dosed in the range of 8-30 mg/kg. Our current efforts are now focused on translating these pre-clinical findings into a therapeutic for the prevention and treatment of noise induced hearing loss in humans. We have completed a phase I study of SPI-1005 capsules in 32 normal healthy volunteers to determi- ne the safety, toxicity, ADME, and Pk. Dose escalation was performed in 4 groups ranging from 200 to 1600 mg po. Subjects were followed in house for a period of 72 hours. Multiple EKGs, orthostatic vitals, Chem20, and CBCs were taken during the period of clinical observation. No significant adverse events were noted in 24 drug treated and 8 placebo treated individuals. Pk analysis of ebselen and its metaboli- tes was performed using WinNonlin®5.1 from plasma and urine samples analyzed by LC-MS/MS. These results closely matched the Pk analysis of total selenium in plasma samples by ICP-MS from the same treated individuals. The plasma Pk of ebselen in these human subjects was similar to that in nonhuman primates dosed with SPI-1005 at comparable levels (10mg/kg). Phase II safety and efficacy trials will be performed in military populations exposed to noise during weapons training. Historically, a Significant Threshold Shift (STS) occurs even with the use of hearing protective devices. The Clinical trial design for these phase II studies will be discussed along with primary and secondary endpoints using STS and the Tinnitus Handicap Inventory.
Effects of Gacyclidine Extracochlear Perfusion on Tinnitus in Humans and Intracochlear Perfusion on ABR Thresholds in Guinea Pigs. (Abstract of ARO Meeting Denver, Colorado) Gentiana I Wenzel1, Hubert H Lim1, Timo Stöver1, Thomas Lobl2, John Schloss2, Burkard Schwab1, Thomas Lenarz1 1Medizinische Hochschule Hannover, 2NeuroSystec
Gacyclidine is a highly specific NMDA receptor antagonist with neuroprotective properties. In guinea pigs, administration of gacyclidine (adsorbed to Gelfoam) into the round window niche or as a bolus injection into the cochlea suppressed salicylate-induced tinnitus. Thus, we investigated in humans and animals if gacyclidine could provide a safe and effective treatment for tinnitus. We administered gacyclidine as a compassionate treatment in unilateral deaf patients with tinnitus. These patients experienced temporary relief from tinnitus after constant perfusion of gacyclidine into the round window niche for 40-60 hours. This demonstrated that gacyclidine has the potential to suppress tinnitus. However, controlled and long-term delivery of the drug will be necessary for effective treatment. Since the main candidates for this therapy will be hearing patients, we needed to assess whether chronic administration of this drug would compromise hearing performance. Thus, we measured the effects of chronic intracochlear gacyclidine perfusion on frequency-specific ABR thresholds in guinea pigs. Guinea pigs were implanted with osmotic pumps that delivered 0.5 μL/h of 0.3 mM gacyclidine for 9 days via a catheter inserted through the round window membrane. The concentration and rate of drug deli- very were selected to provide a dose that was substantially higher than is expected for tinnitus control in humans. Frequency-specific ABRs (1- 40 kHz, 10-80 dB SPL in 10dB steps) were recorded before implantation and compared with those obtained after drug administration. No significant changes in ABR thresholds were observed suggesting that prolonged administration of gacyclidine for tinnitus treatment should be safe in terms of hearing preservation. Further studies investigating the toxicological effects of different dosages and durations are under way to ensure the safety of the drug for long-term human use and to warrant clinical trials.
Intratympanic dexamethasone for sudden sensorineural hearing loss after failure of systemic therapy. Laryngoscope. 2007 Jan;117(1):3-15. Review. Haynes DS, O‘Malley M, Cohen S, Watford K, Labadie RF
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