Local administration of human pancreatic secretory trypsin inhibitor prevents the development of experimental acute pancreatitis in rats and dogs

The objective of this investigation was to test the capacity of recombinant human pancreatic secretory trypsin inhibitor (rhPSTI) to provide prophylaxis against experimental pancreatitis. Acute hemorrhagic pancreatitis was induced by intraductal injection of sodium taurocholate in rats and by intraductal injection of bile in dogs. In one treatment group of rats the injection of taurocholate was preceded by injection of rhPSTI. In a second group of rats the rhPSTI was given intraperitoneally starting 15 min after the induction of acute pancreatitis. The survival rate in a control group of rats was 13%. In contrast, the survival rate in groups receiving rhPSTI intraductally or intraperitoneally was 80% and 63%, respectively. The survival rate in a control group of dogs was 40% at 24 h and 0% at 48 h. In contrast, all the dogs receiving a single intraductal dose of rhPSTI, either immediately before the bile injection or mixed with the bile, survived for up to 6 weeks. Detailed biochemical and immunohistologic studies in the dog indicate that, whereas rhPSTI cannot prevent the initial bile-induced injury, it does prevent the subsequent development of that injury to the point where there is massive damage to the pancreas and the surrounding tissues, and changes in blood chemistry. The development of the initial injury is, therefore, presumed to involve activation of trypsinogen. Since rhPSTI prevents the serious consequences of experimental pancreatic injury by blocking the action of trypsin, and since the pathobiochemistry of human acute pancreatitis also implies an important role for trypsin, it is possible that rhPSTI could protect humans from the pancreatitis that complicates endoscopic retrograde cholangiopancreatography and endoscopic papillotomy.     

Beneficial effect of therapeutic infusion of nafamostat mesilate (FUT-175) on hemodynamics in experimental acute pancreatitis

Acute pancreatitis was induced in 13 anesthetized dogs by retrograde injection of bile mixed with trypsin into the pancreatic duct. Six animals were treated with intravenous infusion of new synthetic antiprotease. Nafamostat Mesilate, at a dose of 1 mg/kg/h. Four out of seven untreated animals died during the experiment. All the treated dogs survived. Hemodynamic data were regularly monitored during a ten-hour observation period. Cardiac output, mean arterial pressure and left ventricular stroke volume decreased rapidly in the untreated animals. An increase in systemic vascular resistance and pulmonary vascular resistance was observed in dogs without treatment. Nafamostat Mesilate given as therapy significantly improved the hemodynamic parameters, and prevented the animals from developing shock. The study demonstrates an advantageous influence of synthetic antiprotease Nafamostat Mesilate on the course of acute experimental pancreatitis.     

Continuous peritoneal dialysis in acute experimental pancreatitis in dogs. Effect of aprotinin in the dialysate medium

In 27 beagle dogs, acute necrotizing pancreatitis was induced by retrograde injection of autologous bile and trypsin into the main pancreatic duct. Animals were randomly assigned to the following treatments: group 1--(9 dogs) aprotinin 600,000 KIU/d by i.v. route; group 2--(9 dogs) peritoneal dialysis for 6 d plus 500,000 KIU/L of aprotinin in the dialysate fluid; group 3--(9 dogs) peritoneal dialysis without aprotinin in the dialysate fluid. All dogs of the group 1 died within 16 h following the induction of pancreatitis and extensive necrotizing and hemorrhagic changes were seen in the pancreatic and peripancreatic areas. Six dogs of the group 2 survived and no necrotizing changes were observed 30 or 50 d after the induction of pancreatitis. Three dogs of the group 3 survived, but slight necrotizing lesions were found at the autopsy. The survival rate was higher in dogs with peritoneal lavage (p = 0.0129) or with peritoneal lavage plus aprotinin (p less than 0.0001) than in those receiving i.v. aprotinin, indicating that the latter treatment has no beneficiary effect on the course of acute pancreatitis.     

