Sustained-release devices in inner ear medical therapy.

Inner ear medical therapy has been gaining increasing popularity during the last 2 decades. Despite the increased use of this therapy,basic questions regarding this type of treatment have not been answered. The authors have used a variety of sustained-release devices in the laboratory to begin to answer some of these basic questions. This article discusses the results of this work and the application and use of sustained-release devices in patients.

Characterizing and treating dizziness after mild head trauma.

OBJECTIVE: The objectives of this study were to characterize patterns of dizziness seen after mild head trauma and to examine the diagnosis and treatment of this disorder. STUDY DESIGN: Prospective patient registry. SETTING: Tertiary referral center. PATIENTS: Fifty-eight cases of active duty and retired military personnel who sustained mild head trauma and had resultant dizziness. INTERVENTIONS: Vestibular evaluation, characterization by group, and treatment. MAIN OUTCOME MEASURES: Outcome measures include characterization of diagnosis types, patient distribution by diagnosis type, and patient outcome. RESULTS: Individuals suffering from dizziness after mild head injury were divided into three diagnostic groups. Forty-one percent of the individuals suffered from posttraumatic vestibular migraines, 28% of the individuals had posttraumatic positional vertigo, and 19% of the individuals were classified as posttraumatic spatial disorientation. The remaining 12% of the patients could not be characterized. The positional group had objective physical examination findings, which cleared with treatment in all cases. The migraine group of patients and the disorientation group of patients had distinct abnormalities of the vestibulo-ocular reflex (VOR) and the vestibulo-spinal reflex (VSR). Eighty-four percent of the migraine group demonstrated an improvement of these test results as compared with 27% of the disorientation group. Mean time to return to work was less than 1 week for the positional group, 3.8 weeks for the migraine group, and greater than 3 months for the disorientation group. CONCLUSIONS: Using our patient registry of individuals suffering from dizziness after mild head trauma, we were able to characterize the majority of these cases into one of three more specific diagnostic groups. We present diagnostic criteria, suggested treatment guidelines, and our prognostic data.

A genetic polymorphism of the alpha2-adrenergic receptor increases autonomic responses to stress.

We hypothesized that individual differences in autonomic responses to psychological, physiological, or environmental stresses are inherited, and exaggerated autonomic responsiveness may represent an intermediate phenotype that can contribute to the development of essential hypertension in humans over time. alpha(2)-Adrenergic receptors (alpha(2)-ARs), encoded by a gene on chromosome 10, are found in the central nervous system and also mediate release of norepinephrine from the presynaptic nerve terminals of the peripheral sympathetic nervous system and the exocytosis of epinephrine from the adrenal medulla. We postulated that, because this receptor mediates central and peripheral autonomic responsiveness to stress, genetic mutations in the gene encoding this receptor may explain contrasting activity of the autonomic nervous system among individuals. The restriction enzyme Dra I identifies a polymorphic site in the 3'-transcribed, but not translated, portion of the gene encoding the chromosome 10 alpha(2)-AR. Southern blotting of genomic DNA with a cDNA probe after restriction enzyme digestion results in fragments that are either 6.7 kb or 6.3 kb in size. Transfection studies of these two genotypes resulted in contrasting expression of a reporter gene, and it is suggested from these findings that this is a functional polymorphism. In a study of 194 healthy subjects, we measured autonomic responses to provocative motion, a fall in blood pressure induced by decreasing venous return and cardiac output, or exercise. Specifically, we measured reactions to 1) Coriolis stress, a strong stimulus that induces motion sickness in man; 2) heart rate responses to the fall in blood pressure induced by the application of graded lower body negative pressure; and 3) exercise-induced sweat secretion. In all of these paradigms of stress, subjective and objective evidence of increased autonomic responsiveness was found in those individuals harboring the 6.3-kb allele. Specifically, volunteers with the 6.3-kb allele had greater signs and symptoms of motion sickness mediated by the autonomic nervous system after off-axis rotation at increasing velocity (number of head movements a subject could complete during rotation before emesis +/- SE: 295 +/- 18 vs. 365 +/- 11; P = 0.001). They also had greater increases in heart rate in responses to the lower body negative pressure-induced fall in blood pressure (increase in heart rate +/- SE: 3.0 +/- 0.4 vs. 1.8 +/- 0.3; P = 0.012), and the 6.3-kb group had higher sweat sodium concentrations during exercise (mean sweat sodium concentration in meq/l over 30 min of exercise +/- SE: 43.2 +/- 7.1 vs. 27.6 +/- 3.4; P < 0.05). This single-nucleotide polymorphism may contribute to contrasting individual differences in autonomic responsiveness among healthy individuals.

The effects of autologous platelet gel on wound healing.

Laser resurfacing techniques have become a popular means of achieving rejuvenation of damaged skin. Interest is great in attempting to speed re-epithelialization and healing so that patients can return to their normal activities as quickly as possible. Previous studies have demonstrated that wounds heal more quickly when they are covered and kept moist than when they are left open to the air. Until now, no study has been conducted to investigate whether the healing process of a superficial skin burn might be accelerated by the use of an autologous platelet gel as a biologic dressing. Our study of five pigs showed that autologous platelet gel can influence wound healing by stimulating an intense inflammatory process that leads to highly significant increases in the production of extracellular matrices and granulation tissue. The platelet gel accelerated vascular ingrowth, increased fibroblastic proliferation, and accelerated collagen production. However, the gel did not appear to accelerate re-epithelialization. The aggressive production of granulation tissue and the acceleration of collagen production might mean that autologous platelet gel will have a future role in the treatment of burns because the highly vascularized bed it helps create should promote the success of skin grafting in patients with deep partial-thickness and full-thickness burns.

