Alec N Salt
Washington University
Project start date: 1992-01-01
Project end date: 2015-02-28
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Alec N Salt, Professor
Otolaryngologywashington University
Grant 5R01DC001368-18 from National Institute On Deafness And Other Communication Disorders IRG: AUD
Abstract: Disturbances of the inner ear fluids are responsible for a number of clinical disorders. The proposed studies focus on the relationships between endolymph volume disorders and inner ear function. Physiologic measures have been developed that are sensitive to small endolymph volume disturbances even when cochlear sensitivity is not impaired. They are based on even-order distortions (second harmonic (2f), f2-f1 and f2+f1 emissions) that change when the organ of Corti is displaced from its normal resting position, thereby altering hair cell transduction properties. Cochlear transducer "operating point" can be derived from cochlear microphonic and from less-invasive acoustic emissions recordings. The interrelationships between distortions and operating point will be characterized during manipulations that disturb operating point or endolymph volume. Results will be compared with models that predict the dependence of distortion on operating point. The ability to document abnormal endolymph volume states through acoustic emissions recordings is clinically relevant as it may allow endolymphatic hydrops to be diagnosed. Techniques for manipulating inner ear fluids in a minimally invasive manner will also be investigated. The distribution of drugs in the cochlea will be quantified following their application to the round window membrane with a variety of protocols. Novel perilymph sampling techniques will be used to document longitudinal drug gradients in the cochlea. Models of drug distribution in the ear will be refined and used to predict drug distribution patterns in the human ear. 3-D models will be compared with our existing simulations of inner ear fluids. Physiologic changes associated with endolymph volume disturbance and recovery will be measured. Treatments will be screened that could potentially influence endolymph volume. The findings from these combined studies are expected to directly impact both the diagnosis and management of Meniere´s disease
Keywords: Meniere`s disease, cochlea, ear disorder diagnosis, edema, endolymph, fluid flow, homeostasis, noninvasive diagnosis, otoacoustic emission auditory threshold, hydrostatic pressure, mathematical model, mechanical pressure, model design /development, osmotic pressure electrode, guinea pig
Project start date: 1992-01-01
Project end date: 2010-02-28
Grants awarded to Alec N Salt
Alec N Salt, Professor
Washington University, Campus Box 1054, Saint Louis, Mo 63130-4899
Grant 2R01DC001368-19 from National Institute On Deafness And Other Communication Disorders
Abstract: Local drug deliveries to the inner ear have become widely used in clinical practice and many new therapies are being developed. However, most of our knowledge of drug pharmacokinetics in the ear is unreliable due to both the technical difficulties in obtaining pure perilymph samples and the highly variable perilymph drug levels produced by round window applications. In the past project period, we developed novel methods of perilymph sampling and highly controlled methods of drug delivery that, when combined, allow meaningful pharmacokinetic studies to be performed for the first time. The experimental studies in our first aim will use cationic and anionic markers to quantify the distribution of substances throughout the cochlear and vestibular systems, following direct injections from pipettes sealed into perilymph at different locations. The role of electrical charge in determining whether substances enter endolymph will be studied. Concentration measurements in vivo will allow the major solute distribution and elimination properties to be quantified and will further validate measurements from fluid sampling procedures. When we understand the basic processes contributing to distribution and elimination from the ear, pharmacokinetic studies of the clinically relevant drugs gentamicin (a cation) and dexamethasone (an anion) will be performed using sequential sampling methods. The pharmacokinetics and pharmacodynamics of the anionic drug salicylate will also be studied, as an agent causing transient sensitivity changes of the ear that can be used as an indirect measure of drug distribution. A second aim will focus on additional factors influencing perilymph drug levels when the drugs are applied intratympanically. This includes study of the rate of drug elimination from the middle ear and how the applied volume affects perilymph concentration. The merits of volume stabilized (gels) or timed release (gel or PLGA nanoparticles) delivery of drugs to the cochlea will be evaluated. In conjunction with these experimental studies, comprehensive 1-D, anatomically based, mathematical models of drug distribution in the fluid and tissue spaces of animal and human ears will be developed. The enhanced models will permit complex experimental protocols to be interpreted quantitatively and will allow realistic prediction of drug distribution patterns in humans. Models will be made available to other groups in the field, permitting quantitative interpretation of a variety of animal and human data. Results from these projects will provide a basic scientific foundation for physiologic studies utilizing drug applications to the ear and will allow the delivery of drugs or other substances to the ears of humans to be optimized for specific purposes. In many cases, ears affected by diseases would benefit from treatments using locally applied drugs. At present, drug delivery protocols are developed by trial and error in humans, sometimes to the detriment of the patient. This project seeks to develop an understanding of pharmacokinetics in the ear that will, in conjunction with computer models, allow drug treatment protocols to be scientifically based
