title: Prevention effects of ND-07, a novel drug candidate with a potent antioxidative action and anti-inflammatory action, in animal models of severe acute pancreatitis.
abstract: Oxidative stress and inflammation both play major roles in the development of the acute pancreatitis. Currently, a pancreatic enzyme inhibitor with limited efficacy is only clinically available in a few countries, and antioxidants or non-steroidal anti-inflammatory drugs (NSAIDs) provide only partial tissue protection in acute pancreatitis animal models. Here, we introduce a new drug candidate for treating acute pancreatitis named ND-07 [chemical name: 2-acetoxy-5-(2-4-(trifluoromethyl)-phenethylamino)-benzoic acid] that exhibits both potent antioxidative and anti-inflammatory activities. In an electron spin resonance (ESR) study, ND-07 almost blocked hydroxyl radical generation as low as 0.05 μM and significantly suppressed DNA oxidation and cell death in a lipopolysaccharide (LPS)-stimulated pancreatic cell line. In a cerulein plus LPS-induced acute pancreatitis model, ND-07 pretreatment showed significant tissue protective effects, with reductions of serum amylase and lipase levels and pancreatic wet weights. ND-07 not only diminished the plasma levels of malondialdehyde (MDA) and nitric oxide but also significantly decreased prostaglandin E₂ (PGE₂) and expression of tumor necrotizing factor-alpha (TNF-α) in the pancreatic tissue. In a severe acute necrotizing pancreatitis model induced by a choline deficient, ethionine-supplemented (CDE) diet, ND-07 dramatically protected the mortality even without any death, providing attenuation of pancreas, lung, and liver damages as well as the reductions in serum levels of lactate dehydrogenase (LDH), amylase and lipase, MDA levels in the plasma and pancreatic tissues, plasma levels of TNF-α, and interleukin-1 (IL-1β). These findings suggest that current dual synergistic action mechanisms of ND-07 might provide a superior protection for acute pancreatitis than conventional drug treatments.
authors.affiliation: Neuroscience Graduate Program, Research Institute for Neural Sciences and Technology, Ajou University School of Medicine, Suwon 443-749, South Korea; GNT Pharma Co., Ltd., Yongin 446-901, South Korea.
authors.forename: Jin Hwan
authors.initials: JH
authors.lastname: Lee
authors.forename: Chun San
authors.initials: CS
authors.lastname: An
authors.forename: Bok Sun
authors.initials: BS
authors.lastname: Yun
authors.forename: Kum Suk
authors.initials: KS
authors.lastname: Kang
authors.forename: Young Ae
authors.initials: YA
authors.lastname: Lee
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Won
authors.forename: Byoung Joo
authors.initials: BJ
authors.lastname: Gwag
authors.forename: Sung Ig
authors.initials: SI
authors.lastname: Cho
authors.forename: Ki-Baik
authors.initials: KB
authors.lastname: Hahm
mesh_terms: D000681:Amylases / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D002460:Cell Line; D045744:Cell Line, Tumor; D002108:Ceruletide; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008049:Lipase / Q000097:blood; D008070:Lipopolysaccharides; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000378:metabolism; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: C575483:2-acetoxy-5-(2-4-(trifluoromethyl)phenethylamino)benzoic acid; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001565:Benzoates; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008315:Malondialdehyde; D002108:Ceruletide; D007770:L-Lactate Dehydrogenase; D008049:Lipase; D000681:Amylases; D015232:Dinoprostone