Based on recent studies in the authors' laboratory on the correlation of cytokines and inflammation in otitis media (OM), the authors hypothesized that in chronic otitis media with effusion (COME) interleukin-8 (IL-8) is responsible for 1. the accumulation of leukocytes in the middle ear cleft and 2. in situ leukocyte activation with subsequent tissue damage. Additionally, the authors hypothesized that IL-8 expression is at least in part under the control of interleukin-1 (IL-1) and tumor necrosis factor (TNF). To begin to test this hypothesis, middle ear effusions (MEE) obtained from children ages 2 to 90 months (mean age, 29 months) undergoing tympanostomy tube placement for the presence of these inflammatory cytokines were analyzed. For these studies, IL-8, interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and tumor necrosis factor-beta (TNF-beta) were measured in MEE by radioimmunoassay (RIA) or enzyme-linked immunoassay (ELISA). IL-8, IL-1 beta, TNF-alpha, and TNF-beta were present in 92%, 67%, 77%, and 0% of effusions, respectively. The mean (+/- SEM) values for IL-8, IL-1 beta, and TNF-alpha were 4805 (+/- 913) pg/mg, 4076 (+/- 1510) pg/mg, and 163 (+/- 90) pg/mg. Further analysis indicated that levels of IL-8 correlated with IL-1 beta (R2 = .500, P = .000) and TNF-alpha (R2 = .387, P = .023). Thus the authors' studies clearly demonstrate that IL-8 is consistently present in the MEE of children with COME and is strongly correlated with levels of IL-1 beta and TNF-alpha, both known inducers of IL-8 production. These results support the authors' hypothesis that IL-1 beta, TNF-alpha, and IL-8 are intimately involved in the inflammatory cascade in the middle ear and suggest regulation of these cytokines as possible sites of future therapeutic intervention in otitis media with effusion (OME).

OTO-104 was safe and well tolerated. Although the sample size was small, the data suggest 12 mg of OTO-104 was associated with a clinically meaningful reduction in vertigo frequency compared to placebo 3 months after treatment.

No abstract

Inhibition of cochlear N-methyl-D-aspartate (NMDA) receptors with AM-101, a small molecule antagonist delivered by intratympanic injection, represents a novel approach to treat acute tinnitus triggered by glutamate excitotoxicity. An earlier double-blind, randomized, placebo-controlled phase II clinical trial (TACTT0) had demonstrated a significant and dose-dependent improvement in tinnitus triggered by acute acoustic trauma or otitis media from baseline to day 90. A second phase II trial (TACTT1) now sought to evaluate the most appropriate dose regimen for this treatment. Outcomes from the TACTT1 trial showed no significant difference in tinnitus improvement between a single-dose treatment and a dose regimen comprising three doses over 2 weeks. Taken together, three injections over 3 consecutive days showed the best results in the two phase II trials, suggesting that repeated and concentrated inhibition of cochlear NMDA receptors provides best treatment effects, while keeping the procedural impact on patients short.

Objective: To evaluate the safety and exploratory efficacy of intratympanic administration of OTO-313 in patients with tinnitus. Study Design: Single intratympanic injection of OTO-313 evaluated in a randomized, double-blind, placebo-controlled Phase 1/2 clinical study. Setting: Tertiary referral centers. Patients: Patients with unilateral tinnitus (moderate-severe) with tinnitus duration 1 to 6 months. Interventions: Intratympanic OTO-313. Main Outcome Measures: Safety and change from baseline in tinnitus functional index (TFI), daily ratings of tinnitus loudness and annoyance, and patient global impression of change (PGIC). Results: OTO-313 was well-tolerated with lower incidence of adverse events than placebo. Mean TFI reduction from baseline favored OTO-313 at Week 2, 4, and 8. A clinically meaningful, 13-point improvement on the TFI was observed in 43% (6/14) of OTO-313 patients at both Weeks 4 and 8 versus 13% (2/16) of placebo patients (ad hoc responder analysis, p-value < 0.05). Reductions in daily ratings of tinnitus loudness and annoyance favored OTO-313 compared with placebo. In OTO-313 responders, a strong correlation existed between change from baseline in TFI score and changes in tinnitus loudness, tinnitus annoyance, and PGIC. Conclusions: OTO-313 was well-tolerated and demonstrated a higher proportion of responders than placebo across consecutive visits (Weeks 4 and 8) supporting further clinical development of OTO-313 for the treatment of tinnitus.