Effects of recombinant canine stem cell factor, a c-kit ligand, and recombinant granulocyte colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation

The effects of recombinant canine stem cell factor (rcSCF) on hematopoiesis were studied in normal dogs and in dogs given otherwise lethal total body irradiation (TBI) without marrow transplant. Results were compared with previous and concurrent data with recombinant granulocyte colony-stimulating factor (rG-CSF). Four normal dogs received 200 micrograms rcSCF per kilogram body weight daily either by continuous intravenous infusion for 28 days (n = 2) or by subcutaneous (SC) injection in two divided doses for 20 days (n = 2). All dogs showed at least a twofold increase in peripheral blood neutrophil counts starting approximately 7 days after the initiation of treatment. Hematocrit level and monocyte, lymphocyte, eosinophil, reticulocyte, and platelet counts were not elevated. Marrow sections after rcSCF treatment showed panhyperplasia. The only toxicity was facial edema during the first few days of rcSCF administration, presumably caused by mast cell stimulation. Ten dogs were given 400 cGy TBI at 10 cGy/min from two opposing 60Co sources. They were given no marrow infusion and received 200 micrograms/kg/d rcSCF SC in two divided doses for 21 days starting within 2 hours of TBI. Five of the 10 dogs showed complete and sustained hematopoietic recovery and survived as compared with 1 of 28 control dogs not receiving growth factor (P < .005). RcSCF treatment allowed for hematopoietic recovery in two of seven dogs administered 500 cGy of TBI but in none of five dogs given 600 cGy of TBI. Results with rcSCF are similar to those obtained with rG-CSF. The rate of neutrophil recovery in rcSCF-treated dogs after 400 cGy TBI was not different from that of rG-CSF-treated dogs (P = .65), but the rate of platelet recovery was faster (P = .06) in the rcSCF-treated animals. Combined treatment with rcSCF and rcG-CSF after 500 cGy TBI did not result in strongly improved survival as compared with results obtained with either factor alone.     

Effects on peritoneal proteolysis and hemodynamics of prophylactic and therapeutic infusions of high doses of aprotinin in experimental acute pancreatitis

Acute pancreatitis was induced in pigs by retrograde injection of Na-taurocholate into the pancreatic duct. Chromogenic peptide substrate assays showed increased trypsin (TRY) and plasma kallikrein activity (KK), parallel with a reduction of plasma prekallikrein (PKK) and functional kallikrein inhibition (KKI) values, in the peritoneal exudate in untreated animals. Intravenous high-dose pretreatment or therapy with aprotinin starting 3 h after the induction of acute pancreatitis resulted in significantly increased KKI capacity and unchanged KK and TRY activities in the peritoneal exudate. In test animals receiving aprotinin intravenously a significantly increased survival rate and improved cardiac output and arterial blood pressure were found during the 6-h observation period. All animals treated with aprotinin survived the observation period, whereas 63% of the untreated animals died. The study emphasizes the pathophysiological importance of the plasma kallikrein-kinin system in acute pancreatitis.     

Outcome of patients with acute, necrotizing pancreatitis requiring drainage-does drainage size matter？

AIM： To assess the outcome of patients with acute necrotizing pancreatitis treated by percutaneous drainage with special focus on the influence of drainage size and number.
METHODS： We performed a retrospective analysis of 80 patients with acute pancreatitis requiring percutaneous drainage therapy for infected necroses. Endpoints were mortality and length of hospital stay. The influence of drainage characteristics such as the median drainage size, the largest drainage size per patient and the total drainage plane per patient on patient outcome was evaluated.
RESULTS： Total hospital survival was 66%. Thirty-four patients out of all 80 patients （43%） survived acute necrotizing pancreatitis with percutaneous drainage therapy only. Eighteen patients out of all 80 patients needed additional percutaneous necrosectomy （23%）. Ten out of these patients required surgical necrosectomy in addition, 6 patients received open necrosectomy without prior percutaneous necrosectomy. Elective surgery was performed in 3 patients receiving cholecystectomy and one patient receiving resection of the parathyroid gland. The number of drainages ranged from one to fourteen per patient. The drainage diameter ranged from 8 French catheters to 24 French catheters. The median drainage size as well as the largest drainage size used per patient and the total drainage area used per patient did not show statistically significant influence on mortality.
CONCLUSION： Percutaneous drainage therapy is an effective tool for treatment of necrotizing pancreatitis.Large bore drainages did not prove to be more effective in controlling the septic focus.     

Combined treatment with C1 esterase inhibitor and antithrombin III improves survival in severe acute experimental pancreatitis.

