Effect of high-dose cisplatin on auditory brainstem responses and otoacoustic emissions in laboratory animals

OBJECTIVE: The role of transient evoked otoacoustic emissions (TEOAE) and distortion product otoacoustic emissions (DPOAE) as early indicators of cisplatin-induced ototoxicity in three different rodent species--the guinea pig. the albino rat, and the fat sand rat (Psammomys obesus)--was investigated. In addition, an attempt was made to determine which of the three rodent species is most susceptible to cisplatin-induced ototoxicity as measured by auditory brainstem responses (ABR), BACKGROUND: There have been numerous clinical and experimental reports on cisplatin-induced ototoxicity, but to the authors' best knowledge, there has been no comparative report on the short-term effects of cisplatin on OAE measured with commercially available equipment between different rodent species. METHODS: Cisplatin was systemically administered as a single high dose (12 mg/kg intraperitoneally) to all three species, and the ototoxic effects were measured before and 3 days after the injection of cisplatin in the same animals, using ABR, TEOAE, and DPOAE. RESULTS: The ABR thresholds were significantly elevated in the guinea pigs and the albino rats but not in the sand rats. Significant depression of TEOAE energy and DPOAE amplitude occurred only in the guinea pigs. The depression of the DPOAE was greater than that of the TEOAE. The guinea pigs showed the greatest degree of ototoxicity (depression of ABR and OAE). CONCLUSIONS: Among the three rodent species, the guinea pig has the potential to be used as a sensitive animal model in studies of cisplatin ototoxicity. The study also showed that the recordings of TEOAE and DPOAE, in addition to ABR, are sensitive techniques for the assessment of cisplatin-induced ototoxicity.     

Systemic dexamethasone for the prevention of cisplatin-induced ototoxicity

Ototoxicity is a common side effect of cisplatin chemotherapy. This study was undertaken to determine the potential protective effects of a systemic administration of dexamethasone against cisplatin-induced ototoxicity. A prospective controlled trial conducted in an animal model. The setting was Animal care research facilities of the Montreal Children’s Hospital Research Institute. An experimental guinea pig model was used. The animals were divided as follows: group 1 (n = 10): 12 mg/kg intraperitoneal (IP) cisplatin, group 2 (n = 14): 15 mg/kg/day dexamethasone IP for 2 days followed by cisplatin 12 mg/kg IP, group 3 (n = 14): 10 mg/kg/day dexamethasone IP for 2 days, on day 3, they received cisplatin 12 mg/kg IP followed by 20 mg/kg/day dexamethasone for 2 days and group 4 (n = 5): 10 ml of saline IP twice a day for 3 days. Auditory brainstem response (ABR) threshold shifts were measured at four frequencies (8, 16, 20 and 25 kHz) for groups 1, 2 and 3. Histological changes in the organ of Corti, the stria vascularis, the spiral ligament and the spiral ganglion neurons as well as scanning electron microscopy for outer hair cells were completed. Immunohistochemistry for tumour necrosis factor-alpha (TNF-α) was performed. ABR threshold shifts were similar in all groups. Histological and scanning electron findings demonstrate that dexamethasone has greater protective effect on the stria vascularis. Systemic dexamethasone administration in a guinea pig model did not provide significant protection against cisplatin-induced ototoxicity. Dexamethasone may be useful in future applications as a complementary treatment.     

黄芪对顺铂耳毒性保护作用的实验研究

目的探讨黄芪是否对顺铂的耳毒性具有保护作用。方法健康SD大鼠40只随机分成4组,每组10只。对照组：生理盐水2ml／d腹腔注射6天;黄芪组：黄芪注射液5g·kg^-1·d。腹腔注射6天;顺铂组：顺铂4mg·kg^-1·d^-1腹腔注射6天;顺铂加黄芪组：腹腔注射黄芪5g·kg^-1·d^-1加顺铂4mg·kg^-1·d^-16天。用药前及用药后第7天行畸变产物耳声发射（DPOAE）检测,然后处死大鼠。每组半数动物冰冻连续切片,DNA末端转移酶介导的缺口末端标记法（TUNEL）检测毛细胞凋亡;半数动物扫描电镜观察毛细胞形态。结果顺铂组用药后DPOAE幅值下降,毛细胞受损,并可观察到凋亡细胞,与对照组及黄芪组比较差异具有显著统计学意义（P〈0．01）。顺铂加黄芪组用药后DPOAE幅值上升,毛细胞受损减轻,凋亡细胞数量减少,与顺铂组比较,差异有统计学意义（P〈0.05）.结论黄芪能有效保护耳蜗免受顺铂的耳毒性损伤。     

