State-of-the-art methods in clinical intracochlear drug delivery.

PURPOSE OF REVIEW: Increasing awareness and prevalence of disorders in hearing and balance have placed emphasis on treatment strategies. With the rapid evolution in molecular, gene, and nanotechnology, alternate delivery methods have advanced intracochlear drug delivery. This review aims to raise awareness of recent developments in technologies to augment current clinical practices. RECENT FINDINGS: Intracochlear drug delivery research has expanded with the familiarity and accessibility to cochlear implantation. Various therapeutics are closely studied for both safety and efficacy as well as biologic effect. Agents including neurotrophins, antiapoptotics, cell therapy, gene therapy, and anti-inflammatory drugs are on the forefront of preclinical research. Cochlear implant electrode modification and drug administration at the time of implantation is a major focus of research. Improvements in study design have focused on overcoming barriers including elucidating the role of the blood-perilymph barrier. SUMMARY: Inner ear drug delivery methods include systemic, intratympanic, and intracochlear administration. Therapeutic technologies aim to overcome delivery barriers and to improve overall biologic effect while minimizing toxicity. Precision of drug application through intratympanic and intracochlear administration with minimal trauma is the future of inner ear drug development.

Remission of Recurrent Cochlear Hydrops Associated With Bromocriptine Treatment for Macroprolactinoma.

Objective Current recommendations for cochlear hydrops treatment include systemic glucocorticoids and diuretics. Cochlear cells express dopamine receptors, although their role is unknown in the pathophysiology of cochlear hydrops. Case Description We report the case of remission of recurrent right-sided cochlear hydrops in a young male patient treated with bromocriptine due to pituitary macroprolactinoma. Transient improvement was observed after oral steroid and diuretic treatment, but cochlear hydrops recurred until the dose of bromocriptine was increased to 10 mg daily. Conclusion Bromocriptine may stimulate dopamine receptors in cochlear cells with potential therapeutic role in patients with cochlear hydrops. There are no widely accepted and effective treatments for endolymphatic hydrops, and identifying potential new and efficacious therapeutics is of high relevance.

Purinergic Signaling and Cochlear Injury-Targeting the Immune System?

Hearing impairment is the most common sensory deficit, affecting more than 400 million people worldwide. Sensorineural hearing losses currently lack any specific or efficient pharmacotherapy largely due to the insufficient knowledge of the pathomechanism. Purinergic signaling plays a substantial role in cochlear (patho)physiology. P2 (ionotropic P2X and the metabotropic P2Y) as well as adenosine receptors expressed on cochlear sensory and non-sensory cells are involved mostly in protective mechanisms of the cochlea. They are implicated in the sensitivity adjustment of the receptor cells by a K+ shunt and can attenuate the cochlear amplification by modifying cochlear micromechanics. Cochlear blood flow is also regulated by purines. Here, we propose to comprehend this field with the purine-immune interactions in the cochlea. The role of harmful immune mechanisms in sensorineural hearing losses has been emerging in the horizon of cochlear pathologies. In addition to decreasing hearing sensitivity and increasing cochlear blood supply, influencing the immune system can be the additional avenue for pharmacological targeting of purinergic signaling in the cochlea. Elucidating this complexity of purinergic effects on cochlear functions is necessary and it can result in development of new therapeutic approaches in hearing disabilities, especially in the noise-induced ones.

Preclinical and clinical otoprotective applications of cell-penetrating peptide D-JNKI-1 (AM-111).

There is a growing interest in the auditory community to develop novel prophylactic and therapeutic drugs to prevent permanent sensorineural hearing loss following acute cochlear injury. The jun-N-terminal protein kinase (JNK) pathway plays a crucial role in acute sensory hearing loss. Blocking the JNK pathway using the cell-penetrating peptide D-JNKI-1 (AM-111/brimapitide) has shown promise as both a prophylactic and therapeutic agent for acute cochlear injury. A number of pre-clinical and clinical studies have determined the impact of D-JNKI-1 on acute sensorineural hearing loss. Given the inner-ear selective therapeutic profile, local route of administration, and ability to diffuse across cellular membranes rapidly using both active and passive transport makes D-JNK-1 a promising oto-protective drug. In this review article, we discuss the application of D-JNKI-1 in various auditory disorders as well as its pharmacological properties and distribution in the cochlea.