Keywords: (11Beta, 16alpha)-9-fluoro-11, 17, 21-trihydroxy-16-methylpregna-1, 4-diene-3, 20-dione; 1-Dehydro-16alpha-methyl-9alpha-fluorohydrocortisone; 16Alpha-methyl-9alpha-fluoro-1, 4-pregnadiene-11beta, 17alpha, 21-triol-3, 20-dione; 16Alpha-methyl-9alpha-fluoro-delta1-hydrocortisone; 16Alpha-methyl-9alpha-fluoroprednisolone; 9Alpha-fluoro-11beta, 17alpha, 21-trihydroxy-16alpha-methylpregna-1, 4-diene-3, 20-dione; 9alpha-Fluoro-16alpha- methylprednisolone; Aacidexam; Abbreviations; Action Potentials; Adexone; Affect; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Ambene; Amplidermis; Anatomic; Anatomical Sciences; Anatomy; Anemul mono; Animals; Anions; Antimicotico; Aquapred; Area; Automobile Driving; Auxiloson; Azona; Baycuten; Baycuten N; Blood; Body Tissues; CAPS; Capsules; Cations; Cavia; Cell Membrane Permeability; Cerebrospinal Fluid; Characteristics; Charge; Cochlea; Cochlear Organ; Cochlear structure; Complex; Computer Simulation; Computerized Models; Concentration measurement; Corson; Cortidexason; Cortisumman; Data; Decacort; Decadrol; Decadron; Decalix; Decameth; Decasone R.p.; Dectancyl; Deenar; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dex-4; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexace; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Diffusion; Dinormon; Disease; Disorder; Drivings, Automobile; Drug Delivery; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug Targetings; Drug usage; Drugs; Ear; Ear structure; Ear, Internal; Endolymph; Fluoro-9alpha Methyl-16alpha Prednisolone; Fluorodelta; Fortecortin; Foundations; Frequencies (time pattern); Frequency; Gammacorten; Garamicin; Garamycin; Gel; Genoptic; Genoptic S.O.P.; Gentamicins; Glycolates; Goals; Guinea Pigs; Hexadecadrol; Hexadrol; Human; Human, General; Injection of therapeutic agent; Injections; Ion-Selective Electrodes; Ion-Sensitive Electrodes; Ions; Knowledge; Labyrinth; Lateral; Liquid substance; Location; Lokalison-F; Loverine; Mammals, Guinea Pigs; Mammals, Mice; Man (Taxonomy); Man, Modern; Maps; Math Models; Mathematical Model Simulation; Mathematical Models and Simulations; Measurement; Measures; Medication; Membrane; Methods; Methods and Techniques; Methods, Other; Methylfluorprednisolone; Mice; Millicorten; Modeling; Models, Computer; Monitor; Murine; Mus; Mymethasone; Ocasa; Orgadrone; Organism-Level Process; Organismal Process; Patients; Pattern; Perilymph; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Physiologic; Physiologic Processes; Physiological; Physiological Processes; Predni-F; Pregna-1, 4-diene-3, 20-dione, 9-fluoro-11, 17, 21-trihydroxy-16-methyl-, (11beta, 16alpha)-; Procedures; Process; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Protocol; Protocols documentation; Protocols, Treatment; RGM; Regimen; Research; Reticuloendothelial System, Blood; Role; Round Window; Sampling; Scala Tympani; Science of Anatomy; Simulation, Computer based; Site; Spersadex; Spersadox; Structure; Structure of cochlear window; System; System, LOINC Axis 4; Techniques; Time; Tissues; Treatment Protocols; Treatment Regimen; Treatment Schedule; Tympanus, Scala; U-Gencin; Visumetazone; Work; anatomy; auricularum; base; capsule (pharmacologic); clinical practice; clinical relevance; clinically relevant; computational modeling; computational models; computational simulation; computer based models; computerized modeling; computerized simulation; disease/disorder; dosage; driving; drug distribution; drug use; drug/agent; experiment; experimental research; experimental study; fenestra cochleae; fluid; human data; in silico; in vivo; inner ear; liquid; local drug delivery; mathematical model; mathematical modeling; membrane permeability; membrane structure; middle ear; nano particle; nanoparticle; novel; poly(lactic acid); polylactic acid; programs; public health relevance; research study; salicylate; seal; simulation; social role; solute; spinal fluid; virtual simulation; web page
Relevance: In many cases, ears affected by diseases would benefit from treatments using locally applied drugs. At present, drug delivery protocols are developed by trial and error in humans, sometimes to the detriment of the patient. This project seeks to develop an understanding of pharmacokinetics in the ear that will, in conjunction with computer models, allow drug treatment protocols to be scientifically based
Project start date: 1992-01-01
Project end date: 2015-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: PA-07-070
2R01DC001368-19 (2010): $323000
3R01DC001368-18S1 (2009): $155823