An Evaluation of the Protective Effects of Thymoquinone on Amikacin-Induced Ototoxicity in Rats

Objectives

In this study we investigated the probable protective effects of thymoquinone on amikacin-induced ototoxicity in rats.

Methods

Thirty-two healthy rats were divided into four groups (amikacin, amikacin+thymoquinone, thymoquinone, and no treatment). Thymoquinone was fed to the rats via oral gavage in a dose of 40 mg/kg/day throughout the study period of 14 days. Amikacin was given by the intramuscular route in a dose of 600 mg/kg/day. Audiological assessment was conducted by the distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) tests, administered to all rats at the beginning of the study, and also on days 7 and 15. Biochemical parameters were calculated at the termination of the study to evaluate the oxidative status.

Results

There were significant decreases in DPOAE values and significant increases in ABR thresholds of the amikacin group on days 7 and 15, as compared to the amikacin+thymoquinone group. While ABR thresholds of the amikacin group increased significantly on days 7 and 15 as compared to their initial values, there were no significant differences between the initial and the 7th and 15th day values of ABR thresholds in the amikacin+thymoquinone group. Total oxidant status and oxidative stress index values of the amikacin+thymoquinone group were significantly lower than those of the amikacin group. Total antioxidant status values of the amikacin+thymoquinone group were significantly higher than those of the amikacin group.

Conclusion

Our study has demonstrated that the ototoxic effect brought forth by amikacin could be overcome with the concurrent use of thymoquinone.     

The protective role of tiopronin in cisplatin ototoxicity in Wistar rats

The purpose of this study was to evaluate cisplatin-induced ototoxicity and the protective effects of tiopronin. Twenty-four adult Wistar rats served as subjects and were divided into three groups. Eight rats receiving only saline (group A) were used as controls. Eight rats received cisplatin (2 mg/kg) injections (group B) and eight rats received cisplatin and tiopronin (300 mg/kg) (group C) for 8 consecutive days. Both ears of all animals were tested by DPOAE before treatment and on the 4th and 9th days. Seventy-two hours after the final recording session, all animals were killed, and the left cochleas were prepared for electron microscopy and analysed. DPOAE responses were significantly reduced in group B compared to controls (p<0.05). When tiopronin was added, DPOAE responses were significantly increased compared to those obtained with the administration of cisplatin alone (p<0.05). The cochleogram showed that tiopronin had a significant protective effect in the basal half and in the lower half of the middle turn. We conclude that tiopronin, a drug effective in protecting against cisplatin nephrotoxicity, is also effective in protecting against cisplatin ototoxicity.     

硫普罗宁对顺铂所致耳毒性的保护作用

目的探讨硫普罗宁对顺铂耳毒性的保护作用。方法将48只豚鼠随机等分为四组,每组12只:生理盐水对照组:生理盐水腹腔注射2ml/d共7天;硫普罗宁组:腹腔注射硫普罗宁0.3g·kg-1·d-1共7天;顺铂组:腹腔注射顺铂4mg·kg-1·d-1共4天;顺铂加硫普罗宁组:先腹腔注射硫普罗宁0.3g·kg-1·d-13天,从第4天起先腹腔注射硫普罗宁0.3g·kg-1·d-1,再腹腔注射顺铂4mg·kg-1·d-1共4天。动物用药前后行听性脑干反应检查。每组半数动物做耳蜗基底膜铺片硝酸银染色,在光镜下观察毛细胞形态,半数动物取耳蜗组织匀浆测局部丙二醛(malonaldehyde,MDA)和超氧化物歧化酶(superoxide dismutase,SOD)的含量。结果顺铂应用后可使(auditory brainstem response,ABR)反应阈上升,波I潜伏期延长,耳蜗组织匀浆内MDA含量增多,SOD活性下降,与生理盐水对照组相比差异具有显著统计学意义(P<0.01)。硫普罗宁可改善顺铂的耳毒性,使ABR反应阈下降,波I潜伏期缩短,局部MDA含量减少,SOD活性提高,与顺铂组相比差异具有显著统计学意义(P<0.05)。光镜下见应用顺铂后外毛细胞明显损伤,而硫普罗宁可减轻上述损伤。结论硫普罗宁可能通过抗自由基原理来改善顺铂的耳毒性。     

