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Dexamethasone phosphate is widely used for intratympanic therapy in humans. We assessed the pharmacokinetics of dexamethasone entry into perilymph when administered as a dexamethasone phosphate solution or as a micronized dexamethasone suspension, with and without inclusion of poloxamer gel in the medium. After a 1-h application to guinea pigs, 10 independent samples of perilymph were collected from the lateral semicircular canal of each animal, allowing entry at the round window and stapes to be independently assessed. Both forms of dexamethasone entered the perilymph predominantly at the round window (73%), with a lower proportion entering at the stapes (22%). When normalized by applied concentration, dexamethasone phosphate was found to enter perilymph far more slowly than dexamethasone, in accordance with its calculated lipid solubility and polar surface area properties. Dexamethasone phosphate therefore has a problematic combination of kinetic properties when used for local therapy of the ear. It is relatively impermeable and enters perilymph only slowly from the middle ear. It is then metabolized in the ear to dexamethasone, which is more permeable through tissue boundaries and is rapidly lost from perilymph. Understanding the influence of molecular properties on the distribution of drugs in perilymph provides a new level of understanding which may help optimize drug therapies of the ear., (© 2018 S. Karger AG, Basel.)

Background: The use of intratympanic (IT) steroids for the treatment of inner ear disorders is promising, but the clinical challenges of prolonged middle ear drug application have proven burdensome, and a sustainable delivery system is yet to be developed., Method: In this study, a guinea pig model was used to determine if dexamethasone in combination with a hyaluronic-acid (HA)-based hydrogel is an efficient, stable and sustainable dexamethasone delivery system to the inner ear. For each animal, right and left middle ear bullae were randomly selected to be filled with dexamethasone alone or dexamethasone-HA (Dex-HA) gel. Perilymph samples were collected at different time points and dexamethasone levels were determined using an ELISA., Results: Dexamethasone was measurable in the perilymph samples up to 72 h after treatment. At 24 h after treatment, the perilymph dexamethasone concentrations were significantly higher (p = 0.01) in the ears treated with Dex-HA gel than in those treated with dexamethasone alone. While the perilymph dexamethasone concentration had decreased at 48 h after treatment with Dex-HA gel, the levels were still higher than those observed at 24 h in ears treated with dexamethasone alone. A high variability in dexamethasone concentration was observed between the samples, and the variability between matched ears receiving different treatments was remarkably lower than the variability within each treatment group, suggesting that individual parameters might play a major role in perilymph dexamethasone concentration. There was no statistically significant correlation between dexamethasone concentration and sex, weight or laterality., Conclusions: Our results show that the Dex-HA gel used in this study provides an effective and sustained dexamethasone release mechanism that might be utilized to treat conditions such as sudden sensorineural hearing loss. This could potentially reduce the morbidity and costs associated with IT treatment., (Copyright © 2010 S. Karger AG, Basel.)

Objective: To investigate the relationship between endolymphatic hydrops and perilymphatic potassium., Methods: 20 pigmented guinea pigs were used: 10 for scala vestibuli study and 10 for scala tympani study. Acute endolymphatic hydrops was produced by microinjection of an artificial endolymph into the scala media. Injections were performed in the second turn at rates up to 500 nl/min for a period of 10 min. The injection volume was up to 5 microl. Endocochlear potential (EP) was monitored during injections. Simultaneous with the injections, the potassium concentrations in scala vestibuli (K(SV)) or tympani (K(ST)) perilymph were measured with ion-sensitive double-barreled microelectrodes sealed into in the scalae in the 3rd turn with cyanoacrylate glue., Results: For endolymphatic injections of

