Cisplatin-induced ototoxicity; electrophysiological evidence of spontaneous recovery in the albino guinea pig.

For 8 days albino guinea pigs (n = 48) were treated with cisplatin (cis-diamminedichloroplatinum(II), 1.5 mg/kg body weight/day). Compound action potentials (CAP), cochlear microphonics (CM) and summating potentials (SP) were recorded from the apical surface of the cochlea in response to tone bursts ranging in frequency from 0.5 to 16 kHz. The recordings were collected in different groups of animals, 1 day, 1 week, 2, 4, 8 and 16 weeks after cisplatin treatment, respectively. One day after the 8-day treatment we found frequency-dependent loss in the amplitudes of the three cochlear potentials, with the larger losses occurring at the higher frequencies. In terms of threshold shift the losses were larger for the CAP than for the hair cell-related potentials SP and CM. A salient improvement in both CAP and CM amplitude occurred over the next 8 weeks. Also, the SP showed improvement. These results indicate that guinea pig cochlear transduction recovers spontaneously after cisplatin injury. Recovery of the hair cell-related potentials suggests that recovery occurs already at the hair cell level. The question whether this recovery originates with the formation of new hair cells or with repair of damaged hair cells should be answered on the basis of subsequent morphological investigations.

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.

Protective effects of a neurotrophic ACTH(4-9) analog on cisplatin ototoxicity in relation to the cisplatin dose: an electrocochleographic study in albino guinea pigs.

Cisplatin is a potent cell cycle non-specific chemotherapeutic agent that produces side effects including high-frequency hearing loss. Hamers et al. (1994) studied electrophysiologically the effect of an ACTH(4-9) analog, also known as ORG2766, on the ototoxicity of cisplatin (administered at 2 mg/kg/day for 8 days) in guinea pigs. ORG2766 was given concomitantly with cisplatin during the 8 day period and an additional dose was given on day 9. The conclusion of this study was that ORG2766 might partially prevent cisplatin ototoxicity, but that the chosen cisplatin dose (2 mg/kg/day; 8 days) might have been too high. Because of the high cisplatin dose the protective power of the co-treatment with ORG2766 might not have stretched to all animals. In this study the results of co-treatment with the same dose and daily schedule of ORG2766 and cisplatin doses of 1.0 mg/kg/day and 1.5 mg/kg/day for 8 days are presented. The measurements were performed over a broad range of frequencies (0.5-16 kHz). Electrocochleography was performed at day 10. In the 1.0 mg/kg/day group there was no beneficial effect of ORG2766, although a tendency towards a division between a subgroup resembling control animals and a subgroup with severe cisplatin effects was noted in the co-treated group. In the 1.5 mg/kg/day co-treated group three animals showed compound action potential (CAP) amplitudes close to those of the controls at all frequencies except the very highest (12 and 16 kHz), the remaining three had CAP amplitudes comparable to those of animals in the cisplatin alone group. The effect of ORG2766 on the latter group of six animals taken together was statistically significant. The dichotomy in the results for the 1.5 mg/kg/day group co-treated with ORG2766 suggests that ORG2766 may have a protective effect against cisplatin ototoxicity which, however, depends on a factor currently unknown.