Effects of cyclodextrin in two patients with Niemann–Pick Type C disease

Matsuo, Muneaki; Togawa, Masami; Hirabaru, Keiko; Mochinaga, Sakiko; Narita, Aya; Adachi, Masao; Egashira, Masayuki; Irie, Tetsumi; Ohno, Kousaku

doi:10.1016/j.ymgme.2012.11.005

Cited by 123 publications

(115 citation statements)

References 10 publications

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…This dose of HPBCD was gradually increased to approximately 2500 mg/kg per dose. As reported previously, 4) intravenous treatment of HPBCD was effective in improving hepatosplenomegaly after 4 months of treatment. Assessment of serum HPBCD concentrations was performed at 8 months of treatment.…”

Section: Measurement Of Serum Hpbcd Concentrations In An Npc Patientsupporting

confidence: 78%

“…Detailed information of the patient and the therapeutic process have been previously described. 4) In brief, the patient, a 4-year-old girl in whom hepatosplenomegaly was detected before birth, was diagnosed as having NPC based on mutations in the NPC1 gene (c.581_592delinsG, Y1088C). Hepatosplenomegaly was present before starting HPBCD intravenous therapy.…”

Section: Measurement Of Serum Hpbcd Concentrations In An Npc Patientmentioning

confidence: 99%

“…[1][2][3] Symptoms of NPC disease include severe progressive neurodegeneration and enlargement of the liver. 3,4) NPC1 protein, localized in late endosomes/lysosomes, has a sterol-sensing domain, and plays an important role in cellular cholesterol transport. 5,6) Marked lysosomal accumulation of unesterified cholesterol and a shortage of esterified cholesterol in other cellular compartments are observed in the cells of NPC patients.…”

mentioning

confidence: 99%

“…Some reports have shown that HPBCD improves cholesterol sequestration in organs and prolongs the lifespan in Npc1 null mice, suggesting that HPBCD is a promising drug candidate against NPC disease. [7][8][9][10] Recently, Matsuo et al 4) reported the effectiveness of HPBCD in treatment of two Japanese patients with NPC disease. One patient was started with intravenous infusion of 80 mg/kg HPBCD for 8 h twice a week, and another patient was started with 80 mg/kg HPBCD for 8 h three times a week.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Efficacy of 2-Hydroxypropyl-β-cyclodextrin in Niemann–Pick Disease Type C Model Mice and Its Pharmacokinetic Analysis in a Patient with the Disease

Tanaka

Yamada

Ishitsuka

et al. 2015

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

Niemann-Pick type C disease (NPC), an autosomal recessive lysosomal storage disorder, is an inherited disease characterized by the accumulation of intracellular unesterified cholesterol. A solubilizing agent of lipophilic compounds, 2-hydroxypropyl-β-cyclodextrin (HPBCD), is an attractive drug candidate against NPC disease. However, establishment of the optimum dosage of HPBCD remains to be determined. In this study, we evaluated the effective dosage of HPBCD in NPC model (Npc1 / ) mice, and determined serum HPBCD concentrations. Subcutaneous injection of 1000-4000 mg/kg HPBCD improved the lifespan of Npc1 / mice. In addition, liver injury and cholesterol sequestration were significantly prevented by 4000 mg/kg HPBCD in Npc1 / mice. Serum HPBCD concentrations, when treated at the effective dosages (1000-4000 mg/kg), were approximately 1200-2500 µg/mL at 0.5 h after subcutaneous injection, and blood HPBCD concentrations were immediately eliminated in Npc1 / mice. Furthermore, we examined serum HPBCD concentrations when treated at 40000 mg (approximately 2500 mg/kg) in a patient with NPC. We observed that the effective concentration in the in vivo study using Npc1 / mice was similar to that in the patient. In the patient, systemic clearance and the volume of distribution of HPBCD were in accordance with the glomerular filtration rate and extracellular fluid volume, respectively. These results could provide useful information for developing the optimal dosage regimen for HPBCD therapy when administered intravenously to NPC patients.

show abstract

Section: Measurement Of Serum Hpbcd Concentrations In An Npc Patientsupporting

confidence: 78%

Section: Measurement Of Serum Hpbcd Concentrations In An Npc Patientmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Efficacy of 2-Hydroxypropyl-β-cyclodextrin in Niemann–Pick Disease Type C Model Mice and Its Pharmacokinetic Analysis in a Patient with the Disease

Tanaka

Yamada

Ishitsuka

et al. 2015

Biological & Pharmaceutical Bulletin

Self Cite

View full text Add to dashboard Cite

show abstract

“…When normalized according to differences in body surface area between species (Reagan-Shaw et al 2008), SQ low and SQ high correspond to 240 and 480 mg/kg, respectively, in humans. These concentrations were chosen based on human equivalent dose ranges initially scheduled in Compassionate Use trials for two NPC patients (Hastings 2009) but are well below escalated doses eventually reached in these and additional NPC patients (maximally 2900 mg/kg) (Hastings 2010;Matsuo et al 2013).…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Hearing Loss and Otopathology Following Systemic and Intracerebroventricular Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin

Cronin

Lin

Thompson

et al. 2015

JARO

View full text Add to dashboard Cite

Cyclodextrins are simple yet powerful molecules widely used in medicinal formulations and industry for their ability to stabilize and solubilize guest compounds. However, recent evidence shows that 2-hydroxypropyl-β-cyclodextrin (HPβCD) causes severe hearing loss in mice, selectively killing outer hair cells (OHC) within 1 week of subcutaneous drug treatment. In the current study, the impact of HPβCD on auditory physiology and pathology was explored further as a function of time and route of administration. When administered subcutaneously or directly into cerebrospinal fluid, single injections of HPβCD caused up to 60 dB threshold shifts and widespread OHC loss in a dose-dependent manner. Combined dosing caused no greater deficit, suggesting a common mode of action. After drug treatment, OHC loss progressed over time, beginning in the base and extending toward the apex, creating a sharp transition between normal and damaged regions of the cochlea. Administration into cerebrospinal fluid caused rapid ototoxicity when compared to subcutaneous delivery. Despite the devastating effect on the cochlea, HPβCD was relatively safe to other peripheral and central organ systems; specifically, it had no notable nephrotoxicity in contrast to other ototoxic compounds like aminoglycosides and platinum-based drugs. As cyclodextrins find expanding medicinal applications, caution should be exercised as these drugs possess a unique, poorly understood, ototoxic mechanism.

show abstract