BACKGROUND: Patients with severe acute pancreatitis die of complications closely related to the systemic activation of protease cascades. AIM: To examine the effects of human C1 esterase inhibitor (C1 INH) and antithrombin III (AT III) on two experimental models of acute pancreatitis. METHODS: Oedematous pancreatitis was induced by continuous intravenous infusion of caerulein and haemorrhagic pancreatitis by retrograde injection of sodium taurocholate into the biliopancreatic duct. C1 INH and AT III were given intravenously, either before or after the induction of pancreatitis. Treatment with C1 INH and AT III had no beneficial effect on oedematous pancreatitis. On the other hand, combined C1 INH and AT III therapy improved the survival in haemorrhagic pancreatitis compared with treatment with human serum albumin. This reduction in mortality was found regardless of whether the treatment was given prophylactically or therapeutically. CONCLUSIONS: Treatment with C1 INH and AT III represents a promising therapeutic concept for patients with severe haemorrhagic pancreatitis.     

Surgical therapy of severe acute pancreatitis: a flexible approach gives excellent results

BACKGROUND/AIMS: To evaluate the effectiveness of our surgical strategy in acute and necrotizing pancreatitis we performed this prospective uncontrolled study. METHODOLOGY: Seventy-six patients with severe acute pancreatitis who were operated on between 1989 and 1995 were included in this study. Laparotomy aimed at removal of necrosis, treatment of ongoing necrosis, and correction of concurrent pathology were the principal goals of surgery. This required multiple interventions in 36 patients. RESULTS: Sixty-nine patients with a mean Ranson score of 3 survived, while 7 patients with a mean score of 7 died (9.2% overall mortality). Fifty-six patients (74%) underwent necrosectomy, followed by continuous lavage in 31 cases and laparostomy (provisional closure of abdominal cavity with absorbable mesh) with staged revisions in 14. Necroses were infected in 39% of initial operations. Twenty-two patients had to be re-operated without being scheduled for planned revisions, mostly for abscess formation, bleeding or intestinal ischemia. Mortality of necrotizing pancreatitis was 12.5%. CONCLUSIONS: Surgical therapy of acute necrotizing pancreatitis has to be tailored to the intra- and post-operative situations. In cases of massive or ongoing necrosis, the goal of surgical therapy will not be achieved by a singular intervention but has to be complemented with further treatment.     

Effect of naloxone on the haemodynamics and the outcome of experimental acute pancreatitis in dogs

Endogenous opioid peptides may play a role in the genesis of pancreatic damage in acute pancreatitis. The effects of naloxone on the haemodynamic changes in acute pancreatitis were investigated by inducing it in dogs with pancreatic ductal injection of fresh trypsin-bile mixture. In the control group (n = 8), acute pancreatitis was characterized haemodynamically by falls in the maximum positive and negative dP/dt (+/- dP/dt), cardiac output (CO) and cardiac index (CI), and increases in the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) as well as an early reduction of pancreatic blood flow (PBF). In another set of eight dogs (naloxone group), naloxone was given intravenously 10 min after the induction of acute pancreatitis (80 micrograms/kg as a bolus + 80 micrograms/kg/h for 3 h). Compared with untreated dogs, naloxone significantly increased PBF and the +/- dP/dtmax; prevented the significant decreases in CO and CI and increases in PVR and SVR, and reduced significantly the severity of pancreatitis, as assessed by both the histological staging and the mortality rate. These results suggest that naloxone limits the progression of acute pancreatitis from oedematous to haemorrhagic form. It is proposed that endogenous opioid peptides may play a role in the pathophysiology of acute pancreatitis.     

Association between probiotics and enteral nutrition in an experimental acute pancreatitis model in rats

