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At least 685 records · Page 38Linked to original sources
PubMed1998

Experimental model of cisplatin ototoxicity in chinchillas.

Cisplatin is an important antineoplastic agent. Its ototoxicity has been well defined, both in human and animal studies. However, animal models of systemic cisplatin administration have been complicated by multiple toxic effects. We studied cisplatin ototoxicity in an animal model involving topical application of cisplatin to the round-window membrane. Adult chinchillas were anesthetized with ketamine and pentobarbital, and auditory function was tested with the use of auditory brain-stem responses to various stimuli (clicks and 8-and 16-kHz tone bursts). Each animal was used as its own control. The middle-ear cavity was exposed through the bulla. In the experimental ear, a 25-microl solution of 0.25 mg cisplatin/1.0 ml normal saline solution was applied to the round-window membrane. In the control ear, 25 microl normal saline solution was applied to the round-window membrane. Follow-up auditory brain-stem response testing was conducted 7 days after treatment. A significant increase in threshold in the experimental ears was seen on comparison with the control ears. This finding suggests that application of cisplatin to the round-window membrane is a useful animal model in which to study cisplatin ototoxicity.

Animals↗
PubMed2006

Cochlear pharmacokinetics with local inner ear drug delivery using a three-dimensional finite-element computer model.

HYPOTHESIS: Cochlear fluid pharmacokinetics can be better represented by three-dimensional (3D) finite-element simulations of drug dispersal. BACKGROUND: Local drug deliveries to the round window membrane are increasingly being used to treat inner ear disorders. Crucial to the development of safe therapies is knowledge of drug distribution in the inner ear with different delivery methods. Computer simulations allow application protocols and drug delivery systems to be evaluated, and may permit animal studies to be extrapolated to the larger cochlea of the human. METHODS: A finite-element 3D model of the cochlea was constructed based on geometric dimensions of the guinea pig cochlea. Drug propagation along and between compartments was described by passive diffusion. To demonstrate the potential value of the model, methylprednisolone distribution in the cochlea was calculated for two clinically relevant application protocols using pharmacokinetic parameters derived from a prior one-dimensional (1D) model. In addition, a simplified geometry was used to compare results from 3D with 1D simulations. RESULTS: For the simplified geometry, calculated concentration profiles with distance were in excellent agreement between the 1D and the 3D models. Different drug delivery strategies produce very different concentration time courses, peak concentrations and basal-apical concentration gradients of drug. In addition, 3D computations demonstrate the existence of substantial gradients across the scalae in the basal turn. CONCLUSION: The 3D model clearly shows the presence of drug gradients across the basal scalae of guinea pigs, demonstrating the necessity of a 3D approach to predict drug movements across and between scalae with larger cross-sectional areas, such as the human, with accuracy. This is the first model to incorporate the volume of the spiral ligament and to calculate diffusion through this structure. Further development of the 3D model will have to incorporate a more accurate geometry of the entire inner ear and incorporate more of the specific processes that contribute to drug removal from the inner ear fluids. Appropriate computer models may assist in both drug and drug delivery system design and can thus accelerate the development of a rationale-based local drug delivery to the inner ear and its successful establishment in clinical practice.

Animals↗
PubMed2002

Ultrastructural characteristics of the round window membrane during pneumococcal otitis media in rat.

To understand better the pathogenesis of inner ear (IE) damage caused by otitis media (OM), the round window membrane(RWM) structure was investigated in a rat model for pneumococcal otitis media (POM). The RWM of 25 rats were evaluated light and electron microscopically on 1 day, 3 days, 6 days, 10 days, and 20 days after the unilateral inoculation of type 3 pneumococcus suspension into their middle ear cavities. The thickness of the RWM increased in various stages of the pneumococcus-evoked otitis media, compared with that of the normal. The thickening was most pronounced on day 1, being about 4 to 5 times greater than that of the normal RWM. All layers of the RWM were affected by the pneumococcal infection, but the major changes were confined to the subepithelial space close to the basement membrane (BM). Together with alterations to the BM, the most distinct pathological features were characterized by an increase and hypertrophy of fibroblasts in association with abundant collagen fibers. Elastic fibers observed close to the inner mesothelial layer under a high power magnification also increased during the experiment. These results will be relevant to a better understanding of the histologic implication of RWM in stages of acute otitis media involving pneumococcus-evoked otitis media.

Animals↗
PubMed1985

Effects of sympathetic stimulation on the round window compound action potential in the rat.