Cisplatin-induced ototoxicity and pharmacokinetics: preliminary findings in a dog model

The early effects of a clinical dose of cisplatin (100 mg/m2) on distortion-product otoacoustic emissions (DPOAE) thresholds and the relationship between DPOAE threshold shifts and changes in plasma concentrations of filterable and total platinum (Pt) following infusion of cisplatin in a dog model were investigated. The DPOAE thresholds (based on input-output function) were measured 2 days before a single high dose of cisplatin administration, and compared with measurements recorded 2 and 4 days after infusion. The results revealed DPOAE thresholds to be elevated by 4 days after the administration of cisplatin. However, this elevation could not be correlated with plasma concentrations of filterable and total Pt, which showed little variation over the 48-hour postinfusion period between animals. The present study demonstrated that DPOAE thresholds have the potential to be used as an indicator of cisplatin-induced ototoxicity, and cisplatin-induced ototoxicity could not be explained by plasma Pt kinetics in individual animals.     

Cisplatin ototoxicity in developing gerbils.

This experimental study was undertaken to investigate the dose-related effect of cisplatin exposure in young gerbils (2 weeks of age) and explore the relationship between different methods used to monitor auditory function after exposure to cisplatin. Four groups of animals, including a control group, were used. The treatment groups, D1 (n = 6), D2 (n = 7) and D3 (n = 6), received one, two, and three doses of cisplatin (5 mg/kg/dose), respectively, at weekly intervals. Treated animals were first exposed to cisplatin at 2 weeks of age. Distortion product otoacoustic emissions (DPOAE) and auditory brainstem responses (ABR) were measured in treated and control animals at 6 weeks of age. The effects of dose and frequency on the DPOAE amplitude, as well as the relationship between the DPOAE and the ABR thresholds were analyzed. Animals in the D1 and D3 groups demonstrated significant elevation of DPOAE and ABR thresholds. Interestingly, animals in the D2 group demonstrated a bimodal distribution of DPOAE and ABR responses, with four animals severely affected and three not showing an effect. A tendency for a bimodal distribution of DPOAE and ABR responses was also observed in the D1 group, at frequencies below 8 kHz.     

The effect of intratympanic vitamin C administration on cisplatin-induced ototoxicity

The Objective of this study is to investigate the effect of intratympanic injection of vitamin C on cisplatin-induced ototoxicity. The study included 24 albino adult female rats (48 ears). The study animals were divided into four groups each of which was composed of six animals including a control (intraperitoneal cisplatin), a cisplatin–saline (saline intratympanic + intraperitoneal cisplatin), a C vit (intratympanic vitamin C) and a cisplatin–C vit group (intraperitoneal cisplatin + intratympanic vitamin C). As two animals had died due to cisplatin-induced ototoxicity (one in the control and one in the cisplatin-saline group) they were excluded from the study. The experiment was terminated, performing distortion product otoacoustic emission (DPOAE) measurement prior to procedures and at the end of the experiment. The results of the statistical analysis were evaluated. In the cisplatin–C vit group, there were no significant decreases in DPOAE amplitudes at 2 kHz (p > 0.05). Although a decrease was observed in DPOAE amplitudes at 2.8, 4, 6, and 8 kHz frequencies, these amplitude reductions were significantly lower than the control group (p < 0.05). Intratympanic vit C infusion provided a protective effect against cisplatin-induced ototoxicity primarily at 2 kHz and at other frequencies (2.8, 4, 6, and 8 kHz), and it did not produce a toxic effect in the cochlea.     

