SmartPAN: In vitro and in vivo proof-of-safety assessments for an intra-operative predictive indicator of postoperative pancreatic fistula.

Pancreatic surgery is complicated by untreated fluid leakage, but no tenable techniques exist to detect and close leakage sites during surgery. A novel hydrogel called SmartPAN has been developed to meet this need and is here assessed for safety before trials on human patients. First, resazurin assays were used to test the cytotoxic effects of SmartPAN's active bromothymol blue (BTB) indicator and its solution of phosphate-buffered saline (PBS) on normal (HPDE: human pancreatic duct epithelial) or carcinomic (FAMPAC) human pancreatic cells. Cells incubated with BTB showed no significant reduction in cell viability below threshold safety levels. However, PBS had a mild cytotoxic effect on FAMPAC cells. Second, SmartPAN's pathological effects were evaluated in vivo by applying 4-ml SmartPAN to a porcine (Sus scrofa domesticus) model of pancreatic resection. There were no significant differences in macroscopic and microscopic pathologies between pigs treated with SmartPAN or saline. Third, measurements using HPLC-MS/MS demonstrate that BTB does not cross into the bloodstream and was eliminated from the body within 2 days of surgery. Overall, SmartPAN appears safe in the short term and ready for first-in-human trials because its components are either biocompatible or quickly neutralized by dilution and drainage.

SmartPAN: A novel polysaccharide-microsphere-based surgical indicator of pancreatic leakage.

Postoperative pancreatic fistula is a major surgical complication that can follow pancreatic resection. Postoperative pancreatic fistula can develop as a consequence of leaking pancreatic fluid, which calls for an intraoperative indicator of leakage. But suitable indicators of pancreatic leakage have yet to be found. This study details the evidence-based development and early efficacy assessments of a novel pancreatic leakage indicator (SmartPAN), following the IDEAL framework of product development. We developed 41 SmartPAN prototypes by combining indicators of pancreatic fluid with a polysaccharide-microsphere matrix. The prototypes were assessed in vitro using porcine (Sus scrofa domesticus) pancreatic tissue and ex vivo with human pancreatic fluid. From these initial tests, we chose a hydrogel-based compound that uses the pH indicator bromothymol blue to detect alkali pancreatic fluid. This prototype was then assessed in vivo for usability, effectiveness and reliability using a porcine model. Treatment groups were defined by SmartPAN-reaction at initial pancreatic resection: indicator-positive or negative. Indicator-positive individuals randomly received either targeted closure of leakage sites or no further closure. We assessed SmartPAN's reliability and effectiveness by monitoring abdominal drainage for amylase and with relaparotomy after 48 h. SmartPAN responses were consistent between both surgical procedures and conformed to amylase measurements. In conclusion, we have developed the first surgery-ready indicator for predicting the occurrence of pancreatic leakage during pancreatic resection. SmartPAN can enable targeted prophylactic closure in a simple and reliable way, and thus may reduce the impact of postoperative pancreatic fistula by guiding peri- and post-operative management.

Regioisomerism in the synthesis of a chiral aminotetralin drug compound: unraveling mechanistic details and diastereomer-specific in-depth NMR investigations.

During chemical process development of a novel 2-aminotetralin derivative intended for use as an antidepressant, scrutiny of the byproduct present in the drug molecule revealed a set of regioisomers. Detailed studies showed that this impurity issue originated from an early synthetic step in which a brominated tetralone motif was generated in a ring-closing protocol. It was found that this reaction was accompanied by a migration of the aromatic bromo substituent via different bromonium species along two discrete pathways. This example of the halogen dance reaction resulted in the formation of a series of tetralone impurities with a bromine distributed across all available aromatic positions of the tetralin nucleus. Subsequently, when subjected to reductive amination conditions, each of these tetralones gave rise to pairs of aminotetralins in a diastereomeric relationship. NMR investigations revealed that the alicyclic portion of the compounds thus formed displayed very complex signal patterns, which required further in-depth studies using a variety of sophisticated techniques. As a result, a deep insight into the structural features of the current 2-aminotetralin family was obtained, which is emphasized by the definition of a novel "0.2 ppm rule" allowing the absolute configuration at tetralin C-2 to be determined.