title: Combination therapies using an intratympanic polymer gel delivery system in the guinea pig animal model: A safety study.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Pediatric Otolaryngology, Head and Neck Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: dsidell@stanford.edu.
authors.forename: Douglas
authors.initials: D
authors.lastname: Sidell
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Jonette A
authors.initials: JA
authors.lastname: Ward
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Angad
authors.initials: A
authors.lastname: Pordal
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Carson
authors.initials: C
authors.lastname: Quimby
authors.affiliation: Division of Pediatric Otolaryngology, Head and Neck Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Nassar
authors.affiliation: Division of Pediatric Otolaryngology, Head and Neck Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Otolaryngology, Head and Neck Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Ear and Hearing Center, Cincinnati Children's Medical Center, Cincinnati, OH, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Choo
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects*; D004338:Drug Combinations; D016503:Drug Delivery Systems; D005500:Follow-Up Studies; D015774:Ganciclovir / Q000008:administration & dosage / Q000009:adverse effects*; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D006168:Guinea Pigs; D034381:Hearing Loss / Q000139:chemically induced* / Q000175:diagnosis; D020100:Hydrogels; D000069555:Injection, Intratympanic; D063065:Organophosphonates / Q000008:administration & dosage / Q000009:adverse effects*; D011091:Polyesters; D011092:Polyethylene Glycols; D011108:Polymers
chemical_list: D000998:Antiviral Agents; D004338:Drug Combinations; D005938:Glucocorticoids; D020100:Hydrogels; D063065:Organophosphonates; D011091:Polyesters; D011108:Polymers; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D011092:Polyethylene Glycols; D003907:Dexamethasone; D003596:Cytosine; D000077404:Cidofovir; D015774:Ganciclovir
keywords: Antiviral; Cidofovir; Dexamethasone; Ganciclovir; Hydrogel; Intratympanic