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).
6
Plauchu H,
de Chadarévian JP,
Bideau A,
Robert JM.
Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989; 32 (03) 291-297
7
McAllister KA,
Grogg KM,
Johnson DW.
, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 1994; 8 (04) 345-351
8
Johnson DW,
Berg JN,
Baldwin MA.
, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996; 13 (02) 189-195
9
Cole SG,
Begbie ME,
Wallace GM,
Shovlin CL.
A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet 2005; 42 (07) 577-582
10
Bayrak-Toydemir P,
McDonald J,
Akarsu N.
, et al. A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet A 2006; 140 (20) 2155-2162
11
Wooderchak-Donahue WL,
McDonald J,
O'Fallon B.
, et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am J Hum Genet 2013; 93 (03) 530-537
15
Zarrabeitia R,
Ojeda-Fernandez L,
Recio L.
, et al. Bazedoxifene, a new orphan drug for the treatment of bleeding in hereditary haemorrhagic telangiectasia. Thromb Haemost 2016; 115 (06) 1167-1177
17
Fernández IS,
Cuevas P,
Angulo J.
, et al. Gentisic acid, a compound associated with plant defense and a metabolite of aspirin, heads a new class of in vivo fibroblast growth factor inhibitors. J Biol Chem 2010; 285 (15) 11714-11729
20
Baird A,
Bohlen P.
Peptide growth factors and their receptors. In:
Sporn MB,
Roberts AB.
, eds. Handbook of Experimental Pharmacology. Berlin: Springer-Verlag; 1990. 95: 369-418
22
Cuevas P,
García-Calvo M,
Carceller F.
, et al. Correction of hypertension by normalization of endothelial levels of fibroblast growth factor and nitric oxide synthase in spontaneously hypertensive rats. Proc Natl Acad Sci U S A 1996; 93 (21) 11996-12001
23
Cuevas P,
Reimers D,
Carceller F,
Xiaobing F,
Gimenez-Gallego G.
Second messengers and protein phosphorylation in health and disease. In:
Martín Municio A,
Miras-Portugal MT.
, eds. Cell Signal Transduction. New York, NY: Plenum Press; 1996: 161-167
26
Jackson A,
Friedman S,
Zhan X,
Engleka KA,
Forough R,
Maciag T.
Heat shock induces the release of fibroblast growth factor 1 from NIH 3T3 cells. Proc Natl Acad Sci U S A 1992; 89 (22) 10691-10695
29
Thomas KA,
Rios-Candelore M,
Giménez-Gallego G.
, et al. Pure brain-derived acidic fibroblast growth factor is a potent angiogenic vascular endothelial cell mitogen with sequence homology to interleukin 1. Proc Natl Acad Sci U S A 1985; 82 (19) 6409-6413
30
Esch F,
Baird A,
Ling N.
, et al. Primary structure of bovine pituitary basic fibroblast growth factor (FGF) and comparison with the amino-terminal sequence of bovine brain acidic FGF. Proc Natl Acad Sci U S A 1985; 82 (19) 6507-6511
33
Pàez-Ribes M,
Allen E,
Hudock J.
, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009; 15 (03) 220-231
34
Loges S,
Mazzone M,
Hohensinner P,
Carmeliet P.
Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 2009; 15 (03) 167-170
35
Fernández-Tornero C,
Lozano RM,
Redondo-Horcajo M.
, et al. Leads for development of new naphthalenesulfonate derivatives with enhanced antiangiogenic activity: crystal structure of acidic fibroblast growth factor in complex with 5-amino-2-naphthalene sulfonate. J Biol Chem 2003; 278 (24) 21774-21781
39
Zhang X,
Liu W,
Wu S,
Jin J,
Li W,
Wang N.
Calcium dobesilate for diabetic retinopathy: a systematic review and meta-analysis. Sci China Life Sci 2015; 58 (01) 101-107
41
Cuevas P,
Díaz-González D,
García-Martín-Córdova C.
, et al. Dobesilate diminishes activation of the mitogen-activated protein kinase ERK1/2 in glioma cells. J Cell Mol Med 2006; 10 (01) 225-230
44
Fernandez-L A,
Garrido-Martin EM,
Sanz-Rodriguez F.
, et al. Gene expression fingerprinting for human hereditary hemorrhagic telangiectasia. Hum Mol Genet 2007; 16 (13) 1515-1533
47
Hata Y,
Rook SL,
Aiello LP.
Basic fibroblast growth factor induces expression of VEGF receptor KDR through a protein kinase C and p44/p42 mitogen-activated protein kinase-dependent pathway. Diabetes 1999; 48 (05) 1145-1155
49
Shovlin CL,
Sulaiman NL,
Govani FS,
Jackson JE,
Begbie ME.
Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism. Thromb Haemost 2007; 98 (05) 1031-1039