Inner ear changes with intracochlear gentamicin administration in Guinea pigs

OBJECTIVES/HYPOTHESIS: Transtympanic administration of gentamicin is reported to be a useful treatment for vertigo in such conditions as Meniere's disease, and determining appropriate clinical dosage of gentamicin is difficult. The authors examined the relation between gentamicin dosages and inner ear function in guinea pigs. STUDY DESIGN: This study is a basic science project designed to examine cochlear and vestibular function in animal models. METHODS: Various concentrations of gentamicin solution were infused into the right inner ear of guinea pigs by osmotic pumps. Caloric nystagmus as a marker of vestibular function and the change in auditory brainstem response (ABR) threshold as a marker of cochlear function were observed. RESULTS: After 14 days of treatment, high gentamicin concentrations of 40 mg/mL caused canal paralysis and a rapid shift in ABR threshold. Animals exposed to low gentamicin concentrations of 4 mg/mL showed no obvious change in either vestibular or cochlear function. Animals exposed to moderate gentamicin concentrations of 12 mg/mL showed a moderate shift in ABR threshold and caloric malfunction. Histopathological examination revealed that after 14 days of treatment with 40 mg/mL gentamicin, severe cytoplasmic damage occurred in both vestibular and cochlear end organs. In animals treated with 12 mg/mL gentamicin, hair cells remained in the cochlear third turn and ampulla of the lateral semicircular canal. CONCLUSION: The authors established an animal model that showed the moderate damage of inner ear with moderate-dose gentamicin. The study results indicated that the appropriate administration of gentamicin could establish a stable effect on the inner ear. It may be important to select the protocol that delivers a stable dosage of gentamicin to treat patients with Meniere's disease safely and effectively.     

Long-term results after interval therapy with intratympanic gentamicin for Menière's disease

Objectives The new single‐shot and interval treatment for Menière's disease with gentamicin was designed to avoid cochlear damage during treatment with gentamicin. Methods To date, 90 patients were treated with the single‐shot or interval gentamicin therapy. Fifty‐seven cases of Menière's disease were followed up prospectively between 2 and 4 years. During one treatment series, a maximum of three intratympanic gentamicin injections within 15 days were applied, each consisting of 0.3 mL (12 mg) of gentamicin (days 1, 8, and 15). Thirty of these 57 patients (53%) needed only one injection to be controlled (single‐shot treatment). Results Vertigo attacks were completely controlled in 95% and partially controlled in 5%, whereas hearing remained unchanged or even improved. Tinnitus as well as aural fullness were controlled in approximately 50% of the cases. Conclusion Our results with this group of patients after interval‐treatment or single‐shot application of intratympanic gentamicin demonstrate the effectiveness of this treatment modality with very low side effects, and, although our experience is still limited, it allows for expanding the indication on early cases of Menière's disease before permanent hearing loss occurs. Even cases of bilateral Menière's disease can be treated successfully using this method. Cochleotoxic side effects can be prevented by treatment intervals of 7 days.     

银杏叶提取物与去铁胺合用防治顺铂耳毒性实验研究

目的银杏叶提取物-金纳多(extract of Ginkgo Biloba leaves injection,EGb)和铁螯合剂-去铁胺(Deferoxamine,DFO)联合应用对抗顺铂(Cisplatin,CDDP)耳毒性的作用。方法将豚鼠随机分为CDDP组、EGb组、DFO组、EGb+DFO组及对照组,测定听性脑千反应(auditory brain—stem response,ABR)、血清超氧化物歧化酶(superoxide dismutase,SOD)活性和丙二醛(MDA)含量及应用光镜、及扫描电镜技术,观察用药前后各指标的变化。结果CDDP组动物ABR阈值较其他各组明显升高(P<0．01),其余各组间差异不显著(P>0．05)。血清SOD活性和MDA含量检测表明,CDDP组血清SOD活性较对照组明显降低(P<0．01),MDA含量显著升高(P<0．01),其他组较对照组则差异无显著性(P>0．05)。耳蜗扫描电镜显示EGb+DFO组和DFO组比CDDP组毛细胞受损程度明显为轻,EGb组较CDDP组毛细胞受损程度略微减轻。结论DFO与EGb合用,可有效减轻CDDP的耳毒性作用,其效果优于单独应用EGb,与单独应用DFO效果相当,二者合用还可能减轻顺铂的骨髓抑制副作用。结果提示铁离子参与的自由基反应可能是顺铂耳毒性机制之一。     

Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood-Brain Barrier Disruption Program,Gleneden Beach,Oregon, March 10, 2001

OBJECTIVES: To summarize the findings relevant to otolaryngology from the annual meeting of the Blood-Brain Barrier Disruption Consortium in Gleneden Beach, Oregon, March 10, 2001. STUDY DESIGN: Summaries are provided by the speakers, as well as related data from the published literature. Findings in otology and oncology regarding ototoxicity that were discussed at the meeting are included. RESULTS: Data considered included physiological research, animal studies, and clinical trials that relate to platinum-based chemotherapy and prevention of toxicity. CONCLUSIONS: The dose-limiting side effects of platinum-based chemotherapy are preventable, but questions about the effect of the protective agents on oncological efficacy remain. Strategies for prevention of chemotherapy-induced toxicity include temporal or anatomical separation of cisplatin or carboplatin from sodium thiosulfate, D-methionine, or N-acetyl-cysteine. Clinical application of these methods has begun. The mechanisms presumably involve free radicals or drug conjugation, or both. Understanding the role of free radicals in medicine is likely to become important in the future.     

