title: Lenvatinib, an oral multi-kinases inhibitor, -associated hypertension: Potential role of vascular endothelial dysfunction.
abstract: Lenvatinib (Lenvima®), an oral multi-kinase inhibitor, is effective in the treatment of differentiated thyroid carcinomas (DTCs). A severe adverse effect of lenvatinib is hypertension, thus limiting its use as an anti-cancer treatment. Although the pathogenesis of hypertension is generally assumed to involve microvascular bed reduction and an increase in peripheral vascular resistance due to a decrease in nitrogen oxide (NOx) production after vascular endothelial growth factor (VEGF) inhibition, the effects of hypertension on vascular endothelial function in actual patients remain unclear. Here, we examined how lenvatinib affects vascular endothelial function.
  
  
  
  Ten consecutive DTC patients who did not take any cardiovascular agents were orally administered 24 mg of lenvatinib once daily. Using an EndoPAT2000®system, we used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of the RH-PAT index (RHI). We expressed the results as %RHI, which indicates the change compared with pretreatment levels. Additionally, we measured serum NOx and plasma VEGF concentrations pre- and post-treatment.
  
  
  
  All of the patients treated with lenvatinib exhibited significant hypertension; the %RHI levels were significantly decreased the day after treatment with lenvatinib. Furthermore, serum NOx and plasma VEGF concentrations were significantly decreased and increased, respectively, compared with pretreatment levels. These results indicate that hypertension induced by lenvatinib may be caused by a decrease in nitric oxide production, as a result of VEGF inhibition and impaired vascular endothelial function.
  
  
  
  We provide the first demonstration that lenvatinib causes hypertension via vascular endothelial dysfunction in human subjects.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sueta
authors.affiliation: Kumamoto University Hospital Cancer Center, Kumamoto University, Kumamoto, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Suyama
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Aiko
authors.initials: A
authors.lastname: Sueta
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tabata
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Tomiguchi
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takeshita
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Yamamoto-Ibusuki
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kaikita
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: shokimot@kumamoto-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Hokimoto
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Iwase
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Tsujita
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D001795:Blood Pressure Determination; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000453:epidemiology / Q000503:physiopathology; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects*; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000097:blood / Q000188:drug therapy; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D014655:Vascular Resistance / Q000187:drug effects*
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; C531958:lenvatinib
keywords: Endothelial dysfunction; Lenvatinib; Vascular endothelial growth factor