Serum levels of gentamicin. Serum levels of ~entamic~n were obtained after 2 and 7 days of treatment as described in ‘Methods’. Values in animals receiving GSH co-therapy did not differ statistically from values in animals receiving gentamicin alone.
The effect of glutathione
co-therapy on the expression of gentamicin ototoxicity was tested in pigmented guinea pigs. The first group of animals was injected with gentamicin (100 mg/kg body weight/day) for two weeks followed by 10 weeks of rest. A second group received glutathione by gastric gavage immediately prior to each gentamicin injection. Two groups of controls were treated either with saline injections or glutathione gavage alone. Auditory brainstem responses, taken at 2-week intervals, revealed a progressive gentamicin-induced hearing loss teaching a 30 to 40 dB threshold shift at 2 kHz, approximately 60 dB at 8 kHz and SO dB at 18 kHz. Glutathione co-therapy slowed the progression of hearing loss and significantly attenuated the final threshold shifts by 20 to 40 dB. Morphological evaluation confirmed hair cell loss after gentamicin treatment and protection by glutathione. Drug serum levels were assayed at 2 and 7 days of treatment. There were no differences between the gentamicin (mean = 183 pg/ml; range, 90 to 300) and the gentamicin/glutathione group (mean = 164 bg/ml; range, 80 to 320). Antimicrobial activity of gentamicin was tested against Staphylococcus aureuf and Pseudomonas aeruginosa. A 30-fold molar excess of glutathione did not influence the efficacy of gentamicin. These studies suggest that glutathione protects against ototoxicity by interfering with the cytotoxic mechanism.
1. Auditory brain stem response
Auditory thresholds were comparable in all groups at the beginning of the study. Animals injected with saline or gavaged with GSH maintained essentially stable hearing at all of the measured frequencies
Cochleae from two animals in each of the four treatment groups were examined histologically. Their morphology supported the electrophysiological findings that treatment with GSH exerted a protective influence on hair cells.
3. Serum levels of gentamicin
Serum levels of gentamicin were unaffected by GSH treatment. On day 2 and 7, gentamicin concentrations averaged 183 pg/ml (range, 80 to 320). This was not statistically different from the mean of 164 pg/ml (range, 90 to 300) in the animals gavaged with GSH prior to their gentamicin injections (Figure 1)
efficacy Gentamicin efficacy against Streptococcus aureus and Pseudomonas aeruginosa was tested in a standard antimicrobial assay. The inhibition zones produced by 10 kg gentamicin remained unaffected by GSH up to a 30-fold molar excess, the highest concentration tested (Table 1).
These studies suggest that glutathione protects against ototoxicity by interfering with the cytotoxic mechanism.