Rectal administration of tacrolimus protects against post-ERCP pancreatitis in mice.

OBJECTIVE: There is an unmet clinical need for effective, targeted interventions to prevent post-ERCP pancreatitis (PEP). We previously demonstrated that the serine-threonine phosphatase, calcineurin (Cn) is a critical mediator of PEP and that the FDA-approved calcineurin inhibitors, tacrolimus (Tac) or cyclosporine A, prevented PEP. Our recent observations in preclinical PEP models demonstrating that Cn deletion in both pancreatic and hematopoietic compartments is required for maximal pancreas protection, highlighted the need to target both systemic and pancreas-specific Cn signaling. We hypothesized that rectal administration of Tac would effectively mitigate PEP by ensuring systemic and pancreatic bioavailability of Tac. We have tested the efficacy of rectal Tac in a preclinical PEP model and in cerulein-induced experimental pancreatitis. METHODS: C57BL/6 mice underwent ductal cannulation with saline infusion to simulate pressure-induced PEP or were given seven, hourly, cerulein injections to induce pancreatitis. To test the efficacy of rectal Tac in pancreatitis prevention, a rectal Tac suppository (1 mg/kg) was administered 10 min prior to cannulation or first cerulein injection. Histological and biochemical indicators of pancreatitis were evaluated post-treatment. Pharmacokinetic parameters of Tac in the blood after rectal delivery compared to intravenous and intragastric administration was evaluated. RESULTS: Rectal Tac was effective in reducing pancreatic injury and inflammation in both PEP and cerulein models. Pharmacokinetic studies revealed that the rectal administration of Tac helped achieve optimal blood levels of Tac over an extended time compared to intravenous or intragastric delivery. CONCLUSION: Our results underscore the effectiveness and clinical utility of rectal Tac for PEP prophylaxis.

Current topics in pediatric enteral nutrition safety.

Enteral nutrition is a cornerstone of nutrition support therapy in patients of all ages and across the care continuum. Safe delivery of enteral nutrition to patients is paramount. This review article will focus on current topics in enteral nutrition safety primarily in children including safety with home-made blenderized feeds, recent infant and enteral formula shortages largely due to formula contamination at the manufacturer level, and concerns with importing infant formulas.

Thickness of commercial blenderized formulas adversely affects successful delivery via enteral feeding pumps.

BACKGROUND: There has been a renewed focus on offering commercial formulas made with real-food ingredients because of their perceived health benefits, such as improved feeding tolerance and gut health. Children receiving enteral nutrition through these formulas often are fed via feeding pumps. Because these formulas vary in thickness, we aimed to explore the relationship between formula thickness and prescribed formula delivery via feeding pumps. We hypothesized that inaccurate volumes of commercial blenderized formula (CBF) are delivered via feeding pumps and that these inaccuracies are directly proportional to the thickness of the formula. METHODS: We performed International Dysphagia Diet Standardisation Initiative (IDDSI) tests for six de-identified CBFs. We then ran these formulas over three feeding pumps using nasogastric and gastric tubes and simulated continuous and bolus feeds. We calculated the difference between programmed volume and actual delivered volume. RESULTS: Moderate and extremely thick formulas (IDDSI level 3-4) delivered a median of 22.5% less volume than programmed in the pump (P < 0.001). In addition, there was a 25.5% reduction in delivered volume for thick formulas compared with thin formulas. This occurred despite using the manufacturer's recommendations for suggested tube size. CONCLUSION: Thicker CBF can provide inaccurate volumes via feeding pumps, which may contribute to poor weight gain when children are switched to these formulas. Based on these findings, we recommend best practices for using these formulas. More studies are needed to investigate the best formula consistency to optimize delivery and caloric intake.

Preclinical safety evaluation of calcineurin inhibitors delivered through an intraductal route to prevent post-ERCP pancreatitis demonstrates endocrine and systemic safety.

OBJECTIVE: There is an urgent need for safe and targeted interventions to mitigate post-ERCP pancreatitis (PEP). Calcineurin inhibitors (CnIs) offer therapeutic promise as calcineurin signaling within acinar cells is a key initiating event in PEP. In previous proof-of-concept studies using experimental models, we showed that concurrent intra-pancreatic ductal administration of the CnIs, tacrolimus (Tac) or cyclosporine A (CsA) with the ERCP radiocontrast agent (RC) prevented PEP. To translate this finding clinically, we investigated potential toxic effects of intraductal delivery of a single-dose RC-CnI formulation on endocrine pancreas function and systemic toxicities in a preclinical PEP model. METHODS: C57BL/6J mice underwent ductal cannulation and received a single, intra-pancreatic ductal infusion of RC or RC with Tac or CsA (treatment groups) or underwent ductal cannulation without infusion ('sham' group). To assess endocrine function, intraperitoneal glucose tolerance test (IPGTT) was performed at two days before infusion and on day 2 and 14 post-surgery. To evaluate off-target tissue toxicities, renal and hepatic function-related parameters including blood urea nitrogen, plasma creatinine, potassium, aspartate aminotransferase, alanine aminotransferase, and total bilirubin were measured at the same time-points as IPGTT. Histological and biochemical indicators of pancreas injury and inflammation were also evaluated. RESULTS: No abnormalities in glucose metabolism, hepatic or renal function were observed on day 2 or 14 in mice administered with intraductal RC or RC with Tac or CsA. CONCLUSION: Intraductal delivery of RC-CnI formulation was safe and well-tolerated with no significant acute or subacute endocrine or systemic toxicities, underscoring its clinical utility to prevent PEP.

A review of the rationale for the testing of the calcineurin inhibitor tacrolimus for post-ERCP pancreatitis prevention.

Endoscopic retrograde cholangiopancreatography (ERCP) is commonly performed for the management of pancreaticobiliary disorders. The most troublesome ERCP-associated adverse event is post-ERCP pancreatitis (PEP), which occurs in up to 15% of all patients undergoing ERCP. A substantial body of preclinical data support a mechanistic rationale for calcineurin inhibitors in preventing PEP. The findings are coupled with recent clinical data suggesting lower rates of PEP in patients who concurrently use the calcineurin inhibitor tacrolimus (e.g., solid organ transplant recipients). In this review, we will firstly summarize data in support of testing the use of tacrolimus for PEP prophylaxis, either in combination with rectal indomethacin or by itself. Secondly, we propose that administering tacrolimus through the rectal route could be favorable for PEP prophylaxis over other routes of administration.