The effect on the ear of stimulating the sympathetic nervous system was studied in rats by recording the compound action potentials (N1N2) in response to 2 kHz tonebursts presented to anesthetized rats before, during, and after electrical stimulation of the superior cervical ganglion, and evaluating the changes in N1 latency which resulted. Stimulation of the superior cervical ganglion was found to cause an increase in the N1 latency which was more pronounced at low stimulus intensities (mean value 0.09 +/- 0.04 ms (S.E.) at 5 dB above threshold) than at moderate stimulation intensities (0.08 +/- 0.04 ms at 15 dB above threshold), with little change in latency occurring at the highest intensity tested (0.02 +/- 0.01 ms at approximately 25-30 dB above threshold). In addition, individual animals varied in their responses to stimulation of the superior cervical ganglion, with some animals evidencing a great change in the latency of the response (0.4 ms increase at 10 dB above threshold) and others showing very little change in latency. This variability could not be related to the condition of the animal at the time of observation of the response. In one of the twelve animals there was a slight decrease in latency as a result of sympathetic stimulation (0.07 ms at 5 dB above threshold), and although not studied systematically, low frequencies seemed to be affected more than high frequencies. Further, the change in the amplitude of N1 was not systematically related to sympathetic stimulation. After the administration of hexamethonium (which blocks transmission in autonomic ganglia) in three rats there was no effect on the latency of the N1 potential from sympathetic stimulation as recorded before sympathetic stimulation.

Animals↗
PubMed1980

Depression of the guinea pig cochlear temperature caused by anesthesia and ventral-approach ear surgery.

A chronic implant of a thermocouple, on the round window membrane of the guinea pig cochlea, was used to determine the cochlear temperature in awake, anesthetized, and surgically dissected animals. The normal cochlear temperature was equal to the core (rectal) temperature of the guinea pig (38.5 degrees C) and, in the intact animal, exactly tracks changes in core temperature at least down to the 33 degrees C level tested here. Ventral surgery to expose the cochlea results in a decrease, to a low value of 31 degrees C, in cochlear temperature because of the removal of tissue mass overlying the auditory bulla. Effective use of a heating pad and blanket cover, over the body of the guinea pig, will regulate core temperature but the exposed cochlea will always have a lower value than either the temperature measured rectally or in the orophraynx.

Anesthesia↗
PubMed1992

Stapedius reflexes to electrical stimulation in the rabbit for the assessment of hearing.

The possibility of using electrically induced stapedius reflexes as a means of objective hearing evaluation was investigated in the rabbit as an animal model. The contralateral stapedius reflex to acoustic and electrical stimulation was measured in anesthetized rabbits. For electrical stimulation, the middle ear was opened surgically and stimulation was applied by a monopolar electrode placed at or into the round window. Contraction of the middle ear muscle was monitored by digital sampling and averaging of the impedance changes in the contralateral ear. Acoustically evoked reflexes were recorded within expected limits despite anesthesia. The level of the electrical stimulus was raised until mass reflexes of the neck muscles were observed. A contralateral stapedius reflex to electrical stimulation could not be demonstrated. In our experiment, monopolar electrical stimulation at the round window could not elicit contralateral stapedius reflexes.

Acoustic Stimulation↗
PubMed2006

[Permeability of different Dexamethasone drugs through round window membrane].

OBJECTIVE: To analysis the effect of sustained delivering two adjuncts alginate sodium (ALG) and carboxymethylated chitosan (CHI) on permeating of dexamethasone (DXM) through experimental apparatus to round window membrane. METHODS: The experimental apparatus for round window membrane in vitro was designed by simulating the environment of middle ear and scala tympani. Different drugs of DXM sodium included variable concentrations of ALG and CHI were prepared. Using the experimental apparatus, DXM permeating from round window membrane was sampled in 9 hours while its quantities were measured with high performance liquid chromatography, and then different pharmaceutical equations were simulated. RESULTS: The releasing quantity of control group (without any adjuncts) rose rapidly within 3 hours, and then approximated to balance. ALG (25 g/L) + CHI(4 g/L) or ALG(25 g/L) + CHI(6 g/L) showed the great effect of sustained release, but ALG (25 g/L) alone took the second place. CHI (4 g/L) alone enhanced the transmembranous permeability. CONCLUSIONS: With the in vitro apparatus, DXM could permeate through the round window membrane. DXM added with appropriate component of ALG and CHI could be good drugs for sustained release.

Alginates↗
PubMed1995

Effect of leukotriene inhibitor on cochlear blood flow in salicylate ototoxicity.

