Delayed sodium thiosulfate as an otoprotectant against carboplatin-induced hearing loss in patients with malignant brain tumors.

Carboplatin is effective in the treatment of malignant brain tumors. However, when administered in conjunction with osmotic opening of the blood-brain barrier (BBB), carboplatin is ototoxic. The purpose of this study was to determine whether delayed administration of sodium thiosulfate (STS), given after BBB closure, provided protection against carboplatin ototoxicity. Patients underwent monthly treatment with intra-arterial carboplatin (200 mg/m2/day x 2) in conjunction with osmotic opening of the BBB, for up to 1 year. Audiological assessment was conducted at baseline and within 24 h before each monthly treatment. STS was administered i.v. as one (20 g/m2) or two (20 g/m2 and 16 g/m2) 15-min doses, depending on baseline hearing status. The initial group received the first STS dose 2 h (or 2 and 6 h) after carboplatin (STS2) and a subsequent group received STS 4 h (or 4 and 8 h) after carboplatin (STS4). Audiological data were compared with a historical comparison group (HCG) treated with carboplatin without STS. Spearman correlation coefficients comparing STS 2 (n = 24), STS4 (n = 17), and HCG (n = 19) indicated significantly lower rates of ototoxicity with increased delay in STS (P = 0.0006). On the basis of the analysis of hearing levels, there were significant differences among the two STS groups and HCG at 8000 Hz (P = 0.0010) and at 4000 Hz (P = 0.0075). The log-rank test for time to ototoxicity indicated a significant difference between STS4 and HCG (P = 0.0018). Delayed STS was effective in protecting against carboplatin-induced hearing loss. STS delayed to 4 h after carboplatin significantly decreased time to development of ototoxicity and rate of ototoxicity when compared with HCG.

Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity.

Platinum-based chemotherapeutic agents, such as carboplatin and cisplatin, are effective against many human tumors, but their use may be limited by a high incidence of ototoxicity. Delayed administration of the chemoprotective agent sodium thiosulfate (STS) reduces the ototoxicity of carboplatin in a guinea-pig model, when given up to 8 h after the chemotherapy, and also reduces hearing loss in patients given carboplatin with osmotic blood-brain barrier opening for treatment of brain tumors. We tested whether STS, given at times that achieved otoprotection, could impact the chemotherapeutic efficacy of carboplatin. The impact of STS was evaluated by measuring the onset of growth of LX-1 human small cell lung carcinoma s.c. xenografts in the nude rat. When STS was administered as two boluses, 2 and 6 h after treatment with carboplatin and etoposide, there was a decrease in the time to tumor progression. In contrast, when STS administration was delayed until 8 h after carboplatin/etoposide, there was no reduction in the antitumor cytotoxicity of the chemotherapy. STS infusion did not significantly affect ultrafilterable platinum pharmacokinetics in the guinea pig. To explore the potential wider applicability of STS, in a pilot study we tested its efficacy against cisplatin ototoxicity. Delayed administration of STS, 2 h after cisplatin, was protective against cisplatin-induced ototoxicity in the guinea pig model, as determined by electrophysiological measures. On the basis of these data, we suggest that delayed administration of STS may provide a mechanism to reduce the ototoxicity caused by administration of carboplatin or cisplatin for both central nervous system and systemic cancer chemotherapy.

First evidence of otoprotection against carboplatin-induced hearing loss with a two-compartment system in patients with central nervous system malignancy using sodium thiosulfate.

Sodium thiosulfate (STS) provides protection against carboplatin-induced ototoxicity in an animal model. The purpose of this study was to determine the STS dose required for otoprotection, in patients with malignant brain tumors treated with carboplatin in conjunction with osmotic blood-brain barrier disruption. Twenty-nine patients received STS intravenously 2 hr after carboplatin. Doses were escalated from 4 g/m2 to 8, 12, 16 and 20 g/m2 on consecutive months. Audiologic assessment was performed at baseline and monthly. The audiograms were compared with those of 19 similarly treated historical control patients who did not receive STS. The incidence of ototoxicity in the historical control group of patients was 79% (15/19). This group had an average loss of 20.8 +/- 5.9 dB (n = 19) at 8 kHz after one treatment with carboplatin, whereas the STS treatment group lost only 3.7 +/- 2 dB (n = 15) after one treatment. This difference was statistically significant as assessed by Student's t test (P < .05). Furthermore, patients in the STS treatment group with excellent base-line hearing showed little change in hearing thresholds at 8 kHz after the second treatment (8.0 +/- 8.3 dB) (n = 5) compared with the historical control patients with excellent base-line hearing, (40.5 +/- 8.6 dB) (n = 11). Our data support that doses of 16 or 20 g/m2 of STS decrease carboplatin-induced hearing loss without central nervous system entry. Clinical demonstration of an otoprotective effect with a two-compartment system to prevent drug-induced hearing loss, while preserving central nervous system cytotoxicity, has not been reported previously.

