Combination therapies using an intratympanic polymer gel delivery system in the guinea pig animal model: A safety study

Int J Pediatr Otorhinolaryngol. 2016 May:84:132-6. doi: 10.1016/j.ijporl.2016.03.002. Epub 2016 Mar 7.

Abstract

Objectives: High dose antivirals have been shown to cause hearing loss when applied via the intratympanic route. The aim of this study was to determine if a combination therapy using dexamethasone (DXA) with either Cidofovir (CDV) or Ganciclovir (GCV), in solution or in PLGA-PEG-PLGA (PPP) hydrogel, is innocuous to the inner ear.

Methods: Cytomegalovirus (CMV)-free guinea pigs were separated into four principal study groups and treated via intratympanic injection (IT) of CDV/DXA solution, CDV/DXA Hydrogel, GCV/DXA solution and GCV/DXA hydrogel. Hearing thresholds were evaluated with pretreatment ABR and post injection weekly ABRs for a total follow up of 28 days. Temporal bone tissue was harvested and stained with Hematoxylin and Eosin for histologic analysis.

Results: ABR analysis revealed that GCV/DXA in solution and in hydrogel led to a mild hearing loss at days 7-21 but returned to baseline by day 28 When administered via PPP hydrogel, CDV/DXA demonstrated mild persistent hearing loss at 32kHz at 28 days. An inflammatory response was identified in the cochlear specimen of the CDV/DXA/PPP hydrogel group, in concert with mild hearing loss, at days 21 and 28.

Conclusion: Results of this study support the safe intratympanic use of higher concentrations of antivirals when combined with DXA, both in solution and when applied via PPP hydrogel.

Keywords: Antiviral; Cidofovir; Dexamethasone; Ganciclovir; Hydrogel; Intratympanic.

Publication types

  • Comparative Study
  • Evaluation Study

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / adverse effects*
  • Cidofovir
  • Cytosine / administration & dosage
  • Cytosine / adverse effects
  • Cytosine / analogs & derivatives*
  • Dexamethasone / administration & dosage
  • Dexamethasone / adverse effects*
  • Drug Combinations
  • Drug Delivery Systems
  • Follow-Up Studies
  • Ganciclovir / administration & dosage
  • Ganciclovir / adverse effects*
  • Glucocorticoids / administration & dosage
  • Glucocorticoids / adverse effects*
  • Guinea Pigs
  • Hearing Loss / chemically induced*
  • Hearing Loss / diagnosis
  • Hydrogels
  • Injection, Intratympanic
  • Organophosphonates / administration & dosage
  • Organophosphonates / adverse effects*
  • Polyesters
  • Polyethylene Glycols
  • Polymers

Substances

  • Antiviral Agents
  • Drug Combinations
  • Glucocorticoids
  • Hydrogels
  • Organophosphonates
  • Polyesters
  • Polymers
  • polyethylene glycol-poly(lactide-co-glycolide)
  • Polyethylene Glycols
  • Dexamethasone
  • Cytosine
  • Cidofovir
  • Ganciclovir