The inhibiting effects of itraconazole, an antifungal drug on vascular endothelial growth factor (VEGF) have recently been discovered. By inhibiting VEGF, itraconazole has shown potential in clinical trials as anti-cancer treatment. In hereditary hemorrhagic telangiectasia (HHT) patients, VEGF levels are elevated and inhibition of VEGF can decrease bleeding. Itraconazole could potentially serve as anti-angiogenic therapy for HHT-related bleeding. We report a proof of concept study with HHT patients and severe epistaxis. Patients were treated with daily 200 mg orally administered itraconazole for sixteen weeks. Twenty-one HHT patients, 8 females (38%), 13 males (62%), median age of 59 years (interquartile range (IQR) 55–69) were enrolled. Of these patients, 13 (62%) were diagnosed with HHT type 1, seven (33%) with HHT type 2 and in one patient (5%), no pathognomonic HHT mutation was found. Four patients (19%) prematurely terminated the study (3 due to mild or moderate side-effects) resulting in 17 patients included in the analyses. The median epistaxis severity score significantly decreased during treatment from 6.0 (IQR 5.1–7.2) to 3.8 (IQR 3.1–5.2) (p = 0.006). The monthly epistaxis frequency decreased from 56 to 38 epistaxis episodes (p = 0.004) and the monthly duration from 407 to 278 minutes (p = 0.005). Hemoglobin levels did not significantly change. The quality of life showed a small but significant improvement. In conclusion, oral itraconazole significantly improved epistaxis in HHT patients. The potential benefit of itraconazole in HHT should be further investigated.
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Activin A receptor like type 1
Argon plasma coagulation
Epistaxis severity score
Hereditary hemorrhagic telangiectasia
Mental component summary
Multidimensional fatigue inventory 20
Physical component summary
Red blood cell
Severe adverse event
Short Form Health Survey 36
Vascular endothelial growth factor
McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE et al (1994) Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8(4):345–351
Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon SJ et al (1996) Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 13(2):189–195
Silva BM, Hosman AE, Devlin HL, Shovlin CL (2013) Lifestyle and Dietary Influences on Nosebleed Severity in Hereditary Hemorrhagic Telangiectasia. Laryngoscope 123(5):1092–1099
Shah RK, Dhingra JK, Shapshay SM (2002) Hereditary Hemorrhagic Telangiectasia: A Review of 76 Cases. Laryngoscope 112(5):767–773
Zarrabeitia R, Fariñas-Álvarez C, Santibáñez M, Señaris B, Fontalba A, Botella LM et al (2017) Quality of life in patients with hereditary haemorrhagic telangiectasia HHT. Health Qual Life Outcomes. 15(1):19
Dupuis-Girod S, Ginon I, Saurin J-C, Marion D, Guillot E, Decullier E et al (2012) Bevacizumab in Patients With Hereditary Telangiectasia. JAMA J Am Med Assoc 307(9):948–955
Lestner J, Hope WW. Itraconazole (2013) An update on pharmacology and clinical use for treatment of invasive and allergic fungal infections. Expert Opin Drug Metab Toxicol 9(7):911–926
Tsubamoto H, Ueda T, Inoue K, Sakata K, Shibahara H, Sonoda T (2017) Repurposing itraconazole as an anticancer agent. Oncol Lett 14(2):1240–1246
Aftab BT, Dobromilskaya I, Liu JO, Rudin CM (2011) Itraconazole Inhibits Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer. Cancer Res. 71(21):6764–72
Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJJ et al (2000) Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 6(1):66–67 91(
de Gussem EM, Snijder RJ, Disch FJ, Zanen P, Westermann CJJ, Mager JJ (2009) The effect of N-acetylcysteine on epistaxis and quality of life in patients with HHT: a pilot study. Rhinology 47(1):85–88
Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C et al (2010) Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med 16(4):420–428
Hoag JB, Terry P, Mitchell S, Reh D, Merlo CA (2010) An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope 120(4):838–843
Ware JE, Sherbourne CD (1992) The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 30(6):473–483
Smets EMA, Garssen B, Bonke B, De Haes JCJM. The multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res. 1995
Medicijnkosten [Internet]. . Available from: https://www.medicijnkosten.nl/databank?zoekterm=ITRACONAZOL&toedieningsvorm=TABLETTEN EN CAPSULES&ddd_per_artikel = 0.5&hoeveelheid = 60,00
Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ, Liu JO (2007) Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol. 2(4):263–70
Choi CH, Ryu JY, Cho YJ, Jeon HK, Choi JJ, Ylaya K et al (2017) The anti-cancer effects of itraconazole in epithelial ovarian cancer. Sci Rep 7(1):1–10
Nacev BA, Grassi P, Dell A, Haslam SM, Liu JO (2011) The antifungal drug itraconazole inhibits Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) glycosylation, trafficking, and signaling in endothelial cells. J Biol Chem 286(51):44045–44056
Abhinand CS, Raju R, Soumya SJ, Arya PS, Sudhakaran PR (2016) VEGF-A/VEGFR2 signaling network in endothelial cells relevant to angiogenesis. J Cell Commun Signal. 10(4):347–54
Rudin CM, Brahmer JR, Juergens RA, Hann CL, Ettinger DS, Sebree R et al (2013) Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer. J Thorac Oncol 8(5):619–623
Bae JH, Hwang AR, Kim CY, Yu HG, Koh HJ, Yang WI et al (2017) Intravitreal itraconazole inhibits laser-induced choroidal neovascularization in rats. PLoS One 12(6):1–13
Sadick H, Riedel F, Naim R, Goessler U, Hörmann K, Hafner M et al. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-β1 as well as high ALK1 tissue expression. Haematologica. 2005
Faughnan ME, Gossage JR, Chakinala MM, Oh SP, Kasthuri R, Hughes CCW et al (2019) Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. Angiogenesis 22(1):145–155
Li W, Zeng S, Yu L-S, Zhou Q (2013) Pharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk management. Ther Clin Risk Manag 9(05):259–271
Whitehead KJ, Sautter NB, McWilliams JP, Chakinala MM, Merlo CA, Johnson MH et al (2016) Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia. JAMA 6(9):943 316(
Dupuis-Girod S, Ambrun A, Decullier E, Fargeton AE, Roux A, Bréant V et al (2016) Effect of bevacizumab nasal spray on epistaxis duration in hereditary hemorrhagic telangectasia: A randomized clinical trial. JAMA - J Am Med Assoc 316(9):934–942
Wang JL, Chang CH, Young-Xu Y, Chan KA (2010) Systematic Review and Meta-Analysis of the Tolerability and Hepatotoxicity of Antifungals in Empirical and Definitive Therapy for Invasive Fungal Infection. Antimicrob Agents Chemother 54(6)(1):2409–2419
Ahmad SR, Singer SJ, Leissa BG (2001) Congestive heart failure associated with itraconazole. Lancet (London, England). 357(9270):1766–7
Letteboer TGW, Zewald RA, Kamping EJ, de Haas G, Mager JJ, Snijder RJ et al (2005) Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet 116(1–2):8–16
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Kroon, S., Snijder, R.J., Hosman, A.E. et al. Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: a proof of concept study. Angiogenesis (2020). https://doi.org/10.1007/s10456-020-09758-2
- Telangiectasia, Hereditary hemorrhagic
- Vascular endothelial growth factors