Oral Administration of Clinical Stage Drug Candidate SENS-401 Effectively Reduces Cisplatin-induced Hearing Loss in Rats
| Autor: | Audrey Broussy, Mathieu Petremann, Christophe Tran Van Ba, Jonas Dyhrfjeld-Johnsen, Charlotte Romanet |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Hearing loss Otoacoustic Emissions Spontaneous Population Administration Oral Antineoplastic Agents Myosins Audiology Pharmacology 03 medical and health sciences 0302 clinical medicine Audiometry Ototoxicity In vivo Evoked Potentials Auditory Brain Stem otorhinolaryngologic diseases medicine Animals Rats Wistar Hearing Loss education Cochlea education.field_of_study medicine.diagnostic_test business.industry medicine.disease Pediatric cancer Sensory Systems Rats Disease Models Animal Hair Cells Auditory Outer 030104 developmental biology Auditory brainstem response Otorhinolaryngology Myosin VIIa 030220 oncology & carcinogenesis Neurology (clinical) Cisplatin medicine.symptom business |
| Zdroj: | Otology & Neurotology. 38:1355-1361 |
| ISSN: | 1537-4505 1531-7129 |
| Popis: | HYPOTHESIS SENS-401, an oral clinical-stage drug, may reduce cisplatin-induced hearing loss and cochlear damage in an in vivo model. BACKGROUND Cisplatin is commonly associated with hearing loss, causing significant learning and behavioral difficulties in the pediatric cancer population, and for which there are currently no clinical solutions. SENS-401 has previously been shown to improve acoustic trauma-induced hearing loss in vivo. METHODS The effect of SENS-401 (R-azasetron besylate) on cisplatin IC50 values was evaluated in a panel of cisplatin-sensitive cell lines (NIH:OVCAR-3, SK-N-AS, NCI-H460, FaDu). Auditory brainstem response and distortion product otoacoustic emission tests were performed in a rat model of cisplatin-induced hearing-loss (8 mg/kg, day 1) at baseline, and after 14 days of SENS-401 (6.6, 13.2, 26.4 mg/kg/d). Cochlear outer hair cells were counted after immunolabeling for myosin-VIIa. RESULTS Cisplatin cytotoxicity was not impacted by the addition of SENS-401 (up to 10 μM) in any of the cell types evaluated. In vivo, all SENS-401 doses significantly improved auditory brainstem response threshold shift (up to 30 dB) and distortion product otoacoustic emission amplitude loss (up to 19 dB) over placebo. Body weight and survival were not significantly different between rats receiving placebo and those receiving 26.4 mg/kg SENS-401. Significantly more surviving outer hair cells were present after SENS-401 treatment compared with placebo (p |
| Databáze: | OpenAIRE |
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