Background/objectivesRecently, a randomized controlled trial showed that probiotic prophylaxis was associated with an increased mortality in enterally fed patients with predicted severe pancreatitis. In a rat model for acute pancreatitis, we investigated whether an association between probiotic prophylaxis and enteral nutrition contributed to the higher mortality rate.MethodsMale Sprague–Dawley rats were allocated to four groups: 1) acute pancreatitis (n = 9), 2) acute pancreatitis and probiotic prophylaxis (n = 10), 3) acute pancreatitis and enteral nutrition (n = 10), and 4) acute pancreatitis, probiotic prophylaxis and enteral nutrition (n = 11). Acute pancreatitis was induced by intraductal glycodeoxycholate and intravenous cerulein infusion. Enteral nutrition, saline, probiotics and placebo were administered through a permanent jejunal feeding. Probiotics or placebo were administered starting 4 days before induction of pancreatitis and enteral nutrition 1 day before start until the end of the experiment, 6 days after induction of pancreatitis. Tissue samples and body fluids were collected for microbiological and histological examination.ResultsIn all animals, serum amylase was increased six hours after induction of pancreatitis. After fulfilling the experiment, no differences between groups were found in histological severity of pancreatitis, degree of discomfort, weight loss, histological examination of small bowel and bacterial translocation (all p > 0.05). Overall mortality was 10% without differences between groups (p = 0.54).ConclusionNo negative association was found between prophylactic probiotics and enteral nutrition in acute pancreatitis. No new clues for a potential mechanism responsible for the higher mortality and bowel ischaemia in the PROPATRIA study were found.     

The endothelin antagonist bosentan does not improve survival in severe experimental pancreatitis in rats.

BACKGROUND: Severity of pancreatitis seems to be aggravated by impairment of vascular perfusion of the gland. Early mortality occurs within the first few days from the acute consequences of pancreatic injury with subsequent inflammatory response. Because vasoactive substances, including endothelin, seem to contribute to early mortality in acute pancreatitis, we tested the hypothesis that the inhibition of endothelin action could alter the outcome after severe experimental pancreatitis. METHODS: In two groups of rats, pancreatitis was induced by intraductal infusion into the pancreatic duct of 1 microL/g body weight (b.w.) of either a 4% or a 5% sodium taurocholate solution. The mixed endothelin A and endothelin B receptor antagonist bosentan (20 mg/kg b.w.) or vehicle was injected intravenously in 12-h intervals for 3 d starting 1 h after induction of bile acid pancreatitis. This dose of bosentan is known to completely inhibit the effect of exogenous endothelin. The survival rate was monitored for 7 d. Thereafter, the surviving rats were sacrificed and the pancreas was prepared for histological and biochemical evaluation. RESULTS: Irrespective of the treatment protocol (bosentan versus saline), survival was not different in animals challenged with either 4% or 5% sodium taurocholate. The corresponding survival rates were 62% with bosentan and 77% without bosentan in the 4% sodium taurocholate group. In the 5% sodium taurocholate group, the survival rates were 20% with and 27% without bosentan. Morphological and biochemical alterations were identical in control as well as in endothelin-antagonist-treated rats. CONCLUSION: Therapy with the mixed endothelin A and endothelin B receptor antagonist bosentan does not influence the outcome after severe experimental pancreatitis. Therefore, blockade of endothelin A and B receptor subtypes may not be of major importance as a therapeutic principle in this model of experimental pancreatitis.     

Effective peritoneal therapy of acute pancreatitis in the rat with glutaryl-trialanin-ethylamide: a novel inhibitor of pancreatic elastase.

The six hour peritoneal lavage with glutaryl-trialanin-ethylamide, a low molecular competitive inhibitor of pancreatic elastase (IC50-8 mumol/l), effectively suppresses the evolution of taurocholate induced acute pancreatitis in the rat. The lavage alone is followed by a marked decrease of fat necrosis and amylase and lipase activity in serum. The area of pancreatic haemorrhage was significantly reduced only after the lavage solution was supplemented with Glt-Ala3-NHEt. The effect was not enhanced by a bolus injection of the inhibitor before starting the lavage. The combination of Glt-Ala3-NHEt with aprotinin or nafamstate mesilate produced only marginal greater benefit. The effect of Glt-Ala3-NHEt on pancreatic haemorrhage is time and dose related even with delayed onset of the lavage. Animals treated with peritoneal lavage without Get-Ala3-NHEt lived longer than controls (p less than 0.05), but by 60 hours the survival rate of both groups was almost the same (76 v 74%). All animals lavaged with Glt-Ala3-NHEt survived 120 hours and the difference in the survival rate between this and both remaining groups was significant (100% v 76% v 74% - p less than 0.05). The results were considered favourable and preliminary clinical trials of Glt-Ala3-NHEt in subjects with acute pancreatitis justified.     

