title: Sustained-release delivery of leupeptin in the chinchilla: hearing results.
abstract: Transtympanic medical therapy is becoming an increasingly popular modality for the treatment of "inner-ear disorders." While investigators continue to examine the best dosing paradigms for gentamicin in the treatment of Ménière's disease and for steroids in the treatment of hearing loss, they have also begun to focus on the use of other agents. In particular, transtympanic therapy has been advocated as a plausible route for the treatment of tinnitus. Transtympanic therapy for tinnitus is not new, and a number of groups have reported success in the past. Despite this success, a number of laboratories have been focusing on newer agents that might yield higher success rates in the treatment of tinnitus and other inner-ear disorders. Many of these agents could have systemic side effects when delivered in high enough doses; therefore, they are ideal candidates for transtympanic administration. The goal of this study is to begin to define the effects of one of these agents--leupeptin, a calpain antagonist--on the normal inner ear of an animal model. In this investigation, we demonstrate the effects of sustained-release delivery of leupeptin (2.5 micrograms/ml) on the hearing of chinchillas. The medicine produced no hearing loss at the early time points but did produce some hearing loss at later time points. We discuss these results and begin to outline the next steps in the investigation of this agent.
authors.affiliation: Department of Defense, Spatial Orientation Center, Department of Otolaryngology, Naval Medical Center San Diego, San Diego, CA 92134-2200, USA. mehoffer@nmcsd.med.navy.mil
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hoffer
authors.forename: J Clay
authors.initials: JC
authors.lastname: Finley
authors.forename: Peter
authors.initials: P
authors.lastname: Killian
authors.forename: Kim R
authors.initials: KR
authors.lastname: Gottshall
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Balough
authors.forename: Derin
authors.initials: D
authors.lastname: Wester
authors.forename: Abraham
authors.initials: A
authors.lastname: Shulman
mesh_terms: D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects*; D002154:Calpain / Q000037:antagonists & inhibitors; D002682:Chinchilla; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D007758:Ear, Inner / Q000187:drug effects*; D016057:Evoked Potentials, Auditory, Brain Stem; D034381:Hearing Loss / Q000139:chemically induced*; D007976:Leupeptins / Q000008:administration & dosage / Q000032:analysis / Q000633:toxicity*; D023421:Models, Animal; D010498:Perilymph / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors
chemical_list: D015853:Cysteine Proteinase Inhibitors; D003692:Delayed-Action Preparations; D007976:Leupeptins; D002154:Calpain; C032854:leupeptin