Methods of providing neuroprotection

Description: TECHNICAL FIELD [Detailed description of the invention]

How to protect nerve cells The present invention relates to the NMDA (N-methyl-D-aspartate) receptor complex. Antagonist drug composition at the lysine site and acute in neurological disorders Or it relates to a method of alleviating (neuroprotection) chronic neuropathy. Background of the invention Some of the 1996 literature described after enumerating conventional inventions is the conventional invention. (USSerlal No.08 / 632,338) Understand the present invention without showing previous techniques. This is to make it easier. The major excitatory neurotransmitter in the central nervous system is L-glutamate. The amino acids glutamate and aspartate are given to the cerebral cortex And convulsions occur (Hayashi, T., Jpn.J. Physiol., 3: 46-64, 1952). Excitability Receptors include AMPA, kainate and NMDA receptors (Wa) tkins, JCAnn.Rev.Pharmacol.Toxicol., 21: 165-204, 1981). The specificity of the NMDA receptor channel complex is the physiological concentration of Mg2 +. Sensitivity to blockade by, high permeability to Ca2 + and mutual by glycine Activation conditions and the like can be mentioned. That is, in the NMDA receptor complex The binding sites of syn and glutamate bind as allosteric (Kemp, JA, Trends Pharmacol sci., 14 (1): 20-5, 1993). Excitatory amino acid receptors are NMDA-type and non-NMDA (kainate) And AMPA) (Monaghan, DT, Annu.Rev.Pharmacol.Toxicol. , 29,365-402,1989). The NMDA receptor complex is located on the surface of nerve cells , Multiple binding sites (ie glycine, polyamines, NMDA) and a few It is composed of ion channels having a partial binding site. MDA receptor is the brain Widely distributed in the cerebral cortex and spinal cord, with the highest distribution density in the cerebral cortex and hippocampal ridges Key (McBain, CJ, Physiol. Rev., 74: 723-760,1994, Leeson, PD, J.Med. Chem., 37 (24): 4053-4067, 1994). MDA receptors for learning and memory processes Plays an important role in essential long-term potentiation (LTP) (Cotman, CW, Annu.R) ev. Neurosci., 11: 61-80, 1988). The major excitatory neurotransmitter in the central nervous system is L-glutamate. Glutamate is the major excitatory neurotransmitter in the brain, cognitive, memory, working and It plays a comprehensive role in neurological functions such as excitement and excitement. Involved in neurological disorders In a recent report, Glutami in the etiology of multiple acute and chronic neurological disorders The role of phosphate is implied (Llpton, SA, MEJM330 (9): 613-622,199) .. In NMDA-type and non-NMDA receptors, glutamate is intracellular Opens an ion channel through which cations (Na + and Ca2 +) flow rapidly. NMD Strychnine insensitivity to the specificity of the A receptor channel complex, physiology Blockade by Mg2 + at target concentrations, high permeability to Ca2 + and mutual activity by glycine There are sexualization conditions and so on. That is, glycine and glycine in the NMDA receptor complex The binding site of glutamate binds as an allosteric, and glycine binds to this. Indispensable for scepter reaction (Carter, AG, Drugs Fut., 17 (7): 595-613,1 992, Leeson, PD, J.Med.Chem., 37 (24): 4053-4067, 1994). Glutamic acid, an amino acid, causes convulsions (Hayashi, T., Jpn.JP) hysiol., 3: 46-64, 1952), resulting in decreased cortical diffusion (Van Harreveld, A., J. Ne) urochem., 3: 300-315,1959), further activated, resulting in complex partial epilepsy (Dur) ing, MJ, Lancer, 341: 1607-1610, 1993). Glycine agonist into the cerebrum It was found that the administration increased the efficacy of NMDA, which promotes seizures in mice (Sing). h, L., Eur.J. Pharmacol., 186: 129-132, 1990). Functional glycine antagonists have high endogenous activity (D-cycloserine) or low Has intrinsic activity (HA-966). Compound HA-966 is partially weak at the glycine