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  Use of aminoguanidine or aminoguanidine analogs for the treatment of diseases of the nervous systemUSPTO Application #: 20070123496Title: Use of aminoguanidine or aminoguanidine analogs for the treatment of diseases of the nervous system Abstract: The present invention relates to the use of aminoguanidine compounds for treating diseases of the nervous system. Aminoguanidine compounds can be used as therapeutically effective agents against a variety of diseases of the nervous system such as diabetic and toxic neuropathies, peripheral nervous system diseases, Alzheimer's disease, Parkinson's disease, stroke, Huntington's disease, amyotropic lateral sclerosis, motor neuron disease, traumatic nerve injury, multiple sclerosis, dysmyelination and demyelination disorders, and mitochondrial diseases. The aminoguanidine compounds which can be used in the present method include (1) aminoguanidine and diaminoguanidine analogs which can act as substrates or substrate analogs for creatine kinase; (2) bisubstrate inhibitors of creatine kinase comprising covalently linked structural analogs of adenosine triphosphate (ATP) and aminoguanidine; (3) aminoguanidine analogs which can act as reversible or irreversible inhibitors of creatine kinase; and (4) N-phosphoroaminoguanidine analogs bearing nontransferable moieties which mimic the N-phosphoryl group. (end of abstract) Agent: Lahive & Cockfield, LLP - Boston, MA, US Inventor: Rima Kaddurah-Daouk USPTO Applicaton #: 20070123496 - Class: 514114000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai, Nitrogen, Other Than Nitro Or Nitroso, Bonded Indirectly To Phosphorus The Patent Description & Claims data below is from USPTO Patent Application 20070123496. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application is a continuation application of Ser. No. 10/193,059, filed Jul. 11, 2002, which is a continuation of Ser. No. 09/698,511, filed Oct. 27, 2000, abandoned, which is a continuation of Ser. No. 09/316,489, filed May 21, 1999, now U.S. Pat. No. 6,169,115 B1, which claims priority to provisional application Ser. No. 60/086,504, filed May 22, 1998. The contents of all of the aforementioned applications are hereby incorporated by reference. The entire contents of each of application Ser. No. PCT/US95/14567, filed Nov. 7, 1995, U.S. application Ser. No. 08/336,388, filed Nov. 8, 1994, and U.S. application Ser. No. 08/853,174, filed May 7, 1997 are hereby also incorporated herein by reference. The entire contents of each of U.S. Provisional Patent Application Ser. No. 60/086,585 filed on May 22, 1998 and U.S. patent application Ser. No. 09/316,918 filed on May 22, 1998, now U.S. Pat. No. 6,288,124 B1 entitled "Methods of Inhibiting Undesirable Cell Growth Using An Aminoguanidine Compound," also are hereby expressly incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] The nervous system is an unresting assembly of cells that continually receives information, analyzes and perceives it and makes decisions. The principle cells of the nervous system are neurons and neuroglial cells. Neurons are the basic communicating units of the nervous system and possess dendrites, axons and synapses required for this role. Neuroglial cells consist of astrocytes, oligodendrocytes, ependymal cells, and microglial cells. Collectively, they are involved in the shelter and maintenance of neurons. The functions of astrocytes are incompletely understood but probably include the provision of biochemical and physical support and aid in insulation of the receptive surfaces of neurons. In addition to their activities in normal brain, they also react to CNS injury by glial scar formation. The principle function of the oligodendrocytes is the production and maintenance of CNS myelin. They contribute segments of myelin sheath to multiple axons. [0003] The ependyma cells react to injury mainly by cell loss. Microglial cells become activated and assume the shape of a macrophage in response to injury or destruction of the brain. These cells can also proliferate and adopt a rod-like form which could surround a tiny focus of necrosis or a dead neuron forming a glial nodule. Microglial degradation of dead neurons is called neuronophagia. [0004] The creatine kinase/creatine phosphate energy system is only one component of an elaborate energy-generating system found in nervous system cells such as, for example, neurons, oligodendrocytes and astrocytes. The components of the creatine energy system include the enzyme creatine kinase, the substrates creatine and creatine phosphate, and the transporter of creatine. The reaction catalyzed by creatine kinase is: MgADP.sub..+-.PCr.sup.=+H.sup.+MgATP.sup.=+Cr. Some of the functions associated with this system include efficient regeneration of energy in cells with fluctuating and high energy demands, energy transport to different parts of the cell, phosphoryl transfer activity, ion transport regulation, and involvement in signal transduction pathways. [0005] The creatine kinase/phosphocreatine system has been shown to be active in neurons, astrocytes, oligodendrocytes and Schwann cells. Manos et al., J. Neurochem. 