =3. Patients were randomly assigned to one of the two schedules of treatment with gabexate mesilate being administered intravenously for at least 7 days. The minimum clinically relevant difference (delta), between groups, in incidence of complications due to acute pancreatitis, during the first month of the study treatment, was predefined as equal to 10%. RESULTS: A total of 199 patients were assigned to gabexate mesilate 900 treatment and 189 to gabexate mesilate 1,500. Complications developed in 88 patients within one month of beginning treatment 44/199: patients (22.1%) in the gabexate mesilate 900 group and 44/189 patients (23.3%) in the gabexate mesilate 1,500 group (difference 1.2%; 95% confidence interval: -7.2; 9.5%). CONCLUSIONS: Gabexate mesilate 900 mg per day is as effective as gabexate mesilate 1,500 mg per day in reducing the complications due to acute pancreatitis.

Is protease inhibitor a choice for the treatment of pre- or mild disseminated intravascular coagulation?

OBJECTIVE: To investigate the effect of a protease inhibitor, gabexate mesylate, on patients with pre- or mild disseminated intravascular coagulation (DIC) in comparison with a control group receiving no anticoagulation therapy. DESIGN: Prospective, randomized, controlled study. SETTING: General intensive care unit at a general hospital. PATIENTS: Adult patients (40) with a DIC score between 6 and 8 (pre- or mild DIC). INTERVENTIONS: In 20 patients, gabexate mesylate (2 mg/kg/hr) was administered as 2 mL/hr in saline (treated group) and in another 20 patients, saline (2 mL/hr; control group) was administered during the study (7 days). MEASUREMENTS AND MAIN RESULTS: The following variables were determined at the time of admission to the intensive care unit before treatment and 1, 3, 5, and 7 days thereafter: platelet count, antithrombin III activity, serum or plasma concentrations of fibrinogen, fibrin degradation product, D-dimer, fibrin monomer, thrombin-antithrombin III complex, and plasmin-plasmin inhibitor complex, prothrombin time ratio, and DIC score. Two patients in the treated group and four in the control group were excluded from the study because they died during the study; therefore, 34 patients were analyzed. The measured variables of coagulation and fibrinolysis were not significantly different between the two groups, except for the D-dimer on day 3 (the treated group showed a higher concentration). D-dimer concentration and DIC score went down more quickly in the control group than the treated group, but not significantly. The mortality rate at 1 month was 40% (8 of 20) in the treated group and 35% (7 of 20) in the control group, without any differences between the two groups. CONCLUSIONS: In a limited number of patients (n = 34), gabexate mesylate (2 mg/kg/hr) could not inhibit coagulation or fibrinolysis and gabexate mesylate could not improve the DIC score or mortality rate in pre- or mild DIC.

Effects of a protease inhibitor on reduction of surgical stress in esophagectomy.

OBJECTIVE: To evaluate the efficacy of gabexate mesilate (GM) in reducing surgical stress after esophagectomy. METHODS: In a prospective, randomized, clinical study, 11 patients with squamous cell carcinoma of the esophagus were randomly assigned to two groups: 5 patients were continuously administered gabexate mesilate 1.5 mg/kg per hour from the beginning of anesthesia until the third postoperative day (preop GM group); and 6 patients were administered gabexate mesilate 1.5 mg/kg per hour continuously from the end of surgery and for the same postoperative period (postop GM group). Blood samples were taken from all patients before surgery, immediately after it, and 3 days after surgery. Serum interleukin-6 (IL-6) level, tumor necrosis factor-alpha (TNF-alpha) production, and Mac-1 antigen expression of peripheral blood monocytes were measured. Clinical courses of patients in the two groups were compared. RESULTS: Time courses of serum IL-6 levels in the preop GM group were significantly lower than those in the postop GM group. Ex vivo TNF-alpha production by lipopolysaccharide (LPS) stimulated monocyte was much higher than that by monocyte without LPS stimulation. Gabexate mesilate showed a little inhibition of TNF-alpha production by monocyte without LPS stimulation. On the other hand, gabexate mesilate significantly inhibited TNF-alpha production by LPS stimulated monocyte. Mac-1 antigen expression by monocyte immediately after operation in the preop GM group was significantly lower than that in the postop GM group. Duration of systemic inflammatory response syndrome was significantly shorter in the preop GM group than in the postop GM group. CONCLUSIONS: Reduction of systemic inflammatory response syndrome duration after esophagectomy by the continuous administration of gabexate mesilate started before operation may be through the suppression of TNF-alpha production capacity and Mac-1 expression on monocytes immediately after operation, and to suppression of increase in serum IL-6 level.

