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  Method of treating tremorsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Five-membered Hetero Ring Containing At Least One Nitrogen Ring Atom (e.g., 1,2,3-triazoles, Etc.), 1,3,4-thiadiazoles (including Hydrogenated), Polycyclo Ring System Having The Oxazole Ring As One Of The CyclosThe Patent Description & Claims data below is from USPTO Patent Application 20080081830. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a continuation under .sctn. 120 of U.S. application Ser. No. 10/663,187 filed Sep. 15, 2003, issued as U.S. Pat. No. 7,273,884 on Sep. 25, 2007, which claims priority under .sctn. 119 to U.S. Provisional Application No. 60/410,399, filed Sep. 13, 2002. FIELD OF THE INVENTION [0002] The present invention relates to methods of treating tremors, particularly essential tremor, with zonisamide (1,2-benzioxazole-3-methanesulfonamide). BACKGROUND OF THE INVENTION [0003] Tremor is defined as an involuntary, rhythmic oscillatory movement of a part or parts of the body, resulting from alternating or irregularly synchronous contractions of antagonist muscles. Tremor is the most common form of involuntary movement. Almost all individuals have experienced tremor at some point in their lives; however, only a small fraction of those with tremor seek medical attention. Tremors may result from normal (physiologic) or pathologic processes and may be characterized by their etiology or phenomenology (i.e., neuropathology, activation state, frequency, amplitude). With the exception of those affecting the facial region, tremors are frequently defined or characterized by the joint around which the body part moves. [0004] Tremor occurs when normal muscle activation is replaced by abnormal synchronous bursts. This evolves through alterations in ionic cell conductance in the cell membrane, causing the cell membrane to produce oscillation in its potential. The tendency to oscillate can be exaggerated by hyperpolarization of the cell away from the normal resting potential. Mainly, tremor is thought to be staged in the thalamic relay nuclei and inferior olive. The activity of neighboring cells can be coupled by electronic gap junctions in the olive and by recurrent axonal projections from the reticular nucleus in the thalamus. So, a large population of cells can oscillate together and exert a powerful rhythmic influence on motor output. Similarly, low-threshold calcium spike burst could be at the origin of rigidity and dystonia through the activation of the supplementary motor area and akinesia, when reaching the pre-supplementary motor area. [0005] Individuals of all ages have tremor (physiological tremor) associated with anxiety, fatigue, anger, caffeine, pain, extreme cold, and other stressful situations. Excessive and persistent tremor is a neuropathologic phenomenon frequently associated with a neurological disorder called essential tremor. The National Institute of Neurological Disorders and Stroke estimates that as many as 10 million people in the United States are affected with essential tremor (ET). Essential tremor affects equally in females and males. Essential tremor may begin at any age, though it is unusual before the age of 20 years. Existing essential tremor often, though not always becomes worse with age, but may also make its initial appearance at an older age. [0006] Pathologic tremor occurs when the normal continuous pattern of muscle activation is replaced by relatively synchronous neuronal bursting. This is characterized as an involuntary rhythmic oscillation of reciprocally innervated antagonistic muscle groups, causing movement of a body part about a fixed plane in space. Frequency of oscillation is divided into three main components: slow (3 to 5 Hz), intermediate (5 to 8 Hz), or rapid (9 to 12 Hz). The amplitude of oscillation is defined as fine, medium or coarse. [0007] Current drug treatments of tremors do not offer long-term sustained efficacy and pose a high risk of complications with prolonged use. The most common and primarily prescribed treatment is a beta-blocker propranolol and its more potent, with longer half-life version, timolol. Many movement disorder specialists also choose to prescribe benzodiazapine (alprazolam, clonazepam, diazepam, lorazepam), anti-depressant (trazadone, mirtazapine), centrally acting alpha-agonist (clonidine), anti-spasmodic (botulinum toxin injection), anti-seizure (gabapentin, primidone, phenobarbital) type medications. It was recently reported that the noncompetitive NMDA channel blocker, MK-801 could block the tremorogenic actions of harmaline. Competitive blockade of harmaline-induced tremor by MK-801 occurs within the calcium channel coupled to the NMDA receptor. A number of surgical treatments have become available to treat these tremors. These procedures, which involve stimulation or ablation of the thalamic region via surgical intervention, have a risk factor of aneurysm and death of about 2 to 3%. Thus, there is a clear need for an effective, low risk therapy for tremors. [0008] Zonisamide is an antiseizure drug classified as a sulfonamide and chemically unrelated to other antiseizure agents. Zonisamide has the chemical structure of 1,2-benzisoxazole-3-methanesulfonamide and is further characterized in the Merck Index (11.sup.th Ed. 1989) at monograph no. 10094. Zonisamide and related structures are described in described in U.S. Pat. No. 4,172,896, which is hereby incorporated herein by reference in its entirety for all purposes. It is approved for use in humans in the United States, Korea and in Japan. The mechanism(s) by which zonisamide exerts its antiseizure activity is unknown. Anticonvulsant activity has been demonstrated by an increase in threshold for generalized seizures in the kindled rat model and by a reduction in the duration of cortical focal seizures