semapimod and Pancreatitis

Acute pancreatitis and hyperamylasemia are frequent complications of an ERCP. Semapimod is a synthetic guanylhydrazone that inhibits the mitogen-activated protein kinase (MAPK) pathway, macrophage activation, and the production of several inflammatory cytokines.. This study evaluated whether intravenous (IV) administration of semapimod given before an ERCP reduces the incidence of post-ERCP hyperamylasemia and pancreatitis.. A single-center, randomized, double-blinded, controlled trial.. An academic medical center.. Between 2001 and 2005, 242 patients who were undergoing a therapeutic ERCP at our institution were included.. Patients received a single IV dose of semapimod or a placebo before an ERCP.. The occurrence of post-ERCP pancreatitis, as well as post-ERCP hyperamylasemia.. The incidence of hyperamylasemia was significantly reduced (29.8% vs 18.4%; P = .031). Moreover, semapimod administration significantly lowered the levels of amylase during the first 24 hours after the ERCP. The incidence of clinical pancreatitis was reduced by 40%, without reaching statistical significance (14.9 vs 9.1%; P = .117).. A relatively small single-center study. One dose of semapimod was used.. A single dose of IV semapimod 1 hour before an ERCP is safe and exerts a biological effect, demonstrated by a statistically significant reduction of the incidence of hyperamylasemia and the levels of post-ERCP amylase. A protective effect for the development of post-ERCP pancreatitis could not be convincingly demonstrated.

Topics: Aged; Cholangiopancreatography, Endoscopic Retrograde; Double-Blind Method; Female; Follow-Up Studies; Humans; Hydrazones; Hyperamylasemia; Incidence; Infusions, Intravenous; Male; Middle Aged; Pancreatic Diseases; Pancreatitis; Preoperative Care; Probability; Prospective Studies; Reference Values; Risk Assessment; Statistics, Nonparametric; Treatment Outcome

Pancreatitis remains the most common severe complication of endoscopic retrograde cholangiopancreatography (ERCP). Detailed information about the findings of previous studies concerning post-ERCP pancreatitis has not been utilized sufficiently. The purpose of the present article was to present guidelines for the diagnostic criteria of post-ERCP pancreatitis, and its incidence, risk factors, and prophylactic procedures that are supported by evidence. To achieve this purpose, a critical examination was made of the articles on post-ERCP pancreatitis, based on the data obtained by research studies published up to 2009. At present, there are no standardized diagnostic criteria for post-ERCP pancreatitis. It is appropriate that post-ERCP pancreatitis is defined as acute pancreatitis that has developed following ERCP, and its diagnosis and severity assessment should be made according to the diagnostic criteria and severity assessment of the Japanese Ministry of Health, Labour and Welfare. The incidence of acute pancreatitis associated with diagnostic and therapeutic ERCP is 0.4-1.5 and 1.6-5.4%, respectively. Endoscopic papillary balloon dilation is associated with a high risk of acute pancreatitis compared with endoscopic sphincterotomy. It was made clear that important risk factors include dysfunction of the Oddi sphincter, being of the female sex, past history of post-ERCP pancreatitis, and performance of pancreaticography. Temporary prophylactic placement of pancreatic stents in the high-risk group is useful for the prevention of post-ERCP pancreatitis [odds ratio (OR) 3.2, 95% confidence interval (CI) 1.6-6.4, number needed to treat (NNT) 10]. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduction in the development of post-ERCP pancreatitis (OR 0.46, 95% CI 0.32-0.65). Single rectal administration of NSAIDs is useful for the prevention of post-ERCP pancreatitis [relative risk (RR) 0.36, 95% CI 0.22-0.60, NNT 15] and decreases the development of pancreatitis in both the low-risk group (RR 0.29, 95% CI 0.12-0.71) and the high-risk group (RR 0.40, 95% CI 0.23-0.72) of post-ERCP pancreatitis. As for somatostatin, a bolus injection may be most useful compared with short- or long-term infusion (OR 0.271, 95% CI 0.138-0.536, risk difference 8.2%, 95% CI 4.4-12.0%). The usefulness of gabexate mesilate was not apparent in any of the following conditions: acute pancreatitis (control 5.7 vs. 4.8% for gabexate mesilate), hyperamylasemia (4

Topics: Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Cholangiopancreatography, Endoscopic Retrograde; Gabexate; Hormones; Humans; Hydrazones; Immunosuppressive Agents; Meta-Analysis as Topic; Pancreatitis; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Risk Factors; Somatostatin; Stents

