Complications and prognosis associated with intra-tympanic steroid injection to treat sudden sensorineural hearing impairment.

PURPOSE: The purpose of this study was to measure the incidence of complications in sudden sensorineural hearing loss (SSNHL) patients treated with intra-tympanic steroid injection (ITSI) and compare hearing recovery rates. MATERIALS AND METHODS: 123 patients with unilateral SSNHL receiving ITSIs were included in this study. Post-ITSI complications were documented including otalgia, dysgeusia, vertigo (duration>1 h), and persistent eardrum perforation. The pain intensity was evaluated with visual analog scale (VAS). Hearing was measured before ITSI and at 1 month after the final ITSI. We compared our patients' hearing threshold between presence and absence of different complications. RESULTS: 47.2% patients experienced post-injection otalgia with the average VAS score 3.2 (range 2-6). Five (4.1%) and six (4.9%) patients exhibited vertigo and persistent eardrum perforations, respectively. The patients were divided into three groups based on the absence of complications and the presence of vertigo and eardrum perforation. The hearing threshold improvements did not differ significantly among the three groups (p = 0.366). Although the difference was not significant (p = 0.664), the proportion of patients experiencing post-ITSI vertigo who were on contemporaneous oral steroids was lower than the proportion of non-vertigo patients on such steroids. CONCLUSION: The incidences of otalgia, vertigo, and persistent eardrum perforation in SSNHL patients treated with ITSI were 47.2%, 4.1% and 4.9%, respectively. We found no association between concurrent oral steroid use and the incidence of post-ITSI eardrum perforation or vertigo. Although statistical significance was lacking, patients who did not take contemporaneous oral steroids may have a higher rate of prolonged post-ITSI vertigo.

Production and Characterization of Chitooligosaccharides: Evaluation of Acute Toxicity, Healing, and Anti-Inflammatory Actions.

The search for promising biomolecules such as chitooligosaccharides (COS) has increased due to the need for healing products that act efficiently, avoiding complications resulting from exacerbated inflammation. Therefore, this study aimed to produce COS in two stages of hydrolysis using chitosanases derived from Bacillus toyonensis. Additionally, this study aimed to structurally characterize the COS via mass spectrometry, to analyze their biocompatibility in acute toxicity models in vivo, to evaluate their healing action in a cell migration model in vitro, to analyze the anti-inflammatory activity in in vivo models of xylol-induced ear edema and zymosan-induced air pouch, and to assess the wound repair action in vivo. The structural characterization process pointed out the presence of hexamers. The in vitro and in vivo biocompatibility of COS was reaffirmed. The COS stimulated the fibroblast migration. In the in vivo inflammatory assays, COS showed an antiedematogenic response and significant reductions in leukocyte migration, cytokine release, and protein exudate. The COS healing effect in vivo was confirmed by the significant wound reduction after seven days of the experiment. These results indicated that the presence of hexamers influences the COS biological properties, which have potential uses in the pharmaceutical field due to their healing and anti-inflammatory action.

Design, Synthesis and Evaluation of 3-Substituted Coumarin Derivatives as Anti-inflammatory Agents.

Coumarin moiety has garnered momentous attention especially in the design of compounds with significant biological activities. In this work, a series of 3-substituted coumarin derivatives 6a-6l were synthesized and fully characterized. Most of the compounds could obviously inhibit the activity of cyclooxygenase-1 (COX-1) at the concentration of 10 µM. Besides, 6h and 6l exhibited highest inhibitory effects against COX-2 with inhibition rates of 33.48 and 35.71%, respectively. Detailed structure-activity relationships (SARs) were also discussed. In vivo studies, 6b, 6i and 6l could remarkably repress the xylene-induced ear swelling in mice at the dose of 20 mg/kg. Especially, 6l seemed to be the most effective compound at the dose of 10 mg/kg, displaying favorable anti-inflammatory activity comparable to indomethacin. All of these findings suggested that 6l might be utilized as a candidate for the treatment of inflammatory diseases.

Effect of Terpenoids and Flavonoids Isolated from Baccharis conferta Kunth on TPA-Induced Ear Edema in Mice.

