Local administration of antioxidants to the inner ear

Laurell, Göran; Teixeira, Marie; Sterkers, Olivier; Bagger‐Sjöbäck, Dan; Eksborg, Staffan; Lidman, Olle; Ferrary, Évelyne

doi:10.1016/s0378-5955(02)00613-5

Cited by 37 publications

(28 citation statements)

References 31 publications

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“…The greatest technical problem associated with local drug administration is the large gradients of drug concentration, with highest levels near the site of application and decreasing levels at more distant sites. These gradients can be predicted by computer simulations (59,62) and have been demonstrated experimentally by ion-electrode measurements (50) and by histological methods (41,63).…”

Section: General Principles Of Drug Distribution In the Inner Earmentioning

confidence: 77%

“…Preclinical animal studies lay the foundation for introducing specific drug delivery protocols into clinical practice. Only a few studies have quantitatively studied drug concentrations in the inner ear fluids (9,34,45,46,63,64,65). However, data from two of these studies show very different perilymph concentrations of a drug after using similar application modes (9,46).…”

Section: Pre-clinical Studies Of Pharmacokinetics In the Inner Earmentioning

confidence: 99%

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Local inner-ear drug delivery and pharmacokinetics

Salt

Plontke

2005

Drug Discovery Today

158

123

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SummaryA number of drugs are in widespread clinical use for the treatment of inner ear disorders by applying them directly to the inner ear. Many new substances and drug delivery systems specific to the inner ear are under development, and in some cases are undergoing evaluations in animal experiments and in clinical studies. The pharmacokinetics of drugs in the inner ear, however, is not well defined and the field is plagued by technical problems in obtaining pure samples of the inner ear fluids for analysis. Nevertheless, a basic understanding of the mechanisms of drug dispersal in the inner ear has emerged that facilitates the design and interpretation of future pharmacokinetic studies.

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Section: General Principles Of Drug Distribution In the Inner Earmentioning

confidence: 77%

Section: Pre-clinical Studies Of Pharmacokinetics In the Inner Earmentioning

confidence: 99%

Local inner-ear drug delivery and pharmacokinetics

Salt

Plontke

2005

Drug Discovery Today

158

123

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“…This approach could help resolve a serious problem that has confounded studies of perilymph kinetics for many years. Even though a number of studies have shown that perilymph sampled from the basal turn of scala tympani is highly contaminated with CSF (Scheibe et al, 1984;Hara et al, 1989;Salt et al, 2003), the lack of an alternative methodology has led many groups to continue using basal turn sampling methods (Parnes et al, 1999;Hoffer et al, 2001;Laurell et al, 2002;Arnold et al, 2005). The published values from these studies are commonly thought to represent the perilymph drug concentration, when the sample may contain a concentration of drug that may be up to an order of magnitude lower than the original perilymph concentration .…”

Section: Discussionmentioning

confidence: 99%

“…Many of the pharmacokinetic studies have used methods 0165 in which a perilymph sample was aspirated from the basal turn of scala tympani (ST) (e.g. Parnes et al, 1999;Hoffer et al, 2001;Laurell et al, 2002;Arnold et al, 2005). Problems with such measurements arise due to the small volume of perilymph in experimental animals.…”

Section: Introductionmentioning

confidence: 99%

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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“…The vulnerability of basal hair cells has been linked to a lower level of antioxidant defenses in the basal hair cells, relative to the apical hair cells (Sha et al, 2001b). Additionally, drug tracer studies have found that drugs delivered to the cochlea through the round window will be present in greater quantities in the base than in the apex (Salt and Ma, 2001;Laurell et al, 2002). Yet in the current study, though mean threshold shifts for each of the three concentrations of PQ were higher in the high frequencies and mean hair cell losses were greater in the basal portion of the cochlea, differences were not statistically significant.…”

Section: Threshold Shift Across Frequenciesmentioning

confidence: 99%

Damage and threshold shift resulting from cochlear exposure to Paraquat-generated superoxide

Bielefeld

Harris

et al. 2005

Hearing Research

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Superoxide has been implicated as a contributing factor to cochlear pathology from a number of sources, including noise and ototoxic drugs. The effects of NADPH oxidase-dependent superoxide on the cochlea were investigated in the current study using paraquat (PQ). PQ is a toxic herbicide that causes tissue damage by generating superoxide through reduction of molecular oxygen in a reaction catalyzed by NADPH oxidase. The current study examined the effects of round window PQ administration on inferior colliculus (IC) evoked potential thresholds (EVP) and hair cell damage. Using implanted IC electrodes, chinchillas were tested for IC EVP thresholds before and after PQ exposure. Ears were exposed to PQ at one of four concentrations: 10, 5, 3 mM, and vehicle control. Thresholds were increased in a dose-dependent manner, and peaked between one and seven days post-exposure. Thresholds then showed a small amount of recovery before reaching PTS by Day 22. Outer and inner hair cell losses were consistent with PTS. The similarities between PQ ototoxicity and noise-induced hearing loss suggest the possibility of similar biochemical pathways involving superoxide.

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Local administration of antioxidants to the inner ear

Cited by 37 publications

References 31 publications

Local inner-ear drug delivery and pharmacokinetics

Local inner-ear drug delivery and pharmacokinetics

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

Damage and threshold shift resulting from cochlear exposure to Paraquat-generated superoxide

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