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Permeability of Round Window Membrane and Its Role for Drug Delivery: Our Own Findings and Literature Review

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Permeability of Round Window Membrane and Its Role for Drug Delivery: Our Own Findings and Literature Review CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector ·34· Journal of Otology 2009 Vol. 4 No. 1 Review Permeability of round window membrane and its role for drug delivery: our own findings and literature review 1, 2, 3 1, 4 DUAN Mao-li , CHEN Zhi-qiang 1 Department of clinical neuroscience, 2, Department of Otolaryngology, Karolinska Hospital, 171 76 Stockholm, Sweden 3 Department of Otolaryngology, Affiliated Hospital of Anhui Medical University, China 4 Department of Otology and Laryngology, Harvard Medical School, 243 Charles Street, Boston, Massachusetts 02114, USA Abstract We investigated the pharmacokinetics of caroverine in the perilymph, cerebrospinal fluid and plasma after systemic and local administrations in guinea pigs by using high-performance liquid chromatography. Auditory brain⁃ stem responses were measured to evaluate auditory functional effect. The results showed that local application was a both safe and efficient method. We further reviewed literature and pinpointed that the round window is effectively lo⁃ cal drug delivery means for future inner ear treatment. Keywords caroverine; glutamate receptor antagonist; antioxidant; pharmacokinetics; round window membrane; noise-induced hearing los The oval window is directly superior to the RWM. Introduction The RWM is thicker at the edges［ ］ and has a slight con⁃ （ ） 2 The round window membrane RWM is located in vexity towards the scala tympani . The average thick⁃ medial wall of the middle ear, within the round window ness in human is 70 ?m and does not change with age. niche. The round window niche, which is posteroinferior The membrane consists of three layers: an outer epitheli⁃ to the promontory, has［ a］ triangular shape and is bound ［um,］ a middle connective tissue, and an inner epithelium 1 3 medially by the RWM . There are commonly folds of . The outer epithelium consists of a single layer of middle ear mucosa, which is termed false round window cells continuous with the mucous membrane lining the membrane, at the entrance of the niche. The RWM sepa⁃ middle ear. The middle connective tissue contains fibro⁃ rates the niche from the scala tympani and its outer sur⁃ blasts, collagen, elastic fibers, and blood and lymph ves⁃ face is directly inferiorly. The cochlear aqueduct, which sels. It is the dominating part of the RWM and is connects the perilymphatic space with the cerebrospinal thought to be in conjunction with the mucoperiosteum of space, is located close to the posterior part of the RWM. the otic capsule. The inner epithelial cells are squamous and consist of several layers of thin cells, which are con⁃ tinuous with the mesothelial cells of the scala tympani. Corresponding author: ， DUAN Maoli, M.D, PhD Department The extracellular spaces are large and no basal lamina of Clinical Sciences, Intervention, Department of Audiology, separates this layer from the middle fibrous layer. Department of Clinical Neuroscience, Department of Otolaryn⁃ The function of the RWM is presumed to release me⁃ gology Head and Neck, Karolinska University Hospital, Stock⁃ holm, 171 76 Stockholm, Sweden chanical［ ］ energy and/or conduct sound to the scala tym⁃ Ｅ 4 mail: [email protected] pani . Based on experimental studies and anatomical Journal of Otology 2009 Vol. 4 No. 1 ·35· observations, the RWM may also act as a barrier to oto⁃ tor antagonists, neurotrophins and vectors for gene thera⁃ toxic substances in the middle ear and participate［ ］ in the py, delivered on or through the RWM,［ as］ treatments for 5, 6 9-14 secretion and absorption of substances . Animal ex⁃ various inner ear disorders . Furthermore, periments show that the RWM behaves like a semiper⁃ several specific delivery systems have been developed meable membrane. Many substances with both low and for more controlled local applications, including round （ high molecular weights have been demonstrated to pene⁃ window microcatheter Durect Inc., Cupertino, CA; In⁃ ） trate through［ ］ the RWM when placed in the round win⁃ traEar, Inc., Denver, CO , the MicroWick inserted 3, 7 dow niche . These substances include sodium ions, through a tympanic［ ］ membrane vent tube into the round 15 antibiotics, antiseptics, arachidonic acid metabolites, lo⁃ window niche , and a bone-anchored, totally implant⁃ （ ） cal anesthetics, toxins and albumin. Tracer studies us⁃ able drug delivery system TI-DDS composed［ ］ of a mi⁃ 16 ing cationic ferritin, horseradish peroxidase, 1 μm latex cropump, a drug reservoir and a septum port . sphere and neomycin gold spheres have shown the per⁃ However, most drug application protocols are empiri⁃ meability of the RWM to these substances when applied cally based because of the unknown pharmacokinetics in the middle ear side in chinchillas, guinea pigs, cats, of the drugs in the inner ear. The amount and distribu⁃ Mongolian gerbils, and rhesus monkeys. The permeabili⁃ tion of applied substances within the inner ear is poorly ty of the RWM can be influenced by the