Perilymphatic application of cisplatin over several days in albino guinea pigs: dose-dependency of electrophysiological and morphological effects.
Cisplatin, at 0, 3, 30 or 300 microg/ml in saline, was applied to the scala tympani of the cochlea of guinea pigs via osmotic mini-pumps, operating at a pump rate of 0.5 microl/h. Electrocochleographic recordings were made from an implanted round window electrode. When an electrocochleographic criterion of ototoxicity was reached (40 dB loss in compound action potential (CAP) threshold at 8 kHz), or after 1 week if this criterion was not reached, the animals were sacrificed for light microscopy. A subgroup of animals had endocochlear potentials (EPs) measured prior to sacrifice. Hearing remained stable in the 0 microg/ml control group, but a sudden drop of auditory sensitivity across the whole frequency range was observed in all other groups. It took 1-5 days before the drop occurred, dependent on cisplatin concentration. CAP and cochlear microphonics were lost simultaneously. The EP was severely depressed in the affected animals, suggesting that cisplatin effects on the EP are primary. However, histology revealed an accompanying loss of outer hair cells, primarily in the basal turn. It is concluded that if cisplatin is given until ototoxicity becomes apparent electrophysiologically, then the cochlear pathology from intrascalar cisplatin administration resembles that from daily parenteral administration at 1.5-2.0 mg/kg. The cochlear pathology from the parenteral treatment was greater than that observed with 30 microg/ml pumps, and less than that from 300 microg/ml pumps.
O'Leary
S J
SJ
Hearing Research Laboratories, University Medical Center, Utrecht, The Netherlands.
Klis
S F
SF
de Groot
J C
JC
Hamers
F P
FP
Smoorenburg
G F
GF
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001300:Audiometry, Evoked Response; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D003055:Cochlear Microphonic Potentials / Q000187:drug effects; D016503:Drug Delivery Systems; D004594:Electrophysiology; D005260:Female; D006168:Guinea Pigs; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects / Q000473:pathology; D010498:Perilymph / Q000378:metabolism*
D002945:Cisplatin