Ototoxicity resulting from combined administration of cisplatin and gentamicin.

The hypothesis that cisplatin can augment the ototoxicity of gentamicin was tested. Seven groups of 11 guinea pigs each were given a single dose of cisplatin either alone or 14 days before, at the beginning, midway through, or at the end of a course of gentamicin administered daily for 14 days. Blood and perilymph gentamicin and cisplatin concentrations were determined in three of the animals from each group. Auditory damage was determined in the remaining 8 animals electrophysiologically by measuring the compound action potential and alternating-current cochlear potential. Hair cell damage was determined using the surface preparation technique. An augmented ototoxic effect occurred when the cisplatin was given early in the 14-day course of gentamicin and did not occur when it was given at the end of treatment.

In vitro and animal studies of sodium thiosulfate as a potential chemoprotectant against carboplatin-induced ototoxicity.

When carboplatin (cis-diammine-1,1-cyclobutane-dicarboxylato-platinum) delivery to brain tumors is optimized with osmotic blood-brain barrier disruption (BBBD), high frequency hearing loss can result. Treatment with sodium thiosulfate (STS) blocked carboplatin cytotoxicity against the LX-1 human small cell lung carcinoma cell line in vitro. STS decreased carboplatin-induced ototoxicity in a guinea pig model, as determined by electrophysiological measurements and analysis of inner ear outer hair cell numbers. Protection was found when STS was administered up to 8 h subsequent to carboplatin but not 24 h after carboplatin. In a rat model of osmotic BBBD, STS was neurotoxic when given immediately after BBBD but not when given 60 min after BBBD, when the barrier is reestablished. Thus, delayed administration of STS may provide a mechanism to reduce the cochlear toxicity caused by BBBD-enhanced carboplatin delivery to the brain.

Safety of silver oxide-impregnated silastic tympanostomy tubes.

Otorrhea occurs after the insertion of tympanostomy tubes in as many as 50% of ears. Although topical antibiotic solutions minimize otorrhea in the immediate postoperative period, recurrent otorrhea is sometimes a clinical problem. The antimicrobial effects of silver oxide when impregnated into a tympanostomy tube may decrease the incidence of recurrent otorrhea. This study demonstrates that silver oxide-impregnated silicone elastomer is well tolerated within the middle ear of gerbils when implanted for 1 year, and the tissue reaction is no more than silicon elastomer without silver oxide. When applied directly to the round window of guinea pigs, there was no evidence of ototoxicity of silver oxide as measured by electrocochleography (N-1 thresholds) and cytocochleography (hair cell counts). These animal studies indicate that silver oxide-impregnated silicone elastomeric tympanostomy tubes may be used safely in clinical trials to determine efficacy.

Toxicity and efficacy of carboplatin and etoposide in conjunction with disruption of the blood-brain tumor barrier in the treatment of intracranial neoplasms.

