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The safety and efficacy of intratympanic (IT) histamine (HIS) injection as an adjuvant to increase the inner ear penetration of dexamethasone (DEX) was investigated in this study. IT injections of DEX-only, 1% HIS+DEX and 4% HIS+DEX were performed in mice with noise-induced hearing loss. An inflammatory reaction in the middle ear was observed only in the 4% HIS+DEX group although no serious cytotoxic effects on the organ of Corti (OC) were observed at that concentration. Compared with the DEX-only group, the perilymphatic concentration of DEX was approximately two times higher in the 1% HIS+DEX group and approximately five times higher in the 4% HIS+DEX group. The expression of the DEX receptor in the cochlea was significantly increased in the 4%-HIS+DEX group. HIS appeared to induce transient damage the microstructure of the RWM with recovery observed within 3 weeks. The 1 and 4% HIS + DEX groups showed a significant recovery of the OC compared with the control group and they also achieved significantly better hearing restoration at 8 kHz in the DPOAE hearing test (P < .05) when compared to the DEX-only group. IT HIS temporarily disrupts the structure of the RWM and middle ear mucosa and significantly enhances the inner ear penetration of DEX. Therefore, IT HIS injection could be a simple and effective adjuvant therapy to increase perilymph concentration of DEX and achieve OC recovery after cochlear damage., (Copyright © 2022. Published by Elsevier B.V.)

Objective: The purpose of this study was to investigate the effectiveness of intratympanic dexamethasone injection (ITDI) in acute tinnitus of presumed cochlear origin., Study Design: A prospective, randomized, placebo-controlled, double-blinded, multicenter study., Methods: Between August 2013 and December 2015, 54 patients with unilateral tinnitus were enrolled at four different centers. Patients were assigned either to an ITDI (n = 27) or an intratympanic normal saline injection (ITNI; n = 27) group through block randomization. Intratympanic injections were administered four times over 2 weeks. At 4 weeks after initial injection, we analyzed the improvement rates of tinnitus using the tinnitus handicap Inventory (THI) and visual analogue scale (VAS) for loudness, awareness, and annoyance. We defined improvement as the reduction of more than 7 points or of more than 20% in the final THI score compared to the initial THI score., Results: The initial mean hearing thresholds and VAS and THI scores of the two groups did not differ significantly. At 4 weeks after initial injection, the mean VAS and THI scores of both groups had significantly reduced. However, the improvement rate did not differ significantly between the groups (ITDI, 51.9%; ITNI, 59.3%)., Conclusion: The results indicate that ITDI might not be more effective than ITNI for the treatment of acute unilateral tinnitus. Therefore, ITDI should not be considered as the main treatment for patients presenting with acute tinnitus as the primary symptom., Level of Evidence: 1b. Laryngoscope, 128:184-188, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Dexamethasone (Dex)-loaded PHEA-g-C18-Arg8 (PCA) nanoparticles (PCA/Dex) were developed for the delivery of genes to determine the synergistic effect of Dex on gene expression. The cationic PCA nanoparticles were self-assembled to create cationic micelles containing an octadecylamine (C18) core with Dex and an arginine 8 (Arg8) peptide shell for electrostatic complexation with nucleic acids (connexin 26 [ Cx26 ] siRNA, green fluorescent protein [GFP] DNA or brain-derived neurotrophic factor [BDNF] pDNA). The PCA/Dex nanoparticles conjugated with Arg8, a cell-penetrating peptide that enhances permeability through a round window membrane in the inner ear for gene delivery, exhibited high uptake efficiency in HEI-OC1 cells. This potential carrier co-delivering Dex and the gene into inner ear cells has a diameter of 120-140 nm and a zeta potential of 20-25 mV. Different types of genes were complexed with the Dex-loaded PCA nanoparticle (PCA/Dex/gene) for gene expression to induce additional anti-inflammatory effects. PCA/Dex showed mildly increased expression of GFP and lower mRNA expression of inflammatory cytokines (IL1b, IL12, and INFr) than did Dex-free PCA nanoparticles and Lipofectamine ® reagent in HEI-OC1 cells. In addition, after loading Cx26 siRNA onto the surface of PCA/Dex, Cx26 gene expression was downregulated according to real-time polymerase chain reaction for 24 h, compared with that using Lipofectamine reagent. After loading BDNF DNA into PCA/Dex, increased expression of BDNF was observed for 30 h, and its signaling pathway resulted in an increase in phosphorylation of Akt, observed by Western blotting. Thus, Dex within PCA/Dex/gene nanoparticles created an anti-inflammatory effect and enhanced gene expression., Competing Interests: The authors report no conflicts of interest in this work.