Acute pancreatitis attributed to the use of interferon alfa-2b

Two patients experienced episodes of acute pancreatitis shortly after starting treatment with interferon alfa-2b (IFN-alpha) for a chronic hepatitis C infection. The first patient was a 40-year-old man who developed acute pancreatitis after 15 weeks of treatment with 3 MU IFN-alpha subcutaneously (SC) 3 times weekly and 1200 mg ribavirin. After disappearance of symptoms and normalization of laboratory values, oral intake of solid foods and IFN-alpha therapy were restarted. Within hours, a relapse of acute pancreatitis occurred. A rechallenge with IFN-alpha 4 days later was followed by a prompt increase in serum lipase level, and IFN-alpha therapy was discontinued. The second patient was a 38-year-old man who developed acute pancreatitis 2 hours after SC administration of 5 MU IFN-alpha. Ultrasound endoscopy showed sludge in the gallbladder. The patient was rechallenged 5 weeks later with 3 MU IFN-alpha SC. Although serum amylase and lipase levels increased after readministration of IFN-alpha, treatment was continued. The patient was readmitted 2 weeks later with severe abdominal pain, and IFN-alpha administration was discontinued. Considering the temporal relationship between the start of IFN-alpha treatment and development of acute pancreatitis, the absence of other clear etiologic factors for acute pancreatitis, disappearance of symptoms after discontinuation of IFN-alpha, and positive reactions to rechallenge, IFN-alpha is the most probable cause for development of acute pancreatitis in these patients.     

急性胆源性胰腺炎早期内镜治疗价值

目的探讨急性胆源性胰腺炎早期内镜治疗的价值及其安全性。方法选择92例急性胆源性胰腺炎患者早期（72h内）行ERCP及内镜治疗（ERCP组），并与同期保守治疗40例（对照组）进行比较。结果ERCP组全部成功实施十二指肠乳头切开取石，72例胆总管结石者行网篮及气囊取石，所有92例均行鼻胆管引流，重症组10例同时行胰管支架引流。ERCP组平均腹痛消失时间、血清淀粉酶恢复时间、平均住院天数及平均费用均明显低于对照组。ERCP组重症组病死率8．3％，对照组重症组病死率33．3％。结论急性胆源性胰腺炎早期ERCP治疗是安全的，能降低患者的病死率，减少患者住院天数和费用。     

Adrenocortical hormones in experimental acute hemorrhagic pancreatitis

Summary and conclusions Acute hemorrhagic pancreatitis was produced in dogs by the injection of a vasotoxic staphylococcal toxin into the nonobstructed pancreatic duct. In one series of experiments, a 33 per cent survival rate in untreated animals increased to 73 per cent in dogs treated with hydrocortisone intramuscularly. In a second series, in which a more concentrated toxin was used, none of the untreated dogs survived, whereas there was a 33 per cent survival rate in dogs treated with intramuscular hydrocortisone.There were no significant differences in white blood cell count, or serum sodium, potassium, chloride, or amylase levels between treated and untreated dogs.The possible mode of action of the adrenocortical hormones in acute hemorrhagic pancreatitis is discussed, and it is suggested that available experimental and clinical evidence warrant further evaluation of the use of the adrenal steroids as a therapeutic adjunct in acute hemorrhagic pancreatitis in human beings.The work described in this article was supported by Research Grant E-1600 from the National Institute of Allergy and Infectious Diseases, U.S.P.H.S.     

合并肾功能衰竭的肝移植患者接受肾脏替代治疗的价值

目的 回顾性分析合并急性肾功能衰竭的肝移植受体移植术前的危险因素,并探讨肾脏替代治疗(RRT)作为其移植前过渡治疗措施的价值. 方法收集2001年1月-2008年1月在卫生部移植医学工程技术研究中心由于急性肾功能衰竭而接受RRT的肝移植受体患者,依据不同预后对肝移植受体的临床特征进行分组对比分析;按接受不同RRT种类对肝移植受体的临床特征进行分组对比分析.用逻辑回归法分析能预测合并肾功能衰竭肝移植受体病死率的指标.对数据进行f检验、χ2检验、Logistic回归分析.结果 在接受RRT的患者中,有31.25%的患者因为肝移植而生存或者出院,68.75%的患者在等待移植期间死亡.死亡组患者与移植组相比,有更高的多器官功能障碍评分(4.98±2.32与4.45±2.02,P=0.008)、更低的平均动脉压[(56.5±7.1)mm Hg与(65.4±12.9)mm HgP=0.040;1 mm Hg=0.133 kPa].RRT的平均治疗天数在连续性肾脏替代治疗组和间歇血液透析组之间的差异没有统计学意义.与间歇血液透析组相比,连续性肾脏替代治疗组有更高的多器官功能障碍评分(4.82±2.12与3.45±1.91,P=0.040)、更低的平均动脉压[(56.0±14.2)mm Hg与(68.5±15.3)mm Hg,P=0.002]、更低的血清肌酐浓度[(320.12±185.15)μmol/L与(420.55±158.32)μmol/L,JP=0.008].肾功能衰竭受体术前平均动脉压越低,则死亡风险越高. 结论对患有急性肾功能衰竭的肝移植受体应用RRT是可取的.尽管病死率仍高,但可使部分患者得以肝移植而生存.     

