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Tinnitus and Hyperacusis
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
Although there has been no demonstrable benefit from using systemic glutamate antagonists in the management of tinnitus, interest in this class of drugs continues. Some glutamate antagonists are too toxic to consider for regular systemic usage and consequently there has been interest in the intratympanic administration of these drugs. Recently there have been some encouraging results from preliminary studies investigating the use of esketamine, the S(+) enantiomer of ketamine, for acute ‘inner-ear’ tinnitus.156 This compound acts as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) subgroup of glutamate receptors. At the time of writing, larger-scale multinational trials are being conducted to decide whether the acute administration of this drug will prove to be a viable treatment in the future. Similarly, clinical trials are shortly expected to start for a sustained-release formulation of another NMDA antagonist, gacyclidine.
Neuroprotection and repair after spinal cord injury
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
One phase II study has been performed using the NMDA ionotropic glutamate receptor antagonist gacyclidine.213 A total of 272 patients were randomized to one of four groups (0.005 mg/kg, 0.01 mg/kg, or 0.02 mg/kg gacyclidine or placebo). The doses selected were similar to those used in a safety and efficacy trial in traumatic brain–injured patients.214 Gacyclidine was administered twice, first within 2 hours of injury in over 75% of participants followed by another administration 4 hours later. While at 1 month there was a trend suggesting outcomes were improved in the high-dose gacyclidine group, no significant differences in ASIA or Functional Independence Measure scores were observed at 1 year.188,213
An update: emerging drugs for tinnitus
Published in Expert Opinion on Emerging Drugs, 2018
Christopher R. Cederroth, Jonas Dyhrfjeld-Johnsen, Berthold Langguth
The use of NMDA receptor antagonists has been investigated in depth by the group of Jean-Luc Puel. They demonstrated a role of cochlear NMDAreceptors in the development of salicylate-induced tinnitus by means of pharmacology, behavioral assays and electrophysiologic approaches in rats [52,53]. NMDA receptors, which are glutamate receptors expressed in the inner hair cell – afferent synapse [53], had long escaped attention because of the lack of apparent role during normal hearing [54]. However, a contribution for NMDA receptors in cochlear excitotoxicity became apparent through a large number of studies where its role in triggering hearing pathophysiologies including tinnitus [52,53,55] and ototoxicity [56–58] was established. In tinnitus models, the first results were obtained using high doses of salicylate, an active metabolite of aspirin, which is known to cause tinnitus in patients as well. Using an active avoidance paradigm, it was shown that tinnitus associated symptoms could be prevented by the local delivery (through the round window of the cochlea) of the NMDA receptor antagonists MK-801 or 7-chlorokynurenate [52]. A follow-up study suggested that a potential underlying mechanism involved was the enhancement of the arachidonic acid cycle by salicylate, which subsequently facilitates NMDA-receptor activation by glutamate [53]. Several animal studies demonstrated a reduction of salicylate-induced tinnitus by the NMDA receptor antagonist memantine [59–61]. Guitton and Dudai could also demonstrate that NMDA receptor blockade was also effective for noise-induced tinnitus in rats but being restricted to the first 4 days after tinnitus induction [55]. In line with these findings, it was recently demonstrated that noise-induced hyperactivity in the dorsal cochlear nucleus could be prevented by pre-treatment with MK801 [62]. These findings formed the basis for the clinical development of NMDA receptor antagonists OTO-313 (Gacyclidine) by Otonomy and the more advanced Keyzilen (AM-101, Esketamine Hydrochloride) by Auris Medical. In a case series, six patients with unilateral deafness and tinnitus received gacyclidine administration near the round window niche, resulting in tinnitus relief in four of them [63]. This finding is important as – in contrast to most animal experiments, where NMDA antagonists were administered before, together or shortly after tinnitus induction – gacyclidine showed effects also in patients with chronic tinnitus.