EFFECTS OF ORGANIC ACIDS ON LOOP DIURETIC OTOTOXICITY

有机酸对袢利尿剂耳毒性的影响

• 批准号: 3405056
• 负责人: LEONARD P RYBAK
• 金额: $ 9.81万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1988-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3405056
• 关键词: action potentials; chromatography; cochlea; diuretics; drug metabolism; electrolytes; electron microscopy; electrophysiology; endolymph; furosemide; organic acid; ototoxin

A number of organic acid compounds such as loop diuretics have been shown to adversely effect cochlear function in patients as well as in experimental animal models. Unfortunately, the molecular basis for these ototoxic effects has not yet been elucidated. Recent experimental findings have suggested that certain organic acid compounds can reduce the cochlear effects of furosemide. The proposed research will examine the interaction of organic acid transport inhibitors with two ototoxic loop diuretics: ethacrynic acid and furosemide. The studies will investigate whether such interactions result in a reduced cochlear effect of these ototoxic loop diuretics. The specific electrophysiologic experiments will look at changes in endocochlear potential, eighth nerve action potential, and the measurement of potassium and chloride concentration in endolymph using ion sensitive microelectrodes. Correlation of these findings with the ultrastructure of the stria vascularis will be made. The blood levels of loop diuretics will be measured in controls and experimental animals to determine whether they are altered by drugs which reduce the cochlear effects. In addition, the diuretic response in control and experimental animals will be evaluated to determine whether drugs which alter the cochlear effects also change the diuretic response to loop diuretics. The findings that specific inhibition of undesirable ototoxic effects of loop diuretics without changing the pharmacokinetics or desired pharmacodynamic effect will strongly suggest the presence of a carrier for organic acids in the cochlear, analogous to that seen in other tissues. Furthermore, such findings would have extremely provocative therapeutic implications. The possibility of manipulation of ototoxic effects of loop diuretics without altering the necessary response of removing excess fluid from the patient would be of major clinical importance.

已经展示了许多有机酸化合物，如环状利尿剂 对患者的耳蜗功能造成不利影响 实验动物模型。不幸的是，这些的分子基础 耳毒性作用尚未阐明。最近的实验发现 已经表明某些有机酸性化合物可以降低耳蜗值 速尿的作用。拟议的研究将检验这种相互作用。 含有两种耳毒性环状利尿剂的有机酸转运抑制剂： 乙丙奈酸和速尿。这些研究将调查这种情况是否 相互作用导致这些耳毒性环路的耳蜗效应减弱 利尿剂。具体的电生理学实验将着眼于 耳蜗内电位、第八神经动作电位和 离子检测法测定内淋巴中钾和氯的浓度 灵敏的微电极。这些发现与 将制作血管纹的超微结构。血液中的水平 环状利尿剂将在对照组和实验动物中进行测量，以 确定它们是否被减少耳蜗量的药物改变 效果。此外，利尿剂在对照组和试验组中的反应 将对动物进行评估，以确定是否有药物改变 耳蜗效应也会改变利尿剂对环状利尿剂的反应。这个 研究发现，特异性抑制LOOP的不良耳毒性作用 利尿剂在不改变药代动力学或所需药效学的情况下 这一效应将强烈表明有机酸载体的存在。 耳蜗耳，类似于在其他组织中所见到的。此外，这样的 这一发现将具有极具挑衅性的治疗意义。这个 环状利尿剂的耳毒性作用在无操作的情况下的可能性 改变患者排出多余液体的必要反应 将具有重要的临床意义。