site It may also exhibit agonist efficacy and may cause prodromal symptoms of convulsions (Wlaz, P., Eur.J. Neurosci, 6 (11): 1710-1919, 1994). US Pat.Nos.2,884,444 (1959) fervamate (2-phenyl-1,3-pro) Pandiol dicarbamate) is a commonly known drug compound. Felva Minate is a glycine site antagonist of the NMDA receptor. In U.S. Pat. No. 4,978,680, fervamic acid for the prevention and control of epileptic seizures It is disclosed regarding the usage of salt. U.S. Pat. No. 5,082,861 with complex partial epilepsy Disclosure regarding the use of fervamate to prevent and control epileptic seizures Has been done. U.S. Pat. No. 5,292,772 states that Lennox-Gastaut syndrome is associated with Disclosure of the use of fervamate to prevent and control seizures ing. U.S. Pat. No. 4,868,327 discloses the synthesis of fervamate. Ferbamate is a modulator of NMDA receptor function and glyci Acts as a site antagonist (McCabe, RT, J.Pharmacol.Exp.Ther., 264 (3)) 1248-1252,1993, Sofia, RD, Ann.Neurol., 36 (4): 677-678,1994, Wamsle y, JK, Exp.Neurol., 129 (2): 244-250,1994, Taylor, LA, Eur.J.Pharm acol.,289 (2): 229-233,1995, White, HS, Epilepsy Res., 20 (1): 41-48,19 95), yet another mechanism of action has been reported (White, HS, Epilepsy, 33 (3): 564-572,1992, DeSarro, G., Eur.J.Pharmacol., 262 (1-2): 11-19,1994, Se rra, M., Eur.J.Pharmacol.,265 (3): 185-188,1994, Rho, JM, Ann.Neuro l., 25: 229-234,1994, Subramanian, S., J.Pharmacol.Exp.Ther., 273: 878 -886, 1995). Ferbamate is found in neurons of the brain after administration of antagonists Does not cause transient neuropathological changes (Olney, JW, Arch.Gen.Ps) ych., 52: 998-1007, 1995). Ferbamate prevents NMDA-induced convulsions in mice (White, H) .S., Epilepsy, 33 (3): 564-572,1992, Sofia, RD, Ann.Neurol., 36 (4): 6 77-678,1994). In patients with epilepsy, 2-phenyl-1,3-propanediol Zika Focal epilepsy was suppressed by rubamate (Wilensky, AJ, Ep) ilepsia, 26 (6): 602-606, 1985). The main anticonvulsant effect of fervamate is NM Due to the interaction of the DA complex at the strychnine insensitive glycine site (McCabe, RT, J.Pharmacol.Exp.Ther., 264 (3): 1248-1252,1993, White, HS, Epilepsy Res., 20 (1): 41-48, 1995,). Rats with neuropathy Ferbamate is glycine-induced in a simulated experiment with hippocampal ridge slices 7-Chloro-kynurenic acid (another glycine site) Antagonist Quality) was found to be toxic (Wallis, RA, Brain Res., 685 (1-2): 115-125, 1995 ). Further reports indicate that fervamine is an AMPA / kainate receptor. And interact with each other (De Sarro, G., Eur.J. Pharmacol., 262 (1-2): 1 1-19,1994), promote GABA receptor function (Serra, M., Eur.J. Pharmac) ol.,265 (3): 185-188,1994, Rho, JM, Ann.Neurol., 25: 229-234,1994), Adjusting the conductivity of Na + channel (White, HS, Epilepsy, 33 (3): 564-572 , 1992), Muscarinic Metabolic Receptors (Libri, V., J. Pharmacol. Exper. Ther., 277: 1759-1769, 1996) and L-type (high potential) calcium channels ( In Stefani, AJ, J.Pharmacol.Exper.Ther., 277: 121-127, 1996) It interacts. Fel after kainic acid causes epileptic symptoms in animals Administration of bamate reduced delayed neuronal cell death (Chronopoulos, A., Ep) ilepsia, 34 (2): 359-366, 1993). Glycine or d-serine is fervamic acid Anticonvulsant effect of salt (Harmsworth, WL, Epilepsia, 34 (suppl 2): 92,1993, Coffee n, V., Eur.J. Pharmacol., 265: 9-10, 1994) and ischemic protection (Wallis, RA, Neuro.Report, 4: 951-954, 1993) was able to retreat functionally. Shi Adjustment of GABA receptor (Ticku, MK, Epilepsy, 32 (3): 389-391, 1995 ), Prevention of toxicity with kainate (Kanthasamy, AG, BrainRes., 705: 97-104) , 1995), or the mechanism of action of glycine site antagonists (Rho, JM, Ann. Neurol. , 25: 229-234,1994, Subramanian, S., J.Pharmacol.Exp.Ther., 273: 878-8 There is no established study on 86, 1995). In cultured tissue, at the glycine site or channel of the NMDA receptor Antagonism prevents