In the stria vascularis (SV), it is known that the Na(+)-K(+)-ATPase is expressed abundantly and its activity in the basolateral membrane of marginal cells is high. Ouabain, an inhibitor of the Na(+)-K(+)-ATPase, causes not only a decline in the endocochlear DC potential but also acute vacuolar formation in marginal cells. We studied the ionic mechanisms underlying the ouabain-induced vacuolar formation in marginal cells using perilymphatic perfusion in guinea pigs. Perilymphatic perfusion with 1 mM ouabain dissolved in the artificial perilymph for 50 min caused many vacuoles of a wide range of sizes in the apical cytoplasm of marginal cells, the bulging of marginal cells into the scala media and strial volume increase. Removal of K(+) from the perilymph reduced the proportion of vacuoles and strial thickening, but the bulging of marginal cells remained. In contrast, the sizes of vacuoles were drastically reduced and extrusion of marginal cells into the scala media could not be observed in the absence of perilymphatic Na(+). Furthermore, the total volume of SV was obviously reduced in comparison with the control. These results indicate that perilymphatic Na(+) and K(+) are responsible for these morphological changes caused by ouabain, and that perilymphatic Na(+) plays an important role in the cellular volume regulation in SV in the presence of ouabain. It is supposed that the transport system of perilymphatic Na(+) and K(+) into marginal cells may contribute to vacuolar formation when ouabain is administered. Regarding Na(+), we hypothesize two possibilities for the perilymphatic Na(+) transporting pathway as follows. Na(+) in the perilymph could enter the endolymph via Reissner's membrane or the basilar membrane; Na(+) in the endolymph would then be taken up by marginal cells via the apical membrane and secreted into the intrastrial space by Na(+)-K(+)-ATPase in the basolateral membrane. Another, less likely, possibility is that Na(+) in the perilymph is transported into basal cells or fibrocytes in the spiral ligament, then into intermediate cells via gap junctions, and finally secreted into the intrastrial space via Na(+)-K(+)-ATPase of intermediate cells. Regarding K(+), it is expected that the K(+) recycling pathway plays a role in ouabain-induced vacuolar formation in marginal cells.

Cortisone is used in various inner ear disorders such as sudden hearing loss. However, it is not known if the doses of prednisolone employed in therapy increase the cortisol level in the inner ear. To evaluate the level of cortisol within the perilymph after intravenous administration of 125 and 250 mg of prednisolone, serum and perilymph samples of 29 consecutive patients with clinical otosclerosis subjected to stapedectomy were collected. Cortisol levels were determined by RIA. The perilymphatic cortisol level was significantly increased in the group with 250 mg of prednisolone while the perilymphatic cortisol levels were not significantly different between the control group and the patients treated with 125 mg. Although the therapeutic dose of prednisolone is not known, we conclude that the application of 250 mg has a greater impact on the inner ear than 125 mg., (Copyright 2003 S. Karger AG, Basel)

An in vivo method for assessment of changes in hydroxyl radical levels in cochlear perilymphatic spaces is described and applied to cochlear ischemia-reperfusion in the mouse. Cochlear blood flow was reversibly reduced by compression of the anterior inferior cerebellar arterial network. Changes in the production of hydroxyl radicals, used as an index of tissue production of reactive oxygen species (ROS), were determined by measuring the conversion of salicylate to 2,3-dihydroxybenzoic acid. Low levels of salicylate (0.1 mM) in artificial perilymph were applied by perfusion of the cochlea using a round window entry and apical exit. Perfusate was collected and analyzed by high-performance liquid chromatography. Forty minutes of partial ischemia led to a > 10-fold average increase over baseline in the concentration of hydroxyl radical, which increase persisted for at least 40-80 min following reperfusion. Our observations support previous results obtained using less direct methods, indicating that cochlear ischemia-reperfusion and related damage is associated with elevated ROS levels. Development of an in vivo method for assessing changes in cochlear ROS in mice will facilitate the study of the relation between deafness genes, vulnerability to insults and dynamics of cellular processes that produce and regulate ROS.

The pharmacokinetics and ototoxicity of the new platinum analogue TRK-710 (3, 9, 15 mg/kg x 3 days) were compared with those of cisplatin (1, 3, 5 mg/kg x 3). The perilymphatic concentration of TRK-710 was one seventh of that of cisplatin even 1 h after the administration. The N1 threshold of the compound action potential was elevated dose-dependently in both groups with a similar degree of hearing impairment. Morphological observation using phase contrast microscopy and scanning electron microscopy revealed the damage of the outer hair cells to almost the same degree mainly in the basal and second turns. Despite its usefulness against cisplatin-resistant tumors and a lesser degree of nephrotoxicity and myelosuppression, TRK-710 should be clinically used with caution similar to cisplatin.