Innovative pharmaceutical approaches for the management of inner ear disorders.

The sense of hearing is essential for permitting human beings to interact with the environment, and its dysfunctions can strongly impact on the quality of life. In this context, the cochlea plays a fundamental role in the transformation of the airborne sound waves into electrical signals, which can be processed by the brain. However, several diseases and external stimuli (e.g., noise, drugs) can damage the sensorineural structures of cochlea, inducing progressive hearing dysfunctions until deafness. In clinical practice, the current pharmacological approaches to treat cochlear diseases are based on the almost exclusive use of systemic steroids. In the last decades, the efficacy of novel therapeutic molecules has been proven, taking advantage from a better comprehension of the pathological mechanisms underlying many cochlear diseases. In addition, the feasibility of intratympanic administration of drugs also permitted to overcome the pharmacokinetic limitations of the systemic drug administration, opening new frontiers in drug delivery to cochlea. Several innovative drug delivery systems, such as in situ gelling systems or nanocarriers, were designed, and their efficacy has been proven in vitro and in vivo in cochlear models. The current review aims to describe the art of state in the cochlear drug delivery, highlighting lights and shadows and discussing the most critical aspects still pending in the field.

A unique case of adolescent neuroborreliosis presenting with multiple cranial neuritis and cochlear inflammation on magnetic resonance imaging.

BACKGROUND: Lyme disease is the most common vector-borne disease in the United States and is caused by infection with the spirochete Borrelia burgdorferi. In children, neuroborreliosis usually presents as peripheral facial nerve palsy and lymphocytic meningitis and only rarely is associated with cranial polyneuritis. PATIENT DESCRIPTION: We present a 15-year-old with tinnitus, hearing loss, and facial nerve palsy in the setting of acute, severe right arm pain and a several week history of malaise and headache. Lumbar puncture was notable for lymphocytic pleocytosis. Serologic testing demonstrated positive Lyme antibody and a positive immunoglobulin M Western blot. Immunofluorescent assay of cerebrospinal fluid was also positive for anti-Lyme immunoglobulin M. Audiologic testing revealed mixed, right-sided hearing loss. Neuroimaging demonstrated cranial polyneuritis and right-sided cochlear inflammation. The patient was treated with parenteral ceftriaxone with resolution of his symptoms at close follow-up. DISCUSSION: Neuroborreliosis with radiculopathy, lymphocytic meningitis, and cranial polyneuritis is a rare presentation of pediatric Lyme disease. Additionally, cochlear inflammation along with cranial nerve VIII inflammation may contribute to hearing loss in patients with neuroborreliosis.

Mitochondria-targeted antioxidant MitoQ reduces gentamicin-induced ototoxicity.

HYPOTHESIS: Oral supplementation with mitoquinone (MitoQ) prevents gentamicin-induced ototoxicity in guinea pigs. BACKGROUND: Antioxidants have been shown to protect against aminoglycoside (AG)-induced ototoxicity. MitoQ, a mitochondria-targeted derivative of the antioxidant ubiquinone, is attached to a lipophilic triphenylphosphonium (TPP) cation, which enables its accumulation inside the mitochondria several hundred-fold over the untargeted antioxidant. MitoQ has improved bioavailability and can reach most tissues and has been used in Parkinson's disease and hepatitis C human trials, which demonstrated that MitoQ can be safely used in humans. Thus, MitoQ is a promising novel therapeutic approach for protecting against AG-induced ototoxicity. METHODS: Gentamicin-treated guinea pigs were supplied with water alone (control), decyl-TPP (positive control), or MitoQ-supplemented drinking water. Auditory function was assessed by auditory brainstem response. Cochlear damage was assessed using scanning electron microscopy. Western blotting was performed to evaluate changes in proteins related to apoptosis and oxidative damage in the cochlea. RESULTS: Threshold shifts at 4 and 8 kHz at 4 and 7 weeks after gentamicin treatment were smaller in animals treated with MitoQ compared with those in the control- and decyl-TPP-treated animals (p < 0.05). Protein carbonyls and levels of the proapoptotic protein Bak were lower (p < 0.05 and p = 0.008, respectively), whereas the level of the antioxidant enzyme manganese superoxide dismutase was higher (p = 0.01) in the cochlea of MitoQ-treated animals. The expression of 3-nitrotyrosine and Hrk were not different between groups (p > 0.05). CONCLUSION: Oral supplementation with MitoQ attenuated gentamicin-induced cochlear damage and hearing loss in guinea pigs. MitoQ holds promise as a means for protecting against AG ototoxicity.