56:2101-2107 (1991); Molloy et al., J. Neurochem. 59:1925-1932. The activity ofthe enzyme has been shown to be up-regulated during regeneration and down-regulated in degenerative states (see, e.g., Annals Neurology 35(3):331340 (1994); DeLeon et al., J. Neurnosci. Res. 29:437-448 (1991); Orlovskaia et al. Vestnik Rossiiskoi Akademii Meditsinskikh Nauk. 8:34-39 (1992). Burbaeva et al.' Shurnal Neuropatholoall Psikhiatrii Imeni S-S-Korsakova 90(7):85-87 (1990); Mitochondrial creatine kinase was recently found to be the major constituent of pathological inclusions seen in mitochondrial myopathies. Stadhouders et al., PNAS, 91 pp 5080-5093 (1994). [0006] It is an object of the present invention to provide methods for treatment of diseases that affect cells of the nervous system that utilize the creatine kinase/phosphocreatine system using compounds which modulate the system. SUMMARY OF THE INVENTION [0007] The present invention pertains to methods of treating diseases of the nervous systems in an individual afflicted with such a disease by administering to the afflicted individual an amount of a compound or compounds which modulate one or more of the structural or functional components of the creatine kinase/phosphocreatine system sufficient to prevent, reduce or ameliorate the symptoms of the disease. Compounds which are effective for this purpose include aminoguanidines, e.g., aminoguanidine, diaminoguanidine, and analogs thereof. [0008] The present invention also provides compositions containing aminoguanidino compounds, e.g., aminoguanidines or diaminoguandines, in combination with a pharmaceutically acceptable carrier, and effective amounts of other agents which act on the nervous system, to prophylactically and/or therapeutically treat a subject with a disease of the nervous system. The present invention further pertains to methods of use of aminoguanidino compounds in combination with other agents which act on the nervous system for treating diseases of the nervous system. [0009] Packaged drugs for treating subjects having a disease of the nervous system or one who is predisposed to such diseases also are the subject of the present invention. The packaged drugs include a container holding the aminoguanidino compound, e.g., an aminoguanidine or diaminoguanidine, in combination with a pharmaceutically acceptable carrier, along with instructions for administering the same for the purpose of preventing, ameliorating, arresting or eliminating a disease of the nervous system. [0010] Some of the diseases susceptible to treatment with aminoguanidino compounds, e.g., aminoguanidines or diaminoguanidines, according to the present invention include, but are not limited to Alzheimer disease, Parkinson's disease, Huntington's disease, motor neuron disease, diabetic and toxic neuropathies, traumatic nerve injury, multiple sclerosis, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, diseases of dysmyelination, mitochondrial diseases, fungal and bacterial infections, migrainous disorders, stroke, aging, dementia, and mental disorders such as depression and schizophrenia. DETAILED DESCRIPTION [0011] The features and other details of the invention will now be more particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention. [0012] The methods of the present invention generally comprise administering to an individual afflicted with a disease of the nervous system an amount of a compound or compounds which modulate one or more of the structural or functional components of the creatine kinase/phosphocreatine system sufficient to prevent, reduce or ameliorate symptoms of the disease. Components of the system which can be modulated include the enzyme creatine kinase, the substrates creatine and creatine phosphate, and the transporter of creatine. As used herein, the term "modulate" means to change, affect or interfere with the normal functioning of the component in the creatine kinase/phosphocreatine enzyme system. [0013] Compounds which are particularly effective for this purpose include aminoguanidine, aminoguanidines, diaminoguanidine, diaminoguanidines and analogs thereof which are described in detail below. The term "aminoguanidine compounds" will be used herein to include aminoguanidines and diaminoguanidines, such as aminoguanidine phosphate, and compounds which are structurally similar to aminoguanidine or aminoguanidine phosphate, and analogs of aminoguanidine and aminoguanidine phosphate. The term "aminoguanidine compounds" also includes compounds which "mimic" the activity of aminoguanidine and diaminoguanidine, such as aminoguanidine, aminoguanidine phosphate or aminoguanidine analogs, i.e., compounds which inhibit or modulate the creatine kinase system. The term "aminoguanidine" is intended to not include guanidine. The term "mimics" is