degeneration due to hypoxia (Priestly, T., Brain Res., 531: 183-8, 1990). Administration of fervamate in animal simulation experiments on seizures (ischemia) Reduced nerve death and delayed ischemic necrosis (Wasterlain, CG, Neurology) , 43: 2303-2310,1993), and also the delayed apoptosis of CAl hippocampal raised granule cells A decrease in cis (Wasterlain, CG, Stroke, 27: 1236-1240, 1996) was observed. Ferbamate has been proposed as a therapeutic treatment for seizure prevention in humans (Flsher, M., Stroke, 25 (5): 1075-1080, 1994). Excessive NMDA receptor due to excitatory amino acids or neurotoxicity regulators of inflammation Activation has been implicated in the etiology of acute and chronic neurological disorders (Be) al, MF, FASEB J, 6: 3338-3344, 1992). In acute neurological disorders, guru When the toxicity of tamate increases sharply, the god of overstimulation of the NMDA receptor Menstrual death may occur. Mitochondrial function in chronic neurological disorders When a deficiency or abnormal cell metabolism occurs, nerve cells respond to endogenous glutamate. Can become vulnerable and lead to excitotoxic death (Novelli, A., Brain Res., 45 1: 205) -212,1988, Simpson, JR, Exper.Neurol., 121: 57-64, 1993, Henneberry, RL, Ann.NY.Acad.Sci., 568: 225-233, 1989). Bioenergetic defects It consumes cellular energy and depolarizes the dormant membrane, resulting in Mg2 + NMD. A receptor blockade is released. Due to such an event, the nerve becomes endogenous glutamine. Sensitive to the normal NOAEL of acid salts, intracellular calcium accumulates and slows Leads to idiopathic nerve death (Cox, JA, Brain Res., 499: 267-272, 1989, Beal, MF, Ann. Neurol., 31: 119-130, 1992). Abnormal NMDA receptors (quantitatively or qualitatively) in diseased states are biological energy It may also increase the probability of nerve death due to rugy defects (Albin, RL, Neu) rology 42: 733-738, 1992). Huntington said he dissected a patient with presymptomatic disease Around the same time, a decrease in NMDA receptors in the brainstem ganglion was observed, and an insidious receipt was observed. It suggests that putter loss is associated with functional changes in the disease (Al). bin, RL, NEJM 322: 1293-1298, 1990). From the above, the NMDA excitotoxicity hypothesis May be the final dogma for neurological death in acute and chronic neurological disorders To. Glycine site NMDA antagonists such as fervamate are chronic neurological disorders The cause of the disease cannot be eliminated, but the lifespan of nerve cells that can withstand chronic energy damage is extended. Prevents late-onset cell necrosis and apoptosis of acute neurological disorders. Ferbamate and adverse events "Compulsive" treatment in patients with refractory seizures in pre-FDA-approved clinical studies (That is, in combination with other standard antiepileptic drugs) and fervamic acid as a monotherapy Salt was evaluated. Decrease in platelets and other hematological factors in some cases Reported, but the degree of reduction is small, reversible, and has these side effects. It was in combination with the standard anti-epileptic drug. Liver damage due to myelosuppression prior to approval No cases reported harm. Serum due to drug interaction with fervamate Dilantin levels, valproate, phenovabirbitol and carbamate Increased levels were observed in pin-toxic epoxide metabolites. Ferbamin The acid salt was approved for use in July 1993. In 1994, died of fervamate 21 patients, including 7 dead, had aplastic anemia (Pennel, PP, Neurology, 45: 456- 460,1995), and 11 patients, including 4 dead, had liver failure (O'Neil, MG, Neu) It was reported that he developed rology, 46: 1457-1459, 1996). As a result, 1994 8 Month, FDA and manufacturers are at higher risk of seizures than risk of aplastic anemia Document all doctors to discontinue fervaminetation to patients except in Obtained by. Some warnings have been added to this