EW-7197, an activin-like kinase 5 inhibitor, suppresses granulation tissue after stent placement in rat esophagus

Jun, Eun Jung; Park, Jung Hoon; Tsauo, Jiaywei; Yang, Su Geun; Kim, Dae Kee; Kim, Kun Yung; Kim, Min Tae; Yoon, Sung Hwan; Lim, Young Je; Song, Ho Young

doi:10.1016/j.gie.2017.01.013

Cited by 32 publications

(42 citation statements)

References 34 publications

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“…Self-expandable metal stent (SEMS) placement is a widely adopted treatment for palliation of a malignant biliary obstruction that improves patients’ quality of life and relieves symptoms of jaundice [ 1 , 2 , 3 , 4 ]. However, SEMSs are susceptible to stent re-obstruction by tissue hyperplasia and/or tumor ingrowth or overgrowth because of mechanical stress on the adjacent tissue caused by the uncovered SEMS mesh framework or both ends of the covered SEMS [ 5 ]. Tissue growth through the stent mesh is also the main obstacle to successful SEMS removal for exchange purposes [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Metallic Stent Mesh Coated with Silver Nanoparticles Suppresses Stent-Induced Tissue Hyperplasia and Biliary Sludge in the Rabbit Extrahepatic Bile Duct

et al. 2020

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Recent therapeutic strategies to suppress restenosis after biliary stent placement are insufficient. Here, we demonstrate the usefulness of a self-expandable metal stent (SEMS), a stent mesh coated with silver nanoparticles (AgNPs), for suppression of both stent-induced tissue hyperplasia and biliary sludge formation in the rabbit bile duct. The AgNP-coated SEMSs were prepared using a simple bio-inspired surface modification process. Then, the prepared SEMSs were successfully placed in 22 of 24 rabbits. Sludge formation in the AgNP-coated SEMS groups was significantly decreased compared to the control group on gross findings. Cholangiographic and histologic examinations demonstrated significantly decreased tissue hyperplasia in the AgNP-coated SEMS groups compared with the control group (p < 0.05 for all). There were no differences between the AgNP-coated SEMS groups (p > 0.05 for all). However, in the group coated with the greatest concentration of AgNPs (Group D), submucosal fibrosis was thicker than in the other AgNP-coated groups (p < 0.05 for all). The AgNP-coated metallic stent mesh significantly suppressed stent-induced tissue hyperplasia and biliary sludge formation in the rabbit bile duct. Taken together, the AgNP coating strategy developed in this study could be widely utilized in non-vascular medical devices for anti-bacterial and anti-inflammatory responses.

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Section: Introductionmentioning

confidence: 99%

Metallic Stent Mesh Coated with Silver Nanoparticles Suppresses Stent-Induced Tissue Hyperplasia and Biliary Sludge in the Rabbit Extrahepatic Bile Duct

et al. 2020

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“…Various attempts to block the TGF-β pathway have been made and EW-7197 is a recently introduced TGF-β type-1 receptor kinase inhibitor [ 13 ]. The safety and efficacy of EW-7197 has been documented in animal models, and several investigators have reported that EW-7197 safely inhibited hepatic, renal, and pulmonary fibrosis and stent-induced granulation tissue formation by blocking the TGF-β/Smad and/or reactive oxygen species (ROS) signaling pathway [ 15 , 16 , 26 ]. As stent-induced benign stricture appeared to be subject to TGF-β, EW-7197 was used as an antifibrotic agent in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…On histological examination, the mean thicknesses of papillary projection, thickness of submucosal fibrosis, number of epithelial layers, and degree of collagen deposition were significantly less in the DS group than in the CS group, whereas inflammatory cell infiltration was not different. Given the key role of TGF-β in fibrosis after stent-induced mechanical injury, a previous study demonstrated that oral administration of EW-7197 after bare metallic stent placement successfully inhibited granulation tissue formation by blocking the TGF-β signaling pathway in a rat esophageal model [ 15 ]. Although inflammatory cells may be continuously recruited by an indwelling stent acting as the stimulus, EW-7197 appears to prohibit the inflammatory phase from progressing to the proliferative phase [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…Of these, EW-7197 is a novel oral TGF-β type-1 receptor kinase inhibitor [ 13 , 14 ]. This drug has been shown to have strong antifibrotic properties in animals [ 15 , 16 ] and the development of a drug-eluting stent using EW-7197 may be an attractive alternative for suppressing granulation tissue formation after stent placement in the urethra. Nanofiber meshes are flexible and highly porous meshes that is suitable for coating metallic stents and providing local drug delivery [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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EW-7197 eluting nano-fiber covered self-expandable metallic stent to prevent granulation tissue formation in a canine urethral model

