Difluoromethylornithine-Induced Reversible Hearing Loss Across a Wide Frequency Range†

Objectives: Alpha-difluoromethylornithine (DFMO) is an antineoplastic agent that causes reversible hearing loss (HL) by an unknown mechanism. Previous neonatal gerbil studies have identified a dosing regimen of 1 g/kg per day of DFMO given for 3 weeks that results in reversible HL on click-evoked auditory brainstem response (ABR). The objectives of this study are 1) to measure HL and recovery at several frequencies in neonatal gerbils after DFMO therapy at two different dosing regimens and 2) to identify any effects of DFMO on cochlear histology. Study Design: Prospective, nonrandomized, experimental design with placebo controls. Methods: ABR to tone pips at 2,4,8,16, and 32 kHz were recorded on 62 21-day-old Mongolian gerbils after daily subcutaneous injections of DFMO (group A at 1 g/kg, group B at 750mg/kg) or saline from day 3 to day 20 after birth. Thirty-seven animals were retested after a 3-week drug-free recovery period. Twenty-seven animals were killed for analysis of cochlear histology. Results: Animals that were administered DFMO demonstrated higher ABR thresholds across all five frequencies, with mean threshold differences of 21 to 29 dB in group A and 11 to 17 dB in group B as compared with controls. Higher thresholds were demonstrated at higher frequencies. Fewer side effects were noted at the lower dose. After a 3-week drug-free recovery period, auditory thresholds returned to pretreatment levels. No significant cochlear structural abnormalities were identified under light microscopy. Conclusion: An 18-day regimen of 750 mg/kg per day of DFMO given subcutaneously in neonatal gerbils causes minimal side effects with broad-frequency HL that, after 3 weeks of recovery, is fully reversible.