information, and blood tests are done every two weeks. It was deemed necessary. In a study reported after the FDA's warning (Li, LM, Euro.Neur) ol., 36: 146-148, 1996), 111 patients with refractory epilepsy received additional treatment with fervamate Received. Aplastic anemia or liver when monitoring serum anticonvulsant levels No insufficiency was observed. In addition, fervamate in suicidal overdose Safety was reported (Nagel, TR, Ped. Emerg. Care., 11 (6): 369-371,199 Five). A young patient took 6900 mg in a hurry at one time, but neurology and hematology No target or liver abnormalities occurred. Other thrombocytopenia (Ney, GC, Neurology, 44: 980-981,1994), toxic epidermis Necrosis (Travagline, MT, Pharmacotherapy, 15 (2): 260-4, 1995), hypersensitivity (0'N) eil, MG, Ann.Pharmacother., 29 (4): 430, 1995), Manic (Hill, RR, Psyc) hosomatics, 36: (4) 404-6, 1995), Psychosis (Knable, MB, J.Clin.Psychoph) armacol., 15 (4): 292-3, 1995) and movement disorders (Kerrick, JM, Neurology, 45) Adverse events such as (1): 185-7, 1995) have been reported. Purpose of the invention An object of the present invention is, firstly, an acute involvement in excessive activation of the NMDA receptor. And to provide drug composition and methods for the treatment of chronic neurological disorders .. Second, preventive medications for patients with asymptomatic or pre-symptomatic neurological disorders Chronically administered to reduce cell death due to excessive activation of NMDA receptors To provide a way to do it. Third, a set of drugs that are effective in controlling or alleviating acute or chronic neurological disorders To provide the process and method. Fourth, acute or chronic neurology associated with excessive activation of NMDA receptors The purpose is to provide a drug composition and a therapeutic method for preventing and suppressing a disease. this The drug composition is relatively non-toxic, highly effective and has a long-term therapeutic response. Continue to wake up. Fifth, life in patients with normal human comparison, asymptomatic or clinical disease The purpose is to provide a method for diagnostic imaging and quantification of NMDA receptors in the body. Sixth, due to increased excitatory amino acid basal levels, seizures or epileptic symptoms, NM To provide a method for reducing neural death caused by overactivation of DA receptors. There is. Seventh, acute and chronic neurology associated with overactivation of NMDA receptors To provide a method for alleviating and controlling a disease. Outline of the invention The present invention uses a glycine site antagonist of the NMDA receptor, such as in humans. How to Treat Acute and Chronic Neurological Disorders in Sentinel and Neurological Disorders It relates to a method for preventing nerve cell death in the body. Reduces neurological disease and death Antagonists are administered acutely or chronically, either intravenously or orally. To. In particular, this antagonist is used in patients with asymptomatic or preclinical neurological disorders. It is administered prophylactically for a long time. In addition, the present invention includes NM in mammals, including administration of labeled fervamine salt. DA Receptor Level Measurements and Labeled Felbami Binds to Neurons It relates to a method for quantifying phosphate. Detailed description of the invention The present invention relates to acute and chronic nerves associated with excessive activation of NMDA receptors. It relates to drug composition and methods for alleviating illness. In particular, the present invention Neuroprotection of neurological diseases by intravenous injection or oral administration of therapeutic agents It relates to a method, and the therapeutic agent generally includes, for example, as an active ingredient. 