CARBOPLATIN AND ETOPOSIDE have been investigated in preclinical studies and a limited toxicity study in 13 patients; these studies have established carboplatin and etoposide as a tolerable combination when administered with blood-brain barrier disruption. The studies also found a predictable dose-limiting toxicity of myelosuppression. Subsequently, a broad efficacy trial of this regimen was carried out. A total of 34 patients, ranging in age from 7 to 72 years, underwent a combination chemotherapy regimen of carboplatin (200 mg/m2 administered intra-arterially) and etoposide (200 mg/m2 administered intravenously) administered with blood-brain barrier disruption on each of 2 consecutive days every 28 days. The diagnoses included glioblastoma multiforme (n = 3), malignant astrocytoma (n = 8), malignant astrocytoma-oligodendroglioma (n = 1), primitive neuroectodermal tumor (n = 4), disseminated germ cell tumor of the central nervous system (CNS) (n = 6), CNS lymphoma (n = 7), and metastatic carcinoma (n = 5). The major toxicity observed in patients treated with multiple courses of this regimen was the expected reversible myelosuppression and an unexpected, irreversible high-frequency hearing loss. Of these 34 patients, 22 had measurable disease, and 9 radiographic responses (50% or more decrease in enhancing tumors) were observed in these patients. Carboplatin and etoposide with blood-brain barrier disruption is an active regimen in the treatment of malignant astrocytomas and has shown dramatic responses in primitive neuroectodermal tumors and CNS lymphoma. Additionally, the durability of responses in patients with disseminated CNS germ cell tumors is encouraging. However, such therapy is associated with unexpected high-frequency hearing loss; even so, on the basis of the favorable responses in patients with primitive neuroectodermal tumors, germ cell tumors, and lymphomas, the study of this regimen for those tumors is being extended in a multiinstitutional trial that also includes cytoxan to further evaluate the potential enhanced drug delivery.

Ototoxic liability of erythromycin and analogues.

This article details clinical reports and studies of ototoxicity associated with the administration of erythromycin and its analogues. Suspected mechanisms of ototoxicity also are discussed. Ototoxicity due to erythromycin appears to be clearly dose related.

Ototoxicity of vancomycin and analogues.

This article details clinical reports and animal studies of ototoxicity associated with vancomycin and its analogues. From these studies, the ototoxicity of these agents is still not clear. In the author's opinion, vancomycin must affect the auditory system in a manner that results in augmentation of the usual ototoxicity of aminoglycoside antibiotics. This postulated effect may manifest as a temporary hearing loss in humans. More studies are needed, however, before a definitive conclusion can be made.

Effect of otologic drill noise on ABR thresholds in a guinea pig model.

The noise generated by the otologic drill has been implicated as a cause of sensorineural hearing loss after ear surgery. However, clinical studies on this subject are contradictory and difficult to interpret. Therefore a guinea pig model was used to study whether the level of noise generated by the otologic drill can cause threshold shifts in the auditory brainstem response (ABR). The source noise was a recording obtained during a human cadaver mastoidectomy using a microphone and an accelerometer. Ten female Topeka-strain guinea pigs were exposed to the recorded drill noise for a period of 55 minutes. Exposure included both air-conducted energy from a speaker and bone-conducted energy from a bone vibrator applied directly to the skull. ABR threshold measurements were taken pre-exposure (baseline), immediately after exposure, and at weekly intervals thereafter for 3 weeks. Three control animals were subjected to the same procedure without the sound exposure. A significant threshold shift (p < 0.0001) was seen for each frequency tested (2, 4, 8, 16, 20, and 32 kHz) immediately after exposure to noise in all experimental animals. Thresholds returned to baseline within 3 weeks. We conclude that the level of noise generated by the otologic drill in mastoid surgery can cause a temporary threshold shift in this guinea pig model.

Quantitative relationships of the interaction between sound and kanamycin.

It is well known that the ototoxicity resulting from the use of aminoglycoside antibiotics in experimental animals can be augmented by intense sound. However, the dose-effect relationship of this interaction is not known. This study was designed to determine the shape of this dose-effect relationship in guinea pigs at sound intensities approaching those that would be experienced by patients receiving aminoglycoside antibiotics. We found a linear relationship between the probit of the percent of missing cochlear outer hair cells and decibel-A scale sound intensity when the animals were treated with kanamycin plus white noise ranging from 115 to 45 dBA.

Steroids and rhinoplasty. A double-blind study.

Many facial plastic surgeons use perioperative steroids to reduce postoperative edema and morbidity. This use of steroids is based more on theory and anecdotal experience than on controlled studies. We studied 49 patients undergoing rhinoplasty in a randomized, double-blind fashion to evaluate the effects of perioperative and postoperative steroid use. We found significantly less postoperative eyelid and paranasal edema in those patients receiving steroids. In addition, trends toward less ecchymosis, less intranasal edema, and less discomfort in the patients receiving steroids were noted.

The incidence of aminoglycoside antibiotic-induced hearing loss.

The definition of ototoxicity in most clinical studies of aminoglycoside antibiotics is an increase in pure-tone threshold from a baseline audiogram greater than or equal to 15 dB at two or more frequencies, or greater than or equal to 20 dB at one or more frequencies. In this study, test-retest auditory threshold differences of this magnitude were found in a group of 20 normal volunteers who were not taking any known ototoxic drugs. Depending on which of the two criteria for ototoxicity are used, these data represent a 20% or 33% incidence of ototoxicity. We believe that many of the audiometric changes reported to represent aminoglycoside antibiotic ototoxicity may actually represent the normal test-retest variability of pure-tone audiometry. If this is true, the reported incidence of hearing loss due to aminoglycoside antibiotics may be exaggerated.

Augmented gentamicin ototoxicity induced by vancomycin in guinea pigs.

Vancomycin has been reported to be an ototoxic drug in the clinical literature. At best, this literature is confusing. There are no reports of ototoxicity of vancomycin in experimental animals, even when it is administered concurrently with ethacrynic acid, a drug known to augment the ototoxic effect of most other ototoxic drugs. In most of the cases of permanent ototoxicity that have been reported, the patient was treated with an aminoglycoside antibiotic as well as vancomycin. This study found no evidence of vancomycin ototoxicity in guinea pigs, but found that vancomycin greatly enhanced the ototoxicity of gentamicin.

Potential hearing loss resulting from MR imaging.

To determine if the loud noise generated by magnetic resonance (MR) imaging equipment is capable of inducing hearing loss, the hearing of 24 patients was tested before and after MR imaging. Fourteen patients were imaged without ear protection, and six (43%) suffered a temporary, mild loss of hearing (less than or equal to 15 dB at at least one frequency). Ten patients were imaged with ear protection, and only one experienced any hearing loss. Therefore, the noise generated by MR imagers may cause temporary hearing loss, and earplugs can prevent this loss. All threshold changes had returned to within 10 dB of baseline by 15 minutes after completion of the second audiometric test.

The influence of tobramycin dosage regimens on nephrotoxicity, ototoxicity, and antibacterial efficacy in a rat model of subcutaneous abscess.

The influence of dosage regimen on the nephrotoxicity, ototoxicity, and antibacterial efficacy of tobramycin was assessed in Fisher rats with Pseudomonas aeruginosa subcutaneous abscesses. A subcutaneous tobramycin dose of 10 mg/kg every 4 h resulted in peak and trough serum concentrations that approximated those currently recommended for patients. Subsequently, the influence of this subcutaneous dosage regimen was compared with three other regimens that administered the same total daily dose: 20 mg every 8 h, 30 mg every 12 h, and 60 mg every 24 h. Renal injury was assessed by measuring inulin clearance and in vivo synthesis of renal DNA and by histopathology. Cochlear histology was also assessed. The number of P. aeruginosa per abscess was quantitated. In animals with infected abscesses, there was a consistent trend of greater kidney injury with the more-frequent dosage regimens. There was no evidence of cochlear toxicity in any group. All regimens were equally effective in reducing the number of P. aeruginosa in subcutaneous abscesses.

Effects of pentoxifylline on experimental skin flap survival.

We studied the effects of pentoxifylline on experimental skin flap survival in the domestic pig. Random skin flaps were designed using a length-width ratio of 5:1. The pigs were then given pentoxifylline (25 mg/kg/d) or placebo for seven days. Fluorescein sodium was used to help determine surviving skin flap length seven days postoperatively. Results showed no significant difference in mean surviving skin flap length between the study and control groups. We question the value of pentoxifylline in increasing skin flap survival.

Absence of ototoxicity of teichomycin A2 in guinea pigs.

Teichomycin A2 is a new antibiotic that is similar to vancomycin. Because vancomycin is reported to be ototoxic, teichomycin A2 was tested for ototoxicity. No evidence of ototoxicity was found. Furthermore, ethacrynic acid, a diuretic that augments the ototoxicity of many drugs, did not enhance ototoxicity with teichomycin A2.