In this study, we isolated from the aerial parts of Baccharis conferta Kunth (i) a new neoclerodane, denominated "bacchofertone"; (ii) four known terpenes: schensianol A, bacchofertin, kingidiol and oleanolic acid; and (iii) two flavonoids: cirsimaritin and hispidulin. All structures were identified by an exhaustive analysis of nuclear magnetic resonance (NMR) and mass spectroscopy (MS). Extracts from aerial parts were screened for anti-inflammatory activity in the mice ear edema model of 12-O-tetradecanoylforbol-13-acetate mice. Dichloromethane extract (BcD) exhibited 78.5 ± 0.72% inhibition of edema, followed by the BcD2 and BcD3 fractions of 71.4% and 82.9% respectively, at a dose of 1 mg/ear. Kingidiol and cirsimaritin were the most potent compounds identified, with a median effective dose of 0.12 and 0.16 mg/ear, respectively. A histological analysis showed that the topical application of TPA promoted intense cell infiltration, and this inflammatory parameter was reduced with the topical application of isolated compounds.

Anti-Inflammatory Effects of Cold Thermal Therapy on Allergic Skin Inflammation Induced by Trimellitic Anhydride in BALB/c Mice.

Cold and hot thermal therapies are widely used as a traditional therapy in many cultures and are often prescribed in the treatment of various musculoskeletal and neurological conditions which present themselves to primary care physicians. However, there are no reports that investigated either the effects of cold and hot thermal therapies on the skin inflammation of trimellitic anhydride- (TMA-) induced dermatitis-like contact hypersensitivity (CHS) mouse model, or the mechanism of thermal therapy on allergic skin inflammation. Therefore, in this study, to reveal the anti-inflammatory effect of thermal therapy and its mechanism on TMA-induced CHS, we analyzed ear-swelling response (ear edema), vascular permeability, serum IgE levels, histological examination, and histamine and Th2 cytokine levels. Cold thermal therapy reduced the ear-swelling response, the vascular permeability, the serum IgE levels, and the infiltration of eosinophils and mast cells as well as the mast cell degranulation. To determine the mechanism by which cold thermal therapy inhibits allergic skin inflammation, detailed studies were carried out revealing that cold thermal therapy suppressed IL-4 and IL-5 secretion and mast cell activation. These results indicated that cold thermal therapy cures skin inflammation of TMA-induced CHS by decreasing Th2 cytokine release, especially IL-4 and IL-5, and mast cell activation. These data suggest that new insight into the mechanism of robust therapeutic effects of cold thermal therapy against allergic dermatitis, and cold thermal therapy may prove to be a useful therapeutic modality on allergic inflammatory diseases as traditional use as well as Th2- or mast cell-mediated allergic responses.

Computational and Biological Comparisons of Plant Steroids as Modulators of Inflammation through Interacting with Glucocorticoid Receptor.

Despite the usefulness of glucocorticoids, they may cause hazardous side effects that limit their use. Searching for compounds that are as equally efficient as glucocorticoids, but with less side effects, the current study compared plant steroids, namely, glycyrrhetinic acid, guggulsterone, boswellic acid, withaferin A, and diosgenin with the classical glucocorticoid, fluticasone. This was approached both in silico using molecular docking against glucocorticoid receptor (GR) and in vivo in two different animal models. All tested compounds interacted with GR, but only boswellic acid and withaferin A showed docking results comparable to fluticasone, as well as similar in vivo anti-inflammatory effects, by significantly decreasing serum levels of interleukin-6 and tumor necrosis factor-α in cotton pellet-induced granuloma in rats. In addition, both compounds significantly decreased the percent of change in ear weight in croton oil-induced ear edema in mice and the granuloma weight in cotton pellet-induced granuloma in rats, to levels comparable to that of fluticasone. Both boswellic acid and withaferin A had no effect on adrenal index, but only withaferin A significantly increased the thymus index. In conclusion, boswellic acid may have comparable anti-inflammatory effects to fluticasone with fewer side effects.

Protective roles of fenofibrate against cisplatin-induced ototoxicity by the rescue of peroxisomal and mitochondrial dysfunction.

Cisplatin is an alkylating agent that interferes with DNA replication and kills proliferating carcinogenic cells. Several studies have been conducted to attenuate the side effects of cisplatin; one such side effect in cancer patients undergoing cisplatin chemotherapy is ototoxicity. However, owing to a lack of understanding of the precise mechanism underlying cisplatin-induced side effects, management of cisplatin-induced ototoxicity remains unsolved. We investigated the protective effects of fenofibrate, a PPAR-α activator, on cisplatin-induced ototoxicity. Fenofibrate prevented cisplatin-induced loss of hair cells and improved cell viability; moreover, fenofibrate significantly attenuated the threshold of auditory brainstem responses (ABR) in cisplatin-injected mice. Fenofibrate significantly increased PPAR-α, PPAR-γ, and PGC-1α expression, which consequently resulted in increased number and functional enzyme levels of peroxisomes and mitochondria, and markedly decreased phospho-p53 (S15), activated caspase-3, cleaved-PARP, and NF-κB p65 nuclear translocation, which reduced NADPH oxidase isoform (NOX3 and NOX4) expression, thereby decreasing reactive oxygen species (ROS) production in cisplatin-treated tissues ex vivo. Taken together, these results indicate that fenofibrate rescues cisplatin-induced ototoxicity by maintaining peroxisome and mitochondria number and function, reducing inflammation, and decreasing ROS levels. Our findings suggest that fenofibrate administration might serve as an effective therapeutic agent against cisplatin-induced ototoxicity.

