Does MAP kinase inhibition with CNI-1493 prevent post-ERCP pancreatitis?

Acute pancreatitis can be due to many causes including biliary stone disease, alcohol abuse, and medication. It can also be caused by medical intervention through manipulation of area of the ampulla of Vater and diagnostic and/or therapeutic interventions in the biliary and pancreatic ductal system (endoscopic retrograde cholangiopancreaticography (ERCP)).




The overall reported incidence of post-ERCP pancreatitis is 7%, in certain subgroups with an increased risk this goes up to 20%. Local damage (temporary increased ductal pressure due to contrast injection andor oedema due to manipulations) is followed by a local inflammatory response (TNF, IL-1, IL-6). In 80% of cases post-ERCP pancreatitis runs a relatively benign course with a few day o (severe) abdominal pain and a uneventful recovery. In other cases a severe pancreatitis develops with necrosis of parenchymal pancreatitis tissue (with or without infection) and a systemic inflammatory response syndrome (SIRS).




In the latter group morbidity and mortality are high. Of these patients 25% will die. Recently, a group of synthetic guanylhydrazone compounds have been developed and one of its representatives CNI-1493 (a p38 MAP kinase inhibitor) proved to be a very powerful inhibitor of TNF-alpha. In addition, CNI-1493 inhibits a host of other macrophage induced pro-inflammatory cytokines (IL-1, IL-6, MIP-1ƒÑ en MIP-1ƒÒ).




The primary question that we want to address is whether it is possible with the prophylactic administration of CNI-1493 to lower the incidence of post-ERCP pancreatitis.




The study is double blind and randomized. Patients with a increased risk to develop post-ERCP pancreatitis will be randomized between prophylactic administration of CNI-1493 (50 mg IV) and placebo.




Patients will be follow-up for 48 hours. Blood samples will be taken at regular intervals for amylase and lipase (and CRP, IL-6, IL-1, TNF, IL-8). Clinical symptoms such as pain are quantified by means of VAS scores and noted.
The primary endpoint is the incidence of post-ERCP pancreatitis.
Other (secondary) endpoints include morbidity, mortality, incidence of post-ERCP hyper hyperamylasemia, serum concentrations of cytokines/chemokines.

Prophylactic administration of p38 MAP/JNK kinase inhibitor may decrease the incidence of post-ERCP pancreatitis through inhibition of the pro-inflammatory cytokines IL-1, IL-6, TNF and MIP. In animal studies CNI-1493 or related compounds have been shown to reduce the severity of experimental pancreatitis and pancreatitis associated lung injury.

N/A

Single infusion of CNI-1493 (50 mg IV or placebo IV (randomized, double blind) 1 h prior to start of ERCP.