EFFECTS OF ORGANIC ACIDS ON LOOP DIURETIC OTOTOXICITY

许多有机酸化合物如袢利尿剂已被证明 对患者的耳蜗功能产生不利影响 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。 最近的实验结果 已经表明某些有机酸化合物可以降低耳蜗 呋塞米的影响。 拟议的研究将检验相互作用 有机酸转运抑制剂与两种耳毒性袢利尿剂的组合： 依他尼酸和呋塞米。 这些研究将调查是否存在这样的情况 相互作用导致这些耳毒性环的耳蜗效应降低 利尿剂。 具体的电生理实验将着眼于 耳蜗内电位、第八神经动作电位和 使用离子测量内淋巴中的钾和氯浓度 灵敏的微电极。 这些发现与 将制作血管纹的超微结构。 血液水平为 将在对照和实验动物中测量袢利尿剂，以 确定它们是否被减少耳蜗的药物改变 影响。 此外，对照和实验中的利尿反应 将评估动物以确定药物是否会改变 耳蜗效应也会改变袢利尿剂的利尿反应。 的 研究发现，特异性抑制环的不良耳毒性作用 利尿剂，不改变药代动力学或所需的药效学 效应将强烈表明有机酸载体的存在 耳蜗，类似于在其他组织中看到的。 此外，这样的 研究结果将具有极具启发性的治疗意义。 的 控制袢利尿剂耳毒性作用的可能性，无需 改变从患者体内排出多余液体的必要反应 将具有重要的临床意义。

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.