Perilymph Pharmacokinetics of Markers and Dexamethasone Applied and Sampled at the Lateral Semi-Circular Canal

Salt, Alec N.; Hartsock, Jared J.; Gill, Ruth; Piu, Fabrice; Plontke, Stefan K.

doi:10.1007/s10162-012-0347-y

Cited by 61 publications

(53 citation statements)

References 42 publications

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“…Thus, the first two samples represented fluid from the inner ear, the first sample from the vestibular organs and the second from the cochlea, and the third and subsequent samples originated from the cerebrospinal fluid almost exclusively. Although this pattern of inner ear fluid flow was established in guinea pigs, the cochlear and vestibular anatomy of the mouse supports a similar interpretation (Salt and Stopp 1979;Salt et al 2012). …”

Section: Inner Ear Volumessupporting

confidence: 56%

“…The second sample that had a lower fluorescein percent than the first could be lower due to faster entry of fluorescein into scala vestibuli and the vestibule than into scala tympani. A lower concentration in scala tympani could also result from physiological entry of CSF into the basal turn of the mouse cochlea comparable to that found in guinea pig (Salt et al 2012). At present, the degree to which CSF enters the mouse cochlea under conditions where the otic capsule is not perforated is unknown.…”

Section: Differences In Fluorescein Content In Vestibular Versus Cochmentioning

confidence: 87%

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Systemic Lipopolysaccharide Compromises the Blood-Labyrinth Barrier and Increases Entry of Serum Fluorescein into the Perilymph

Hirose

Hartsock

Johnson

et al. 2014

JARO

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The blood vessels that supply the inner ear form a barrier between the blood and the inner ear fluids to control the exchange of solutes, protein, and water. This barrier, called the blood-labyrinth barrier (BLB) is analogous to the blood-brain barrier (BBB), which plays a critical role in limiting the entry of inflammatory and infectious agents into the central nervous system. We have developed an in vivo method to assess the functional integrity of the BLB by injecting sodium fluorescein into the systemic circulation of mice and measuring the amount of fluorescein that enters perilymph in live animals. In these experiments, perilymph was collected from control and experimental mice in sequential samples taken from the posterior semicircular canal approximately 30 min after systemic fluorescein administration. Perilymph fluorescein concentrations in control mice were compared with perilymph fluorescein concentrations after lipopolysaccharide (LPS) treatment (1 mg/kg IP daily for 2 days). The concentration of perilymphatic fluorescein, normalized to serum fluorescein, was significantly higher in LPS-treated mice compared to controls. In order to assess the contributions of perilymph and endolymph in our inner ear fluid samples, sodium ion concentration of the inner ear fluid was measured using ion-selective electrodes. The sampled fluid from the posterior semicircular canal demonstrated an average sodium concentration of 145 mM, consistent with perilymph. These experiments establish a novel technique to assess the functional integrity of the BLB using quantitative methods and to provide a comparison of the BLB to the BBB.

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Section: Inner Ear Volumessupporting

confidence: 56%

Section: Differences In Fluorescein Content In Vestibular Versus Cochmentioning

confidence: 87%

Systemic Lipopolysaccharide Compromises the Blood-Labyrinth Barrier and Increases Entry of Serum Fluorescein into the Perilymph

Hirose

Hartsock

Johnson

et al. 2014

JARO

Self Cite

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“…Here, we focused on direct injections into perilymph but the same homeostatic processes will also influence drug levels with other delivery methods, such as intratympanic applications. When used with injection methods that maintain the ear in the physiologic, sealed state, FITC-dextran was found to be retained in perilymph better than other substances studied (Salt et al 2012). …”

