Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-10-13
2001-07-24
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S014800, C424S236100, C424S239100
Reexamination Certificate
active
06265379
ABSTRACT:
BACKGROUND
The present invention relates to methods for treating otic disorders. In particular the present invention relates to methods for treating otic disorders by local administration of a neurotoxin to a human ear.
The human ear can be divided into an outer ear, a middle ear and an inner ear. The outer ear comprises the auricle (commonly referred to as the ear) and the external acoustic meatus (the auditory canal). The tympanic membrane (commonly called the eardrum) separates the auditory canal from the middle ear (the tympanic cavity). Three small, mobile bones, the incus, malleus and stapes make up an ossicular system which conducts sound through the middle ear to the cochlea. The handle of the malleus is attached to the center of the tympanic membrane. At its opposite end, the malleus is bound to the incus by ligaments, so that movement of the malleus causes the incus to also move. The opposite end of the incus articulates with the stem of the stapes. The faceplate of the stapes rests against the membranous labyrinth in the opening of the oval window, where sound waves are conducted into the inner ear. In the cochlea the sound waves are transduced into coded patterns of impulses transmitted along the afferent cochlear fibers of the vestibulocochlear nerve for analysis in the central auditory pathways of the brain.
The air filled tympanic cavity contains various muscles including the tensor tympani and stapedius muscles. The tensor tympani is a long slender muscle which occupies the bony canal above the osseous pharyngotympanic tube, from which it is separated by a thin bony septum. The tensor tympani muscle receives both motor and proprioceptive innervation. A motor branch derived from the nerve to the medial pterygoid (mandibular division of the V, parasympathetic, trigeminal nerve) passes through the otic (a peripheral, parasympathetic cholinergic) ganglion to the tensor tympani. The stapedius muscle extends from the wall of a conical cavity in the pyramidal eminence, located on the posterior wall of the tympanic cavity. The stapedius is innervated by a branch of the (VII, parasympathetic) facial nerve.
Middle ear structures can be examined endoscopically, as set forth by Karhuketo et al.,
Endoscopy of the Middle Ear Structures
, Acta Otolaryngol (Stockh) 1997; Suppl 529:34-39, the contents of which publication are incorporated herein by reference. There are many diseases of the ear including otis media. Otis media is an inflammation of the middle ear, commonly due to infection, and treatable by antibiotics. Alternate treatments for otis media include analgesics, antipyretics and myringotomy.
Loud noise can cause a muscular reflex to arise which attenuates the effect of excessive loud sound upon the middle and inner ear. Thus, the tensor tympani muscle can contract and pull the handle of the malleus inward while the stapedius muscle contracts and pulls the stapes outward. These two forces oppose each other and result in a high degree of rigidity developing in the ossicular system, thereby greatly reducing (by about 30-40 decibels) conduction of low frequency sounds by the ossicular system. This attenuation reflex can protect the cochlea against the damaging vibrations which would otherwise be induced by loud noise and may also act, mask out low frequency sound in a loud environment, and decrease a person's hearing sensitivity to his own voice.
The inner ear comprises the osseous labyrinth and the contained membranous labyrinth. The osseous labyrinth has three regions, the vestibule, the semicircular canals and the cochlea. The membranous labyrinth can be divided into the vestibular apparatus and the cochlear duct. In the walls of the membranous labyrinth within the vestibular apparatus are five distinct area of specialized sensory epithelium to which the terminal fibers of the vestibular nerve are distributed. Hair cells (epitheliocyti pilosi) in the cochlea are the sensory transducers which collectively detect the amplitude and frequency of sound waves entering the cochlea. The efferent innervation of at least the outer hair cells is cholinergic. Afferent innervation of the hair cells is complex and may involve release of one or more neurotransmitters, including glutamate.
Tinnitus
Tinnitus is a perception of sound which originates in the head. It has been estimated that 36 million Americans have some form of tinnitus and that one third of these have severe tinnitus, that is 12 million Americans hear tinnitus all the time (Vernon. J. A.,
Tinnitus Treatment and Relief
, Allyn & Bacon (1998)). In objective tinnitus, the sound is audible, can be heard upon examination of the patient, and frequently corresponds to respiration. In the more frequent subjective tinnitus the sound cannot be heard by someone other than the patient. Tinnitus can be due to myoclonus of the palatal, tensor tympani and/or stapedius muscles.
Myoclonus is a sudden, involuntary movement caused by a muscle contraction or muscle inhibition and can be classified as physiologic, essential, epileptic and symptomatic myoclonus. Palatal myoclonus is characterized by involuntary movements of the soft palate and pharynx. The rhythmic involvement of the eustachian tube can result in the production of audible clicking sound synchronous with the palatal myoclonus. In palatal myoclonus the patient hears an irregular clicking sound coming form one or both ears The condition is caused by myoclonic contractions in tensor or levator palati muscles or both. The injection of botulinum toxin into the soft palate has been effective to treat palatal myoclonus.
Myoclonus of the middle ear is characterized by abnormal repetitive muscle contractions in the tympanic cavity and can result in subjective or objective tinnitus. Permanent relief has been obtained by sectioning or by lysis of the tendons of the stapedius and tensor tympani muscles.
Inner ear tinnitus has been treated by section of the auditory nerve. Animal studies have shown that drugs, such a aspirin, which are known to cause tinnitus, do so with an increase in activity of the auditory nerve. It has therefore been speculated that a decrease in the endocochlear potential by down regulation of the auditory nerve may alleviate tinnitus.
A particular form of inner ear tinnitus is cochlear synaptic (cochlear nerve dysfunction) tinnitus which is due to functional disturbances of the synapse between cochlear hair cells and afferent dendrites of the auditory nerve. The neurotransmitter at the afferent cochlear synapse is glutamate. The majority of patients with cochlear synaptic tinnitus intravenously infused with the glutamate antagonists glutamic acid diethyl ester and caroverine have noted a tinnitus reduction. Drug therapy for inner ear tinnitus has included benzodiazepine tranquilizers such as valium and Xanas (alprazolam), a powerful anxiolytic drug which has strong addictive properties and can cause personality changes. The local anesthetic lidocaine has been proven to relive tinnitus. Unfortunately, because of serious toxicity, lidocaine must be given intravenously and it's effect lasts for only about 5-30 minutes.
Tensor tympani syndrome is a condition in which increased tension in the tensor tympani muscle produces a fluttering low frequency sound in the ear. In many cases the sound is also felt, as if there is a fluttering insect in the bottom of the ear canal. This is caused by the tympanic membrane being rapidly moved by the fibrillation of this middle ear muscle. Therapy includes section of the tendon of the tensor tympani muscle behind the neck of the malleus.
Tinnitus resulting from Meniere's disease can be treated by sectioning the vestibular nerve. Auditory nerve section has been used as a means of treating intractable tinnitus, often with the condition worsening because the tinnitus was not due to a cochlea disorder, prior to irreversible ablative surgery, after which no residual hearing will remain in the ear operated upon.
Botulinum Toxin
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide ne
Allergan Sales Inc.
Baran Robert J.
Fisher Carlos A.
Jagoe Donna
Krass Frederick
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