2-Phenyl-1,3-propanediol dicarbame called fervamate Is included. The compound fervamate is suitable for the symptoms of various neurological disorders It may be administered prophylactically, acutely, subacutely, or chronically. .. This compound has multiple mechanisms of action, one of which is NMDA (N-methyl-D-a). Spalaginate) Receptor Glycine site It acts as an antagonist. NMDA receptor antagonists are non-antagonistic (in the receptor channel complex) (Acts on) and antagonistic (NMDA recognition or regulation site glycine, poly It can be classified as (acting on amines). Antagonistic channel blockers suppress harmful overstimulation of receptor excitatory parts However, at the same time, the normal physiological function of the receptor may be eliminated. In other words Most blockers are thrown into humans, as cognitive and memory brain function is impaired. Giving is dangerous. In contrast, antagonists that act on receptor regulatory sites are Toxic effect of high concentration of glutamate while retaining the physiological function of glutamate Suppress. Therefore, regulated antagonists such as glycine site antagonists are safe. Can be administered to Compound of invention The compounds of the invention include fervamate and ACEA compounds (1011, 1021, 1031, 1328). ) Such as quinoxaline dione, pyridazinoindole, ACPC (1-aminocyclop) Lopancarboxylic acid), 1,4 dihydroquinoxaline-2,3-dione, 4-hydroxy-2- Kinaron, 4-amino-2-carboxytetrahydroquinoline and trans-4-hydr Loki Includes cypipecholinic acid-4-sulfate. Imaging diagnosis of NMDA receptor in vivo In the present invention, the NMDA receptor complex for neurological diseases is imaged in vivo. Provide a method of cutting and quantifying. In this method, glyces such as fervamate Radiolabeled compounds that bind to the site 13N-fervamine or 11 C-fervamate, this labeled compound administered to patients before positron release Perform Detomography (PET) scanning. By this method, glutamate and And patients with preclinical asymptomatic neurological disorders associated with NMDA receptors Can be diagnosed. Furthermore, clinical therapeutic effects are confirmed and evaluated. Animal's The synthesis of 11C-ferbamate has been reported for radioactivity photography of the brain (Co) rnford, EM, Epilepsy, 37 (1): 15-18, 1996). Postmortem brain tissue studies from patients with Huntington's disease show disease progression Reflecting NMDA receptor glycine site binding is in the caudate nucleus (62%) and frontal Decreased in cortex (20%) (Reynolds, GP, J. Neurol. Sci., 25 (2): 46- 49,1994). Radiolabeled fervamine is an NMDA receptor for preclinical asymptomatic patients -Quantify. Significant number of neuronal cell deaths with radiolabeled fervamine The disease state can be diagnosed before clinical manifestations of sickness (Albin, RL, NEJM 322: 1293-1298, 1990). Symptoms appear in various neurological disorders It is only after the NMDA receptor level has decreased significantly. This diagnostic method Parkinson's disease, Huntington's chorea, and Alzheimer's disease are particularly effective diseases. , Tourette's disease, adrenoleukodystrophy, CNS vasculitis, mitochondrial muscle disease, HIV deficiency There are dementia, depression, ALS, movement disorders and Down's syndrome. Therapeutic use of the compounds of the invention Ferbamate and other antagonists at the glycine site of the NMDA receptor Effective in treating a number of nervous system disorders, such as inflammatory neurotoxins and irritating amino acids And its at least glutamate shadows functional changes associated with certain syndromes Give a sound. ACEA compounds are used for each of the diseases described below for a day. The dosage is 1 to 150 mg / kg, and the most effective is 20 to 40 mg / kg. Prevention of neurodegeneration and brain atrophy in epilepsy Epilepsy is genetic or acquired in development and in mechanism. Seizures that are physiological or systematic, self-maintaining and self-suppressing cerebral rhythm disorders It is a disease characterized as. Other factors (alcohol withdrawal, metabolic conditions , Cocaine, etc.) causes seizures in a healthy brain, referred to as non-epileptic seizures. To. Epilepsy is usually classified into four stages by clinical encephalography. 