title: Measurement of Ototoxicity Following Intracochlear Bisphosphonate Delivery.
abstract: Assessing the maximum safe dose for local bisphosphonate delivery to the cochlea enables efficient delivery without ototoxicity.
  
  
  
  Otosclerosis is a disease of abnormal bone metabolism affecting the otic capsule, which can cause conductive hearing loss. Larger otosclerotic lesions involving the cochlear endosteum and spiral ligament can result in sensorineural hearing loss. Bisphosphonates are used to treat patients with metabolic bone diseases, including otosclerosis. Local delivery is the most efficient way of delivery to the cochlea while avoiding systemic side effects. To attain intracochlear bisphosphonate delivery without ototoxicity, the maximum safe dose of bisphosphonates requires definition. In the present study, we tested increasing concentrations of zoledronate, a third-generation bisphosphonate in an intracochlear delivery system. We measured ototoxicity by monitoring distortion product otoacoustic emissions and compound action potentials.
  
  
  
  Artificial perilymph and increasing molar concentrations of zoledronate were administered to the cochlea in guinea pigs via a cochleostomy. Hearing was measured at multiple time points. A fluorescently labeled zoledronate derivative (6-FAM-ZOL) was coadministered as an internal control for drug delivery. Specimens embedded in the resin blocks were ground to a mid-modiolar section and fluorescent photomicrographs were taken.
  
  
  
  No significant shift in hearing was observed in animals treated either with artificial perilymph or with 4% of the human systemic zoledronate dose. However, compound action potentials thresholds increased during infusion of 8% of the human systemic zoledronate dose, improved 4 hours later, and then increased again 4 weeks later. Using fluorescent photomicrography, intracochlear bisphosphonate delivery up to the apical cochlear turn was confirmed by visualizing 6-FAM-ZOL.
  
  
  
  These findings provide reference values for intracochlear bisphosphonate delivery in the treatment of cochlear otosclerosis and describe a useful method for tracking cochlear drug delivery.
authors.affiliation: *Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea†Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A.‡Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, U.S.A.§Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts, U.S.A.¶Department of Chemistry, University of Southern California, Los Angeles, California, U.S.A.
authors.forename: Woo Seok
authors.initials: WS
authors.lastname: Kang
authors.forename: Kim
authors.initials: K
authors.lastname: Nguyen
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
authors.forename: William F
authors.initials: WF
authors.lastname: Sewell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McKenna
authors.forename: David H
authors.initials: DH
authors.lastname: Jung
mesh_terms: D000818:Animals; D003051:Cochlea / Q000187:drug effects* / Q000502:physiology; D004164:Diphosphonates / Q000008:administration & dosage / Q000633:toxicity*; D006168:Guinea Pigs; D007093:Imidazoles / Q000008:administration & dosage / Q000633:toxicity*; D017084:Otoacoustic Emissions, Spontaneous / Q000187:drug effects; D010040:Otosclerosis / Q000473:pathology*; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid