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.

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.

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.

Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients.

We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin (17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin-treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin-treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin-treated patients. The number of greater than or equal to 15-dB increases in auditory threshold as a proportion of total greater than or equal to 15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin- vs tobramycin and piperacillin-treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin.

Comparative ototoxicity of bumetanide and furosemide when used in combination with kanamycin.

The ototoxicity of bumetanide and furosemide was compared in Topeka strain guinea pigs pretreated with kanamycin. The animals, anesthetized with pentobarbital, received a single dose of 400 mg/kg kanamycin subcutaneously and the diuretics via indwelling catheter in the jugular vein 2 hours later. Ototoxic drug effects were determined by measuring the electrophysiological responses of the cochlea to sound stimuli and by determining the presence or absence of cochlear sensory hair cells from the organ of Corti. Both bumetanide and furosemide produced permanent alteration of cochlear activity in the kanamycin-pretreated animals. The ototoxic effect of bumetanide is five times that of furosemide on a milligram-for-milligram basis. The ototoxic potential of bumetanide is one eighth that of furosemide when the doses are adjusted for diuretic potency difference between the two diuretics.

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.

Detection of ototoxicity from drugs applied topically to the middle ear space.

This paper summarizes data obtained from two separate studies done in our laboratory. Both studies were done to investigate the possibility that drugs commonly applied to the middle ear space could be the cause of sensori-neural hearing loss. The two drugs that were felt to be the most likely candidates for the studies were neomycin and polymyxin B. In the neomycin study, the various drug concentrations were administered three times a day for four weeks. In the polymyxin B study, the administration was three times a day for two weeks. Cochlear function was evaluated electrophysiologically and by examination of surface preparations of the organ Corti. The data show that both neomycin and polymyxin B can, in concentrations similar to those found in commercially available otic drops, induce cochlear damage when they are applied to the middle ear space of guinea pigs. The degree of damage produced is related. In the case of neomycin, it was shown that the effect worsens as the duration of the dosage administration is extended...

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.

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.

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.

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.

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.

Wound healing and the Shaw scalpel.

The Shaw heated scalpel is now widely used in head and neck surgery because it provides better hemostasis intraoperatively. Concerns persist over the immediate and long-term effects of this instrument on wound healing. This study compares heated and unheated Shaw scalpel incisions in the skin of 7-week-old piglets. Tensile strength measurements and histologic evaluations were made at frequent intervals up to nine weeks after incision. Histologic studies showed no differences in the two groups at any time in the study. Tensile strength of wounds was significantly less two weeks after incision in the Shaw scalpel group, but following that time, the wounds increased in strength, and by seven weeks, the two groups were equal in this respect. Thus, we conclude that the Shaw scalpel wounds in pigs are, ultimately, similar to standard scalpel wounds, although there is a period of diminished tensile strength.

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.

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.

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.

The relationship between the cytotoxicity of kanamycin and ethacrynic acid for mammalian cells in vitro and their ototoxicity in vivo.

Dose-effect curves for inhibition of growth of P388/P mouse lymphoma cells by ethacrynic acid and kanamycin used alone and in combination were determined in vitro. Ethacrynic acid was 600 times more potent than kanamycin and combinations of the drugs resulted in overall additive effects. These results were compared with known dose-effect data on the ototoxicity of these drugs in vivo. Kanamycin was highly selective in its toxicity for cochlear hair cells compared to cultured cells. The dose-effect data for ethacrynic acid was coincident with that reported for functional and biochemical effects on the cochlea following perilymphatic perfusion with the drug. The potentiation observed following the ototoxic interaction the two drugs in vivo was not observed following combinations of the drugs in vitro.

Cochlear damage resulting from kanamycin and furosemide.

Permanent cochlear damage has been shown to occur in guinea pigs following the combined administration of kanamycin and furosemide. At the doses used, only a transient effect was measured with furosemide alone and no effect was detectable with kanamycin alone. This interaction results when a single subcutaneous dose of 400 mg/kg of kanamycin is followed in 2 hours by a single intravenous dose of furosemide. The dosage range for furosemide was 50 mg/kg for a just-detectable effect to 100 mg/kg for a very severe effect. Damage to the cochlea was ascertained by measures of the a.c. cochlear potential as well as surface preparation histology.

Combined effects of noise and neomycin. Cochlear changes in the guinea pig.

Cochlear damage resulting from the combination of neomycin with acoustic overstimulation was investigated in guinea pigs. Four groups of animals received subcutaneous injections and exposure to broad band noise daily for 7 days, as follows: I. Neomycin (200 mg/kg) followed by 10 hours of noise at 115 dB SPL; II. Saline followed by 115 dB noise: III. Neomycin followed by low intensity noise (45 dB as an acoustic control); or IV. Saline followed by 45 dB noise. After a 30 day stabilization period, each ear was examined electrophysiologically and histologically. Measures of cochlear integrity included AC cochlear potentials from 100 Hz through 20 kHz as well as outer hair cell (OHC) counts. A marked interaction leading to augmentation of damage was found when neomycin was combined with 115 dB noise (Group I). Losses in cochlear sensitivity, averaged across all frequencies, amounted to 62 dB in Group I, whereas the averaged losses for Groups II and III were only 16 dB and 17 dB respectively. Loss of OHC's was close to 100% in Group I, while OHC losses were only 17% in Group II and 26% in Group III.