A clinically derived guinea pig dosing model of cisplatin ototoxicity.

The guinea pig is a commonly-used animal model in hearing research, as their audible frequency range is similar to that of humans, and they possess comparatively large cochleae among rodents. Numerous studies have investigated the ototoxic effects of cisplatin in guinea pigs, but these have been mostly limited to single high-dose bolus injections of cisplatin. This method of drug administration is not consistent with human treatment schedules, and therefore lacks translational value to clinical applications. We tested several different cisplatin dosing schedules in guinea pigs based on common research based and clinical regimens, measuring the resulting hearing loss and morbidity (weight loss). We propose a dosing paradigm of once-weekly 4 mg/kg cisplatin injections for three weeks to best mimic clinical treatment schedules. This method resulted in a configuration of hearing loss similar to what is observed in humans along with minimal changes in weight.

Cool OtOprotective Ear Lumen (COOL) Therapy for Cisplatin-induced Hearing Loss.

HYPOTHESIS: Localized cooling of the external ear has a protective effect on the susceptibility to cisplatin-induced hearing loss. BACKGROUND: We previously demonstrated significant protection from cisplatin-induced hearing loss using cool water ear canal irrigation. However, the study was limited to a single bolus injection of cisplatin and an acute time period. Here, we examined the application of localized cooling of the ear canal with repeated doses of cisplatin, over an expanded period of time, and using two methods of cooling. METHODS: Twenty-four guinea pigs (12 male and 12 female) underwent auditory physiological testing (auditory brainstem response and distortion product otoacoustic emissions at 8-32 kHz) and pre/postadministration of cisplatin. Cisplatin (4 mg/kg i.p.) was administered in 3 weekly single injections for a total of 12 mg/kg. While anesthetized, the left ears of the guinea pigs were exposed to either cool water (22°C; ICS Water Caloric Irrigator), a cool ear bar (15°C, cooled by a Peltier device; TNM, Scion NeuroStim), or left uncooled as a sham control. The animals were tested 3 days post each dosage and 1 month post the final dose. At the end of the experiment the animals were euthanized for histological evaluation. RESULTS: We found that hearing loss was significantly reduced, and hair cell survival greatly improved, in animals that received cooling treatments compared to cisplatin-only control animals. No significant difference was observed between the two methods of cooling. CONCLUSION: Localized cooling of the ear canal during administration of cisplatin mitigated loss of auditory function and loss of hair cells.