Chang Hao, Telang Ravindra S, Sreebhavan Sreevalsan, Tingle Malcolm, Thorne Peter R, Vlajkovic Srdjan M
Department of Physiology and Centre for Brain Research, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Auckland Cancer Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Biomed Res Int. 2017;2017:8091462. doi: 10.1155/2017/8091462. Epub 2017 Jan 18.
Noise-induced hearing loss (NIHL) is a global health problem affecting over 5% of the population worldwide. We have shown previously that acute noise-induced cochlear injury can be ameliorated by administration of drugs acting on adenosine receptors in the inner ear, and a selective A adenosine receptor agonist adenosine amine congener (ADAC) has emerged as a potentially effective treatment for cochlear injury and resulting hearing loss. This study investigated pharmacokinetic properties of ADAC in rat perilymph after systemic (intravenous) administration using a newly developed liquid chromatography-tandem mass spectrometry detection method. The method was developed and validated in accordance with the USA FDA guidelines including accuracy, precision, specificity, and linearity. Perilymph was sampled from the apical turn of the cochlea to prevent contamination with the cerebrospinal fluid. ADAC was detected in cochlear perilymph within two minutes following intravenous administration and remained in perilymph above its minimal effective concentration for at least two hours. The pharmacokinetic pattern of ADAC was significantly altered by exposure to noise, suggesting transient changes in permeability of the blood-labyrinth barrier and/or cochlear blood flow. This study supports ADAC development as a potential clinical otological treatment for acute sensorineural hearing loss caused by exposure to traumatic noise.
噪声性听力损失（NIHL）是一个全球性的健康问题，影响着全球超过5%的人口。我们之前已经表明，通过给予作用于内耳腺苷受体的药物，可以改善急性噪声诱导的耳蜗损伤，并且一种选择性A腺苷受体激动剂腺苷胺类似物（ADAC）已成为治疗耳蜗损伤及由此导致的听力损失的一种潜在有效疗法。本研究使用一种新开发的液相色谱-串联质谱检测方法，研究了全身（静脉）给药后ADAC在大鼠外淋巴中的药代动力学特性。该方法是根据美国食品药品监督管理局（FDA）的指南开发和验证的，包括准确性、精密度、特异性和线性。从耳蜗顶端采集外淋巴以防止脑脊液污染。静脉给药后两分钟内，在耳蜗外淋巴中检测到ADAC，并且其在外淋巴中的浓度保持在最低有效浓度以上至少两小时。暴露于噪声会显著改变ADAC的药代动力学模式，这表明血迷路屏障通透性和/或耳蜗血流发生了短暂变化。本研究支持将ADAC开发为一种潜在的临床耳科治疗方法，用于治疗由暴露于创伤性噪声引起的急性感音神经性听力损失。
