title: Effects of intracerebroventricular administration of 2-hydroxypropyl-β-cyclodextrin in a patient with Niemann-Pick Type C disease.
abstract: Niemann-Pick Type C disease (NPC) is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration. Previously, we reported that intravenous administration of 2-hydroxypropyl-β-cyclodextrin (HPB-CD) in two patients with NPC had only partial and transient beneficial effects on neurological function. The most likely reason for HPB-CD not significantly improving the neurological deficits of NPC is its inability to cross the blood-brain barrier. Herein, we describe the effects of intrathecal HPB-CD in an eight-year-old patient with a perinatal onset of NPC, administered initially at a dose of 10 mg/kg every other week and increased up to 10 mg/kg twice a week. Clinically, the patient maintained residual neurological functions for two years, at which time nuclear magnetic resonance spectroscopy showed a decreased choline to creatine ratio and increased N-acetylaspartate to creatine ratio, and positron emission tomography revealed increased standardized uptake values. Total-tau in the cerebrospinal fluid (CSF) was also decreased after two years. No adverse effects were observed over the course of treatment. The CSF concentrations of HPB-CD during the distribution phase after the injections were comparable with those at which HPB-CD could normalize cellular cholesterol abnormality in vitro. Further studies are necessary to elucidate the mechanisms of action of HPB-CD in NPC, and to determine the optimal dose and intervals of HPB-CD injection.
authors.affiliation: Department of Pediatrics, Saga University, Faculty of Medicine, Saga, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Shraishi
authors.affiliation: Research Institute, Nihon Shokuhin Kako Co., Ltd, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Wada
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ishitsuka
authors.affiliation: Department of Pediatrics, Saga University, Faculty of Medicine, Saga, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Doi
authors.affiliation: Department of Pharmacology, Saga University, Faculty of Medicine, Saga, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Department of Pediatrics, Saga University, Faculty of Medicine, Saga, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Mizoguchi
authors.affiliation: Department of Pediatrics, Saga University, Faculty of Medicine, Saga, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Eto
authors.affiliation: Department of Pharmacology, Saga University, Faculty of Medicine, Saga, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Mochinaga
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Irie
keywords: CD, cyclodextrin; CSF, cerebrospinal fluid; Cho, choline; Cholesterol; Cr, creatine; Cyclodextrin; HPB-CD, 2-hydroxypropyl-β-cyclodextrin; Intracerebroventricular administration; Intrathecal administration; MRS, nuclear magnetic resonance spectroscopy; NAA, N-acetylaspartate; NPC, Niemann–Pick Type C disease; Niemann–Pick Type C disease; PET, positron emission tomography; Pharmacokinetics