Memantine’s action against aminoglycoside-induced ototoxicity

The objectives of this study were (1) to assess the protective role of NMDA antagonists against the ototoxic effects of aminoglycosides, (2) to provide any possible evidence between ototoxicity due to aminoglycosides and excitotoxicity. An animal experiment was conducted. Twenty-eight, 3-month-old female New Zealand rabbits, weighing 1,000–1,500 g, were studied prospectively for 28 days after intramuscular administration of amikacin (15 mg/kg/day divided into two equal doses) for 14 days. Twenty-one rabbits were categorized into three equal treatment groups and seven animals received no medication and served as the control group. The animals of A, B and C groups were injected, intramuscularly, with amikacin 15 mg/kg/day, divided into two equal doses every day for 14 days. Animals of group A received in parallel memantine (per os) and those of group B received p.o. the same volume of placebo solution. The rabbits of the third group (group C) received on the 15th day and every 2 days for the next 2 weeks, until the day 28, memantine of the same quantity as the members of group A. Differences in DPOAE amplitudes, and therefore in cochlear activity, between group A and group B were revealed. DPOAE amplitudes of group B were further reduced compared to the respective amplitudes in rabbits of group A. No improvement was observed in DPOAE measurements performed after the discontinuation of injections. The findings in group C should be examined separately. The measurements showed apparent reversal ototoxic effects in four of the animals. The development of aminoglycoside otoprotective strategies is a primary goal in ototoxicity research. The administration of NMDA antagonists has been shown to prevent, at least to some extent, toxic damage to hair cells in guinea pigs, treated with aminoglycoside antibiotics.     

WR-2721 (Amifostine) Ameliorates Cisplatin-Induced Hearing Loss But Causes Neurotoxicity In Hamsters: Dose-Dependent Effects

Chemoprotective agents reduce the toxic side effects of chemotherapy agents such as cisplatin. The conventional belief is that the chemoprotective agent WR-2721 (Amifostine), while protecting against most cisplatin-induced side effects, does not protect against cisplatin-induced ototoxicity (i.e., hearing loss). There is no knowledge, however, about the efficacy of high doses of WR-2721 (WR) in possibly protecting against cisplatin-induced ototoxicity. Thus, the dose-dependent effects of WR in possibly ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 18, 40, 80, or 400 mg/kg/injection of the rescue agent WR (n = 5 or 10/group). Other groups received either 80 mg/kg/injection WR alone (n = 5) or were untreated (n = 14). Ototoxicity was assessed by auditory brain stem responses (ABR). WR provided dose-dependent rescue from cisplatins ototoxicity with no protection at the low dose of 18 mg/kg, moderate protection at 40 mg/kg, and nearly complete protection at 80 and 400 mg/kg. However, WR doses of 40 mg/kg or higher caused neurotoxicity as evidenced by prolongations in the ABRs interpeak latencies. Thus, high doses of WR provided the beneficial effect of protecting against cisplatin-induced ototoxicity, but had the harmful side effect of neurotoxicity. Previous failures to find chemoprotection from cisplatin-induced ototoxicity were likely due to the use of WR doses that were too small. The clinical implications of the beneficial and harmful effects of high doses of WR are discussed.     

Reduction of cisplatin ototoxicity in rats by oral administration of pomegranate extract

The aim of this study was to investigate the effectiveness of the oral administration of pomegranate extract (PE) as a protective agent against cisplatin-induced ototoxicity. The study included a prospective, controlled animal study Group 1 (n = 6), received no cisplatin or PE, and group 2 (n = 6) received cisplatin at 8 mg/kg/day for 3 consecutive days. Group 3 (n = 6) received not only cisplatin at 8 mg/kg/day for 3 consecutive days, but also received PE (100 μL/day) via gavage for 5 days prior to the cisplatin injection and for 3 days concomitantly with the cisplatin injections. To measure cisplatin ototoxic effects, “distortion product otoacoustic emissions” (DPOAE) were analyzed 3 days before and after the cisplatin injections. Histological changes in the cochleas were observed by light microscopy. Compared with group 3, the DPOAE amplitudes of group 2 decreased significantly. Among the groups, there was a statistically significant difference in basal and mid turn external ciliated cells (ECC) number, but there was no statistically significant difference in apical turn. Differences in stria vascularis (SV) changes were statistically significant between the groups, and the median score for SV injury was significantly greater in group 2 than in group 3. Differences in the median scores for SGC changes being significantly greater in group 2 than in group 3. In conclusion, these results indicated that oral administration of PE afforded statistically significant protection to the cochlea in rats from cisplatin toxicity, and thus, oral experimental dose of PE administration may have a protective effect against cisplatin ototoxicity in rats.     

