High Variability of Perilymphatic Entry of Neutral Molecules Through the Round Window

Chelikh, L.; Teixeira, Marie; Martin, C.; Sterkers, Olivier; Ferrary, Évelyne; Couloigner, V.

doi:10.1080/00016480310001042

Cited by 23 publications

(14 citation statements)

References 5 publications

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“…A similar high variability in permeability has been reported in other studies (Salt and Ma, 2001;Salt et al, 2003;Chelikh et al, 2003;Hahn et al, 2005). The sources of variability are uncertain at the present time but permeability appears to be influenced by the hydrostatic pressure difference across the membrane , whether the membrane is allowed to dry (this study), and on the chemical composition of the solution that contacts the RWM (Imamura and Adams, 2003).…”

Section: Discussionsupporting

confidence: 74%

Perilymph sampling from the cochlear apex: A reliable method to obtain higher purity perilymph samples from scala tympani

Salt

Hale

Plonkte

2006

Journal of Neuroscience Methods

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Measurements of drug levels in the fluids of the inner ear are required to establish kinetic parameters and to determine the influence of specific local delivery protocols. For most substances, this requires cochlear fluids samples to be obtained for analysis. When auditory function is of primary interest, the drug level in the perilymph of scala tympani (ST) is most relevant, since drug in this scala has ready access to the auditory sensory cells. In many prior studies, ST perilymph samples have been obtained from the basal turn, either by aspiration through the round window membrane (RWM) or through an opening in the bony wall. A number of studies have demonstrated that such samples are likely to be contaminated with cerebrospinal fluid (CSF). CSF enters the basal turn of ST through the cochlear aqueduct when the bony capsule is perforated or when fluid is aspirated. The degree of sample contamination has, however, not been widely appreciated. Recent studies have shown that perilymph samples taken through the round window membrane are highly contaminated with CSF, with samples greater than 2microL in volume containing more CSF than perilymph. In spite of this knowledge, many groups continue to sample from the base of the cochlea, as it is a well-established method. We have developed an alternative, technically simple method to increase the proportion of ST perilymph in a fluid sample. The sample is taken from the apex of the cochlea, a site that is distant from the cochlear aqueduct. A previous problem with sampling through a perforation in the bone was that the native perilymph rapidly leaked out driven by CSF pressure and was lost to the middle ear space. We therefore developed a procedure to collect all the fluid that emerged from the perforated apex after perforation. We evaluated the method using a marker ion trimethylphenylammonium (TMPA). TMPA was applied to the perilymph of guinea pigs either by RW irrigation or by microinjection into the apical turn. The TMPA concentration of the fluid sample was compared with that measured in perilymph prior to taking the sample using a TMPA-selective microelectrode sealed into ST. Data were interpreted with a finite element model of the cochlear fluids that was used to simulate each aspect of the experiment. The correction of sample concentration back to the perilymph concentration prior to sampling can be performed based on the known ST volume (4.7microL in the guinea pig) and the sample volume. A more precise correction requires some knowledge of the profile of drug distribution along the cochlear prior to sampling. This method of sampling from the apex is technically simple and provides a larger sample volume with a greater proportion of perilymph compared to sampling through the RW.

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Section: Discussionsupporting

confidence: 74%

Perilymph sampling from the cochlear apex: A reliable method to obtain higher purity perilymph samples from scala tympani

Salt

Hale

Plonkte

2006

Journal of Neuroscience Methods

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“…However, the variation of RWM permeability was large, which is in accordance with the high variability of intracochlear gentamicin concentrations measured in other studies 18,19 and for other substances, such as marker ions, 11,20 glucocorticoids, [21][22][23] and inulin and mannitol. 24 With the limited sample size in the present study, we cannot definitively conclude that RW permeability varies as a function of application time. In the analysis of data, we continued to assume that RWM permeability was constant with time for each experiment.…”

Section: Discussionmentioning

confidence: 67%

“…Measured drug levels after 30 minute applications of gentamicin provide preliminary evidence that the rate of gentamicin entry for brief applications may be lower than that found with 2 or 3 hour applications. However, the variation of RWM permeability was large, which is in accordance with the high variability of intracochlear gentamicin concentrations measured in other studies 18,19 and for other substances, such as marker ions, 11,20 glucocorticoids, 21–23 and inulin and mannitol 24 . With the limited sample size in the present study, we cannot definitively conclude that RW permeability varies as a function of application time.…”