induced by electrical stimulation of the visual cortex in cats. Furthermore, zonisamide suppressed both interictal spikes and the secondarily generalized seizures produced by cortical application of tungstic acid gel in rats or by cortical freezing in cats. [0009] Zonisamide may produce anti-epileptic and anti-convulsant effects through action at both sodium and calcium channels. In vitro pharmacological studies suggest that zonisamide blocks voltage-gated sodium channels and reduces voltage-dependent, transient inward calcium currents (T-type Ca.sup.2+ currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization. In vitro binding studies have demonstrated that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion that does not produce changes in chloride flux. Other in vitro studies have demonstrated that zonisamide (10-30 .mu.g/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [3H]-GABA (rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies demonstrated that zonisamide facilitates both dopaminergic and serotonergic neurotransmission. [0010] Murata, et al., (Neurocsci Res. 41:397 (2001)) report that patients given 50-200 mg/day zonisamide in addition to their anti-Parkinson Disease drug showed lessening of symptoms. Takigawa, et al., (Rinsho ShinKeigaKa, 37:1006-9 (1997)) report symptoms of cortical myoclonic tremor of one patient improved after treatment with zonisamide, clonazepam and valpolate. Taira (NoToShinKei 44:16-3 (1992)) reports that two patients developed resting and postural hand tremor after administration of zonisamide. [0011] Based on the ability of zonisamide to suppress seizures generated in thalamic regions, Applicants have discovered that zonisamide is efficacious in treating tremors. SUMMARY OF THE INVENTION [0012] The present invention is directed to a method of treating tremors in a subject in need of such treatment. The method comprises administering to a subject a pharmaceutical composition comprising zonisamide, or a pharmaceutically acceptable salt thereof, in an amount effective to reduce symptoms of tremors. The invention provides a method for treating action tremor such as essential tremor, postural tremor, drug-induced or toxic tremor, primary orthostatic tremor, dystonic tremor, neuropathic tremor, and cerebellar tremor in mammals. The invention also provides a method for treating rest tremor, such as severe essential tremor. [0013] The pharmaceutical composition can be administered in the range of 0.5-10 mg/kg/day through a variety of routes of administration, including oral, topical, rectal, injection, or implantation. A preferred route of administration is via oral dosing. DETAILED DESCRIPTION OF THE INVENTION [0014] The present invention provides a method of treating subjects afflicted with pathologic tremors, particularly action tremors, which includes postural tremor and kinetic tremor. The present invention is also useful in treating rest tremor such as severe essential tremor. The method comprises administering to a subject a pharmaceutical composition comprising an effective amount of zonisamide, or a pharmaceutically acceptable salt thereof, to reduce symptoms of tremors. A preferred salt is an alkaline metal salt of zonisamide, such as sodium, lithium, potassium, which is stable. [0015] Tremor is defined as an involuntary, rhythmic oscillatory movement of a part or parts of the body, resulting from alternating or irregularly synchronous contractions of antagonist muscles. Tremor is the most common form of involuntary movement. Tremor can be classified according to the clinical phenomenology as rest tremors and action tremors. [0016] Rest tremor is present when skeletal muscles are not voluntarily activated and the relevant body part is fully supported against gravity. Rest tremor may occur with Parkinson's disease, or as hereditary chin quivering, or with severe essential tremor. [0017] Action tremor occurs during voluntary muscle contraction and includes postural and kinetic tremor. Postural tremor is an action tremor that is present while voluntarily maintaining a position against gravity. Postural tremor is often associated with essential tremor or may occur as primary orthostatic tremor, physiologic and enhanced physiological tremors, drug-induced or toxic tremors (including alcohol-related tremors), neuropathic tremor, cerebellar head tremor (titubation) or dystonic tremor. [0018] Kinetic tremor is an action tremor which may occur during any form of voluntary movement including visually- or nonvisually-guided actions, such as speaking, pouring water into a cup, or finger-to-nose testing. Kinetic tremor is often associated with essential tremor, classic cerebellar tremor (e.g., seen in multiple sclerosis, infarction), dystonic tremor, drug-induced or toxic tremors, or midbrain lesions. Kinetic tremor also includes dynamic or terminal tremor, which occurs with target-directed movements, and simple kinetic tremor, which is present with nontarget-directed actions. Task- or position-specific tremor is a kinetic tremor that occurs during performance of highly specialized, complex movements, such as writing, speaking, or smiling. Isometric tremor is a kinetic tremor present during voluntary muscle contraction against a rigid stationary object, such as making a fist or flexing the wrist against a horizontal, flat surface. [0019] The present invention is useful for treating action tremors such as essential tremor, postural tremor, drug-induced or toxic tremor (including alcohol-related tremor), cerebellar tremor, primary orthostatic tremor, dystonic tremor and neuropathic tremor. Continue reading... Full patent description for Method of treating tremors Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method of treating tremors patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. 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