The purpose of these studies is fourfold: 1) to determine the maximum time before noise exposure that the otoprotective agent D-methionine (D-met) can first be effectively administered and then stopped prior to noise exposure, an administration strategy termed pre-loading, and still prevent or reduce subsequent permanent noise induced hearing loss (NIHL) with no further D-met administration 2) to determine optimal D- met dosing levels for various preloading time periods, 3) to determine optimal D-met dosing levels at the various rescue time periods, meaning that the otoprotective agent D-met is first administered up to 36 hours after noise cessation and still provides NIHL protection and 4) to investigate a variety of possible serum and cochlear biomarkers that could be used to indicate optimal or non-optimal dosing in a given patient given probable intersubject variability in the patients oxidative status prior to and during D-met treatment. These biomarkers could then be used to guide D-met dosing and dose adjustment for a given patient for optimal otoprotection for either systemic or round window D-met administration. These studies will be conducted for both steady state and impulse noise exposures because we have found that optimal dosing may vary by noise exposure type. Permanent NIHL is the most common hearing loss world-wide and the third leading chronic health condition in America. D-met, patented in my lab, is the first otoprotective agent approved for Phase 3 clinical trials under a Food and Drug Administration (FDA) Investigational New Drug (IND) filing to prevent NIHL and tinnitus, administering D-met before, during and after the 2 week noise exposure. We are currently collecting data for this Department of Defense (DoD) funded clinical trial in soldiers during M-16 weapons training. However optimal dosing for pre-loading or rescue dosing may be different than for this clinical trial dosing regimen. As we move closer to possible FDA approval for the first otoprotective agent, we need to prepare for possible clinical guidance's for optimal patient treatment strategies to accommodate clinical variability in noise exposures, the practicalities of when the patient can actually be treated relative to the noise exposure and the probable endogenous intrasubject variability in oxidative state and possibly response to treatment. Biomarkers may be helpful in signaling optimal and non-optimal dosing levels in a given patient allowing for dose adjustment .The proposed studies will correlate optimal protective D-met dose and affiliated cochlear and serum biomarkers for each D-met administration time and dose level before or after a single steady state or impulse noise exposure. Our overall goal is to optimize and provide clinical guidance for a safe and effective pharmacologic agent to prevent NIHL worldwide in a variety of settings. These studies are critical to achieve that goal.
These proposed studies will optimize D-methionine (D-met) dosing to prevent permanent noise-induced hearing loss (NIHL) from two different noise exposure types. We will measure preloaded and rescue dose- response curves to optimize D-met protection from NIHL. We will also seek possible biomarkers in blood and cochlea that may guide individualized protective dosing in future patients.
|Campbell, Kathleen C M; Martin, Seth M; Meech, Robert P et al. (2016) D-methionine (D-met) significantly reduces kanamycin-induced ototoxicity in pigmented guinea pigs. Int J Audiol 55:273-8|
|Fox, Daniel J; Cooper, Morris D; Speil, Cristian A et al. (2016) d-Methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models. J Cyst Fibros 15:518-30|
|Sun, Pengfei; Qin, Jun; Campbell, Kathleen (2015) Fatigue Modeling via Mammalian Auditory System for Prediction of Noise Induced Hearing Loss. Comput Math Methods Med 2015:753864|