急性胰腺炎994例病因与治疗分析

目的 探讨急性胰腺炎(AP)的病因及其治疗方法 的选择.方法 回顾性分析2003年1月至2007年1月瑞金医院胰腺普外科收治的994例AP患者资料,根据病因及治疗方式进行分类统计.结果 994例AP患者中,胆源性AP 825例(83.0%),酒精性AP 24例(2.41%),高脂血症性AP29例(2.92%),妊娠性AP16例(1.61%),特发性AP 71例(7.14%),外伤性4例(0.40%),两种病因以上的混合性AP 25例(2.52%).轻症急性胰腺炎(MAP)767例(77.2%),重症急性胰腺炎(SAP)227例(22.8%).总的治愈好转率91.2%,病亡87例,病死率8.8%,其中酒精性AP的病死率达37.5%,显著高于胆源性AP.对胆源性AP患者分别采用非手术治疗、内镜逆行胰胆管造影+乳头括约肌切开(ERCP+EST)、胆囊切除术+胆总管探查或ERCP术后腹腔镜下胆囊切除术及清创引流术.采用清创引流术的患者均为SAP患者,术后病死率高达25.0%,显著高于其他治疗方法 者(P＜0.01).其他3种治疗方法 间的SAP病例比及病死率均无显著差异.结论胆道因素仍是AP的首要病因.酒精性AP病情较危重,预后较差.对胆源性AP,多种治疗方法 的疗效无显著差异.     

The therapeutic effect of a new synthetic protease inhibitor (E-3123) on hemodynamic changes during experimental acute pancreatitis in dogs

The therapeutic effect of a new synthetic protease inhibitor on hemodynamic changes was studied in experimental acute pancreatitis. Pancreatitis was induced by the injection of autologous bile mixed with trypsin into the main pancreatic duct after ligating the accessory duct. Plasma beta-endorphin concentrations and cardiovascular function were measured. Seventeen dogs (control group) were given 10 ml/kg/hr of lactate Ringer’s solution intravenously 1 hr before the induction of pancreatitis and throughout the experiment. Seven dogs (the low protease inhibitor group) were given an intravenous bolus injection of 0.4mg/kg of a new synthetic protease inhibitor, E-3123 (4-(2-succiminido-ethylthio)4-geranidinobenzoate methanesulfate) 30 min after the induction of pancreatitis and then a continuous intravenous infusion at 3 Μg/kg/min throughout the experiment. Seven dogs (the high protease inhibitor group) received an intravenous bolus injection of 3 mg/kg and a continuous intravenous infusion at 50 Μg/kg/min of E-3123 according to the same method as in the low protease inhibitor group. The mortality rate during the experiment was 41% (7/17) in the control group, 28.5% (2/7) in the high protease inhibitor group and 0% in the low protease inhibitor group. The increase in the plasma beta-endorphin levels in the control group was statistically significant. When E-3123 was given 30 min after the induction of pancreatitis, the increase in the plasma beta-endorphin levels in the high protease inhibitor group was also found to be increased statistically significant, compared with preinduction levels, but the increase was statistically significantly lower than that in the control group. Plasma beta-endorphin levels in the low protease inhibitor group, however, did not increase. The protease inhibitor infusion as used in this experiment can bring about improvement in hypotension and myocardial depression to an extent by inhibiting the release of betaendorphin, suggesting that the inhibitory effect of the protease inhibitor on beta-endorphin release contributes to the improvement in hemodynamic changes during pancreatitis. There may also be an optimal therapeutic dose of this drug for the treatment of hypotension and myocardial depression secondary to betaendorphin release. This work was supported in part by a grant-in-aid from the Japanese Ministry of Health and Welfare (Pancreatic Disease) and Grant 03670638 from the Japanese Ministry of Education, Science and Culture.     

