High variability of perilymphatic entry of neutral molecules through the round window

Objective-To improve the efficacy of intratympanic therapy using perilymphatic entry through the round window membrane. Material and Methods-The perilymphatic entry characteristics of 2 neutral molecules, mannitol (182.2 Da) and inulin (7,000 Da), were studied. A polyethylene catheter was placed in contact with the guinea pig round window membrane and sealed with cyanoacrylate glue. This catheter was linked to an osmotic minipump that delivered 100 mul portions of H-3-mannitol or H-3-inulin solutions over a 7-day period at a constant rate (0.5 mul/h). Perilymph in the scala vestibuli and scala tympani, cerebrospinal fluid (CSF) and plasma were sampled after 4-7 days of delivery. Results-Despite the constant rate of infusion, perilymphatic radioactivity varied widely from one animal to the other, probably as a function of the position of the microcatheter within the round window niche and/or the permeability of the round window. Even a large molecule such as inulin entered the perilymphatic space. Seven days after the beginning of H-3-mannitol administration, the radioactivity was higher in the perilymph of the scala tympani than in that of the scala vestibuli. The perilymphatic radioactivity on Day 7 was approximate to 50% lower than that measured on Day 4 (p = NS). Finally, round window membrane delivery did not preclude distant spread of the molecules into the blood and CSF. Conclusions-Using round window membrane delivery, the perilymphatic entry of mannitol and inulin depended on their molecular weight. Intratympanic delivery induced a high inter-individual heterogeneity of the drug concentration within the inner ear, with subsequent variability of the therapeutic effects.