Section: Discussionmentioning

confidence: 99%

Concentration Gradient Along the Scala Tympani After Local Application of Gentamicin to the Round Window Membrane

et al. 2007

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Objectives-The distribution of gentamicin along the fluid spaces of the cochlea following local applications has never previously been demonstrated. Computer simulations have predicted that significant basal-apical concentration gradients might be expected and histological studies indicate that hair cell damage is greater at the base than at the apex following local gentamicin application. In the present study, gradients of gentamicin along the cochlea were measured.Methods-A recently-developed method of sampling perilymph from the cochlear apex of guinea pigs was used, in which the samples represent fluid originating from different regions along scala tympani. Gentamicin concentration was determined in sequential apical samples which were taken following up to three hours of local application to the round window niche.Results-Substantial gradients of gentamicin along the length of scala tympani were demonstrated and quantified, averaging more than 4000 times greater concentration at the base compared to the apex at the time of sampling. Peak concentrations and gradients for gentamicin varied considerably between animals, likely resulting from variations in round window membrane permeability and rates of perilymph flow. Conclusions-The large gradients for gentamicin demonstrated here in guinea pigs account for how it is possible to suppress vestibular function in some patients with a local application of gentamicin without damaging auditory function. Variations in round window membrane permeability and in perilymph flow could account for why hearing losses are observed in some patients.

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“…Therefore, the quantification of RWM permeability is extremely important as this factor appears to dramatically influence the perilymph levels of drug achieved. A high inter-individual heterogeneity of the drug concentration within the inner ear due to variability in RWM permeability with subsequent variability of the therapeutic effects was specifically suggested by Chelikh et al (2003) who applied inulin or mannitol topically to the RWM. The radioactivity in cochlear perilymph measured at day four after application of 3 H-mannitol and 3 H-inulin were 156 ± 80.3 and 16 ± 10.6 cpm/μl, respectively.…”

Section: Discussionmentioning

confidence: 99%

Cochlear microdialysis for quantification of dexamethasone and fluorescein entry into scala tympani during round window administration

et al. 2006

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Before new drugs for the treatment of inner ear disorders can be studied in controlled clinical trials, it is important that their pharmacokinetics be established in inner ear fluids. Microdialysis allows drug levels to be measured in perilymph without the volume disturbances and potential cerebrospinal fluid contamination associated with fluid sampling. The aims of this study were to show: (i) that despite low recovery rates from miniature dialysis probes, significant amounts of drug are removed from small fluid compartments, (ii) that dialysis sampling artifacts can be accounted for using computer simulations and (iii) that microdialysis allows quantification of the entry rates through the round window membrane (RWM) into scala tympani (ST). Initial experiments used microdialysis probes in small compartments in vitro containing sodium fluorescein. Stable concentrations were observed in large compartments (1000 μl) but significant concentration declines were observed in smaller compartments (100, 10 and 5.6 μl) comparable to the size of the inner ear. Computer simulations of these experiments closely approximated the experimental data. In in vivo experiments, sodium fluorescein 10 mg/ml and dexamethasone-dihydrogen-phosphate disodium salt 8 mg/ml were simultaneously applied to the RWM of guinea pigs. Perilymph concentration in the basal turn of ST was monitored using microdialysis. The fluorescein concentration reached after 200 min application (585 ± 527 μg/ml) was approximately twice that of dexamethasone phosphate (291 ± 369 μg/ml). Substantial variation in concentrations was found between animals by approximately a factor of 34 for fluorescein and at least 41 for dexamethasone phosphate. This is, to a large extent, thought to be the result of the RWM permeability varying in different animals. It was not caused by substance analysis variations, because two different analytic methods were used and the concentration ratio between the two substances remained nearly constant across the experiments and because differences were apparent for the repeated samples obtained in each animal. Interpretation of the results using computer simulations allowed RWM permeability to be quantified. It also demonstrated, however, that cochlear clearance values could not be reliably obtained with microdialysis because of the significant contribution of dialysis to clearance. The observed interanimal variation, e.g., in RWM permeability, is likely to be clinically relevant to the local application of drugs in patients.

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High Variability of Perilymphatic Entry of Neutral Molecules Through the Round Window

Cited by 23 publications

References 5 publications

Perilymph sampling from the cochlear apex: A reliable method to obtain higher purity perilymph samples from scala tympani

Perilymph sampling from the cochlear apex: A reliable method to obtain higher purity perilymph samples from scala tympani

Concentration Gradient Along the Scala Tympani After Local Application of Gentamicin to the Round Window Membrane

Cochlear microdialysis for quantification of dexamethasone and fluorescein entry into scala tympani during round window administration

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