Efficacy and safety of AM-111 in the treatment of acute sensorineural hearing loss: a double-blind, randomized, placebo-controlled phase II study.

OBJECTIVE: To evaluate the efficacy and safety of AM-111, a c-Jun N-terminal Kinase (JNK) ligand, in patients with acute sensorineural hearing loss (ASNHL). STUDY DESIGN: Prospective, double-blind, randomized, placebo-controlled study with follow-up visits on Days 3, 7, 30, and 90. SETTING: Twenty-five European sites (academic tertiary referral centers, private ENT practices). PATIENTS: Approximately 210 patients aged 18 to 61 years presenting within 48 hours after acute acoustic trauma or idiopathic sudden sensorineural hearing loss with mean hearing loss of 30 dB or greater at the 3 most affected contiguous test frequencies. INTERVENTIONS: Single-dose intratympanic injection of AM-111 (0.4 or 2.0 mg/ml) or placebo; optionally, oral prednisolone if hearing improvement was less than 10 dB at Day 7. MAIN OUTCOME MEASURES: Efficacy was assessed by absolute hearing improvement (primary end point, Day 7), percentage hearing improvement, complete hearing recovery, speech discrimination improvement, and complete tinnitus remission. Safety was evaluated by the frequency of clinically relevant hearing deterioration and adverse events. RESULTS: The study failed to demonstrate a treatment benefit for the entire study population because mild-to-moderate ASNHL cases showed unexpectedly strong spontaneous recovery. In severe-to-profound ASNHL patients (threshold ≥60 dB), AM-111 0.4 mg/ml showed statistically significant, clinically relevant, and persistent improvements in hearing and speech discrimination and higher tinnitus remission compared with placebo. The study drug and the intratympanic injections were well tolerated. CONCLUSION: The study established proof of concept for AM-111 in the treatment of severe-to-profound ASNHL. Control for spontaneous hearing recovery is essential for ASNHL studies.

Fibrinogen/LDL apheresis is a promising rescue therapy for sudden sensorineural hearing loss.

BACKGROUND: Fibrinogen/LDL apheresis has been proven to be effective in treatment of sudden sensorineural hearing loss (SSNH). This study is aimed to investigate if reduction of fibrinogen and serum LDL is also effective in patients with SSNH non-responding toward treatment with corticosteroids and plasmaexpanders. METHODS: Remission rates of 217 patients suffering from SSHL were investigated after treatment with apheresis. All patients were non-responders after other therapies such as high doses of steroids or plasmaexpanders. RESULTS: Single apheresis resulted in complete or partial remissions in 61% of patients when given after other unsuccessful conducted therapies such as corticosteroids and plasmaexpanders. CONCLUSION: Fibrinogen/LDL apheresis is a promising rescue therapy for sudden sensorineural hearing loss even after unsuccessful other therapies.

Modeling the measurements of cochlear microcirculation and hearing function after loud noise.

OBJECTIVE: Recent findings support the crucial role of microcirculatory disturbance and ischemia for hearing impairment especially after noise-induced hearing loss (NIHL). The aim of this study was to establish an animal model for in vivo analysis of cochlear microcirculation and hearing function after a loud noise to allow precise measurements of both parameters in vivo. STUDY DESIGN: Randomized controlled trial. Setting. Animal study. Subjects and Methods. After assessment of normacusis (0 minutes) using evoked auditory brainstem responses (ABRs), noise (106-dB sound pressure level [SPL]) was applied to both ears in 6 guinea pigs for 30 minutes while unexposed animals served as controls. In vivo fluorescence microscopy of the stria vascularis capillaries was performed after surgical exposure of 1 cochlea. ABR measurements were derived from the contralateral ear. RESULTS: After noise exposure, red blood cell velocity was reduced significantly by 24.3% (120 minutes) and further decreased to 44.5% at the end of the observation (210 minutes) in contrast to stable control measurements. Vessel diameters were not affected in both groups. A gradual decrease of segmental blood flow became significant (38.1%) after 150 minutes compared with controls. Hearing thresholds shifted significantly from 20.0 ± 5.5 dB SPL (0 minutes) to 32.5 ± 4.2 dB SPL (60 minutes) only in animals exposed to loud noise. CONCLUSION: With regard to novel treatments targeting the stria vascularis in NIHL, this standardized model allows us to analyze in detail cochlear microcirculation and hearing function in vivo.