factors such as understood due to the considerable technical difficulties size, configuration, concentration, liposolubility and in making such measurements. As a result, the conse⁃ electrical charge of the substance,［ ］ and the thickness and quences of changes in delivery method, applied drug 8 the condition of the RWM . The substances placed on concentration, or even small alterations in treatment pro⁃ the RWM may traverse through the cytoplasm as pinocy⁃ tocols have been difficult to predict. For instance, genta⁃ totic vesicles or through different channels in between micin has been applied onto the RWM by single or re⁃ cells in the epithelium. In the connective tissue layer, peated intratympanic injection, by application onto the cells can phagocytize the substance and traverse to⁃ gelfoam placed on the RWM, by applying onto a wick, or wards perilymph［ and/or］ penetrate blood or lymph ves⁃ by continuous delivery via implanted catheters. The ther⁃ 7 sels in this layer . Theoretically, after the substance apeutic［ results］ varied significantly among these ap⁃ 17 reaches the perilymph it would go towards the CSF proaches . The variation among different groups may through the cochlear aqueduct, up to the scala tymphi, be attributable to both different dosing regimens and ap⁃ or find way to the endolymph. plication methods, although a correlation of outcome to Local RWM application for the treatment of inner ear dis⁃ both dosage and application method has yet to be estab⁃ orders lished. The variability in results and the lack of unifor⁃ Clinically, there is increasing interest in the local de⁃ mity in treatment protocols make it important to investi⁃ livery of drugs directly into the inner ear across the in⁃ gate the distribution and elimination of the drugs in the tact RWM. The main advantage of the local method is cochlea fluid spaces and the influence of different meth⁃ that the drug will bypass the blood-labyrinth barrier and ods of application. directly enter the inner ear, resulting in higher inner ear Pharmacokinetics of caroverine in the inner ear and concentration and reduced systemic absorption and tox⁃ its effects on the auditory function following local RWM icity. In cases of Ménière's disease, the instillation of and systemic applications gentamicin or streptomycin solutions into the middle ear There is growing interest in inner ear medication by has been widely used as a method［ ］ of suppressing vestib⁃ local routes instead of systemic application, in order to 9 ular function in the affected ear . This approach avoids achieve therapeutic drug levels in the inner ear while the risk of damaging the non-affected ear, as would oc⁃ avoiding undesirable systemic side effects. Caroverine, cur with systemic treatments. Experimental studies are as a glutamate receptor antagonist and an antioxidant in developing uses for a wide variety of agents, including combination with calcium channel blocking activity, is a steroids, local anesthetics, antioxidants, glutamate recep⁃ spasmolytic drug and also clinically used for the treat⁃ ·36· Journal of Otology 2009 Vol. 4 No. 1 ment of tinnitus, sudden hearing loss, speech discrimina⁃ drug directly onto the RWM than in those animals given tion disorders and other neurotoxic effects, such as isch⁃ a much higher dose systemically. In the perilymph, emia/reperfusion,［ ］ hypoglycemia, anoxia, hypoxia, shock caroverine might be removed not only by passive diffu⁃ 18-20 and dementia . However, the risk of inducing un⁃ sion to endolymph or to the CSF through the cochlear aq⁃ wanted side effects appears in most glutamate receptor ueduct, but also by［ active］ elimination such as blood flow 26 antagonists if given in large enough doses. Low doses and lymphatic flow . It is possible that the elimination are associated with altered sensory perception, dyspho⁃ of caroverine is faster than what was shown in the two lo⁃ ria, hypertension, nystagmus and disorientation, with cal groups. The maintenance of caroverine concentration progression to agitation, paranoia, hallucinations, severe in the perilymph in local groups is most likely due to the motor［ ］ retardation and ultimately catatonia at higher dos⁃ continuous absorption of caroverine from the gelfoam 21 es . These potentially detrimental adverse effects obvi⁃ through the RWM. It is well known that the RWM is per⁃ ously limit their clinical use for treatment of inner ear meable to various drugs and substances placed in the diseases by systemic administration. Thus, it is impor⁃ round window niche area. These include antibiotics, an⁃ tant to find alternative ways for the drug administration. tiseptics, arachidonic acid［ ］ metabolites, local anesthet⁃ 7 Delivery of agents into the inner ear via the RWM is ics, toxins and albumin showing that not only small being increasingly used clinically. For instance, this ap⁃ molecules but also macromolecules can pass through the proach has been utilized for the delivery of steroids and RWM. Caroverine is a low-molecular-weight substance （ ） gentamicin to the inner ear in the treatment of autoim⁃ molecular weight of caroverine hydrochloride=420 and mune diseases, sensorineural［ ］ hearing loss, tinnitus and should pass through the RWM quite freely.
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