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SUMMARY:Salicylate has recently been demonstrated to protect against the auditory and vestibular side effects of aminoglycoside antibiotics. Similarities in the toxic mechanisms suggest salicylate as a treatment strategy to prevent the ototoxic side effects of cisplatin (CDDP). We first tested protection of the inner ear in Wistar rats receiving a single infusion of 16 mg CDDP/kg body weight with or without treatment with 100 mg/kg salicylate (bid) for 5 days beginning one day before the CDDP infusion. Cisplatin induced a threshold shift of more than 30 dB (at 14 kHz; measured by auditory evoked brain stem response) that was significantly reduced by salicylate. We then examined the protective potential of salicylate on the cochlea, peripheral nerves, and kidney in a rat model of breast cancer-Fisher344 rats implanted with highly metastatic MTLn3 breast cancer cells. Animals received 3 ϫ 5 mg CDDP/kg (given every third day), and salicylate was administered at 100 mg/kg (bid) from 2 days before to 3 days after CDDP treatment. Salicylate significantly attenuated the CDDP-induced threshold shift from approximately 20 dB (at 16 and 24 kHz) to approximately 5 dB, and drastically reduced the loss of cochlear outer hair cells. Likewise, salicylate protected kidney function (measured as plasma blood urea nitrogen and creatinine levels) from CDDP toxicity. Protection of nerve conduction velocities of both sensory and motor nerves was minimal. The chemotherapeutic efficacy of CDDP on suppression of tumor mass and cancer cell metastasis remained unaffected by salicylate. The results suggest that administration of salicylate may become the basis of an effective therapeutic intervention against the ototoxic and nephrotoxic side effects associated with CDDP chemotherapy. (Lab Invest 2002, 82:585-596).

Formation of the cartilaginous otic capsule is directed by otic epithelial-periotic mesenchymal interactions. In response to induction by otic epithelium, condensations of mesenchyme appear in the periotic region and form a chondrified otic capsule that serves as the template for the subsequent formation of the endochondral bony labyrinth. Previous studies indicate that members of the transforming growth factor beta superfamily, including transforming growth factor beta 1 , participate in guiding these tissue interactions. In this study, we report the localization of bone morphogenetic protein 4 (BMP4) to the mesenchymal and epithelial-derived tissues of the mouse inner ear between 10.5 and 14 days of embryonic development. We demonstrate modulation of chondrogenesis in cultured mouse periotic mesenchyme by exogenous BMP4 protein and investigate the function of endogenous BMP4 in otic capsule chondrogenesis. We show that in the presence of the BMP antagonist, Noggin, otic capsule chondrogenesis is suppressed in culture in a dose-dependent manner. Consistent with this finding, addition of BMP4-specific antisense oligonucleotide to cultures of mouse periotic mesenchyme containing otic epithelium decreases levels of endogenous BMP4 protein and suppresses the chondrogenic response of the cultured periotic mesenchyme, providing evidence of the necessity for BMP4 in mediating otic capsule chondrogenesis. Supplementation of either Noggin-or BMP4 antisense oligonucleotide-treated cultures with BMP4 protein can restore the extent of chondrogenesis to normal levels. Our findings support BMP4 as an essential mediator of chondrogenesis in the developing otic capsule in situ. Developmental Dynamics 226:427-438, 2003.

Objective: To evaluate the efficacy of esterified hyaluronic acid (MeroGel) as a middle ear (ME)-packing material.Design: Randomized controlled trial.Material: Twenty-four guinea pigs.Intervention: Group 1, MeroGel-treated animals (n=10), bilateral wounding of ME mucosa with 5 of the animals receiving the MeroGel packing in the left ME and 5 of the animals receiving MeroGel in the right ME; group 2, absorbable gelatin sponge-treated animals (n=10), with the same experimental protocol as in group 1 except that the absorbable gelatin sponge was the packing material; group 3, untreated animals (n=4), unilateral wounding of the left ME mucosa in 2 animals and in 2 animals in the right ME, with no packing material. Auditory brainstem recordings were performed for all groups before the ME operation and 5 days and 6 weeks after the operation.Results: Auditory brainstem response recordings at postoperative day 5 showed that all ears with ME packing had hearing losses in the frequency range of 500 to 4000 Hz. The recovery of hearing acuity at postoperative week 6 was significantly better in group 1 (MeroGel-treated) guinea pigs compared with group 2 (the absorbable gelatin sponge-treated) animals. In group 2 animals, 20% of the packing material remained in the ME cavities and new bone formation was observed, while in group 1 animals, there was less packing material in the ME and no formation of new bone. Conclusions:MeroGel is a nonototoxic packing material with a high level of biocompatibility for ME mucosa; it is an effective supportive material following ME surgery and is easily expelled from the ME cavity.