Dexamethasone levels and base-to-apex concentration gradients in the scala tympani perilymph after intracochlear delivery in the guinea pig.

HYPOTHESIS: To determine whether intracochlearly applied dexamethasone will lead to better control of drug levels, higher peak concentrations, and lower base-to-apex concentration gradients in the scala tympani (ST) of the guinea pig than after intratympanic (round window [RW]) application. BACKGROUND: Local application of drugs to the RW results in substantial variation of intracochlear drug levels and significant base-to-apex concentration gradients in ST. METHODS: Two microliters of dexamethasone-phosphate (10 mg/ml) were injected into ST either through the RW membrane, which was covered with 1% sodium hyaluronate gel or through a cochleostomy with a fluid tight seal of the micropipette. Perilymph was sequentially sampled from the apex at a single time point for each animal, at 20, 80, or 200 min after the injection ended. Results were mathematically interpreted by means of an established computer model and compared with previous experiments performed by our group with the same experimental techniques but using intratympanic applications. RESULTS: Single intracochlear injections of 20 minutes resulted in approximately 10 times higher peak concentrations (on average) than 2 to 3 hours of intratympanic application to the RW niche. Intracochlear drug levels were less variable and could be measured for over 220 minutes. Concentration gradients along the scala tympani were less pronounced. The remaining variability in intracochlear drug levels was attributable to perilymph and drug leak from the injection site. CONCLUSION: With significantly higher, less variable drug levels and smaller base-to-apex concentration gradients, intracochlear applications have advantages to intratympanic injections. For further development of this technique, it is of importance to control leaks of perilymph and drug from the injection site and to evaluate its clinical feasibility and associated risks.

Dexamethasone concentration gradients along scala tympani after application to the round window membrane.

HYPOTHESIS: Local application of dexamethasone-21-dihydrogen-phosphate (Dex-P) to the round window (RW) membrane of guinea pigs produces a substantial basal-apical concentration gradient in scala tympani (ST) perilymph. BACKGROUND: In recent years, intratympanically applied glucocorticoids are increasingly being used for the treatment of inner ear disease. Although measurements of intracochlear concentrations after RW application exist, there is limited information on the distribution of these drugs in the inner ear fluids. It has been predicted from computer simulations that substantial concentration gradients will occur after RW application, with lower concentrations expected in apical turns. Concentration gradients of other substances along the cochlea have recently been confirmed using a sequential apical sampling method to obtain perilymph. METHODS: Dexamethasone-21-dihydrogen-phosphate (10 mg/ml) was administered to the RW membrane of guinea pigs (n = 9) in vivo for 2 to 3 hours. Perilymph was then collected using a protocol in which 10 samples, each of approximately 1 mul, were taken sequentially from the cochlear apex into capillary tubes. Dexamethasone-21-dihydrogen-phosphate concentration of the samples was analyzed by high-performance liquid chromatography. Interpretation of sample data using a finite element model allowed the longitudinal gradients of Dex-P in ST to be quantified. RESULTS: The Dex-P content of the first sample in each experiment (dominated by perilymph from apical regions) was substantially lower than that of the third and fourth sample (dominated by basal turn perilymph). These findings qualitatively demonstrated the existence of a concentration gradient along ST. After detailed analysis of the measured sample concentrations using an established finite element computer model, the mean basal-apical concentration gradient was estimated to be 17,000. Both absolute concentrations of Dex-P in ST and the basal-apical gradients were found to vary substantially. CONCLUSION: The existence of substantial basal-apical concentration gradients of Dex-P in ST perilymph were demonstrated experimentally. If the variability in peak concentration and gradient is also present under clinical conditions, this may contribute to the heterogeneity of outcome that is observed after intratympanic application of glucocorticoids for various inner ear diseases.