Protective effects of resveratrol on cisplatin-dependent inner-ear damage in rats

Cisplatin is a common chemotherapeutic agent used in many solid and hematologic malignancies. The main unwanted effect of cisplatin is ototoxicity, for which no standard treatment has been reported. The present study examined the protective efficacy of resveratrol on cisplatin-dependent ototoxicity through an experimental model. Fifteen rats were randomized into three groups. Group 1 (control group) (n = 5) received intraperitoneal (i.p.) 15 mg/kg cisplatin; group 2 (resveratrol group) (n = 5) received i.p. 100 mg/kg resveratrol, followed by i.p. 15 mg/kg cisplatin; group 3 (n = 5) served as a vehicle group and received i.p. 1 ml dimethyl sulfoxide. All rats underwent the auditory brainstem response (ABR) test before and 72 h after the treatment. Pretreatment ABR values of the groups were not significantly different. The pretreatment hearing threshold values of the groups were 30 ± 6.60 and 28.5 ± 5.29 dB in groups 1 and 2, respectively (p > 0.05). The post-ABR-I and post-ABR-IV values were, respectively, 1.41 ± 0.18 and 5.83 ± 0.16 ms in the control subjects and 1.19 ± 0.22 and 4.58 ± 0.27 ms in the study group. The ABR-I and ABR-IV durations in rats treated with resveratrol were significantly shorter (p < 0.01). A comparison of threshold values shows that the resveratrol-treated rats had significantly lower values than the control rats. After cisplatin injection, ABR I–IV intervals were compared among the groups. The ABR I–IV interval duration was 4.42 ± 0.16 ms in the control group, while the resveratrol-treated rats showed a significantly shorter ABR I–IV interval duration of 3.49 ± 0.27 ms (p < 0.001). Resveratrol attenuated cisplatin-dependent inner-ear damage, as shown by the ABR-I, ABR-IV, ABR I–IV interval, and hearing threshold values. Our results suggest that this natural antioxidant may be effectively used in reducing the unwanted effects of cisplatin on the ear physiology of patients, particularly those undergoing chemotherapy.     

The protective role of tiopronin in cisplatin ototoxicity in Wistar rats

The purpose of this study was to evaluate cisplatininduced ototoxicity and the protective effects of tiopronin. Twenty-four adult Wistar rats served as subjects and were divided into three groups. Eight rats receiving only saline (group A) were used as controls. Eight rats received cisplatin (2 mg/kg) injections (group B) and eight rats received cisplatin and tiopronin (300 mg/kg) (group C) for 8 consecutive days. Both ears of all animals were tested by DPOAE before treatment and on the 4th and 9th days. Seventy-two hours after the final recording session, all animals were killed, and the left cochleas were prepared for electron microscopy and analysed. DPOAE responses were significantly reduced in group B compared to controls ( p_0.05). When tiopronin was added, DPOAE responses were significantly increased compared to those obtained with the administration of cisplatin alone ( p_0.05). The cochleogram showed that tiopronin had a significant protective effect in the basal half and in the lower half of the middle turn. We conclude that tiopronin, a drug effective in protecting against cisplatin nephrotoxicity, is also effective in protecting against cisplatin ototoxicity.     

Protective effects of Salvia miltiorrhiza against cisplatin-induced ototoxicity in guinea pigs

Objective

The aim of the study was to investigate the protective effects of Salvia miltiorrhiza (SM) against cisplatin-induced ototoxicity in guinea pigs.

