DDT October 1 2005.qxp

1299 www.drugdiscoverytoday.com In recent years there has been increasing interest in the treatment of inner-ear disorders by local rather than systemic application of drugs. Substances are applied intratympanically, which means they are injected into the middle-ear cavity. This procedure is based on the premise that the drug will contact the round window membrane (RWM) of the cochlea, enter the scala tympani (ST) and spread throughout the ear. The target tissues of such treatments might include the sensory hair cells, the afferent nerve fibers and supporting cells of the cochlea (hearing) or vestibular (balance) portions of the inner ear. The idea of a topical application of drugs to the inner ear is not new. Local anesthetics and aminoglycosides were applied decades ago to treat inner-ear disorders [1–3]. The present, most widely used form of intratympanic therapy is the injection of gentamicin into the middle ear in patients with Menière’s disease [3–8]. Gentamicin is toxic to the sensory cells of the balance system and thereby suppresses the vertigo in these patients by partially ablating their vestibular system. There is also an increasing number of clinical reports related to the local application of glucocorticoids for acute hearing loss [9–16], glucocorticoids for Menière’s disease [17–20] or for tinnitus [21–25]. Other substances that have been tested in humans include local anesthetics, neurotransmitters and neurotransmitter antagonists [26,27], and the use of growth factors, antioxidants, apoptosis inhibitors and antisense oligonucleotides is also increasing. Animal experiments have shown promising results by using locally applied drugs to provide otoprotection from noise and drug toxicity∗ [28–36]. An extension of such studies is local viral and nonviral gene transfer for the sustained treatment of inner-ear disorders [37–42]. It has recently been shown that Atoh1, a key regulator gene of hair cell development also known as Math1, induces regeneration of hair cells and substantially improves hearing thresholds in the mature deaf inner ear after delivery to nonsensory cells through adenoviral vectors [43]. Although the above examples show that local therapy has many advantages over systemic Alec N. Salt Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA e-mail: [email protected] Stefan K.R. Plontke Tübingen Hearing Research Center and Department of Otorhinolaryngology, Head and Neck Surgery, University of Tübingen, D-72076, Germany Local inner-ear drug delivery and pharmacokinetics