Acute Pancreatitis as a Common Complication of 2'', 3''-Dideoxyinosine Therapy in the Acquired Immunodeficiency Syndrome

Acute pancreatitis is observed in patients with the acquired immunodeficiency syndrome (AIDS) (4-22%), and is reported with increasing frequency as a complication of therapy in human immunodeficiency virus-spectrum disease. The cause is multifactorial (virus, neoplasm, drugs), and the natural history generally mild and uncomplicated. 2',3'-Dideoxyinosine (ddI) is an experimental antiretroviral agent implicated as a cause of acute pancreatitis in a small number (0.9-2%) of patients. To better define this relationship, we conducted a retrospective analysis of a prospective clinical trial involving 51 homosexual males with AIDS treated with ddI (10-12 mg/kg/day) and reported on the incidence and natural history of pancreatitis. Clinical pancreatitis (symptoms, elevated serum amylase, and lipase and, in most cases, abnormal radiographic studies of the pancreas) was observed in 12 patients (23.5%). Asymptomatic elevations of amylase and lipase were identified in 10 additional patients (39.2%). The onset of pancreatitis was consistently delayed in both groups (overall mean 14.1 +/- 1.2 wk, 98% confidence interval). Ten of 12 symptomatic patients required hospitalization (mean length of stay, 9.4 days); two of 12 progressed to fulminant pancreatitis and died. Two patients with asymptomatic pancreatitis which occurred after starting ddI were rechallenged; severe symptomatic pancreatitis developed shortly after drug reinstitution. In each case, complete recovery followed discontinuation of the drug. We conclude that 1) The incidence (62.7%) and severity of pancreatitis in patients with AIDS receiving ddI therapy are significantly greater than expected, 2) the onset is predictably delayed about 14 wk, 3) ddI should be added to the list of drugs that cause acute pancreatitis, and 4) careful sequential monitoring of pancreatic function and early identification of potential "risk factors" for pancreatitis in AIDS patients treated with ddI may be essential in avoiding this serious complication.     

Selective inhibition of cyclooxygenase-2 (COX-2) reduces prostaglandin E2 production and attenuates systemic disease sequelae in experimental pancreatitis

BACKGROUND/AIMS: Prostaglandins and prostaglandin-derived mediators play an important role in mediating the systemic inflammatory response in acute pancreatitis. COX (cyclooxygenase) is the key enzyme of prostaglandin synthesis. Whereas COX-1 produces prostaglandin mediators for physiological reactions, COX-2 is overexpressed in acute pancreatitis. The aim of this study was to investigate whether a selective COX-2 inhibitor alters prostaglandin production and attenuates systemic disease sequelae in severe acute pancreatitis in rats. METHODOLOGY: Severe acute pancreatitis was induced in 36 rats by standardized intraductal infusion of bile salt and intravenous cerulein infusion. Six hours after acute pancreatitis induction, rats were randomized to receive either no COX inhibition (saline), nonselective COX inhibition by indomethacin (3 mg/kg, i.v.) or selective COX-2 inhibition by NS-398 (10 mg/kg, i.v.). Serum concentrations of prostaglandin E2 were measured before and after acute pancreatitis induction and 24 hrs after starting therapy. Routine cardiorespiratory and renal parameters were monitored to assess organ function. RESULTS: Animals treated with the selective COX-2 inhibitor had significantly lower prostaglandin E2 values (211 +/- 17 vs. 366 +/- 37 and 435 +/- 13 pg/mL), produced more urine (18 +/- 4 vs. 13 +/- 3 and 12 +/- 3 mL/6-24 h) and had significantly fewer episodes of respiratory distress (defined as a pO2 < 80 mmHg or pCO2 > 50 mmHg for > 15 min; 12 vs. 57 and 71%) during the observation period than animals without or with nonselective COX inhibition. CONCLUSIONS: Selective inhibition of COX-2 reduces prostaglandin E2 serum levels in this model of acute pancreatitis. This together with improved renal and respiratory function suggests an attenuation of the systemic response to pancreatic injury. COX-2 inhibition may be another step toward optimizing therapy in severe acute pancreatitis.