Role of SCO-792, A Novel Enteropeptidase Inhibitor, In the Prevention of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis

Abstract

Acute pancreatitis is the most common iatrogenic dilemma of endoscopic retrograde cholangiopancreatography, and it is associated with significant morbidity and mortality. Several factors have been implicated in the pathogenesis of post-endoscopic retrograde cholangiopancreatography pancreatitis, and preventive measures were practiced accordingly. This study aims to refine the potential mechanisms that trigger post-endoscopic retrograde cholangiopancreatography pancreatitis and define the role of enteropeptidase in the pathogenesis of post-endoscopic retrograde cholangiopancreatography pancreatitis. Furthermore, address the role of a new novel medication known as SCO-792, a potent enteropeptidase inhibitor, in the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis.

Post-endoscopic retrograde cholangiopancreatography pancreatitis is caused by premature activation of the pancreatic enzymes within the pancreatic parenchyma. This activation is either an autoactivation due to direct provocation of intra-acinar enzymes as a result of the procedure or due to activation by enterpeptidase, a rate-limiting enzyme. Endoscopic retrograde cholangiopancreatography interjects duodenal juice that is rich in enterokinase into the pancreatic-biliary tract, which in turn leads to intra-ductal activation of trypsinogen and subsequent enzymes. Given the vital role of enterokinase in initiating the pathogenesis of pancreatitis, enteropeptidase inhibition may prevent and reduce the severity of post-endoscopic retrograde cholangiopancreatography pancreatitis.

SCO-792, a novel enteropeptidase inhibitor, is developed by SCOHIA Pharma, and pre-clinical trials confirmed its efficacy in inhibiting enteropeptidase. Studies are needed to confirm the efficacy of enteropeptidase inhibitors in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis.

