Corticosteroid Pharmacokinetics in the Inner Ear Fluids: An Animal Study Followed by Clinical Application

Parnes, Lorne S.; Sun, Aihua; Freeman, David J.

doi:10.1097/00005537-199907001-00001

Cited by 566 publications

(604 citation statements)

References 45 publications

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“…Systemic corticosteroids, for example, are used in the otologic management of idiopathic sudden and immune-mediated sensorineural hearing losses (e.g., [51][52][53]). Their clinical usefulness, however, is limited by undesirable side effects arising from the high systemic doses required to achieve sufficient cochlear fluid levels of drug to produce the intended inner ear effects [54]. Middle ear application has advantages over systemic drug delivery, in that drugs so applied can reach their desired targets at higher concentrations and with fewer unwanted systemic side effects.…”

Section: Comparison To Other Delivery Methodsmentioning

confidence: 99%

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

Chen

Kujawa

McKenna

et al. 2005

Journal of Controlled Release

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Rapid progress in understanding the molecular mechanisms associated with cochlear and auditory nerve degenerative processes offers hope for the development of gene-transfer and molecular approaches to treat these diseases in patients. For therapies based on these discoveries to become clinically useful, it will be necessary to develop safe and reliable mechanisms for the delivery of drugs into the inner ear, bypassing the blood-labyrinthine barrier. Toward the goal of developing an inner ear perfusion device for human use, a reciprocating microfluidic system that allows perfusion of drugs into the cochlear perilymph through a single inlet hole in scala tympani of the basal turn was developed. The performance of a prototype, extracorporeal reciprocating perfusion system in guinea pigs is described. Analysis of the cochlear distribution of compounds after perfusion took advantage of the place-dependent generation of responses to tones along the length of the cochlea. Perfusion with a control artificial perilymph solution had no effect. Two drugs with wellcharacterized effects on cochlear physiology, salicylate (5 mM) and DNQX (6,7-Dinitroquinoxaline-2,3-dione; 100 and 300 μM), reversibly altered responses. The magnitude of drug effect decreased with distance from the perfusion pipette for up to 10 mm, and increased with dose and length of application.

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Section: Comparison To Other Delivery Methodsmentioning

confidence: 99%

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

Chen

Kujawa

McKenna

et al. 2005

Journal of Controlled Release

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“…Substances have been shown to enter scala tympani and from there are distributed in the inner ear (Goycoolea, 2001). Recent pharmacokinetic studies have shown that substances applied locally to the RWM produce significantly higher drug levels in the inner ear fluids compared to systemic applications (Bachmann et al, 2001;Chen et al, 2003a;Parnes et al, 1999). Thus, applying drugs locally may avoid potential systemic complications and side effects.…”

Section: Introductionmentioning

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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“…Parnes et al [20] in a well-designed animal study, compared the concentration of hydrocortisone, methylprednisolone, and dexamethasone in cochlea fluids after intravenous and topical administration. Intratympanic administration resulted in higher endolymph and perilymph levels.…”

Section: Discussionmentioning

confidence: 99%

Recovery of Hearing in Cisplatin-Induced Ototoxicity in the Guinea Pig with Intratympanic Dexamethasone

Çallı¹,

Pınar²,

Öncel³

et al. 2011

Indian J Otolaryngol Head Neck Surg

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The purpose of this study was to investigate the effectiveness of intratympanic dexamethasone injection as a therapeutic agent against cisplatin-induced ototoxicity. Animals were randomly divided into three groups. Group one received intraperitoneal cisplatin alone, group two, received intratympanic dexamethasone after cisplatin ototoxicity had been demonstrated. Group three, which is control group, received intratympanic dexamethasone.Then we made three measurements. First we measured the baseline distortion product otoacustic emission (DPOAEs) of all the guine pigs. Second we injected cisplatin intraperitoneal group one and two the same day. Third we measured DPOAEs after 72 h of group one and two. Moreover DPOAEs were measured at the end of the first and second week only in group two. Cochleae were harvested and processed for electron microscopy after then. Values of The DPOAEs amplitudes and signal-to-noise ratio (SNR) at 1-6 kHz frequencies for group 1 after the injections significantly decreased over those before injections (P \ 0.05). In group 3, there were no significant differences in DPOAE amplitude and SNR values When they are compare before and after their intratympanic dexamethasone injections (P [ 0.05). In group 2, the DPOAEs measurements were close to significance at the end of the second week (P = 0.056). Intratympanic dexamethasone injection did not cause any ototoxic effect. Although intratympanic dexamethasone did not reach the statistically significant results, the measurements were close to significance. Intratympanic dexamethasone might have a significant therapeutic effect after cisplatin ototoxicity with different dose and application regimens.

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Corticosteroid Pharmacokinetics in the Inner Ear Fluids: An Animal Study Followed by Clinical Application

Cited by 566 publications

References 45 publications

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig

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

Recovery of Hearing in Cisplatin-Induced Ototoxicity in the Guinea Pig with Intratympanic Dexamethasone

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