Evaluation of Biological Activity and Computer-Aided Design of New Soft Glucocorticoids.

Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17ß-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC50 values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity.

Self-Nanoemulsifying Drug Delivery Systems Containing Plantago lanceolata-An Assessment of Their Antioxidant and Antiinflammatory Effects.

The most important components of Plantago lanceolata L. leaves are catalpol, aucubin, and acteoside (=verbascoside). These bioactive compounds possess different pharmacological effects: anti-inflammatory, antioxidant, antineoplastic, and hepatoprotective. The aim of this study was to protect Plantago lanceolata extract from hydrolysis and to improve its antioxidant effect using self-nano-emulsifying drug delivery systems (SNEDDS). Eight SNEDDS compositions were prepared, and their physical properties, in vitro cytotoxicity, and in vivo AST/ALT values were investigated. MTT cell viability assay was performed on Caco-2 cells. The well-diluted samples (200 to 1000-fold dilutions) proved to be non-cytotoxic. The acute administration of PL-SNEDDS compositions resulted in minor changes in hepatic markers (AST, ALT), except for compositions 4 and 8 due to their high Transcutol contents (80%). The non-toxic compositions showed a significant increase in free radical scavenger activity measured by the DPPH test compared to the blank SNEDDS. An indirect dissolution test was performed, based on the result of the DPPH antioxidant assay; the dissolution profiles of Plantago lancolata extract were statistically different from each SNEDDS. The anti-inflammatory effect of PL-SNEDDS compositions was confirmed by the ear inflammation test. For the complete examination period, all compositions decreased ear edema as compared to the positive (untreated) control. It can be concluded that PL-SNEDDS compositions could be used to deliver active natural compounds in a stable, efficient, and safe manner.

Nodules behind the ears: IgG4-related skin disease.

A 53-year-old healthy factory worker consulted our hospital complaining of small nodules of similar size, shape and location on both ears. The nodules revealed focal and massive infiltration of lymphocytes, plasma cells and eosinophils with fibrosis. They had no specific structure on pathological staining with haematoxylin and eosin. Immunostaining for IgG4 revealed that a large majority of the IgG+ cells were positive for IgG4. The ratio of IgG4+ to IgG+ plasma cells was approximately 40%. IgG4+ plasma cells were present at approximately 250 per high-power field. The patient was diagnosed with IgG4-related skin disease without multiple organ involvement in the systemic syndrome of IgG4-related diseases. Because the patient was a factory worker and exposed to an environment of metallic dust, a skin patch test that included a metal series was performed. Zinc and manganese produced positive reactions. Because only skin lesions were observed in this case, not multiple organ involvement, tissue infiltration by IgG4+ plasma cells might have resulted from continuous sensitization to zinc and/or manganese.

A systematic review and meta-analysis of the efficacy and safety of N-acetylcysteine in preventing aminoglycoside-induced ototoxicity: implications for the treatment of multidrug-resistant TB.

BACKGROUND: Ototoxicity is a severe side effect of aminoglycoside antibiotics. Aminoglycosides are recommended for the treatment of multidrug-resistant TB (MDR-TB). N-Acetylcysteine (NAC) appears to protect against drug- and noise-induced hearing loss. This review aimed to determine if coadministering NAC with aminoglycoside affected ototoxicity development, and to assess the safety and tolerability of prolonged NAC administration. METHODS: Eligible studies reported on the efficacy of concomitant NAC and aminoglycoside administration for ototoxicity prevention or long-term (≥ 6 weeks) administration of NAC regardless of indication. Pooled estimates were calculated using a fixed-effects model. Heterogeneity was assessed using the I(2) statistic. RESULTS: Three studies reported that NAC reduced ototoxicity in 146 patients with end-stage renal failure receiving aminoglycosides. Pooled relative risk for otoprotection at 4-6 weeks was 0.14 (95% CI 0.05 to 0.45), and the risk difference was -33.3% (95% CI 45.5% to 21.2%). Eighty-three studies (N=9988) described the administration of NAC for >6 weeks. Abdominal pain, nausea and vomiting, diarrhoea and arthralgia were increased 1.4-2.2 times. DISCUSSION: This review provides evidence for the safety and otoprotective effect of NAC when coadministered with aminoglycoside. It represents a strong justification for a clinical trial to investigate the effect of concomitant NAC treatment in patients receiving aminoglycosides as part of MDR-TB treatment.