Recent evidence suggests that pancreatitis-associated hepatic injury is regulated by inflammatory mediator production. Our laboratory demonstrated in vitro that pancreatic elastase is a pancreatic enzyme that can induce inflammatory cell cytokine production. Therefore we now explore the in vivo effects of elastase on the liver.. Elastase (1.5 U) +/- CNI-1493, which attenuates mediator production through p38 MAP kinase inhibition, was administered intraperitoneally to mice while control animals received saline. Acute pancreatitis (AP) was induced with a choline-deficient, ethionine-supplemented (CDE) diet. Serum hepatic enzymes and hepatic neutrophil infiltration by myeloperoxidase (MPO) activity were measured as indicators of hepatic insult. Serum tumor necrosis factor (TNF) protein (ELISA), hepatic TNF mRNA (reverse transcription polymerase chain reaction), and hepatic activation of the transcription factor nuclear factor kappa B (electrophoretic mobility shift assay) were also determined.. A significant increase in hepatic enzymes and MPO activity was induced by AP and mirrored by intraperitoneal elastase. Both types of liver injury resulted in near identical elevations in serum TNF protein and hepatic TNF mRNA. Elastase-treated animals with mediator production inhibited (CNI-1493) had attenuated hepatic enzymes, MPO activity, TNF protein, and TNF mRNA. Activation of nuclear factor kappa B occurred 30 min after elastase administration.. Exposure of the liver to pancreatic elastase results in hepatic inflammation and injury which appears identical to that seen during severe AP. Prevention of inflammatory mediator production by intrahepatic leukocytes attenuates injury and supports recent adult respiratory distress syndrome and in vitro data suggesting that elastase is the principal factor that propagates pancreatic inflammation into a systemic illness through direct activation of systemic inflammatory cells.

Topics: Adjuvants, Immunologic; Animals; Aspartate Aminotransferases; Enzyme-Linked Immunosorbent Assay; Gene Expression; Hydrazones; Immunosuppressive Agents; L-Lactate Dehydrogenase; Liver Diseases; Mice; Neutrophils; NF-kappa B; Pancreatic Elastase; Pancreatitis; RNA, Messenger; Tumor Necrosis Factor-alpha

Adult respiratory distress syndrome (ARDS) is responsible for a significant portion of the morbidity and mortality during severe acute pancreatitis. Because inflammatory mediators such as tumor necrosis factor (TNF)-alpha and nitric oxide (NO) produced within the lungs have been implicated in sepsis-induced ARDS, we aimed to determine the role of these mediators in pancreatitis-induced ARDS using a model whereby ascites from animals with pancreatitis is transferred to otherwise healthy animals resulting in pulmonary injury.. Prospective, randomized, controlled trial.. Research laboratory at a university medical school.. Pathogen-free Sprague-Dawley rats weighing 225-250 g.. Sterile, endotoxin- and cytokine-free pancreatic ascites tested for interleukin (IL)-1beta , TNF-alpha, interferon-gamma, and IL-6 was obtained from rats 18 hrs after the induction of severe, acute pancreatitis. Ascites was subsequently administered intravenously (20 mL/kg) to healthy rats. Sham animals were administered intravenous saline. Healthy animals administered intravenous ascites were randomized to receive a single intraperitoneal injection of the p38 mitogen activated kinase inhibitor CNI-1493 (1 mg/kg) or vehicle.. Pulmonary injury was assessed at 24 hrs by histology and leukocyte and protein concentrations via bronchoalveolar lavage. Pulmonary TNF-alpha protein was detected by immunohistochemistry. Serum nitrite, as a measure of NO production, was measured utilizing the Griess reaction.. After the intravenous administration of pancreatic ascites, the number of leukocytes and the protein concentration within the bronchoalveolar fluid were increased and pulmonary histology was worsened consistent with acute lung injury (all p < .001 vs. sham). Each of these variables of pulmonary injury was lessened in animals receiving CNI-1493 and intravenous ascites (p < .05 vs. vehicle). Pulmonary TNF-alpha protein and serum nitrites were decreased with the administration of CNI-1493 (p < .005 vs. vehicle).. A component of pancreatic ascites other than endotoxin, bacteria, or cytokines (IL-1beta, TNF, interferon-gamma, or IL-6) is capable of inducing ARDS in healthy animals. Inhibition of p38 mitogen activated kinase decreases the pulmonary injury through attenuated production of TNF-alpha and NO suggesting a primary role for these mediators in pancreatitis-induced ARDS.