Vestibular testing abnormalities in individuals with motion sickness.

HYPOTHESIS: The goal of this study was to compare the results of vestibular testing in individuals with motion sickness to a group of control subjects. BACKGROUND: Studying motion sickness is difficult, because no animal model has been developed and symptoms rarely occur outside motion environments. Tests that can be performed in normal laboratory settings, which help to identify individuals with motion sickness, may be valuable in characterizing this disorder. METHODS: Twenty active duty military individuals with well-documented motion sickness were tested. The test battery included sinusoidal rotational chair testing to calculate vestibulo-ocular reflex function, step-velocity testing to calculate vestibular time constants, and posturography testing to assess vestibulo-spinal reflex status. The results of this test battery were compared with a set of age- and sex-matched controls without motion sickness. RESULTS: Vestibular test abnormalities were demonstrated in individuals with motion sickness. Vestibulo-spinal reflex function on posturography was normal in the control group but abnormal in 70% of the individuals with motion sickness. In addition, 5% of the control group demonstrated a minimal shortening of the absolute time constant, whereas 60% of the individuals with motion sickness had abnormal absolute time constants. CONCLUSION: A significant percentage of individuals with motion sickness demonstrate abnormalities in their time constant or vestibulo-spinal reflex function. These abnormalities can be detected using standard, land-based vestibular tests. These preliminary results have implications in understanding the etiology of motion sickness and may provide outcome measures to be used in treating motion sickness.

Transtympanic management of tinnitus.

Transtympanic therapy is becoming and important treatment modality for many inner ear disorders. The current therapies aimed at Meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, and the tinnitus associated with these disorders and idiopathic tinnitus, however, represents simply an evolutionary step in this treatment modality and must be validated by further scientific study. A number of promising developments including newer more targeted neuroactive medicines, a better understanding of medicine delivery, and the knowledge of the site, origin, and pathophysiology of the symptoms complex will make this therapy more effective. In the future it is possible that many inner ear disorders will be amenable to inner ear medical therapy. Ideally in the future with knowledge of the disease and its etiology the physician will simply pick the established medicine, the established dose, and the established route of administration and achieve a relatively predictable result.

Sustained-release delivery of leupeptin in the chinchilla: hearing results.

Transtympanic medical therapy is becoming an increasingly popular modality for the treatment of "inner-ear disorders." While investigators continue to examine the best dosing paradigms for gentamicin in the treatment of Ménière's disease and for steroids in the treatment of hearing loss, they have also begun to focus on the use of other agents. In particular, transtympanic therapy has been advocated as a plausible route for the treatment of tinnitus. Transtympanic therapy for tinnitus is not new, and a number of groups have reported success in the past. Despite this success, a number of laboratories have been focusing on newer agents that might yield higher success rates in the treatment of tinnitus and other inner-ear disorders. Many of these agents could have systemic side effects when delivered in high enough doses; therefore, they are ideal candidates for transtympanic administration. The goal of this study is to begin to define the effects of one of these agents--leupeptin, a calpain antagonist--on the normal inner ear of an animal model. In this investigation, we demonstrate the effects of sustained-release delivery of leupeptin (2.5 micrograms/ml) on the hearing of chinchillas. The medicine produced no hearing loss at the early time points but did produce some hearing loss at later time points. We discuss these results and begin to outline the next steps in the investigation of this agent.

Lateral inhibition in the auditory cortex: an EEG index of tinnitus?

Auditory ERPs were recorded from eight tinnitus patients and 12 controls. Tone pips of 1000 and 2000 Hz, as well as the patient's tinnitus pitch (around 4000 Hz) were used. Controls received tone pips at 1000, 2000, and 4000 Hz. Tones were presented at 30, 36, 42, 48 and 54 dB/SL. The intensity dependence of the auditory N100 was calculated for each frequency in each group. Patients showed a steeper response to the tinnitus frequency than responses to the 4000 Hz tone in controls. In contrast, intensity-dependence to the 2000 Hz tones was significantly decreased in patients (two-tailed Wilcoxon-Mann-Whitney U-test, p < 0.05). Responses to the 1000 Hz tones were similar for both groups. This reduced intensity dependence is hypothesized to result from lateral inhibition arising from tinnitus related activity in the 4000 Hz isofrequency region.

The early kinetics of gentamicin uptake into the inner ear.

Transtympanic gentamicin administration has become a popular modality in the treatment of Ménière's disease. This modality and other inner-ear medical therapy are gaining increased clinical and scientific attention. We previously described the kinetics and effects of gentamicin uptake into the inner ear after delivery of the medicine into the middle ear using a variety of different techniques and sustained-release modalities [1]. In our previous work, we reported an early peak perilymph concentration and the presence of intracellular gentamicin at the 4-hour time point. We also demonstrated the activation of inner-ear damage pathways at this early time point. In this report, we examine the kinetics of gentamicin at very early time points, 1 and 2 hours after administration. Healthy adult chinchillas underwent implantation of middle-ear sustained-release devices (one to each ear) containing gentamicin. The animals then were maintained in a neutral position and underwent perilymph gentamicin sampling at the two predetermined time points. This technique allowed us to assess accurately very early time point inner-ear gentamicin kinetics and to compare the activity. The samples then were run for concentration using mass spectrometry. The information gained from this study may increase our scientific understanding about the effects of gentamicin on the inner ear and may allow clinicians to treat patients more effectively for inner-ear disorders.