[The estimation of the efficacy of manual therapy included in the combined treatment of cochlear-vestibular disorders based on the results of computed stabilography].

The objective of the present study was to estimate the efficacy of the combined treatment of spondylogenic cochlear-vestibular disorders with the use of both medicamental and non-medicamental modalities. Computed static stabilometry was applied for diagnostics of postural disbalance and evaluation of the treatment outcomes. It was shown that the application of manual therapy for the management of 56 patients presenting with spondylogenic cochlear-vestibular disorders resulted in the decrease of tinnitus and the improvement of vestibular and cochlear functions.

Deterioration of hearing in a cochlear implantee with relapsing polychondritis.

We report on a rare case of cochlear implantation in a patient affected by relapsing polychondritis (RP), which over time induced cochlear fibrosis/ossification and deterioration of previously excellent hearing performance. The clinical course was determined by CT scan, electrophysiology, and speech perception data. We conclude that RP is a severe autoimmune connective disorder that can cause profound sensorineural hearing loss. Cochlear implantation in these patients can provide excellent performance. Continuation of therapy may improve prognosis, but relapses involving inner ear structures can determine fibrosis/ossification of the modiolus and interfere with cochlear implant use.

[Cochleovestibular disorders: approaches to diagnostics and treatment].

The aim of this work was to evaluate the efficacy of introduction of milgamma and milgamma compositum in the treatment of 52 patients with cochleovestibular disorders of different etiology. Thirteen patients enrolled in the study received standard therapy and 39 others were given its combination with milgamma preparations. Combined therapy with milgamma and milgamma compositum ensured faster vestibular compensation including posturographic characteristics than the standard treatment (within 3-4 weeks compared with 5 weeks in controls). The results of the study give reason to recommend milgamma and milgamma compositum as neurotropic medicines in addition to standard therapy for the management of the patients presenting with cochleovestibular disorders for the acceleration of the vestibular compensation.

Ginkgo biloba extract (EGb761) protects against aging-related caspase-mediated apoptosis in rat cochlea.

CONCLUSIONS: EGb761 treatment has a significant benefit with an early and preventive effect, reversing the deleterious effect of aging in the integrity of the rat cochlea, even in the late stage of the rat lifespan. OBJECTIVES: We previously reported a significant relationship between aging and apoptosis in the rat cochlea. This study was designed to investigate the effects of Ginkgo biloba leaf extract (EGb761) on age-associated cochlear caspase activation. METHODS: Sprague-Dawley rats (n = 80) divided into two groups according to their age (4 months old, younger, YR, and 12 months old, aged-mature, AM) were treated with 100 mg/kg/day body weight of EGb761 extract dissolved in tap water for two periods: 4 and 12 months. Then cochleae were harvested to measure caspase activities, ATP levels, total superoxide dismutase (SOD) activity, and caspase-3 gene expression. Auditory steady-state responses (ASSR) threshold shifts were also measured before sacrifice of the rats. RESULTS: EGb761 treatment prevents significantly aging-related caspase-induced activities within the cochleae in YR and AM rats. In the short EGb761 treatment, YR rats showed lower levels of caspase-3/7 than AM rats. In contrast, longer treatment did not show significant differences between YR and AM rats. Reduced caspase-3/7 activity in presence of EGb761 correlates with significant improvements of ASSR threshold shifts.

Geranylgeranylacetone ameliorates acute cochlear damage caused by 3-nitropropionic acid.