Methods

Thirty-nine guinea pigs were randomly divided into 3 groups. The first group (control group) received physiologic saline by intraperitoneal (i.p.) injection for 5 days. The second group (cisplatin group) was treated with cisplatin (2 mg/kg per day, i.p. injection) for 5 days. The third group (SM group) was given SM (8 g/kg per day, i.p. injection) for 2 days and then was given SM (8 g/kg per day, i.p. injection) and cisplatin (2 mg/kg per day, i.p. injection) for 5 days. Auditory brain stem response (ABR) and cochlea blood flow measurement were used to evaluate cochlea function. The structures of cochlea were observed by light microscope, scanning electron microscope, transmission electron microscope (TEM), and immunohistochemical examination.

Results

Cisplatin could cause severe acoustic damages including significant elevation of ABR threshold, substantial losses of outer hair cells and inner hair cells, and severe damage on the stria vascularis and spiral ganglion cells (SGCs). Although in SM group, the increased tendency of threshold was milder than that in cisplatin group. The damages in cochlea and stria vascularis were also less severe than those in cisplatin group. The expression of induced nitric oxide synthase in the cochlea and SGC in SM group was lower than that in cisplatin group.

Conclusions

Salvia miltiorrhiza can significantly reduce the cisplatin-induced side effects.     

Are Systemic Voriconazole and Caspofungin Ototoxic? An Experimental Study with Rats

Objectives

To determine whether systemic administration of voriconazole and caspofungin causes ototoxicity.

Methods

This study was conducted on 32 healthy male Wistar albino rats. The baseline auditory brainstem response (ABR) thresholds of all animals were obtained under general anesthesia. Then, the rats were randomly divided into 4 groups (groups I-IV), each group consisting of 8 rats. Rats in group I were injected intraperitoneally with voriconazole 10 mg/kg/day for 7 days, and the rats in the group II were injected intraperitoneally with caspofungin 5 mg/kg/day for 7 days. Group III received 120 mg/kg/day gentamicin for 7 days. Group IV received saline for 7 days. The animals were then observed for 7 days, and on 14th day of the trial, posttreatment ABRs of both ears were recorded.

Results

We did not find any significant differences between pretreatment and posttreatment median ABR thresholds in the voriconazole, caspofungin, or saline groups. In the gentamicin group, there was a statistically significant difference between pretreatment and posttreatment ABR thresholds.

Conclusion

Caspofungin and voriconazole did not change ABR thresholds in speech frequencies after a 7-day-period of their administration. We believe that further animal studies must be performed after administration of these agents for a longer time period, and these findings must be consolidated with histopathological investigations.     

灯盏花对庆大霉素内耳毒性的防护作用

目的　探讨灯盏花对庆大霉素耳毒性的防护作用。方法　选用听力正常豚鼠 4 0只 ,随机分为 2组 :非治疗组 (庆大霉素组 ) ;治疗组 (庆大毒素 +灯盏花组 )。两组皆肌肉注射庆大霉素注射液 (12 0mg·kg-1·d-1) ,治疗组同时腹腔注射灯盏细辛注射液 (4 5mg·kg-1·d-1)连续 10天。分别于停药后第 1、7、14、2 1天随机抽取一定数量的豚鼠处死行毛细胞及血管纹的电镜及光镜观察 ,于处死前行畸变产物耳声发射 (DPOAE)、听性脑干反应 (ABR)检测。结果　非治疗组耳蜗功能和结构损害严重 ,外毛细胞的外形及核已固缩 ,血管纹毛细血管数量随用药后时间的延长逐渐稀少、管径狭窄。治疗组耳蜗功能和结构损伤较轻 ,除可见轻度胞质水肿及线粒体固缩外 ,外毛细胞基本正常 ,血管纹毛细血管管径有所增宽 ,DPOAE振幅和ABR波潜伏期、阈值两组比较有显著性差异 (P <0 .0 1)。结论　灯盏花对庆大霉素耳毒性有一定的防护作用     

The protective role of thymoquinone in the prevention of gentamicin ototoxicity

Objective

To investigate the potential protective effect of thymoquinone in gentamicin-induced ototoxicity through auditory brain stem responses (ABR) testing and histomorphological evaluation of the cochlea.

