Schacht J
Kresge Hearing Research Institute, University of Michigan School of Medicine, Ann Arbor.
Otolaryngol Clin North Am. 1993 Oct;26(5):845-56.
The basis for the development of a rational explanation of aminoglycoside toxicity now appears to exist. The acute effects of these drugs are primarily based on calcium antagonism and block of ion channels. The chronic toxicity requires metabolism, and the expression of tissue-specific toxicity is a balance between synthesis of the toxin and its detoxification. Further investigations into the nature of the toxic metabolite should allow us to combine this information with previously established intracellular actions of aminoglycosides to create a unified hypothesis of action. The ability of glutathione to block toxin formation or to increase detoxification (or both) may have clinical implications for the prevention of aminoglycoside-induced ototoxicity. The clinical use of aminoglycosides has somewhat decreased over the last decade because of the introduction of the less toxic cephalosporins of the third generation and the quinolones, which are effective against Pseudomonas infections. Development of bacterial resistance against aminoglycosides is another factor, although resistance to the cephalosporins is also rapidly becoming a serious problem that eventually will limit their usefulness. Only through a detailed knowledge of the molecular basis of toxicity can we rationally pursue the development of new aminoglycosides with less ototoxic and nephrotoxic potential and devise treatments that will prevent the adverse side effects of these antibiotics.
现在似乎已经有了对氨基糖苷类毒性作出合理阐释的基础。这些药物的急性效应主要基于钙拮抗作用和离子通道阻断。慢性毒性则需要代谢参与，而组织特异性毒性的表现是毒素合成与其解毒作用之间的一种平衡。对有毒代谢物本质的进一步研究应能使我们将这些信息与先前确定的氨基糖苷类的细胞内作用相结合，从而形成一个统一的作用假说。谷胱甘肽阻断毒素形成或增强解毒作用（或两者兼具）的能力可能对预防氨基糖苷类所致耳毒性具有临床意义。在过去十年间，由于毒性较低的第三代头孢菌素和喹诺酮类药物的问世，氨基糖苷类药物的临床应用有所减少，这些药物对铜绿假单胞菌感染有效。细菌对氨基糖苷类产生耐药性是另一个因素，尽管对头孢菌素的耐药性也正迅速成为一个严重问题，最终将限制其效用。只有通过详细了解毒性的分子基础，我们才能合理地研发出耳毒性和肾毒性潜力较小的新型氨基糖苷类药物，并设计出能预防这些抗生素不良反应的治疗方法。