3-Nitropropionic acid (3-NP) induces hearing loss by impairing mitochondrial energy generation. Geranylgeranylacetone (GGA) is known to protect the cochlea from various injuries. The present study was designed to investigate the protective effect of GGA against acute 3-NP-induced damage to the cochlear mitochondria. Female Hartley guinea pigs were divided into 4 groups. The 3-NP vehicle was injected to control animals and in animals receiving GGA alone, only GGA was administered for 7 days. 3-NP (500 mM, 4 microl) was administered with (animals receiving both GGA and 3-NP) or without (animals receiving 3-NP alone) GGA pretreatment (800 mg/kg, 7 days). The auditory brainstem response (ABR) was recorded at click and at 8, 16 and 32 kHz before and after injection, respectively. After cochlear harvest, hematoxylin/eosin staining and immunohistochemistry for anti-HSP70 antibody were done. 3-NP exposure resulted in elevated ABR thresholds that exceeded the maximum recording limit, while GGA pretreatment before 3-NP exposure led to a significant decrease in hearing threshold shift. Histological analysis of above former group revealed loss of type II fibrocytes in the spiral ligament, hair cells in the organ of Corti, stellate fibrocytes in the spiral limbus and spiral ganglion cells, while in above latter group, these cells were preserved. Control animals revealed weak HSP70 expression in the nuclei of some supporting cells (pillar cells, Deiters' cells and Hensen's cells) and interdental cells. Animals receiving GGA alone showed strong HSP70 expression in the same area as in control animals, while animals receiving both GGA and 3-NP demonstrated slightly decreased HSP70 expression in that area. These results suggest that GGA may protect the cochlea against acute injury resulting from mitochondrial dysfunction.

The injured cochlea as a target for inflammatory processes, initiation of cell death pathways and application of related otoprotectives strategies.

One of the causes of sensorineural hearing loss is the loss of auditory hair cells following exposure to environmental stresses. Auditory hair cell death in response to cochlear trauma occurs via both necrosis and apoptosis. Apoptosis of hair cells involves the caspase and MAPK/JNK pathways which are activated by oxidative stress and secretion of inflammatory cytokines in response to trauma. Identification of the pathways that lead to apoptosis provides therapeutic targets for the conservation of hearing. Antioxidants reduce the level of reactive oxygen species and reactive nitrogen species generated by oxidative stress in response to acoustic trauma, aminoglycoside and platinum-based drugs. Caspase inhibitors affect both the extrinsic and intrinsic apoptotic pathways thereby reducing cisplatin, aminoglycoside, hydraulic trauma and ischemia-induced hearing losses. Corticosteroid therapy reduces inflammation and inhibits apoptosis while activating pro-survival pathways in the organ of Corti following exposure to noise, vibration, cisplatin, aminoglycoside, ischemia/reperfusion injury, bacterial meningitis and electrode insertion trauma. Inhibitors of JNK signaling pathway prevent apoptosis of auditory hair cells following electrode insertion trauma, acute labyrinthitis, acoustic trauma and aminoglycoside ototoxicity. This review provides an overview of the different pathways involved in auditory hair cell death following an environmental stress and both traditional and newly developed drugs that are currently being studied or used for the treatment of acute hearing loss. Recent patents related to otoprotective strategies to conserve hearing and auditory hair cells are also discussed in this review.

Blockade of interleukin-6 signaling suppressed cochlear inflammatory response and improved hearing impairment in noise-damaged mice cochlea.

Hearing impairment can be the cause of serious socio-economic disadvantages. Recent studies have shown inflammatory responses in the inner ear co-occur with various damaging conditions including noise-induced hearing loss. We reported pro-inflammatory cytokine interleukin-6 (IL-6) was induced in the cochlea 6h after noise exposure, but the pathophysiological implications of this are still obscure. To address this issue, we investigated the effects of IL-6 inhibition using the anti-IL-6 receptor antibody (MR16-1). Noise-exposed mice were treated with MR16-1 and evaluated. Improved hearing at 4kHz as measured by auditory brainstem response (ABR) was noted in noise-exposed mice treated with MR16-1. Histological analysis revealed the decrease in spiral ganglion neurons was ameliorated in the MR16-1-treated group, while no significant change was observed in the organ of Corti. Immunohistochemistry for Iba1 and CD45 demonstrated a remarkable reduction of activated cochlear macrophages in spiral ganglions compared to the control group when treated with MR16-1. Thus, MR16-1 had protective effects both functionally and pathologically for the noise-damaged cochlea primarily due to suppression of neuronal loss and presumably through alleviation of inflammatory responses. Anti-inflammatory cytokine therapy including IL-6 blockade would be a feasible novel therapeutic strategy for acute sensory neural hearing loss.

Early small bowel perforation and cochleovestibular impairment as rare complications of typhoid fever.

