None listed
Conditions
Brief summary
Sensorineural hearing loss following chemotherapy or ear surgery is common and significantly impairs patients’ quality of life. A number of otoprotective agents have shown promise in animal models and the next step is to translate these into clinical use. We have identified two otoprotective agents which act on the adenosine A2a receptor (A2AR) both of which are FDA approved and have established safety profiles. Istradefylline, used in Parkinson’s disease, reduces deafferentation of inner hair cells and improves the survival of afferent synapses after excitotoxic injury. Regadenoson, used as a cardiac stimulant in myocardial perfusion tests, also has strong anti-inflammatory effects in the cochlea. Intratympanic administration of these drugs minimises any potential systemic side effects and provides adequate concentrations in the cochlea, especially the basal cochlea which is more susceptible to injury. Slow release of the drug within the middle ear permits better diffusion across the round window membrane. Poloxamer 407 gel has been used as a slow delivery vehicle both in animal studies and clinically. We plan to suspend the adenosine receptor ligands in this delivery vehicle. We aim to study the pharmacokinetic properties of both of these agents. First, in vitro experiments will measure drug elution from the gel over time to establish peak drug concentrations and duration. Then in patients already having their inner ear opened we will deliver a trans-tympanic injection of these agents and measure both the perilymph and plasma levels at different time points to help establish therapeutic concentrations and safety profiles.
Interventions
This is a phase I/IIA study, examining the pharmacokinetics and safety of intratympanic delivery of adenosine receptor ligands. Two ligands, Regadenoson and Istradefylline, already FDA approved for separate clinical uses, have demonstrated efficacy in animal models in prevention of hearing loss associated with trauma and certain chemotherapeutics. Regadenoson has been approved for use as a pharmacological stress agent for radionuclide myocardial perfusion imaging. Istradefylline is used in Parki
This is a phase I/IIA study, examining the pharmacokinetics and safety of intratympanic delivery of adenosine receptor ligands. Two ligands, Regadenoson and Istradefylline, already FDA approved for separate clinical uses, have demonstrated efficacy in animal models in prevention of hearing loss associated with trauma and certain chemotherapeutics. Regadenoson has been approved for use as a pharmacological stress agent for radionuclide myocardial perfusion imaging. Istradefylline is used in Parkinson’s disease as adjunctive treatment to levodopa/carbidopa The intervention is to place the adenosine ligand within the middle ear at the commencement of a long neurosurgical operation. During the operation for resection of a vestibular schwannoma, the inner ear is opened routinely. We are then able to sample the perilymph, to assess the penetration of the adenosine ligand through the round window into the desired site of action, without added morbidity to the patient. As the patient is under an anaesthetic and is closely monitored we will be able to assess any safety concerns. The dosage will be determined by a clinical pharmacologist based on prior in-vitro as well as animal studies. The adenosine ligand will be prepared for topical application in a polaxomer 407 gel by a pharmacist. The topical application will be transtympanically by an ENT surgeon. There are two adenosine ligands being studied, Istradefyline and Regadenoson. One of these will be randomly assigned to each patient.
Sponsors
Eisdell Moore Centre
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
Patients undergoing elective translabyrithine resection of vestibular schwannoma
Exclusion criteria
i. Unstable cardiac disease (Arrhythmias, recent MI/stent) ii. Renal impairment (Creatinine >100 umol/L)
Outcome results
None listed