Gentamicin tympanoclysis: effects on the labyrinthine sensory cells

OBJECTIVES: The objective of the study was to determine whether a selective vestibular hair cell toxicity with sparing of the cochlear hair cells could be achieved by infusing different concentrations of gentamicin into the middle ears of adult cats. STUDY DESIGN: Prospective experimental animal study treating only the left ear of each cat, the right ear serving as individual control. METHODS: Gentamicin solution at concentrations of either 30 or 3 mg/mL was infused daily into the left middle ear of adult cats until overt ataxia occurred. After 1 month or 6 months, each cat was killed and its temporal bones prepared for optical microscopy. RESULTS: Animals treated with 30 mg/mL gentamicin until ataxic required a median of five daily doses. These animals had clear-cut cochlear basal turn hair cell losses accompanying toxic lesions in the utricle and cristae. In contrast, animals treated with 3 mg/mL gentamicin until ataxic required an average of 19 daily doses. These animals had lesions restricted to the utricle and cristae with sparing of the cochlea hair cells. Animals that failed to develop ataxia manifested neither lesions of the cochlear nor vestibular hair cells. CONCLUSION: Gentamicin tympanoclysis in the cat animal model, using a dilute solution and continued once daily until clinical ataxia occurs, is capable of producing selective vestibular hair cell toxicity while sparing cochlea hair cells.     

Delayed, reversible hearing loss caused by difluoromethylornithine (DFMO)

OBJECTIVES/HYPOTHESIS: Difluoromethylornithine (DFMO) is an anticancer experimental drug that is ototoxic. The objectives of these three experiments were to: 1) determine a dose and dosing schedule of DFMO that produces significant hearing loss (HL) in newborn gerbils; 2) compare the HL level for control and newborn gerbils receiving daily subcutaneous injections of DFMO; and 3) to determine if DFMO-related HL is significantly reversible following discontinuation of DFMO treatment. STUDY DESIGN: Prospective, non-randomized experimental design with placebo controls. METHODS: Click-evoked auditory brainstem response (ABR) testing was performed for 21-day-old Mongolian gerbils following daily subcutaneous injections of DFMO or saline. Three experiments were carried out using different injection schedules and doses of DFMO. In experiment 3, animals were retested at 42 days of age following a 3-week recovery from DFMO. RESULTS: Animals administered an 18-day regimen of DFMO at 1 g/kg per day (from day 3 to day 20) had click thresholds of 25 to 65 dB nHL, whereas animals receiving daily injections of saline had thresholds of 5 to 20 dB nHL. Animals retested after 3 weeks of recovery from DFMO treatment had thresholds ranging from 5 to 20 dB nHL. Differences were statistically significant. CONCLUSIONS: DFMO causes mild to moderate HL in neonatal gerbils that recovers after discontinuation of the drug.     

磷霉素在减轻卡那霉素耳毒中的作用

为研究磷霉素减轻卡那霉素耳毒的作用机理,我们选用了50只健康豚鼠分两组进行实验,对照组用卡那霉素400mg·kg~(-1)/d 肌注,连续7天;实验组肌注卡那霉素,用量同对照组,连续7天,第四天起肌注磷霉素300mg.kg~(-1)/d,连续7天。两组豚鼠均行 ABR,再用扫描电镜、透射电镜及组织化学反应来检查耳蜗结构.ABR 示自第11天起对照组Ⅳ波消失,而实验组Ⅳ波除1例外均存在,且波形清晰。电镜检查及组织化学反应检查均显示实验组耳蜗外毛细胞损伤明显比对照组耳蜗外毛细胞损伤轻。结果表明,磷霉素可以减轻卡那霉素的耳毒性。     

Potentiation of noise-induced hearing loss by low concentrations of hydrogen cyanide in rats.

Noise-induced hearing loss is the most prevalent occupational injury in the United States despite the adoption of clear permissible exposure limits and protocols for hearing conservation. This study identifies low-level chemical asphyxiant exposure as a risk factor capable of potentiating noise-induced hearing loss. Rats were exposed to 10, 30, and 50 ppm hydrogen cyanide (HCN) alone for 3.5 h (n = 28) or in combination with 2 h octave band noise exposure (100 dB(lin); n = 28). Additional groups received noise exposure alone (n = 16) and no treatment other than placement in an inhalation chamber with clean air and quiet (n = 16). Pure tone compound action potential (CAP) thresholds were determined 4 weeks following the exposure in order to assess pure tone auditory sensitivity and permanent threshold impairment. Cochleae from an additional 13 subjects were processed for light microscopy to permit assessment of hair cell loss. The results demonstrate that the noise exposure alone impaired CAP threshold by about 10 dB, averaged between 12-40 kHz, and produced a 5% loss of outer hair cells at the base of the cochlea, but no inner hair cell loss. The combined exposure to noise and HCN caused a cyanide dose-dependent CAP threshold impairment that exceeds the noise exposure alone. This effect reached statistical significance at a HCN level of 30 ppm. Combined exposure also produced more outer hair cell loss than noise alone. HCN alone did not cause significant hearing loss or hair cell loss. A risk assessment analysis was conducted for the auditory threshold data using benchmark dose software published by the U. S. EPA (BMDS version 1.3). A continuous model showed that the data could be described by a linear function. For a benchmark response corresponding to a 5 dB increase in auditory threshold above the effect of noise alone, the lower bound on the 95% confidence interval for the benchmark dose was 9 ppm. The benchmark dose that impaired auditory threshold 10% above the effect of noise alone had a lower bound of 2 ppm. The lower bound to the HCN dose that produced a 1 SD elevation in noise-induced hearing loss was 16 ppm. These exposure levels provide a range of concentrations below to slightly above the short-term exposure limit for HCN. However, if these levels are adjusted for an 8 h time-weighted average (TWA), the resulting levels are below the permissible exposure level (PEL) for HCN.