Our previous studies showed that salicylate ototoxicity is associated with decreased levels of vasodilating prostaglandins (PGs) and increased vasoconstricting leukotrienes (LTs) in the perilymph and reduced cochlear blood flow (CoBF). The purpose of this study was to test the hypothesis that leukotriene inhibitor prevents salicylate ototoxicity by preventing abnormal elevation of LT levels in the inner ear, thus averting a decrease in CoBF resulting from abnormal levels of arachidonic acid metabolites in the inner ear. Ototoxicity was induced in chinchillas by either local round window membrane (RWM) application or systemic treatment with salicylate both with and without pretreatment with leukotriene inhibitor (Sch 37224). A moderate reduction in CoBF was documented with both local RWM and systemic treatment with salicylate. Salicylate induced hearing loss and reduction in CoBF were prevented by pretreatment with a leukotriene inhibitor. This study suggests that leukotriene inhibitor prevents salicylate ototoxicity by averting a decrease in CoBF mediated by abnormal levels of arachidonic acid metabolites in the inner ear.

Animals↗
PubMed2004

Localization of endotoxin in the inner ear following inoculation into the middle ear.

Sensorineural hearing loss is known to be a significant sequela of otitis media (OM). The pathophysiology of such hearing loss in OM is thought to be due to transmission of toxins and other bacterial products through the round window membrane, damaging the hair cells of the basal turn of the cochlea. Other routes, such as those involving the oval window, blood vessels and lymphatics, may also be involved. The purpose of this study was to elucidate the routes from the middle ear cavity to the inner ear and also the distribution pattern of endotoxin in the inner ear after injection of fluorescence-labelled endotoxin into the tympanic cavity and detection of fluorescence in the cochleae, vestibular end organs and facial nerves. This fluorescence was far more intense in the lower turns of the cochlea. These findings suggest that endotoxin can reach the inner ear by various routes, e.g. the round window, blood vessels or lymphatics, and/or interscala exchange, resulting in a disturbance not only of the cochlea but also of the vestibular end organs.

Animals↗
PubMedDate not supplied

The penetration of gentamicin and neomycin into perilymph across the round window membrane.

Many commonly employed otic drops contain aminoglycoside antibiotics that may be toxic to the inner ear. A variety of chemicals such as ionic solutions, certain anesthetics, and epinephrine have been shown to diffuse across the round window membrane into the perilymph. Twelve adult cats were studied in this experiment. The auditory bulla was exposed and solutions containing gentamicin or neomycin concentrations similar to that commonly used in otic drops were applied to the round window niche for 15 minutes and washed with saline solution. The gentamicin and neomycin concentrations in the round window niche wash and the perilymph were then assayed by a radioenzymatic method. Concentrations of both antibiotics were observed in the perilymph. Thus, the round window membrane is a route through which these ototoxins may gain access to the inner ear.

Animals↗
PubMed1988

Experimental studies on round window structure: function and permeability.

Current research and an overall review of 12 years of round window membrane studies is presented. The approach, rationale, and concepts that have evolved from the studies are described. An ultrastructural study of the round window membrane of rhesus monkeys disclosed three basic layers: an outer epithelium, a middle core of connective tissue, and an inner epithelium. Morphologic evidence in monkeys, cats, and chinchillas suggests that these layers of the round window participate in absorption and secretion of substances to and from the inner ear, and that the entire membrane could play a role in the defense system of the ear. Cationic ferritin, horseradish peroxidase, 1-micron latex spheres, and neomycin-gold spheres placed in the middle ear of these experimental animals were observed to traverse the round window membrane through pinocytotic vesicles. Three-micron latex spheres and anionic ferritin were not incorporated by the membrane. Cationic ferritin and 1-micron latex spheres placed in perilymph were incorporated by the inner epithelial cells, suggesting absorptive capabilities of the round window membrane. Cationic ferritin was observed within the mesothelial cells underlying the scala tympani side of the basilar membrane, suggesting a role for these cells in the inner-ear defense system. A review of the subject and a general perspective from the author's viewpoint are discussed.

Animals↗
PubMedDate not supplied

Temporal bone findings in cases of salt water drowning.

The otologic literature contains no description of the histopathological features of temporal bones of persons who perished in drowning accidents. Three temporal bones from two fatal cases of drowning were studied in serial sections. Two temporal bones were from a man aged 31 years who collapsed after scuba diving and died three days later. One temporal bone was from a 32-year-old man, serving in the navy, who drove his car, probably accidentally, into the sea and drowned in it. Histopathological findings appeared to be similar in the two cases. Diffuse hemorrhage was evident throughout the middle ear and inner ear. The tympanic and round window membranes appeared to be intact although hemorrhage had occurred within the tissue layers of the membranes. This finding contrasts with observations of ruptured membranes by other investigators.

Adult↗
PubMed2005

Novel strategy for treatment of inner ears using a biodegradable gel.

