Method for preventing/treating damage to sensory hair cells and cochlear neurons

A drug and auditory technology, applied in the prevention and/or treatment of hearing loss and loss of balance sense, protection of sensory hair cells and cochlear neurons, can solve problems such as ineffective prevention or treatment of vestibular system hair cell damage

Inactive Publication Date: 2007-08-01
CEPHALON INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is currently no effective way to prevent or treat damage to the sensory hair cells of the vestibular system

Method used

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  • Method for preventing/treating damage to sensory hair cells and cochlear neurons
  • Method for preventing/treating damage to sensory hair cells and cochlear neurons
  • Method for preventing/treating damage to sensory hair cells and cochlear neurons

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1141] Example 1 - Prevention of hearing damage / cell death

[1142] Eight pigmented guinea pigs (200-300 g) were tested for baseline hearing by ABR as described below. ABR is a measure of auditory function. Four animals were treated with subcutaneous injection (s.c.) of the compound represented by formula II (1 mg / kg) once a day, starting 24 hours before the noise trauma and continuing until the 21st day after exposure to the noise trauma. 4 animals were used as controls and received vehicle only (the 4th animal died while under anesthesia). All animals were exposed to traumatic octave noise at a center frequency of 4.0 kHz and 125 dB SPL (sound pressure level) for 105 minutes.

[1143] ABR thresholds were measured again 21 days after exposure to noise trauma. ABR thresholds were determined using System II hardware and BioSig software (Trucker Davis Technology). Stimulation of an lms cos2 rise and fall and an 18 ms plateau was delivered at a frequency of 20 Hz with a Beyer...

Embodiment 2

[1152] Example 2 - Prevention of hearing damage / apoptosis

[1153] noise damage

[1154]Mature Dunkin-Hartley female guinea pigs (body weight 300-500 g) were exposed to octave band noise for 6 hours as described in Example 1, center frequency 4.0 kHz, 120 dB SPL, 4 animals each time. Fragmented hair cell nuclei from noise-exposed cochleae were assessed immediately and at days 1, 2, 4, 6, 8, and 14 after noise exposure. Noise-exposed and non-noise-exposed guinea pigs were decapitated under deep anesthesia, and the inner ear was perfused with 4% paraformaldehyde in PBS solution, and then processed into 5 mm thick paraffin-embedded sections (YliKoski et al., "Aural Res. (Hear Res) 65:69-78, 1993; Ylikoski et al., Hearing Research (Hear Res) 124:17-26, 1998). TUNEL-staining was performed as described below. DNA fragmentation was also detected by DAPI nuclear counterstaining (see below). In addition, trauma-induced nuclear fragments were detected by morphological analysis of th...

Embodiment 3

[1173] The protective effect of the compound shown in embodiment 3-formula II to neomycin in neonatal rat cochlear explant

[1174] The compound represented by formula II can reduce the loss of cochlear sensory hair cells caused by neomycin in vitro. The effect of the compound represented by formula II on neomycin-induced hair cell degeneration was determined in organ cultures of neonatal Organ of Corti.

[1175] cochlear culture

[1176] The lower half of the cochlea containing the basal and middle turns was excised from 2-day postnatal Wistar rats. Cultures were maintained on nuclear microporous filter paper (0.1 mm pore size; Pleasanton, CA) placed on metal grids in F12 broth (Life Technologies, Gaithersburg, MD) containing 15% fetal bovine serum (Life Technologies). After a 2 hour stabilization period, the explants were exposed to 100 mM neomycin sulfate (Sigma, St Louis, MO) for 48 hours. 500 nM of the compound represented by formula II was added at the beginning of th...

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Abstract

Methods for preventing or treating damage to sensory hair cells and cochlear neurons are disclosed. The methods comprise the administration of an effective amount of a compound of Formula I or Formula II. The method provides for the prevention / treatment of both hearing loss and loss of the sense of balance.

Description

technical field [0001] The present invention provides methods of preventing and / or treating hearing loss and loss of sense of balance. More specifically, the present invention provides a method of protecting sensory hair cells and cochlear neurons in an individual by administering an effective amount of a compound represented by formula I and / or formula II. [0002] cross related application [0003] This application claims priority to US Provisional Application Serial No. 601101,763, filed September 25, 1998, the disclosure of which is incorporated herein by reference in its entirety. Background of the invention [0004] The function of the mammalian ear is to convert sound waves or airborne vibrations into electrical impulses. The brain then recognizes these electrical impulses as sounds. The ear has three main parts, the outer ear, middle ear and inner ear. Sound waves enter the outer ear and cause the eardrum to vibrate. Vibrations from the ear drum are transmitted ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/55A61P27/16A61P39/00C07D487/04A61K31/403A61K31/407A61K31/4439A61K31/553C07D495/14C07D498/22
CPCA61K31/4439A61K31/553A61K31/407A61K31/403A61P27/16A61P39/00A61K31/404
Inventor 尤卡·于利科斯基乌拉·皮尔沃拉马特·萨尔玛凯文·沃尔顿罗伯特·L·赫德金斯
Owner CEPHALON INC
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