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J Assoc Res Otolaryngol. 2015 Oct;16(5):599-611. doi: 10.1007/s10162-015-0528-6. Epub 2015 Jun 9.

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

Author information

1
Department of Otolaryngology-Head and Neck Surgery, University of Michigan, 1500 East Medical Center Drive, Taubman Clinic 1A, Ann Arbor, MI, 48109, USA.
2
Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research Institute, University of Michigan, 1150 West Medical Center Drive, 5323 Medical Science Building I, Ann Arbor, MI, 48109-5616, USA.
3
Unit for Laboratory Animal Medicine, University of Michigan, North Campus Research Complex, Building 36, Room 178, 2800 Plymouth Road, Ann Arbor, MI, 48103, USA.
4
Department of Otolaryngology-Head and Neck Surgery, University of Michigan, 1500 East Medical Center Drive, Taubman Clinic 1A, Ann Arbor, MI, 48109, USA. rkduncan@umich.edu.
5
Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research Institute, University of Michigan, 1150 West Medical Center Drive, 5323 Medical Science Building I, Ann Arbor, MI, 48109-5616, USA. rkduncan@umich.edu.

Abstract

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.

KEYWORDS:

cochlea; cyclodextrin; drug delivery; hearing loss; ototoxicity

PMID:
26055150
PMCID:
PMC4569609
DOI:
10.1007/s10162-015-0528-6
[Indexed for MEDLINE]
Free PMC Article

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