Fe2+ and Zn2+ levels in perilymph of guinea pigs injected with gentamicin (GM) were examined and compared with the corresponding concentrations in CSF, serum and hairs. We observed a preventive and therapeutic action of sea buckthorn oil and injectio gastrodini to hearing loss. The results showed that: (1) the Fe2+ content in GM-injected guinea pigs was increased in perilymph and hairs; it was decreased after prevention and treatment, but there was no obvious change in CSF and serum; (2) the Zn2+ content in perilymph and CSF was increased in GM-injected guinea pigs. It rose further after prevention, but in serum and hairs it decreased. The results indicate that the ototoxic reaction to GM is related to the rise of the Fe2+ content in perilymph. The elevation of Zn2+ is a compensatory reaction. The changes in the chemical composition of perilymph are more important than those in CSF, serum and hairs for pathological changes of the cochlea. Sea buckthorn oil can prevent GM ototoxicity.

A pharmacokinetic profile of the antibiotic ceftazidime was established for perilymph, cerbrospinal fluid (CSF) and plasma in 12 guinea pigs using the technique of high-performance liquid chromatography. The mean peak levels of 13.35 mg/l in perilymph and 140.54 mg/l in plasma were reached within the first hour after a single intravenous dose of 100 mg/kg. The CSF mean peak level of 5.36 mg/l, however, was not attained until 3 h after injection. The half-life was about 4 h in perilymph, more than 6 h in CSF and less than 2 h in plasma. Six hours following administration, the perilymph drug concentration remained higher than the plasma level. The study indicates that ceftazidime has excellent penetration into perilymph. It is concluded that ceftazidime should be a very useful agent in the treatment of bacterial labyrinthitis caused by susceptible organisms.

The distribution of rat alpha-atrial natriuretic polypeptide (ANP) was studied in the adult inner ear of the Sprague-Dawley rat using immunohistochemical methods. Immunostaining, in particular of the subepithelial stroma cells of the spiral ligament, the spiral prominence and below neuroepithelial areas of all five vestibular organs, was identified. We hypothesize that alpha-ANP is involved in perilymphatic dynamics rather than generating endolymph. The strong staining for alpha-ANP of outer hair cells indicates specific mechanisms for volume control as compared with inner hair cells and vestibular hair cells which all lack this immunostaining. The functional significance of the specific staining of nerve calyces in only the three cristae ampullaris but not in the two maculae remains to be clarified. The positivity of epithelial cells in the endolymphatic sac supports a previous hypothesis which looks upon this organ as a pressure regulation system in the inner ear.

This study was conducted in order to evaluate ototoxic potential and passage through the round window membrane of ciprofloxacin, a newly developed antimicrobial drug with an antibacterial spectrum well suited for the treatment of suppurative otitis media. Ciprofloxacin was injected intraperitoneally in 40 guinea pigs in doses ranging from 25 to 150 mg/kg body weight for 14 consecutive days. Sixteen inner ears of chinchillas were exposed to ciprofloxacin at a concentration of 0.1 mg/ml applied directly to the intact round window membrane. Despite severe deterioration of the animals injected with the highest doses, no behavioral or definite morphological evidence of inner ear or vestibular damage could be seen. Ciprofloxacin concentrations in the perilymph were determined with high-performance liquid chromatography. Direct passage of ciprofloxacin, presumably via the round window membrane, was demonstrated. After 1 h and 15 min, an arithmetic mean concentration of 0.165 micrograms/ml (95% confidence interval +/- 0.053) could be demonstrated in the perilymph. It can be concluded that ciprofloxacin has no ototoxic effect when administered systemically. Furthermore, when locally applied into the middle ear, it has the capacity to pass into the inner ear.