Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-01-19
2003-02-25
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S468000
Reexamination Certificate
active
06524619
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is in the field of pharmacology and relates specifically to the improvement of clinical conditions associated with symptomatic or presymptomatic hearing loss and/or tinnitus and the reduction of risks associated with their onset.
2. Description of the Prior Art
Pertinent Anatomy of the Ear
The ear of humans consists of three parts: the outer, middle and inner ear. The outer ear consists of the external ear and the auditory canal. The external ear modifies sound waves and the air-filled auditory canal conducts the sound waves to the middle ear, which consists of the tympanic membrane, or eardrum; the eustachian tube; and three tiny bones called the hammer, anvil, and stirrup. Membranes and bone surround the middle ear with the eustachian tube connecting it to the pharynx, equalizing the air pressure between the middle ear and the atmosphere.
Within the middle ear, sound first vibrates the tympanic membrane, which in turn vibrates the hammer, the anvil, and the stirrup. These bones transmit vibrations from the tympanic membrane to a much smaller membrane, the oval window. The oval window covers the opening of the inner ear, in which sound vibrations are transmitted through fluid. The fluid-filled hollow bones of the inner ear form the spiral shaped cochlea and the vestibular apparatus where vibrations are translated into neural signals.
The senses of hearing and equilibrium depend on sensory receptors called hair cells located on the basilar membrane of the cochlea. These hair cells can detect motions of atomic dimensions and respond more than 100,000 times a second. Biophysical studies suggest that mechanical forces control the opening and closing of transduction channels by acting through elastic components in each hair cell's mechanoreceptive hair bundle. Other ion channels, as well as the mechanical and hydrodynamic properties of hair bundles, tune individual hair cells to particular frequencies of stimulation.
Even though well characterized at a biophysical level, the mechanical transduction mechanism of hair cells is still not completely understood in molecular terms. This discrepancy is in part due to the extreme scarcity of hair cells; instead of the millions or even hundreds of millions of receptor cells that the olfactory and visual systems possess, only a few tens of thousands of hair cells are found in the internal ears of most vertebrate species. The small number of hair cells and the direct transduction mechanism has greatly impeded molecular biological and biochemical characterization. Molecular description of hair-cell transduction has consequentially lagged behind description of vision and olfaction.
A comprehensive model for hair-cell transduction has emerged. Residing in the mechanoreceptive organelle of a hair cell, the hair bundle (the transduction apparatus) consists of at least three components: the transduction channel, a mechanically gated ion channel; the tip link, an extracellular filament that transmits force to the channel's gate; and the adaptation motor, a mechanism that maintains an optimal tension in the tip link so that the channel can respond to displacements of atomic dimensions.
The tip link appears to be the anatomical correlate of a gating spring, an elastic element through which stimulus energy can affect the transduction channel. A cluster of myosin molecules constitutes the adaptation motor. Hair cells express a variety of myosin isozymes.
The specialized innervation of hair cells makes the restoration of hearing potentially a practical form of neural-replacement therapy. Hair cells lack axons and dendrites; instead, the basolateral surfaces of these cells make afferent synaptic contacts with VIIIth nerve terminals and receive efferent contacts from neurons in the brainstem. When hair cells are destroyed, this innervation often remains intact; indeed, the integrity of the afferent innervation underlies the success of cochlear prosthetics. If hair cells can be successfully regenerated, it follows that their re-innervation may be possible. In contrast, in other proposed neural-replacement therapies, transplanted neurons are called upon to extend their axons substantial distances in order to make appropriate connections. It is questionable whether such axiogenesis is possible in the adult brain or spinal cord.
Axons in the cochlear component of the VIIIth VIIIth nerve project to each of the three cochlear nuclei; an orderly representation of stimulus frequency is preserved at each subsequent level of the ascending pathway. Extensive decussation occurs at the pontine and midbrain levels. Then, via the superior olivary nuclei process, information is transmitted to an auditory spatial map in the inferior colliculus and finally via the medial geniculate nucleus to the temporal cerebral cortex.
Pertinent Physiology of the Ear
The defining event in the hearing process is the transduction of mechanical stimuli into electrical signals by hair cells, the sensory receptors of the internal ear. Stimulation results in the rapid opening of ionic channels in the mechanically sensitive organelles of these cells, their hair bundles. These transduction channels, which are non-selectively permeable, are directly excited by hair-bundle displacement. Hair cells are selectively responsive to particular frequencies of stimulation, due to both the mechanical properties of their hair bundles and because of an ensemble of ionic channels that constitutes an electrical resonator.
The unique structural feature of the hair cell is the hair bundle, an assemblage of microscopic processes protruding from the cell's top or apical surface. Each of these processes, which are termed stereocilia, consists of a straight rod of fasciculated actin filaments surrounded by a membranous tube. Because the microfilaments are extensively cross-bridged, each stereocilium behaves as a rigid rod. When mechanically disturbed, it remains relatively straight along its length but pivots about a flexible basal insertion. When the fluid moves in response to sound, the force of viscous drag bends the bundles, thereby initiating a response.
At any instant, each transduction channel at a stereocilium's tip may be either closed or open. The relative values of the rate constants for channel opening and closing determine the fraction of the transduction channels open in the undisturbed steady state. When the hair bundle is deflected with a positive stimulus, the values of the rate constants are altered; the opening rate constant is larger and the closing rate constant smaller than the original values. The new steady-state transduction current is therefore greater and the cell is depolarized. Pushing the hair bundle in the opposite direction has a contrary effect on the rate constants, culminating in a hyperpolarizing response.
When the hair bundle is deflected, transduction channels open and positive ions, largely K
+
, enter the cell. The depolarization evoked by this transduction current activates voltage-sensitive Ca
2+
channels. As Ca
2+
ions flow into the cell they augment depolarization and raise the intracellular concentration of Ca
2+
, especially the local concentration just beneath the surface membrane. Elevated Ca
2+
concentrations activate Ca
2+
-sensitive K
+
channels. As K
+
exits through these pores it initiates membrane repolarization and diminishes the activation of Ca
2+
channels. The fluid bathing the apical surface of a hair cell characteristically has a much higher K
+
concentration than that contacting the basolateral surface; as a consequence, K
+
can both enter and leave the cell passively. Once the membrane potential becomes more negative than its steady-state value, intracellular Ca
2+
concentration is reduced by sequestration of the ion within cytosolic organelles and by extrusion through Mg
+
-cofactored, ATPase-fueled ion pumps. The Ca
2+
-sensitive K
+
channels have now closed and the hair cell retu
Pearson Don C.
Richardson Kenneth T.
Chronorx, Inc.
Spear James M.
Townsend and Townsend / and Crew LLP
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