OBJECTIVE: The present study aimed to evaluate the efficacy of a biodegradable hydrogel as a drug-delivery medium for the inner ear. Brain-derived neurotrophic factor (BDNF) was chosen as the agent to be administered. METHOD: First, we used an enzyme-linked immunosorbent assay to measure BDNF concentrations in the cochlear fluid after placing a hydrogel containing this agent onto the round-window membrane of the ear. Second, the functional and histologic protection of the auditory primary neurons (spiral ganglion neurons [SGNs]) by BDNF applied through the hydrogel was examined using an animal model of SGN degeneration. RESULTS: The results revealed sustained delivery of BDNF into the cochlear fluid by way of the hydrogel. Second, the functional and histologic protection of the auditory primary neurons (SGNs) by BDNF applied through the hydrogel was examined using an animal model of SGN degeneration. The measurement of electrically evoked auditory-brainstem responses demonstrated that BDNF delivered by way of the hydrogel significantly reduced the threshold elevation. Immunohistochemistry for neurofilament 200 kD demonstrated increased survival of SGNs because of BDNF application through the hydrogel. CONCLUSION: These findings indicate that biodegradable hydrogels can be used for drug delivery to the inner ear.

Animals↗
PubMed1995

Effects of experimental round window membrane laceration on the free amino acid profile of perilymph.

To evaluate biochemical changes of inner ear fluid following perilymphatic fistula (PLF), free amino acid (FAA) profiles of perilymph in experimental PLF were determined using high performance liquid chromatography (HPLC). Thirty-five guinea pigs were anesthetized and prepared as PLF models by perforating the round window membrane (RWM) of the left ear. Right ears served as controls. Samples (2 microliters) were aspirated from scala tympani through a RWM perforation. Animals were divided into two groups according to time of sampling following PLF induction: 2-week group (n = 17) and 4-week group (n = 18). Compound action potential (CAP) evoked by 1, 2, 4 and 8 kHz tone bursts were measured using a round window electrode from the left ear before PLF induction and from both ears before final sampling. RWM perforations were completely closed at the time of the final sampling in 8 of 17 animals from the 2-week group, and 15 of 18 animals from the 4-week group. In comparison with that in control ears, concentrations of FAA throughout all profiles was dramatically elevated in the PLF ears with a healed RWM perforation. Most PLF ears with persistent RWM perforation showed minimal differences between 2-week and 4-week groups. No remarkable CAP threshold changes were found at any frequencies tested following PLF induction in both the 2-week and 4-week groups. The unchanged 8 kHz threshold suggests that FAA concentration increases only at the basal end of the cochlea. FAAs accumulate within the basal end of scala tympani in ears with a healed RWM.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1983

Electron microscopic structure of the human round window membrane.

The fine structure of the human round window membrane has been investigated. It was found to consist of three layers: the tympanic cavity layer, the middle connective tissue layer, and the scala tympani layer. The middle connective tissue layer is considered the most important part of the round window membrane as it permits the movements of the inner ear fluid caused by the movements of the stapedial foot plate. The strength and elasticity of the membrane is guaranteed by three-dimensionally arranged collagen and elastic fibres and elastic networks in the middle connective tissue layer. The rupture of the round window membrane seems to be due to the diminished number and elasticity of the elastic elements in the middle connective tissue layer of the round window membrane.

Adult↗
PubMed1985

Specification of the acoustical input to the ear at high frequencies.

The sound fields that arise in the auditory canals of cats have been examined both experimentally and theoretically. Of particular interest was the spatial variation of sound pressure near the eardrum, where reference probes are typically located. Using a computer controlled data acquisition system, sound pressure was measured between 100 Hz and 33 kHz for constant driver input at 14 different locations in the ear canal of a cat, and the standing wave patterns formed. The shape of the patterns could be predicted quite well above 12 kHz using a theory that requires specification of only the geometry of the ear canal. This theory, an extension of the one-dimensional horn equation, applies to three-dimensional, rigid-walled tubes that have both variable cross section and curvature along their lengths. Large variations of sound pressure along the ear canal and over the surface of the eardrum are found above about 10 kHz. As a consequence it is not possible to define the acoustical input to the ear from sound pressure level measured at any single location. Even in comparative experiments, in which only the constancy of the acoustical input is important, any uncertainty in reference probe location would lead to an uncertainty in sound pressure level when different sets of measurements are compared. This error, calculated for various probe locations and frequencies, is especially large when the probe is near a minimum of the sound field. Spatial variations in pressure can also introduce anomalous features into the measured frequency response of other auditory quantities when eardrum sound pressure is used as a reference. This is illustrated with measurements of the round window cochlear microphonic.

Animals↗