Facial cutaneous necrosis associated with suspected levamisole toxicity from tainted cocaine abuse.

OBJECTIVE: This study aimed to illustrate the otorhinolaryngologic manifestations of levamisole toxicity and illuminate the features of this diagnosis. METHODS: We describe a case of a known cocaine abuser with suspected levamisole toxicity who developed cutaneous necrosis of the cheeks, earlobes, nose, upper and lower lip, and the midline hard palate. We also review the existing clinical literature about this emerging phenomenon. RESULTS: Levamisole is a common adulterant in cocaine distributed in the United States and has been reported to cause microvascular thrombosis and vasculitis with resultant skin necrosis in cocaine abusers. The distribution of skin findings characteristically involves the cheeks, earlobes, nose, lips, and hard palate and responds variably to cessation of cocaine use. In its most severe cases, immune suppression and/or surgical debridement may be required. CONCLUSION: Levamisole toxicity can frequently involve the ears, nose, and throat tissues. Otorhinolaryngologists should recognize these manifestations to expeditiously diagnose and manage this condition. Failure to do so promptly can lead to complications that may necessitate reconstructive or amputation surgery.

Preventing amikacin related ototoxicity with N-acetylcysteine in patients undergoing peritoneal dialysis.

Amikacin is a frequently used antibiotic in the treatment of peritoneal dialysis (PD)-related peritonitis. Ototoxicity is a well-known complication of amikacin for which increased oxidative stress and free oxygen radicals are thought to be responsible. In this study, the effect of N-acetyl-cysteine (NAC) on cochlear function and oxidant situation in the amikacin related ototoxicity in PD-related peritonitis patients are investigated. Forty-six patients who had their first PD-related peritonitis attacks receiving empirical amikacin treatment were enrolled in the study. The patients were randomized into two groups; the first group (n = 23) as NAC receiving and the second group (n = 23) as a placebo receiving, control group. Otoacoustic emissions were measured before, 1 week after and 4 weeks after the treatment. Oxidative stress measurements were performed concurrently in order to evaluate the effectiveness of NAC. The results of screening with otoacoustic emission testing after amikacin treatment showed that cochlear function is protected especially in higher frequencies in NAC group when compared with the control group. Evaluation of the antioxidant status of the two groups showed no differences in the basal values, but at the first week there was an increase in the NAC group compared with the control group, and this increase became significant at the fourth week. NAC is found to be safe and effective in amikacin-related ototoxicity in patients with PD-related peritonitis. We suggest a close monitoring of the patients receiving amikacin containing treatment protocols and if amikacin is administrated supplementing the treatment with NAC.

Is there a gender-related susceptibility for cisplatin ototoxicity?

Ototoxicity is a well-known side effect of cisplatin. Some genetic and non-genetic risk factors were described for cisplatin ototoxicity. Although there are some studies which point out a sex-related difference for cisplatin nephrotoxicity and neurotoxicity, sex-related differences for cisplatin ototoxicity have not been studied. The aim of this study is to reveal whether there is any gender-related difference for susceptibility to cisplatin ototoxicity in rats. Fourteen male, 14 female Wistar albino rats were divided into four groups; a female control, a male control, a female cisplatin and a male cisplatin group. Distortion Product Otoacoustic Emission and, Auditory Brainstem Response measurements were obtained. For the cisplatin groups 16 mg/kg of cisplatin was applied. On the 4th day audiological examinations were repeated. After killing, cochleae and brainstem tissues were evaluated by light and electron microscopy. The hearing of the female rat cisplatin group was found to have deteriorated more than the hearing of the male rat cisplatin group. Histopathological evaluation revealed more serious damage in the spiral ganglion and brainstem tissues of female rats. Hearing of female rats deteriorated more than the hearing of male rats upon application of cisplatin. This difference in hearing can be attributed to the more severe damage seen in neuronal tissues such as spiral ganglion cells and brainstem neurons.

[Current aspects of ototoxicity. Ototoxic substances and their effects]. / Aktuelle Aspekte zur Ototoxizität : Ototoxische Substanzen und deren Effekte.