Two Indian migrant workers suffering from fever and malaise were admitted to the hospital directly after arrival in the Netherlands. The first patient was 25-year-old man who had fever and rigors on admission. The patient was treated for presumptive typhoid fever with ciprofloxacin. Cefotaxime was added the following day because of the possibility of a nalidixic-acid resistant strain of S. typhi. The clinical course was complicated by a small bowel perforation on the third day of the disease. Blood cultures grew a nalidixic acid resistant strain of Salmonella enterica serovar typhi. The patient recovered completely. The second patient, a 22-year-old man, suffered from fever, malaise and hearing loss. A sensorineural hearing loss with vestibular dysfunction was diagnosed. Cultures of blood and bone marrow aspirate showed a nalidixic acid resistant strain of S. typhi. Treatment with ciprofloxacin and ceftazidime improved the hearing loss significantly. The clinical features of typhoid fever are heterogeneous and rare complications may occur. The emergence of multidrug and nalidixic acid resistance may complicate further the treatment of this serious systemic infection.

Preventing hearing damage using topical dexamethasone during reversible cochlear ischemia: an animal model.

HYPOTHESIS: Local application of dexamethasone to the round window (RW) niche prevents cochlear damage caused by local reversible ischemia. BACKGROUND: Cochlear ischemia induced by internal auditory artery (IAA) compression/stretching is thought to cause postoperative sensory hearing loss after attempted hearing preservation removal of acoustic neuroma tumors. Dexamethasone administered to the RW niche traveling through the membrane to the cochlear fluids may prevent ischemic damage. MATERIALS AND METHODS: Ten young albino rabbits were used for this study. Ischemic episodes were induced by compressing the IAA. Laser Doppler cochlear blood flow was measured using a probe positioned at the RW niche. Transtympanic electrocochleography was measured at 4, 8, and 12 kHz. In 5 test ears, dexamethasone was administered topically at the RW for approximately 50 minutes before the IAA compressions, whereas in 5 control ears, saline was applied in the same way. Each ear underwent one 10-minute IAA compression with a 60-minute postischemic period of transtympanic electrocochleography monitoring. RESULTS: In both control- and dexamethasone-treated ears, ischemic episodes measured by Laser Doppler cochlear blood flow were comparable. Fifty minutes after IAA decompression, in dexamethasone-pretreated ears, cochlear microphonic and compound action potential amplitudes at all test frequencies were 10 to 15% less reduced than those in control ears. Compound action potential latencies in dexamethasone-pretreated ears resulted in shorter latency delay than in control ears. CONCLUSION: The RW seems to be an efficacious route for the administration of dexamethasone into the inner ear. Dexamethasone showed a protective effect on cochlear function after local ischemia. Transtympanic electrocochleography was found to be a sufficient and effective tool in monitoring hearing.

Routes, dynamics, and correlates of cochlear inflammation in terminal and recovering experimental meningitis.

OBJECTIVES/HYPOTHESIS: To examine the routes, dynamics and correlates of cochlear inflammation in meningitis to provide information on the pathogenesis of the associated hearing loss and indications for rational pharmacotherapeutical intervention. STUDY DESIGN: A well-established rat model of Streptococcus pneumoniae meningitis was employed. METHODS: Eight rats were inoculated intrathecally and not treated, whereas 26 were inoculated and treated with ceftriaxone. Six rats were sham-inoculated, making a total of 40 rats. The rats were sacrificed when reaching terminal illness or after 7 days, followed by light microscopy. Routes of cochlear inflammatory infiltration were examined. The volume fraction of inflammatory infiltration was estimated and correlated to bacterial and leukocyte counts in cerebrospinal fluid (CSF) and blood. RESULTS: The perilymphatic space was infiltrated with inflammatory cells via cochlear aqueduct, whereas the endolymphatic space was infiltrated from the spiral ligament. Rosenthal's canal was infiltrated through osseous spiral lamina canaliculi. In the untreated group, the degree of inflammation correlated with time of death, whereas antibiotic treatment reversed this development. Perilymphatic inflammation correlated significantly with the CSF leukocyte count, whereas endolymphatic inflammation correlated with spiral ligament inflammation. CONCLUSIONS: Meningogenic inflammation of the rat cochlea occurs via the cochlear aqueduct and the spiral ligament capillary bed. The spiral ganglion is infiltrated through the osseous spiral lamina. The degree of inflammation correlates positively with time of death in untreated meningitis, whereas antibiotic treatment leads to subsiding infiltration during recovery.