Severe cutaneous and venous damage after DIC therapy.

A 79-year-old woman with skin ulcers caused by disseminated intravascular coagulation (DIC) therapy is reported. The patient had been treated by injection of drugs, including gabexate mesilate, into the right great saphenous vein. The maximum concentration of gabexate mesilate was calculated as 0.893%. Although the drugs did not extravasate, purpura initially appeared around the affected vein, followed by brown pigmentation with infiltration and ulcers with widely necrotic tissue from the middle portion of her thigh to the malleolus along her right great saphenous vein. As the ulcer showed no tendency to heal for more than 3 months, surgical debridement and skin grafts were performed.

Panniculitis with eosinophilic infiltration due to gabexate mesilate (FOY): possibility of allergic reaction.

A 59-year-old Japanese man developed septal panniculitis with eosinophilic infiltration in both forearms and the dorsum of the left hand after a gabexate mesilate intravenous drip infusion for acute pancreatitis through catheters implanted in these sites. Gabexate mesilate at a dose of 1000 mg per day had been given continuously for 8 days, and antibiotics were added by the same infusion route twice a day. All the infusion routes, however, became occluded one after the other. Reddish swelling first occurred at the left wrist 6 hours after occlusion of the infusion route, and, on both forearms, reddish swelling occurred about one week after the occlusion of each route. Patch testing revealed a +2 reaction to gabexate mesilate (10% pet) at days 3 and 7, and skin testing revealed indurated erythema to gabexate mesilate (0.1% aq) at days 2 and 3. The specimens biopsied from the positive skin testing reaction sites showed perivascular infiltrate and slight septal panniculitis. The inflammatory infiltrate consisted predominantly of lymphocytes with small numbers of eosinophils. Staining of the specimen biopsied from the right forearm lesion with anti-eosinophil cationic protein (ECP) antibodies (EG1 and EG2) showed deposition of eosinophil-derived granule proteins at the damaged septal connective tissues of the panniculitis. The panniculitis improved with topical steroid treatment. This case suggested that the concentration of infused gabexate mesilate may have been high enough to damage blood vessels and that gabexate mesilate may have leaked into the surrounding connective tissues, inducing allergic reactions and resulting in lesions.

Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography. Gabexate in digestive endoscopy--Italian Group.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is associated with elevated levels of pancreatic enzymes and pancreatitis. Gabexate, a protease inhibitor, has been used to prevent pancreatic damage related to ERCP. METHODS: We conducted a multicenter, double-blind comparison of gabexate (1 g given by intravenous infusion starting 30 to 90 minutes before endoscopy and continuing for 12 hours afterward) with placebo (mannitol and sodium chloride, administered in the same fashion). A total of 435 adults scheduled to undergo ERCP and, when indicated, endoscopic sphincterotomy underwent randomization; 17 were excluded from the final analysis for various reasons. The remaining 418 patients (mean age, 60.4 years)--208 in the gabexate group and 210 in the placebo group--were analyzed. Acute pancreatitis was considered to be present if serum amylase or lipase levels (or both) were five times greater than the upper limits of normal in association with the onset of pancreatic pain. RESULTS: After the procedures, 276 patients (66 percent) had elevated pancreatic-enzyme levels; the frequency was similar in the two groups. Mean serum amylase values were higher in the placebo group than in the gabexate group through 24 hours of observation (P=0.03). Twelve patients in the gabexate group and 29 in the placebo group had abdominal pain (6 percent vs. 14 percent, P=0.009). Sixteen patients in the placebo group and five in the gabexate group had acute pancreatitis (8 percent vs. 2 percent, P=0.03). Two patients treated with gabexate and six given placebo had adverse events, all of which resolved. Two patients given placebo died of acute pancreatitis; one was excluded from the evaluation because pancreatitis was present before endoscopy. One patient in the gabexate group died, from a myocardial infarction. CONCLUSION: Prophylactic treatment with gabexate reduced pancreatic damage related to ERCP, as reflected by reductions in the extent but not the frequency of elevated enzyme levels and in the frequency of pancreatic pain and acute pancreatitis.