Ototoxicity describes reversible or irreversible disorders of inner ear functions due to the influence of chemical, biological, or physical substances. Ototoxicity should be kept in mind during differential diagnosis of hearing loss, tinnitus, dizziness, and vertigo. In clinical practice, drug-induced ototoxic effects play a major role. The otorhinolaryngologist should also be involved in interdisciplinary cooperation, e.g., during treatment with antineoplastic chemotherapeutic agents with potential ototoxic side effects. In clinical practice, multimedication and interactions between different agents can complicate precise correlation in individual cases. Recent studies also show that noncellular components, such as otoconia, are extremely sensitive to chemical attacks.

[Current aspects of ototoxicity : Local ototoxic effects, diagnosis, prevention, and treatment]. / Aktuelle Aspekte zur Ototoxizität : Lokale ototoxische Wirkungen, Diagnostik, Prävention und Therapie.

The otorhinolaryngologist is often involved in an interdisciplinary approach to diagnose ototoxic side effects. Under certain conditions, chemical agents-particularly drugs-can have ototoxic effects. This is not only true for systemic administration, but also for local application (e.g., transdermal and transtympanal). Identifying and avoiding ototoxicity is still a challenge in clinical practice. The audiological monitoring of patients receiving potentially cochleotoxic drugs is now standardized. For diagnosis of suspected vestibulotoxic effects, the video head impulse test and vestibular evoked myogenic potentials seem to be suitable procedures for objective assessment. The early detection of such ototoxic effects has important implications for the prevention of hearing and balance disorders. Recent studies show that intratympanic delivery of medications might play an important role in the limitation of ototoxically induced hearing loss. In peripheral vestibulopathies with episodic vertigo, which strongly affect quality of life, ototoxic effects can be used for therapeutic purposes.

A novel role of cytosolic protein synthesis inhibition in aminoglycoside ototoxicity.

Ototoxicity is a main dose-limiting factor in the clinical application of aminoglycoside antibiotics. Despite longstanding research efforts, our understanding of the mechanisms underlying aminoglycoside ototoxicity remains limited. Here we report the discovery of a novel stress pathway that contributes to aminoglycoside-induced hair cell degeneration. Modifying the previously developed bioorthogonal noncanonical amino acid tagging method, we used click chemistry to study the role of protein synthesis activity in aminoglycoside-induced hair cell stress. We demonstrate that aminoglycosides inhibit protein synthesis in hair cells and activate a signaling pathway similar to ribotoxic stress response, contributing to hair cell degeneration. The ability of a particular aminoglycoside to inhibit protein synthesis and to activate the c-Jun N-terminal kinase (JNK) pathway correlated well with its ototoxic potential. Finally, we report that a Food and Drug Administration-approved drug known to inhibit ribotoxic stress response also prevents JNK activation and improves hair cell survival, opening up novel strategies to prevent and treat aminoglycoside ototoxicity.

External auditory canal stenosis due to the use of powdered boric acid.

Acquired stenosis of the external auditory canal (EAC) may occur because of chronic external otitis, recurrent chronic catarrhal otitis media associated with tympanic membrane perforation, chronic dermatitis, tumors, and trauma. Stenosis occurs generally at the one-third bone part of the external auditory canal. In this article, we present 3 cases of acquired EAC stenosis due to the previous powdered boric acid application. Besides the presentation of surgical intervetions in these cases, we want to notify the physicians not to use or carefully use powdered boric acid because of the complication of EAC stenosis.

Cocaine-associated Eustachian tube stenosis causing chronic 'glue ear': a rare cocaine-induced destructive lesion.

BACKGROUND: Cocaine is one of the most used recreational drugs. Whilst medical uses exist, chronic recreational nasal use of cocaine is associated with progressive destruction of the osseocartilaginous structures of the nose, sinuses and palate - termed cocaine-induced midline destructive lesions. CASE REPORT: A 43-year-old male with a history of chronic cocaine use, presented with conductive hearing loss and unilateral middle-ear effusion. Examination under anaesthesia revealed a completely stenosed left Eustachian tube orifice with intra-nasal adhesions. The adhesions were divided and the hearing loss was treated conservatively with hearing aids. Whilst intra-nasal cocaine-induced midline destructive lesions are a well-described condition, this is the first known report of Eustachian tube stenosis associated with cocaine use. CONCLUSION: This unique report highlights the importance of thorough history-taking, rhinological and otological examination, and audiometric testing when assessing patients with a history of chronic cocaine use. This paper demonstrates the complexity of managing hearing loss in such cases, with multiple conservative and surgical options available.