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Optimizing a Novel Intraductal Delivery of Calcineurin Inhibitors as a Radiocontrast Infusion Formulation to Prevent Post-ERCP Pancreatitis
[Technical Report, Annual Report]
STANFORD UNIV CA
Pagination or Media Count:
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 present project funded by Award W81XWH-19-1-0683 was proposed based on our recent discovery that calcineurin Cn signaling pathway contributes to the development of PEP. It aims to optimize the delivery of calcineurin inhibitors to prevent PEP. In the first project year, we conducted mouse experiments designed for Aim 1, including pancreatic and systemic safety testing of intraductal infusion of Cn inhibitors Tacrolimus Tac and cyclosporine A CsA within the radiocontrast. Our proposed project has been progressing smoothly. Due to the COVID-19 pandemic and related social distancing policy, we postponed rabbit safety testing which usually requires two or more researchers working together and efficacy studies to third project years. This allowed us to perform mouse studies, which were originally proposed for the third project year in the grant proposal. In this reporting period the second project year, we have successfully developed rectal suppository delivery of Cn inhibitor Tac alone or in combination with non-steroidal anti-inflammatory drugs NSAIDs such as indomethacin and diclofenac. We also have defined the pharmacokinetic features of rectal Tac suppositories. In efficacy testing, our data demonstrate that Tac suppositories significantly decrease pancreatic damage and systemic inflammation in PEP models elicited in mice. It was further found that rectal suppository delivery of Tac in combination with NSAID diclofenac achieved synergistic interaction in the prevention of pancreatic damage in a severe pancreatitis models elicited in mice.
[A, Approved For Public Release]