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1 KISEP Otology Korean J Otolaryngol 1998;412: 기니픽에서 Cisplatin 이독성에대한 Fosfomycin 의예방적효과 김춘동 2 변성완 2 정원호 1 김종선 1 Preventive Effect of Fosfomycin on Cisplatin Induced Ototoxicity in Cochlea of Guinea Pig Chun Dong Kim, MD 2, Sung-Wan Byun, MD 2, Won Ho Chung, MD 1 and Chong Sun Kim, MD 1 1 Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Seoul National University, 2 Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Ewha Womans University, Seoul, Korea ABSTRACT Background and ObjectivesThe use of cisplatin as a therapeutic drug in malignant neoplasm is known to have associated side effects such as nephrotoxicity and ototoxicity. Although the nephrotoxic effect of this drug can be somewhat decreased by use of the hydration method, prevention of the ototoxic effect, which is known to induce irreversible change on the cochlea, has not been well established. The purose of this study is to evaluate the preventive effect of fosfomycin in cisplatin induced ototoxicity. MethodsFosfomycin was used to reduce the ototoxic effects of cisplatin, and its efficacies were evaluated anatomically as well as physiologically. Anatomically, a histologic study of cochleas was carried out by scanning electromicroscopy, and physiologically, cochlear microphonics and compound action potentials were studied in guinea pigs. ResultsProtection against distortion and loss of outer hair cells in the basal turn of cochlea caused by cisplatin was found to be statistically significant in the groups injected with fosfomycin. ConclusionFosfomycin was found to be effective in providing protection against cisplatin induced ototoxicity. Korean J Otolaryngol 1998;412: KEY WORDSOtotoxicity Cisplatin Fosfomycin. 168

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등이 었으며 외유모세포 제일 바 상의 정도도 가장 바깥열인 외유모세포 제3열의 손상이 가 깥열인 제3열의 손상이 가장 많았으며 외유모세포의 2열, 장 많았으며 외유모세포의 2열, 1열

3 Cisplatin 이독성의 예방 1열, 내유모세포의 순으로 손상이 진행되었다(Fig. 1.). U.S.A.)를 사용하였다. 결 과 Cisplatin과 Fosfomycin 동시 투여군의 주사전자현미 경 검사 소견 Cisplatin 투여군의 주사전자현미경 검사 소견 Cisplatin 투여군에서 보이는 와우의 주된 이상 소견인 Cisplatin 투여군의 와우의 주된 이상 소견은 섬모의 왜 섬모의 왜곡변형, 경직성 상실, 탈락 등을 볼 수 있었고 손 곡변형, 경직성 상실, 탈락 등이 었으며 외유모세포 제일 바 상의 정도도 가장 바깥열인 외유모세포 제3열의 손상이 가 깥열인 제3열의 손상이 가장 많았으며 외유모세포의 2열, 장 많았으며 외유모세포의 2열, 1열, 내유모세포의 순으로 Fig. 1. Scanning electron microscopic findings of cochleas in guinea pig injected with cisplatin (8 mg/kg) the outer hair cells lose their stiffness and are distorted ( 1,500). Fig. 2. Scanning electron microscopic findings of cochleas in guinea pig injected with cisplatin (8 mg/kg) and fosfomycin (320 mg/kg) the outer hair cells lose their stiffness ( 1,250). 170 Korean J Otolaryngol 1998;41(2):

4 Table 1. Outcomes of two groups induced by intraperitoneal injection of cisplatin 8 mgkg and the cisplatin 8 mgkg followed by fosfomycin 320 mgkg for 7 days in basal turn of guinea pig Group Row Percentage of hair cells counted Grade 0 Grade 1 Grade 2 Grade 3 Cisplatin OHC OHC OHC IHC Fosfomycin OHC OHC OHC IHC Table 2. Analysis of Chi square for trend by the Mantel extension method Group by turn Odds ratio Chi square for linear trend p value Basal turn p= Cisplatin 1.0 Cisplatinfosfomycin 0.36 Fig. 3. Variations of evoked potentials in a cisplatin-treated guinea pigthe square traces the differences of CAP thresholds in decibels under the control and treated conditions. The circle indicates the corresponding differences of CM magnitudes in percentages under the same treatment. The x-axis denotes the frequencies tested in this animal. Fig. 4. Variations of evoked potentials in a cisplatin-fosfomycin-treated guinea pigthe square traces the differences of CAP thresholds in decibels under the control and treated conditions. The circle indicates the corresponding differences of CM magnitudes in percentages under the same treatment. The x-axis denotes the frequencies tested in this animal. 171

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6 REFERENCES 1) Hultcrantz M, Anniko M, Borg E. Structure and function of the adult cochlea following prenatal irradiation. Acta Otolaryngol Stockh suppl ) Piel IJ, Meyer D, Perlia CP et al. Effects of cis-diamminedichloroplatinum NSC on hearing function in man. Canc Chemother Rep ) Boheim K, Bichler E. Cisplatin-induced ototoxicity: Audiometric findings and experimental cochlear pathology. Arch Otorhinolaryngol ) Rybak LP. Cisplatin associated hearing loss. J Laryngol Otol ) Laurell G, Jungnelius U. High-dose cisplatin treatment Hearing loss and plasma concentration. Laryngoscope ) Laurell G, Engstrom B, Hirsch A, Bagger-Sjoback D. Ototoxicity of cisplatin. Int J Androl ) Blakley BW, Gupta AK, Myers SF, Schwan S. Risk factors for ototoxicity due to cisplatin. Arch Otolaryngol Head Neck Surg ) Barr-Hamilton RM, Matheson LM, Keay DG. Ototoxicity of cisplatinum and its relationship to eye colour. J Laryngol Otol ) euman M. Recent developments in the field of phosphonic acid antibiotics. J Antimicro Chemother ) Ohtani I, Ohtsuki K, Aikawa T. Reproduction of cisplatin toxicity by fosfomycin in animal models. Jpn J Ca Chemoter ) Ohtani I, Ohtsuki K, Aikawa T. Protective effects of fosfomycin against amonoglycoside ototoxicity. ORL ) Ohtani I, Okamura H, Kobari M, Yamanobe S, Hoshino T, Yamaguchi M, Yamada H. Potentiation of inner ear damage following electron beam irradiation with CDDP administration. Fukushima J Med Sci ) Kurebe M, Niizato T, Sanda M. Preventive effect of fosfomycin on the renal toxicity of cisplatin. Jpn J Antibiot ) Schweitzer VG, Dolan DF, Abrams GE, Davidson T, Snyder R. Amelioration of cisplatin-induced ototoxicity by fosfomycin. Laryngoscope ) Schweitzer VG, Rarey KE, Dolan DF, Abrams G, Litterst CJ, Sheridan C. Ototoxicity of cisplatin vs. platinum analogs CBDCA JM-8 and CHIP JM-9. Otolaryngol Head Neck Surg ) McAlpine D, Johnstone BM. The ototoxic mechanism of cisplatin. Hear Res ) Ravi R, Somani SM, Rybak LP. Mechanism of cisplatin ototoxicity antioxidant system. Pharmacology & Toxicology

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