title: Ototoxicity of 12 mg/kg cisplatin in the Fischer 344/NHsd rat using multiple dosing strategies.
abstract: Ototoxicity continues to be a major dose-limiting side effect of cis-diamminedichloroplatinum(II) (cisplatin). With an ongoing need to develop pharmaceutical protection strategies for cisplatin's ototoxicity, there is also a need to develop stable in-vivo mammalian models of cisplatin ototoxicity. The current study examined the difference in ototoxicity of a cumulative 12 mg/kg dose of cisplatin in the Fischer 344/NHsd rat when administered over four different dosing protocols. Hearing sensitivity was measured using free-field auditory brainstem response thresholds under anesthesia. Rats were divided into four groups. The first group was administered 12 mg/kg of cisplatin in a single bolus infusion. The second group was administered two 6 mg/kg infusions separated by 7 days. The third group was administered 3 mg/kg injections once per day for 4 consecutive days. The fourth group was administered 3 mg/kg injections in four injections separated by 3 days each. Hearing thresholds and body weights were measured at 3 and 7 days after the final cisplatin exposure. Postmortem sensory cell counts were used to confirm injury to the auditory system. The 4 consecutive days of 3 mg/kg induced a greater mortality rate and greater hearing loss at day 3 than the other experimental protocols. The 3 mg/kg administered every 3 days induced less sensory cell loss than the other conditions. The findings indicate that 4 consecutive days of 3 mg/kg cisplatin is not a viable ototoxicity model in the Fischer 344/NHsd rat, but that the other models are all effective in inducing comparable cochlear injuries.
authors.affiliation: Department of Speech and Hearing Science, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Harrison
authors.forename: Brittany M
authors.initials: BM
authors.lastname: Seiler
authors.forename: Eric C
authors.initials: EC
authors.lastname: Bielefeld
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001309:Auditory Threshold / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects*; D004334:Drug Administration Schedule; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005260:Female; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000473:pathology; D034381:Hearing Loss / Q000139:chemically induced*; D008297:Male; D011916:Rats, Inbred F344
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin