Dexamethasone Levels and Base-to-Apex Concentration Gradients in the Scala Tympani Perilymph After Intracochlear Delivery in the Guinea Pig

Abstract

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 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 μL 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 the means of an established computer model and compared with prior experiments performed by our group with the same experimental techniques but using intratympanic applications. Results Single intracochlear injections over 20 min resulted in approximately ten times higher peak concentrations (on average) than 2-3 hours of intratympanic application to the round window niche. Intracochlear drug levels were less variable and could be measured for at least up to 220 min. Concentration gradients along 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.

Oral versus Short-Term Intratympanic Prednisolone Therapy for Idiopathic Sudden Hearing Loss

“…The distinction of the different audiometric curves, rarely employed in the literature [Battaglia et al, 2008;Filipo et al, 2010;Plontke et al, 2009], is particularly useful in the predictive determination of the effectiveness of the steroid therapy. This greater efficacy in down-sloping curves, observed analyzing the hearing outcome according to the two criteria, may be attributed to the higher concentration of the drug in the basal turn of the cochlea [Hahn et al, 2012], whilst it is still unclear as to why up-sloping curves present better results with local therapy compared to systemic therapy.…”

Intracochlear Drug Injections through the Round Window Membrane: Measures to Improve Drug Retention

“…Perilymph drug levels appear to become less variable when drug is delivered for more prolonged periods [Wang et al, 2009]. However, concentration levels in the basal part of scala tympani (ST) typically reach less than 3% of the applied concentration (summarized in [Hahn et al, 2012]). More consistent and efficient delivery would be expected when the solution was directly injected into perilymph.…”

“…More consistent and efficient delivery would be expected when the solution was directly injected into perilymph. With applications by intracochlear injection into the cochlear apex [Salt et al 2006] or by injections through the RW membrane [Salt et al 2007, Hahn et al 2012], concentrations in perilymph were found to be higher, with lower variation and the substances were distributed more uniformly along scala tympani. Effective deliveries of viral vectors have been accomplished with single intracochlear injection procedures [Stover et al 1999; Kawamoto et al, 2001; Staecker et al, 2014].…”

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

“…There have been numerous pharmacokinetic studies of locally-applied corticosteroids in animals (Nomura 1984;Parnes et al 1999;Chandrasekhar et al 2000;Bachmann et al 2001;Hahn et al 2006Hahn et al , 2012Liu et al 2006;Plontke et al 2008b;Yang et al 2008;Wang et al 2009;Borden et al 2011;Salt et al 2011a) and humans (Bird et al 2007;Bird et al 2011), but only a subset of these studies has been analyzed quantitatively to derive an elimination rate. Plontke and analyzed prednisoline data of Bachmann et al (2001) from guinea pigs and found it to be consistent with an elimination half-time from perilymph of 130 min.…”