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2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease.

ABSTRACT: 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) is a promising experimental therapy for Niemann-Pick type C disease that improved intracellular cholesterol transport, substantially reduced neurodegeneration and hepatic disease, and increased lifespan in npc1 mice. On the basis of favorable treatment outcome in mice, HPbetaCD is being evaluated as a therapy in children with Niemann-Pick type C (NPC) disease. We evaluated the efficacy of HPbetaCD in the feline model of NPC disease and recognized a dose-dependent increase in hearing threshold associated with therapy as determined by brain stem auditory evoked response (BAER) testing. To further assess the effect of HPbetaCD on hearing threshold, normal cats were administered the drug s.c. at either 4000 mg/kg or 8000 mg/kg body weight, or intrathecally at a dose of 4000 mg/kg brain weight. HPbetaCD caused a significant increase in hearing threshold following one dose of 8000 mg/kg s.c. or 120 mg intrathecally, and the effect was maintained for at least 12 weeks. Repeated weekly s.c. administration of 4000 mg/kg HPbetaCD resulted in a similar increase in hearing threshold. These studies are the first to describe a specific negative effect of HPbetaCD on the auditory system and suggest the need for auditory testing in patients receiving similar doses of HPbetaCD.

SUBMITTER: Ward S

PROVIDER: S-EPMC2913583 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease.

Ward Sarah S O'Donnell Patricia P Fernandez Steven S Vite Charles H CH

Pediatric research 20100701 1

2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) is a promising experimental therapy for Niemann-Pick type C disease that improved intracellular cholesterol transport, substantially reduced neurodegeneration and hepatic disease, and increased lifespan in npc1 mice. On the basis of favorable treatment outcome in mice, HPbetaCD is being evaluated as a therapy in children with Niemann-Pick type C (NPC) disease. We evaluated the efficacy of HPbetaCD in the feline model of NPC disease and recognized a do ...[more]

PMID: 20357695

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Project description:2-Hydroxypropyl-beta-cyclodextrin (HPβCD) has gained recent attention as a potential therapeutic intervention in the treatment of the rare autosomal-recessive, neurodegenerative lysosomal storage disorder Niemann-Pick Disease Type C1 (NPC1). Notably, HPβCD formulations are not comprised of a single molecular species, but instead are complex mixtures of species with differing degrees of hydroxypropylation of the cyclodextrin ring. The degree of substitution is a critical aspect of the complex mixture as it influences binding to other molecules and thus could potentially modulate biological effects. VTS-270 (Kleptose HPB) and Trappsol® Cyclo™ are HPβCD products under investigation as novel treatments for NPC1. The purpose of the present work is to compare these two different products; analyses were based on ion distribution and abundance profiles using mass spectrometry methodology as a means for assessing key molecular distinctions between products. The method incorporated electrospray ionization and analysis with a linear low-field ion mobility quadrupole time-of-flight instrument. We observed that the number of hydroxypropyl groups (the degrees of substitution) are substantially different between the two products and greater in Trappsol Cyclo than in VTS-270. The principal ions of both samples are ammonium adducts. Isotope clusters for each of the major ions show doubly charged homodimers of the ammonium adducts. In addition, both products show doubly charged homodimers from adduction of both a proton and ammonium. Doubly charged heterodimers are also present, but are more intense in Trappsol Cyclo than in VTS-270. Based on the analytical differences observed between VTS-270 and Trappsol Cyclo with respect to the degree of substitution, the composition and fingerprint of the complex mixture, and the impurity profiles, these products cannot be considered to be the same; the potential biological and clinical implications of these differences are not presently known.

Dataset Information

2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease.

Publications

2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease.

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