Section: Discussionmentioning

confidence: 93%

Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid

Salt

Gill

Hartsock

2015

JARO

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Understanding how drugs are distributed in perilymph following local applications is important as local drug therapies are increasingly used to treat disorders of the inner ear. The potential contribution of cerebrospinal fluid (CSF) entry to perilymph homeostasis has been controversial for over half a century, largely due to artifactual contamination of collected perilymph samples with CSF. Measures of perilymph flow and of drug distribution following round window niche applications have both suggested a slow, apically directed flow occurs along scala tympani (ST) in the normal, sealed cochlea. In the p r e s e n t s t u d y , w e h a v e u s e d f l u o r e s c e i n isothiocyanate-dextran as a marker to study perilymph kinetics in guinea pigs. Dextran is lost from perilymph more slowly than other substances so far quantified. Dextran solutions were injected from pipettes sealed into the lateral semicircular canal (SCC), the cochlear apex, or the basal turn of ST. After varying delays, sequential perilymph samples were taken from the cochlear apex or lateral SCC, allowing dextran distribution along the perilymphatic spaces to be quantified. Variability was low and findings were consistent with the injection procedure driving volume flow towards the cochlear aqueduct, and with volume flow during perilymph sampling driven by CSF entry at the aqueduct. The decline of dextran with time in the period between injection and sampling was consistent with both a slow volume influx of CSF (∼30 nL/min) entering the basal turn of ST at the cochlear aqueduct and a CSF-perilymph exchange driven by pressure-driven fluid oscillation across the cochlear aqueduct. Sample data also allowed contributions of other processes, such as communications with adjacent compartments, to be quantified. The study demonstrates that drug kinetics in the basal turn of ST is complex and is influenced by a considerable number of interacting processes.

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“…As the pipette was sealed into the ear, the cochlear aqueduct acted as the outlet for volume flow as a number of marker studies have shown (Salt et al, 2012b, Salt et al 2015). The pressure increase in the cochlea during injection is estimated to be less than 2 mm Hg and control injections produced only slowly-occurring, small changes of AP threshold, unrelated to the pressure changes at the start and end of injection (Salt et al, 2012b). The injection results in flow through the LSCC, the vestibule, scala vestibuli and scala tympani, allowing almost the entire perilymphatic space to be filled with drug.…”

Section: Methodsmentioning

confidence: 99%

Perilymph pharmacokinetics of locally-applied gentamicin in the guinea pig

et al. 2016

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Intratympanic gentamicin therapy is widely used clinically to suppress the vestibular symptoms of Meniere’s disease. Dosing in humans was empirically established and we still know remarkably little about where gentamicin enters the inner ear, where it reaches in the inner ear and what time course it follows after local applications. In this study, gentamicin was applied to the round window niche as a 20 μL bolus of 40 mg/ml solution. Ten 2 μL samples of perilymph were collected sequentially from the lateral semi-circular canal (LSCC) at times from 1 – 4 hours after application. Gentamicin concentration was typically highest in samples originating from the vestibule and was lower in samples originating from scala tympani. To interpret these results, perilymph elimination kinetics for gentamicin was quantified by loading the entire perilymph space by injection at the LSCC with a 500 μg/ml gentamicin solution followed by sequential perilymph sampling from the LSCC after different delay times. This allowed concentration decline in perilymph to be followed with time. Gentamicin was retained well in scala vestibuli and the vestibule but declined rapidly at the base of scala tympani, dominated by interactions of perilymph with CSF, as reported for other substances. Quantitative analysis, taking into account perilymph kinetics for gentamicin, showed that more gentamicin entered at the round window membrane (57%) than at the stapes (35%) but the lower concentrations found in scala tympani were due to greater losses there. The gentamicin levels found in perilymph of the vestibule, which are higher than would be expected from round window entry alone, undoubtedly contribute to the vestibulotoxic effects of the drug. Furthermore, calculations of gentamicin distribution following targeted applications to the RW or stapes are more consistent with cochleotoxicity depending on the gentamicin concentration in scala vestibuli rather than that in scala tympani.

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Perilymph Pharmacokinetics of Markers and Dexamethasone Applied and Sampled at the Lateral Semi-Circular Canal

Cited by 61 publications

References 42 publications

Systemic Lipopolysaccharide Compromises the Blood-Labyrinth Barrier and Increases Entry of Serum Fluorescein into the Perilymph

Systemic Lipopolysaccharide Compromises the Blood-Labyrinth Barrier and Increases Entry of Serum Fluorescein into the Perilymph

Perilymph Kinetics of FITC-Dextran Reveals Homeostasis Dominated by the Cochlear Aqueduct and Cerebrospinal Fluid

Perilymph pharmacokinetics of locally-applied gentamicin in the guinea pig

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