intended to include compounds which may not be structurally similar to aminoguanidine or diaminoguanidine but mimic the therapeutic activity of these compounds, such as aminoguanidine, aminoguanidine phosphate or structurally similar compounds. The term "inhibitors of creatine kinase system" are compounds which inhibit the activity of the creatine kinase enzyme, molecules that inhibit the creatine transporter or molecules that inhibit the binding of the enzyme to other structural proteins or enzymes or lipids. The term "modulators of the creatine kinase system" are compounds which modulate the activity of the enzyme, or the activity of the transporter of creatine or the ability of other proteins or enzymes or lipids to interact with the system. The term "aminoguanidine analog" is intended to include compounds which are structurally similar to aminoguanidine or diaminoguanidine compounds such as aminoguanidine phosphate compounds which are art-recognized as being analogs of aminoguanidine or aminoguanidine phosphate, and/or compounds which share the same or similar function as aminoguanidine or aminoguanidine phosphate. [0014] The language "treating diseases of the nervous system" is intended to include prevention of the disease, amelioration and/or arrest of a preexisting disease, and the elimination of a preexisting disease. The aminoguanidine analogs, e.g., aminoguanidine and/or diaminoguanidine compounds, described herein have both curative and prophylactic effects on disease development and progression. [0015] The language "therapeutically effective amount" is intended to include the amount of the aminoguanidine compound sufficient to prevent onset of diseases of the nervous system or significantly reduce progression of such diseases in the subject being treated. A therapeutically effective amount can be determined on an individual basis and will be based, at least in part, on consideration of the severity of the symptoms to be treated and the activity of the specific analog selected if an analog is being used. Further, the effective amounts of the aminoguanidine compound may vary according to the age, sex and weight of the subject being treated. Thus, a therapeutically effective amount of the aminoguanidine compound can be determined by one of ordinary skill in the art employing such factors as described above using no more than routine experimentation in clinical management. [0016] The language "pharmaceutically acceptable carrier" is intended to include substances capable of being coadministered with the aminoguanidine compound and which allows the active ingredient to perform its intended function of preventing, ameliorating, arresting, or eliminating a disease(s) of the nervous system. Examples of such carriers include solvents, dispersion media, adjuvants, delay agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media and agent compatible with the aminoguandine compound may be used within this invention. [0017] The term "pharmaceutically acceptable salt" is intended to include art recognized pharmaceutically acceptable salts. Typically these salts are capable of being hydrolyzed under physiological conditions. Examples of such salts include sodium, potassium and hemisulfate. The term further is intended to include lower hydrocarbon groups capable of being hydrolyzed under physiological conditions, i.e. groups which esterify the carboxyl moiety, e.g. methyl, ethyl and propyl. [0018] The term "subject" is intended to include living organisms susceptible to having diseases of the nervous system, e.g. mammals. Examples of subjects include humans, dogs, cats, horses, cows, goats, rats and mice. The term "subject" further is intended to include transgenic species. [0019] The language "diseases of the nervous system" is intended to include diseases of the nervous system whose onset, amelioration, arrest, or elimination is effectuated by the aminoguanidine compounds described herein. Examples of types of diseases of the nervous system include demyelinating, dysmyelinating and degenerative diseases Examples of locations on or within the subject where the diseases may originate and/or reside include both central and peripheral loci. As the term "disease" is used herein, it is understood to exclude, and only encompass maladies distinct from, neoplastic pathologies and tumors of the nervous system, ischemic injury and viral infections of the nervous system. Examples of types of diseases suitable for treatment with the methods and compounds of the instant invention are discussed in detail below. Diseases of the Nervous System Continue reading... Full patent description for Use of aminoguanidine or aminoguanidine analogs for the treatment of diseases of the nervous system Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Use of aminoguanidine or aminoguanidine analogs for the treatment of diseases of the nervous system patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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