Methods

This study was conducted on 48 adult female Sprague–Dawley rats that were randomized into 4 groups. Group 1 received intraperitoneal gentamicin; group 2 received intraperitoneal gentamicin plus corn oil solution; group 3 received intraperitoneal thymoquinone; and group 4 received intraperitoneal gentamicin plus thymoquinone. All groups received the drugs (once daily) in the above-mentioned protocols over 15 days. After conducting repeated ABR measurements, the rats were sacrificed, and their cochleae were isolated.

Results

ABR thresholds were preserved in the gentamicin plus thymoquinone group when compared with the group receiving gentamicin alone. There were fewer TUNEL-positive cells and caspase-3 and caspase-9 expressions were weaker in the inner and outer hairy cells of the organ of Corti in the gentamicin plus thymoquinone group compared with the group receiving gentamicin alone.

Conclusion

The ABR values and number of apoptotic cells did not significantly increase in the group receiving gentamicin plus thymoquinone when compared to the group receiving gentamicin alone. Again, the cochlear histomorphological findings were supportive of the auditory findings. In light of these findings, we conclude that gentamicin-induced ototoxicity may be prevented by thymoquinone use in rats.     

Amikacin ototoxicity enhanced by Ginkgo biloba extract (EGb 761)

An animal study was realized to investigate the possible beneficial effect of EGb 761 as an antioxidant agent on amikacin ototoxicity by measuring distortion product otoacoustic emissions (DPOAEs). Twenty-eight adult rats were grouped equally as follows. GROUP AMIKACIN: rats received amikacin 600 mg/kg/day intramuscularly between postnatal days (PND) 30 and PND44. Group amikacin/EGb 761: rats received amikacin 600 mg/kg/day intramuscularly between PND30 and PND44 and EGb 761 100 mg/kg/day orally between PND30 and PND50. Group EGb 761: rats received equivolume saline intramuscularly between PND30 and PND44 and EGb 761 100 mg/kg/day orally between PND30 and PND50. NO TREATMENT GROUP: rats received nothing. Group amikacin was found to be affected only on the last measurement day of study (PND57). The frequencies greater than 2002 Hz were significantly reduced compared with the amplitudes of PND30 (P<0.05). Group amikacin/EGb 761 was most and earliest affected by amikacin-induced ototoxicity. DPOAE amplitudes were found in this group to be decreased at 2-6 kHz starting on PND50. The results of Group EGb 761 and No treatment group were not significantly changed. For the DPOAE input/output amplitude thresholds, Group amikacin (P<0.05) and Group amikacin/EGb 761 (P<0.01) had significantly elevated thresholds on PND57, except at 5 kHz for Group amikacin (P=0,06). According to the results of the study, EGb 761 may be regarded as a facilitating drug for the development of amikacin ototoxicity. The results of the present study may warn against concomitant use of aminoglycosides, specifically amikacin, with EGb 761.     

Intracochlear administration of thiourea protects against cisplatin-induced outer hair cell loss in the guinea pig

Amelioration of cisplatin-induced side-effects is of great clinical importance. Local administration of a cytoprotective agent to the inner ear offers a possibility to prevent cisplatin-induced ototoxicity without risk of interference with the antitumour effect. The ideal substance for local administration has yet to be identified. Thiourea (TU) has unique properties that make it an interesting candidate. This study was initiated to test the hypothesis that TU given by local administration protects against cisplatin ototoxicity in the guinea pig. After baseline auditory brainstem response (ABR) assessment, the left cochlea was implanted with a microtip catheter connected to an osmotic pump filled with either 27 mg/ml TU in artificial perilymph (AP), or AP administered for the full duration of the study. Three days post-implant, animals with normal ABRs received an intravenous injection of 8 mg/kg body-weight cisplatin. Five days after the cisplatin treatment ABRs were reassessed, animals decapitated and bilateral cytocochleograms prepared. TU-treated ears demonstrated significantly lower outer hair cell (OHC) loss as compared to contralateral untreated ears, and significantly lower OHC loss compared to AP-treated ears. ABR threshold shift did not differ significantly between the two groups. It can be postulated that TU demonstrates partial protection against cisplatin-induced ototoxicity.