Topics: Analysis of Variance; Animals; Ascites; Bronchoalveolar Lavage Fluid; Cytokines; Hydrazones; Immunosuppressive Agents; Male; Mitogen-Activated Protein Kinases; Nitric Oxide; Nitrites; p38 Mitogen-Activated Protein Kinases; Pancreatitis; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Severity of Illness Index; Tumor Necrosis Factor-alpha

Macrophage overproduction of inflammatory mediators is detrimental in the progression of acute pancreatitis. Although inhibition of inflammatory mediators has been shown to decrease the severity of experimental pancreatitis and improve overall survival, less is known about the mechanism by which blockade produces these benefits. Prior to the induction of lethal acute pancreatitis, rats were randomized to receive a single dose (.01, .1, 1.0, or 10 mg/kg) of a macrophage-pacifying compound (CNI-1493) or vehicle. Escalating doses provided incremental increases in survival from 10% (vehicle) to a maximum of 70% (CNI-1493, 1.0 mg/kg). To evaluate the physiologic mechanism responsible for the improved survival, continuous arterial blood pressure, serial hematocrit, ascites volume, pancreatic edema, bronchoalveolar leukocytes and protein, and pancreatic histology were determined in additional rats receiving CNI-1493 (1.0 mg/kg). Serum tumor necrosis factor-alpha and nitrites were also determined to assess the mechanism of action of CNI-1493. Macrophage pacification decreased pancreatitis severity as determined by enzyme release and pancreatic histology score. Ascites volume and bronchoalveolar protein levels were also decreased, indicating that CNI-1493 prevents the loss of circulating blood volume and maintains hematocrit and mean arterial pressure, thus improving survival. CNI-1493 prevented the increase of serum tumor necrosis factor-alpha but not serum nitrites, implicating macrophage-derived cytokines and not nitric oxide in the pathogenesis of physiologic decompensation and death in this model of pancreatitis.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Ascites; Bile Acids and Salts; Blood Pressure; Bronchoalveolar Lavage; Dose-Response Relationship, Drug; Hematocrit; Hydrazones; Lipase; Macrophages; Male; Nitrites; Pancreatitis; Proteins; Rats; Rats, Sprague-Dawley; Survival Rate; Tumor Necrosis Factor-alpha

Overproduction of tumor necrosis factor (TNF-), interleukin-1beta (IL-1beta), and nitric oxide (NO) is believed to be detrimental during the progression of acute pancreatitis, yet little is known about the hepatic production of these mediators and their role in mediating pancreatitis-induced hepatic dysfunction. Rats were randomized to receive a single intraperitoneal injection of the macrophage-pacifying compound, CNI-1493 (1.0 mg/kg), or vehicle 1 hour before the induction of retrograde bile salt pancreatitis. Sham-operated animals served as controls. Animals were killed 18 hours later, with serum and livers harvested to determine the degree of hepatocellular injury and the induction of TNF-, IL-1beta, and inducible nitric oxide synthase (iNOS). In addition, serum TNF- and nitrites (end-product of NO breakdown) were determined in each group to assess the mechanism of action of CNI-1493. TNF-, IL-1beta, and iNOS gene expression (by reverse-transcription polymerase chain reaction) as well as aspartate transaminase (AST), alanine transaminase (ALT), and lactic dehydrogenase (LDH) (but not alkaline phosphatase [ALP]) increased following the development of pancreatitis (all P < .05). Macrophage pacification significantly prevented the induction of TNF- and IL-1beta mRNA (but not iNOS), resulting in lessened serum AST, ALT, and LDH (all P < .05). Serum TNF- protein and nitrites correlated with gene induction in that both were increased following the onset of pancreatitis, and TNF- protein production was significantly attenuated in animals receiving CNI-1493. Hepatocellular, but not bile duct, injury occurs during experimental pancreatitis that is associated with hepatic TNF-, IL-1beta, and iNOS mRNA gene induction, as well as TNF- protein and nitrite production. Preventing the production of TNF- and IL-1beta by macrophage pacification attenuates the hepatocellular damage, suggesting that these mediators play a role in pancreatitis-induced hepatic injury.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspartate Aminotransferases; Gene Expression Regulation; Hydrazones; Interleukin-1; L-Lactate Dehydrogenase; Liver Diseases; Macrophages; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Pancreatitis; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Transcriptional Activation; Tumor Necrosis Factor-alpha