CC BY 4.0 · TH Open 2019; 03(03): e230-e243 DOI: 10.1055/s-0039-1693710
Original Article
Georg Thieme Verlag KG Stuttgart · New York
Topically Applied Etamsylate: A New Orphan Drug for HHT-Derived Epistaxis (Antiangiogenesis through FGF Pathway Inhibition)
Virginia Albiñana
1
Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
2
Centro de Investigación Biomédica en Red, CIBERER, Instituto de Salud Carlos III, Madrid, Spain
,
Guillermo Giménez-Gallego
1
Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
,
Angela García-Mato
1
Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
,
Patricia Palacios
1
Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
,
Lucia Recio-Poveda
1
Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
,
Angel-M Cuesta
1
Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
2
Centro de Investigación Biomédica en Red, CIBERER, Instituto de Salud Carlos III, Madrid, Spain
,
José-Luis Patier
3
Department of Internal Medicine, University Hospital Ramón y Cajal; Department of Medicine and Medical Specialities, Faculty of Medicine, University of Alcalá, IRYCIS, Madrid, Spain
,
Luisa-María Botella
1
Molecular Biomedicine Department, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain
2
Centro de Investigación Biomédica en Red, CIBERER, Instituto de Salud Carlos III, Madrid, Spain
› Author AffiliationsFunding The present work was funded by public projects of the Spanish Ministry of Economy and Competitiveness: MINECO SAF 2014 52374 R and SAF2017–83351 to L.M. Botella as the main researcher; PIE-201820E073 CSIC to Lucia Recio, CIBER Rare Diseases ISCIII, Madrid, Spain, funded Virginia Albiñana, and the Spanish HHT association acted as a sponsor of the clinical trial.
Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by recurrent and spontaneous epistaxis (nose bleeds), telangiectases on skin and mucosa, internal organ arteriovenous malformations, and dominant autosomal inheritance. Mutations in Endoglin and ACVRL1/ALK1, genes mainly expressed in endothelium, are responsible in 90% of the cases for the pathology. These genes are involved in the transforming growth factor-β(TGF-β) signaling pathway. Epistaxis remains as one of the most common symptoms impairing the quality of life of patients, becoming life-threatening in some cases. Different strategies have been used to decrease nose bleeds, among them is antiangiogenesis. The two main angiogenic pathways in endothelial cells depend on vascular endothelial growth factor and fibroblast growth factor (FGF). The present work has used etamsylate, the diethylamine salt of the 2,5-dihydroxybenzene sulfonate anion, also known as dobesilate, as a FGF signaling inhibitor. In endothelial cells, in vitro experiments show that etamsylate acts as an antiangiogenic factor, inhibiting wound healing and matrigel tubulogenesis. Moreover, etamsylate decreases phosphorylation of Akt and ERK1/2. A pilot clinical trial (EudraCT: 2016–003982–24) was performed with 12 HHT patients using a topical spray of etamsylate twice a day for 4 weeks. The epistaxis severity score (HHT-ESS) and other pertinent parameters were registered in the clinical trial. The significant reduction in the ESS scale, together with the lack of significant side effects, allowed the designation of topical etamsylate as a new orphan drug for epistaxis in HHT (EMA/OD/135/18).
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