Objective: Dexamethasone is commonly used clinically to treat noise-induced hearing loss (NIHL) because the drug exerts multiple anti-inflammatory effects. In the present study, we investigated the post-noise therapeutic effects of dexamethasone given systemically or via intratympanic injection in the mouse., Animals: Twenty-four C57BL/6J mice were used. Eighteen experimental mice were exposed to 110 dB sound pressure level white noise and then divided into three groups: the noise, intraperitoneal dexamethasone injection (IP), and intratympanic dexamethasone injection (IT) groups., Methods: Dexamethasone (3 mg/kg/d) was injected intraperitoneally for five successive days in the IP group. Intratympanic injections were given on post-noise days 1 and 4 in the IT group. We compared hearing levels, the architecture of the organ of Corti (OC), and the microscopic appearance of the medial olivocochlear efferent terminals (MOC ETs) among the groups., Results: Both the IP and IT groups exhibited hearing recovery as revealed by auditory brainstem responses (ABRs), but recovery was not apparent in distortion product otoacoustic emissions (DPOAEs). OC degeneration as revealed by light microscopy was most extensive in the noise group and least extensive in the IP group. Scanning electron microscopy showed that the OC ultrastructure was better preserved in the IP than the IT group. Confocal microscopy showed that the ETs were shrunken in all noise-exposed groups as compared to the control group, but more shrunken in the dexamethasone-treated groups. Transmission electron microscopy showed that the MOC ET-outer hair cell (OHC) synapses were damaged in all noise-exposed groups, but the extent of degeneration was less in the IT than in the noise group., Conclusion: Dexamethasone exerts reliable therapeutic effects when used to treat NIHL. It seems that the protective effects may differ by the routes of administration as the OCs were better preserved in the IP group and the ET-OHC synapses were more intact in the IT group.

Conclusion: Intratympanic steroid therapy (IT-S) was as effective as systemic steroid therapy (SST) or combined therapy (CT) and could be considered a first-line therapeutic modality for idiopathic sudden sensorineural hearing loss (SSNHL). Due to its known safety and efficacy, IT-S will be particularly suitable for patients with SSNHL who have chronic diseases such as diabetes mellitus, hypertension, or chronic renal failure., Objectives: Systemic high dose steroid therapy is the main therapeutic modality for SSNHL. Comparable therapeutic efficacies for IT-S and CT with SST and IT-S for SSNHL have been reported recently. We compared the efficacy of IT-S, SST, and CT for treating SSNHL., Methods: A retrospective, multicenter study investigating the therapeutic efficacy of SST, IT-S, and CT for SSNHL was designed and involved 735 patients with idiopathic SSNHL who were diagnosed and treated at seven tertiary referral medical centers of the Catholic University of Korea between 2007 and 2011. Patients were divided into three groups according to the treatment methods they received: IT-S group, SST group, and CT group (SS plus IT-S). Hearing was evaluated by pure tone audiogram performed before initial treatment and at 4 weeks following the final treatment. More than a 10 dB HL decrease in average air conduction threshold of hearing at 500, 1000, 2000, and 3000 Hz was defined as improved hearing., Results: Among 735 patients with SSNHL, 94 were included in the IT-S group, 444 in the SST, and 197 in the CT group. Age, gender, interval from disease onset to start of treatment, and initial hearing level were not different among the three groups. Patients who had concomitant medical disorders such as diabetes mellitus, hypertension, or chronic renal failure were more frequently treated with IT-S. No difference in the level of hearing gain or ratio of hearing improvement was observed among the three groups (p = 0.147 and p = 0.067, respectively).

The prevention of mucosal changes induced by experimental pneumococcal otitis media by means of antibiotics has been demonstrated previously. However, the effect of combined antibiotic and steroid therapy on the middle ear mucosa in acute otitis media (AOM) has not been determined. The right middle ears of 27 rats were inoculated with a log-phase type 3 Streptococcus pneumoniae, with the left ears serving as controls. Penicillin G was administered to nine rats and penicillin G and dexamethasone in combination were administered to nine rats after bacterial challenge; the remaining nine rats were not treated. Three animals from each group were sacrificed on Days 4, 7 and 14 after challenge. Tympanic membranes and middle ear mucosa were examined using otomicroscopy and light microscopy. Structural changes were diminished in both the antibiotic-treated and antibiotic + steroid-treated groups, compared with those in the untreated infected controls. The antibiotic + steroid-treated group showed the most marked decrease in structural change, especially in the mucosal metaplasia to the secretory epithelium. The results suggest that combination therapy with antibiotics and steroid in AOM is the most effective at reducing the treatment period and preventing persistent mucosal changes, which may decrease the risk of development of secretory otitis media as a sequela of AOM.