Keywords

pancreatitis - ERCP - post-ERCP pancreatitis - enteropeptidase - SCO-792

Publication History

Received: 23 January 2021

Accepted: 24 August 2021

Article published online:
06 October 2021

• References

• 1 Freeman ML, Nelson DB, Sherman S. et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med 1996; 335 (13) 909-918 DOI: 10.1056/NEJM199609263351301.
• 2 Cheon YK, Cho KB, Watkins JL. et al. Frequency and severity of post-ERCP pancreatitis correlated with extent of pancreatic ductal opacification. Gastrointest Endosc 2007; 65 (03) 385-393 DOI: 10.1016/j.gie.2006.10.021.
• 3 Testoni PA. Why the incidence of post-ERCP pancreatitis varies considerably? Factors affecting the diagnosis and the incidence of this complication. JOP 2002; 3 (06) 195-201
• 4 Mann N, Mann S. : Enterokinase. Exp Biol Med. 1994; 206: 114-118 . Doi: 10.3181%2F00379727–206–43728
• 5 Zheng XL, Kitamoto Y, Sadler JE. Enteropeptidase, a type II transmembrane serine protease. Front Biosci (Elite Ed) 2009; 1: 242-249
• 6 Light A, Janska H. Enterokinase (enteropeptidase): comparative aspects. Trends Biochem Sci 1989; 14 (03) 110-112 DOI: 10.1016/0968-0004(89)90133-3.
• 7 Abita JP, Delaage M, Lazdunski M, Savrda J. The mechanism of activation of trypsinogen. The role of the four N-terminal aspartyl residues. Eur J Biochem 1969; 8 (03) 314-324 DOI: 10.1111/j.1432-1033.1969.tb00530.x.
• 8 Freeman ML, Guda NM. Prevention of post-ERCP pancreatitis: a comprehensive review. Gastrointest Endosc 2004; 59 (07) 845-864 DOI: 10.1016/s0016-5107(04)00353-0.
• 9 Christoforidis E, Goulimaris I, Kanellos I, Tsalis K, Demetriades C, Betsis D. Post-ERCP pancreatitis and hyperamylasemia: patient-related and operative risk factors. Endoscopy 2002; 34 (04) 286-292 DOI: 10.1055/s-2002-23630.
• 10 Rabenstein T, Schneider HT, Bulling D. et al. Analysis of the risk factors associated with endoscopic sphincterotomy techniques: preliminary results of a prospective study, with emphasis on the reduced risk of acute pancreatitis with low-dose anticoagulation treatment. Endoscopy 2000; 32 (01) 10-19 DOI: 10.1055/s-2000-138.
• 11 Freeman ML, DiSario JA, Nelson DB. et al. Risk factors for post-ERCP pancreatitis: a prospective, multicenter study. Gastrointest Endosc 2001; 54 (04) 425-434 DOI: 10.1067/mge.2001.117550.
• 12 Loperfido S, Angelini G, Benedetti G. et al. Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study. Gastrointest Endosc 1998; 48 (01) 1-10 DOI: 10.1016/s0016-5107(98)70121-x.
• 13 Vandervoort J, Soetikno RM, Tham TC. et al. Risk factors for complications after performance of ERCP. Gastrointest Endosc 2002; 56 (05) 652-656 DOI: 10.1067/mge.2002.129086.
• 14 Ogura T, Imoto A, Okuda A, Fukunishi S, Higuchi K. Can iodixanol prevent post-endoscopic retrograde cholangiopancreatography pancreatitis? A prospective, randomized, controlled trial. Dig Dis 2019; 37 (03) 255-261 DOI: 10.1159/000496349.
• 15 Andriulli A, Clemente R, Solmi L. et al. Gabexate or somatostatin administration before ERCP in patients at high risk for post-ERCP pancreatitis: a multicenter, placebo-controlled, randomized clinical trial. Gastrointest Endosc 2002; 56 (04) 488-495 DOI: 10.1016/S0016-5107(02)70431-8.
• 16 Lin Y, Liu X, Cao DQ. et al. Analysis of risk factors and prevention strategies of post-ERCP pancreatitis. Eur Rev Med Pharmacol Sci 2017; 21 (22) 5185-5190 DOI: 10.26355/eurrev_201711_13838.
• 17 Cheng CL, Sherman S, Watkins JL. et al. Risk factors for post-ERCP pancreatitis: a prospective multicenter study. Am J Gastroenterol 2006; 101 (01) 139-147
• 18 Koike H, Steer ML, Meldolesi J. Pancreatic effects of ethionine: blockade of exocytosis and appearance of crinophagy and autophagy precede cellular necrosis. Am J Physiol 1982; 242 (04) G297-G307 DOI: 10.1152/ajpgi.1982.242.4.G297.
• 19 Watanabe O, Baccino FM, Steer ML, Meldolesi J. Supramaximal caerulein stimulation and ultrastructure of rat pancreatic acinar cell: early morphological changes during development of experimental pancreatitis. Am J Physiol 1984; 246 (4 Pt 1): G457-G467 DOI: 10.1152/ajpgi.1984.246.4.g457.
• 20 Saluja A, Hashimoto S, Saluja M, Powers RE, Meldolesi J, Steer ML. Subcellular redistribution of lysosomal enzymes during caerulein-induced pancreatitis. Am J Physiol 1987; 253 (4 Pt 1): G508-G516 DOI: 10.1152/ajpgi.1987.253.4.g508.
• 21 Saito I, Hashimoto S, Saluja A, Steer ML, Meldolesi J. Intracellular transport of pancreatic zymogens during caerulein supramaximal stimulation. Am J Physiol 1987; 253 (4 Pt 1): G517-G526 DOI: 10.1152/ajpgi.1987.253.4.g517.
• 22 Greenbaum LM, Hirshkowitz A. Endogenous cathepsin activation of trypsinogen in extracts of dog pancreas. Proc Soc Exp Biol Med 1961; 107: 74-76 DOI: 10.3181/00379727-107-26539.
• 23 Mann NS. Effect of intraductal enterokinase, 5-azacytidine and cycloheximide on pancreatic protein content. Am J Proctol Gastroenterol Colon Rectal Surg 1980; 31 (09) 15-16 , 21
• 24 Hammond JB, Mann NS. Pancreatitis following the intraductal injection of partially purified enterokinase in dogs. Am J Dig Dis 1977; 22 (03) 182-188 DOI: 10.1007/bf01072274.
• 25 Mann NS, Kadian RS, Narenderan K. Enterokinase induced pancreatitis: its prevention with Trasylol and soybean trypsin inhibitor. Am J Proctol Gastroenterol Colon Rectal Surg 1978; 29 (06) 13-17
• 26 Sasaki M, Miyahisa I, Itono S. et al. Discovery and characterization of a small-molecule enteropeptidase inhibitor, SCO-792. Pharmacol Res Perspect 2019; 7 (05) e00517 DOI: 10.1002/prp2.517.
• 27 Zamolodchikova TS, Sokolova EA, Lu D, Sadler JE. Activation of recombinant proenteropeptidase by duodenase. FEBS Lett 2000; 466 (2-3): 295-299 DOI: 10.1016/S0014-5793(00)01092-9.
• 28 Hadorn B, Tarlow MJ, Lloyd JK, Wolff OH. Intestinal enterokinase deficiency. Lancet 1969; 1 (7599): 812-813 DOI: 10.1016/s0140-6736(69)92071-6.
• 29 Holzinger A, Maier EM, Bück C. et al. Mutations in the proenteropeptidase gene are the molecular cause of congenital enteropeptidase deficiency. Am J Hum Genet 2002; 70 (01) 20-25 DOI: 10.1086/338456.
• 30 Braud S, Ciufolini MA, Harosh I. Enteropeptidase: a gene associated with a starvation human phenotype and a novel target for obesity treatment. PLoS One 2012; 7 (11) e49612 DOI: 10.1371/journal.pone.0049612.
• 31 Katayama Y, Sugama J, Suzuki T. et al. Enteropeptidase inhibitor SCO-792 effectively prevents kidney function decline and fibrosis in a rat model of chronic kidney disease. Nephrol Dial Transplant 2020; 1-9 DOI: 10.1093/ndt/gfaa349.
• 32 Gasparian ME, Ostapchenko VG, Dolgikh DA, Kirpichnikov MP. Biochemical characterization of human enteropeptidase light chain. Biochemistry (Mosc) 2006; 71 (02) 113-119 DOI: 10.1134/s0006297906020015.