et al. 2018

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PurposeTo evaluate an EW-7197-eluting nanofiber-covered stent (NFCS) for suppressing granulation tissue formation after stent placement in a canine urethral model.Materials and methodsAll experiments were approved by the committee of animal research. A total of 12 NFCSs were placed in the proximal and distal urethras of six dogs. Dogs were divided into two groups with 3 dogs each. The control stent (CS) group received NFCSs and the drug stent (DS) group received EW-7197 (1000 μg)-eluting NFCSs. All dogs were sacrificed 8 weeks after stent placement Histologic findings of the stented urethra were compared using the Mann-Whitney U test.ResultsStent placement was technically successful in all dogs without procedure-related complications. On urethrographic analysis, the mean luminal diameter was significantly larger in the DS group than in the CS group at 4 and 8 weeks after stent placement (all p < 0.001). On histological examination, mean thicknesses of the papillary projection, thickness of submucosal fibrosis, number of epithelial layers, and degree of collagen deposition were significantly lower in the DS group than in the CS group (all p < 0.001), whereas the mean degree of inflammatory cell infiltration was not significantly different (p > 0.05).ConclusionThe EW-7197-eluting NFCS is effective and safe for suppressing granulation tissue formation after stent placement in a canine urethral model.

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“…Vactosertib exhibited subnanomolar ALK5 inhibitory activity in a kinase assay and in a cell-based luciferase reporter assay 15 , high selectivity against a panel of 320 protein kinases including p38a 15 , moderate oral bioavailability in rats 15 , and high efficacy in animal models of cancer [19][20][21] and fibrosis [22][23][24][25][26] . In this report, we examined whether structural modification of vactosertib could increase its subnanomolar ALK5 inhibitory activity, thus further increasing its selectivity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, biological evaluation and molecular modelling of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1H-imidazoles as ALK5 inhibitors

Park

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1H-imidazoles, 7a-c, 11a-h, and 16a-h has been synthesised and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Incorporation of a quinoxalin-6-yl moiety and a methylene linker at the 4-and 2-position of the imidazole ring, respectively, and a m-CONH 2 substituent in the phenyl ring generated a highly potent and selective ALK5 inhibitor 11e. Docking model of ALK5 in complex with 11e showed that it fitted well in the ATP-binding pocket with favourable interactions.

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EW-7197, an activin-like kinase 5 inhibitor, suppresses granulation tissue after stent placement in rat esophagus

Cited by 32 publications

References 34 publications

Metallic Stent Mesh Coated with Silver Nanoparticles Suppresses Stent-Induced Tissue Hyperplasia and Biliary Sludge in the Rabbit Extrahepatic Bile Duct

Metallic Stent Mesh Coated with Silver Nanoparticles Suppresses Stent-Induced Tissue Hyperplasia and Biliary Sludge in the Rabbit Extrahepatic Bile Duct

EW-7197 eluting nano-fiber covered self-expandable metallic stent to prevent granulation tissue formation in a canine urethral model

Synthesis, biological evaluation and molecular modelling of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1H-imidazoles as ALK5 inhibitors

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