title: High variability of perilymphatic entry of neutral molecules through the round window.
abstract: OBJECTIVE
  To improve the efficacy of intratympanic therapy using perilymphatic entry through the round window membrane.
  
  
  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 microl portions of 3H-mannitol or 3H-inulin solutions over a 7-day period at a constant rate (0.5 microl/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 3H-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 approximately 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.
authors.affiliation: INSERM EMI-U 0112, Faculté Xavier Bichat, Paris, France.
authors.forename: Larbi
authors.initials: L
authors.lastname: Chelikh
authors.forename: Marie
authors.initials: M
authors.lastname: Teixeira
authors.forename: Christian
authors.initials: C
authors.lastname: Martin
authors.forename: Olivier
authors.initials: O
authors.lastname: Sterkers
authors.forename: Evelyne
authors.initials: E
authors.lastname: Ferrary
authors.forename: Vincent
authors.initials: V
authors.lastname: Couloigner
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001682:Biological Availability; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006168:Guinea Pigs; D007444:Inulin / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008353:Mannitol / Q000493:pharmacokinetics / Q000494:pharmacology*; D010498:Perilymph / Q000187:drug effects* / Q000378:metabolism; D011336:Probability; D011868:Radioisotopes; D012405:Round Window, Ear / Q000187:drug effects*; D012680:Sensitivity and Specificity
chemical_list: D011868:Radioisotopes; D008353:Mannitol; D007444:Inulin