A novel gelatin sponge for accelerated hemostasis.

To more effectively manage the substantial bleeding encountered during surgical procedures in oto-rhino-laryngology, we developed a novel hemostatic sponge made of pharmaceutical grade, chemically cross-linked gelatin. The sponge is characterized by a high pore density, reduced ligaments, and a high nanoscale roughness of lamella surfaces in the matrix. In vitro blood uptake assays revealed a very rapid absorption of human blood, which was two to three times faster than that measured with comparative hemostyptic devices. In an in vitro hemorrhage model using human veins, the novel gelatin sponge matrix induced hemostasis less than a minute after bleeding was induced. The sponge was shown to bring about rapid hemostasis when it was administered in a young patient suffering from acute bleeding of a pharyngeal angiofibroma, even though the patient had been treated with an anticoagulant because of a transient ischemic attack. As the gelatin matrix of the sponge is biocompatible and resorbable, the hemostyptic device could be left in place and was shown to be resorbed within 2 weeks. We hypothesize that the excellent hemostatic performance of the sponge might be linked to enhanced capillary effects in conjunction with optimized anchoring of fibrinogen on the nano-rough material surface, as suggested by scanning electron microscopy. The novel gelatin sponge appears to be a promising hemostatic matrix, which could be of great benefit for patients suffering from epistaxis and other acute injuries resulting in severe bleeding.

An animal model for the analysis of cochlear blood flow [corrected] disturbance and hearing threshold in vivo.

Impairment of cochlear blood flow (CBF) is considered to be important in inner ear pathology. However, direct measurement of CBF is difficult and has not been investigated in combination with hearing function. Six guinea pigs were used to show feasibility of an animal model for the analysis of cochlear microcirculation by intravital microscopy in combination with investigation of the hearing threshold by brainstem response audiometry (ABR). By the application of sodium nitroprusside (SNP), CBF was increased over 30 min. Reproducibility of measurements was shown by retest measurements. Mean baseline velocity of CBF was 109 +/- 19 mum/s. Vessel diameters had a mean value of 9.4 +/- 2.7 mum. Mean hearing threshold was 19 +/- 6 dB. In response to SNP, CBF velocity increased significantly to 161 +/- 26 mum/s. Mean arterial pressure decreased significantly to 36 +/- 11 mmHg. After the end of the application, CBF velocity recovered to a minimum of 123 +/- 17 microm/s. Within the retest, CBF velocity significantly increased to a maximum of 160 +/- 31 microm/s. Second recovery of CBF velocity was 125 +/- 14 mum/s. Within the second retest, CBF increased significantly to 157 +/- 25 microm/s. ABR thresholds did not change significantly. The increase in blood flow velocity occurred in spite of substantial hypotension as induced by a vasodilator. This may explain the fact that ABR threshold remained unchanged reflecting a maintained blood supply in this part of the brain. This technique can be used to evaluate effects of treatments aimed at cochlear microcirculation in inner ear pathologies.

Fibrinogen/LDL apheresis as successful second-line treatment of sudden hearing loss: a retrospective study on 217 patients.

BACKGROUND: Sudden sensorineural hearing loss (SSHL) may be caused by a reduction of cochlear perfusion. Cholesterol and fibrinogen negatively influence rheological properties of blood thus leading to alteration of microcirculation. Fibrinogen/LDL apheresis improves cochlear blood flow by acutely decreasing plasma cholesterol and fibrinogen. METHODS: Remission rates of 217 patients with SSHL were analysed retrospectively after single apheresis. All patients had been treated otherwise before without any improvement of hearing. We investigated data in regard to frequency of hearing loss and time between onset of symptoms and apheresis. RESULTS: 15% of all patients had complete remissions, whereas partial remissions were seen in 46%. No change of hearing threshold was seen in 33%, 2% worsened. Remission rates decreased from 70% for a time of 2 weeks between onset of SSHL and apheresis to 63% and 21% for 6 weeks and 3 months. CONCLUSION: The present study shows that apheresis was followed by complete or partial remissions in 61% of patients even as second line therapy. The window for good therapeutic success is approximately 6 weeks.