Optimizing a Novel Intraductal Delivery of Calcineurin Inhibitors as a Radiocontrast Infusion Formulation to Prevent Post-ERCP Pancreatitis
Abstract
An endoscopic retrograde cholangiopancreatography (ERCP) procedure is a common and life-saving gastrointestinal procedure that is performed in about half a million American each year, among which about 3-15% of patients were found to develop post-ERCP pancreatitis (PEP), the most common adverse effect of ERCP without effective preventative modalities. The current project funded by Award W81XWH-19-1-0683 was proposed based on our recent discovery showing the critical role of calcineurin (Cn) signaling pathway in the development of PEP. Its overarching goal is to optimize the delivery of calcineurin inhibitors (CnIs) to prevent PEP. In the first project years, we conducted mouse experiments designed for Aim 1, including endocrine and systemic safety testing of novel formulations of CnIs. We also developed the conceptual model to evaluate the preventive effect of rectal delivery of CnI tacrolimus (Tac) against post-ERCP pancreatitis. Our proposed project has been progressing smoothly. Our request of a second one-year non-cost extension was approved which allows us to schedule experiments to the fifth project year. In the fourth year, we have finished (1) 90% of Aim 1 to perform the safety testing of infusion with CnI formulations, (2) 90% of Aim 2 to analyze the pharmacokinetic features of rectal suppository delivery of Tac versus intravenous or intragastric administration, and (3) confirmed the preventive efficacy of rectal suppository administration of Tac in mouse models of post-ERCP pancreatitis and cerulein-induced pancreatitis. Our results demonstrate that (1) Tac or Cyclosporin A (CsA) formulation are safe at high single doses in a mouse model of post-ERCP pancreatitis, (2) rectal suppository delivery of Tac retains a higher blood Tac level compared with intravenous or intragastric administration, and (3) rectal Tac administration significantly decreases pancreatic injury and inflammation in both mouse models of pancreatitis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1222259
Entities
People
- Sohail Z Husain
Organizations
- Stanford University