Читать книгу Clinical Pancreatology for Practising Gastroenterologists and Surgeons - Группа авторов - Страница 154

The observation that somatostatin or its analog, octreotide, caused a dose‐dependent reduction in exocrine pancreatic secretions prompted much interest in their consideration as therapeutic options for AP [63] (Figure 12.2). Although a reduction in organ failure was observed from delivery of both agents in clinical trials, detailed assessment found them to have flawed designs with no benefit on overall mortality [64]. Prevention of trypsinogen activation by inhibition of cathepsin B [65] or deletion of the cathepsin B gene [66] has resulted in a decrease in pancreatic injury in experimental AP, stressing the importance of trypsinogen activation for pancreatic damage. A further study in which genetically modified mice expressed an endogenously activated trypsinogen within pancreatic acinar cells found intra‐acinar activation of trypsinogen to initiate AP with rapid induction of acinar cell death via apoptosis, facilitating resolution of inflammation. Nevertheless, serine protease inhibition with ulinastatin, a multifunctional serine protease inhibitor, has shown promise in preclinical and small clinical observational studies [67] (see Figure 12.1). However, larger clinical trials with ulinastatin have not demonstrated benefit [64], possibly due to trial design. Further, well‐planned trials of ulinastatin remain to be conducted.

Protein kinase D (PKD/PKD1) activation is necessary for nuclear factor (NF)‐κB activation in vitro in pancreatic acinar cells [68], which in turn is a crucial early regulator of inflammatory and cell death responses in AP (see Figure 12.1). The novel small molecule PKD inhibitors CID755673 and CRT0066101 have both demonstrated efficacy in in vitro and in vivo models of experimental AP, likely through significant attenuation of NF‐κB activation [69], holding promise for translational drug discovery.

Figure 12.2 Strategies modulating pancreatic secretion. Cystic fibrosis transmembrane conductance regulator (CFTR) is found on the luminal surface of pancreatic ductal cells, contributing chloride and water secretion; defects resulting from CFTR gene mutations are associated with recurrent pancreatitis. CFTR correctors (VX770 and VX809) significantly reduce the number of acute pancreatitis attacks in patients with cystic fibrosis and may hold promise if their use is widened to other indications. Somatostatin and its synthetic analog octreotide inhibit acinar cell enzyme secretion and although not beneficial in reducing mortality in clinical trials, have shown a reduction in organ failure and may benefit from improved future trial design.