Cisplatin ototoxicity. An electrophysiological dose-effect study in albino guinea pigs

Recently, the effect of the ACTH(4-9) analog, ORG2766, on cisplatin ototoxicity was studied by Hamers et al. (1994). This study showed that the ACTH(4-9) analog partially prevents the ototoxicity of cisplatin. The authors suggested that the daily dose of 2.0 mg/kg/day for 8 days might have been too high to obtain full protection. Knowledge about dose-effect relations for cisplatin ototoxicity is rather meager. Therefore, we conducted a basic dose-effect study for cisplatin without any concomitant additives. A follow-up of the Hamers et al. (1994) study, based on dose-effect data from this paper, is presented in a companion paper. The effects of cisplatin on the compound action potential (CAP), cochlear microphonics (CM) and summating potential (SP) were determined in acute experiments, in different groups of albino guinea pigs, each group injected with a different dose of cisplatin. Daily doses ranged from 0.7 to 2.0 mg/kg/day cisplatin (i.p.) for 8 consecutive days. Electrocochleography was performed at day 10. The measurements were performed over a broad range of frequencies (0.5-16 kHz). The results showed clustering of the data in two groups, the first group concerning the treatments of 1.5 and 2.0 mg/kg/day with large frequency-dependent losses in the three cochlear potentials, the second group concerning the treatments with lower doses of cisplatin (0.7, 1.0 and 1.25 mg/kg/day) where almost no losses in the three cochlear potentials were found. The threshold curves regarding the lower doses (0.7-1.25 mg/kg/day) were almost indistinguishable from the control threshold curve except at the higher frequencies (12 and 16 kHz). Thus, a marked transition from almost no ototoxic effect to a large effect seems to occur between cisplatin doses of 1.25 and 1.5 mg/kg/day for 8 days. The small difference between the effects found for 1.5 mg/kg/day and 2 mg/kg/day suggests that a smaller dose than the one of 2 mg/kg/day for 8 days used previously (Hamers et al., 1994) might better suit research into protection against cisplatin ototoxicity.