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Updated: Jul 11, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
Functional and morphological effects of fotemustine on the auditory system of the rat
C Gocer1, A Eryilmaz, M E Kulak Kayikci
1Department of Otorhinolaryngology, Ankara Numune Hospital, Turkey. celilgocer@yahoo.com
Objective:
This study aimed to elucidate the potential inner-ear effects of fotemustine, a chemotherapeutic agent which crosses the blood-brain barrier and is used in the treatment of primary and metastatic brain tumours and metastatic melanoma.
Methods:
This study utilised distortion product otoacoustic emissions and transmission electron microscopy in order to conduct electrophysiological and morphological assessments, using a rat experimental model. Twelve ears of six male rats were examined two months following intraperitoneal slow infusion of fotemustine (100 mg/m2 or 7.4 mg/kg). Pre- and post-treatment measurements were compared. Finally, electron microscopy was performed on three rat temporal bones.
Results:
After infusion of fotemustine, distortion product otoacoustic emissions revealed a significant reduction in signal-to-noise ratios only at 3600 Hz (from 11.95 +/- 7.52 to -0.26 +/- 9.45 dB) and at 3961 Hz (from 18.09 +/- 7.49 to 6.74 +/- 12.11 dB) (referenced to 2f1 - f2). Transmission electron microscopy of the temporal bone revealed ultrastructural changes in the outer hair cells, stria vascularis and cochlear ganglion at the cochlear basal turn. The ganglion cell perikarya were unaffected.
Conclusions:
Fotemustine was administered via intraperitoneal slow infusion in a rat experimental model. Twelve ears of six survivors, from 10 rats, were evaluated at the second month. Fotemustine was determined to have a potential for ototoxicity at 3600 and 3961 Hz. Three randomly chosen rats underwent electron microscopy for morphological analysis. Morphological effects in the cochlear basal turn were observed. Oedematous intracytoplasmic spaces and perivascular areas of the stria vascularis, as well as distorted chromatin content, were detected, thereby suggesting potential ototoxic effects for this agent. Further experimental and clinical studies are required in order to determine whether the effect seen in this pilot study is reversible, and to analyse effects in humans.
Insights
Fotemustine, a chemotherapy drug, may cause hearing damage (ototoxicity) at specific frequencies, affecting inner ear structures like outer hair cells. Further studies are needed to confirm these findings in humans and assess reversibility.
Area of Science:
- Ototoxicology
- Neuroscience
- Pharmacology
Background:
- Fotemustine is a chemotherapy agent used for brain tumors and melanoma.
- Its ability to cross the blood-brain barrier raises concerns about potential central nervous system side effects.
- Inner ear toxicity is a critical consideration for chemotherapeutic agents.
Purpose of the Study:
- To investigate the potential ototoxic effects of fotemustine on the inner ear.
- To assess both electrophysiological and morphological changes in the cochlea following fotemustine administration.
- To utilize a rat model for evaluating fotemustine-induced hearing damage.
Main Methods:
- Distortion product otoacoustic emissions (DPOAEs) were used for electrophysiological assessment.
- Transmission electron microscopy (TEM) was employed for morphological evaluation of cochlear structures.
- Male rats received intraperitoneal slow infusion of fotemustine, with pre- and post-treatment measurements compared.
Main Results:
- Significant reductions in DPOAE signal-to-noise ratios were observed at 3600 Hz and 3961 Hz post-fotemustine infusion.
- TEM revealed ultrastructural alterations in outer hair cells, stria vascularis, and cochlear ganglion cells in the cochlear basal turn.
- While ganglion cell perikarya remained unaffected, morphological changes in the stria vascularis included oedematous spaces.
Conclusions:
- Fotemustine demonstrates potential ototoxicity, particularly affecting specific high frequencies (3600 and 3961 Hz).
- Morphological evidence supports ototoxicity, with observed changes in the cochlear basal turn's outer hair cells and stria vascularis.
- Further research is warranted to determine the reversibility of these effects and their relevance to human patients.
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