1) Major seizures 2) Small seizures 3) Psychomotility (partially complex) 4) Autonomic nervous system These epileptic distresses are one or some of the above types of seizures. Has a combination of. All drugs used to treat epilepsy prior to the present invention are seizure sequelae. That is, prevention of epilepsy symptoms rather than prevention of brain atrophy and cognitive dysfunction. It acted as a control and control of seizures of epilepsy. Approximately 50% of epilepsy patients are generally controlled by currently over-the-counter antiepileptic drugs However, the need for highly selective and less toxic antiepileptic agents has long been desired. ing. The hopes of the industry are non-toxic, non-sedative, long-lasting and high. To provide an effective antiepileptic agent. The NMDA receptor is the onset of epilepsy and seizures, especially the onset of epilepsy and / Rui plays an important role in propagation. Increased quantity of NMDA and glycine receptor Most have been shown in the firing model of partially complex epilepsy (Yeh, GC, Proc. Natl. Aca) d. Sci., 86: 8157-8160, 1989). Epilepsy and seizure status are extremely frequent seizures Known to be associated with great future hazards (Falconer, MA, Lancet, 2: 767-770, 1974). Elevated amino acids (eg glutamate, aspartate, glycine) Contains focal epilepsy of epilepsy sources removed by neurosurgery (Perry, TL, Neurology, 31: 872-876, 1981) and the human epileptic cortex (Sherwin, A., Neurology, 39: 920) -923,1988, Carlson, H., Neurosci. Lett., 140: 30-32, 1992) There is. In addition, both epilepsy patients and first-degree relatives have altered epilepsy. Elevated plasma glutami suggesting a genetic basis for lutamine metabolism It had acid levels (Janjuna, NA, Epilepsy Res., 11: 37-44, 1992). The activity of epilepsy is the neurological damage seen in brain cells (ie, glioma, tissue deterioration). Many theories as to whether it is the cause or effect of withdrawal, decrease in the number of dendrites in nerve cells) There is a dispute (Thompson, SM, Brain Pathol., 3: 413-419, 1993). Gu before a seizure Elevated levels of stimulant toxic effects of lutamine and aspartate are neurological It was proposed that it was not enough to cause a loss (Meldrum, BS, Brain Pat) hol., 3: 405-412, 1993). In addition, a single quantitative data from animal experiments is available in a short time. Seizures (shorter than 5 minutes) have not been shown to cause neuronal loss (Me) ldrum, BS, Brain Pathol., 3: 405-412, 1993), neurological loss is short for each individual It is not usually considered to be accompanied by seizures. Glycine antagonists with low intrinsic potency have convulsive activity (Wlaz, P., Eu) rJ Neurosci., 6 (11): 1710-1919,1994) Antagonists at the glycine site are anticonvulsants It has been shown to work (Croucher, MJ, Neuroscl. Lett., 118: 29-3) 2,1990, Croucher, MJ, Brain Res., 543: 91-96, 1991). Convulsive treated Non-antagonistic NMDA antagonists cannot reduce cell death in cultured tissues It was good (Thompson, SM., Brain Pathology, 3: 413-419). In the etiologic study of partially complex seizures using microdialysis, human partial complex Elevated levels of glutamate occur before seizures (During, MJ, Lance) t, 341: 1607-1610). In addition, glutamate resting levels in these patients It was elevated in 1/3 of the temporal lobe. Congenital or environmental abnormalities are glutamate metabolism and other amino acid substitutions It presents a new hypothesis that it alters Xie. Elevated rest glutamate level Both pre- and post-epileptic elevations of le and glutamate are acute but generally NMD Produces chronic hyperstimulation of the A receptor. Long chronic exposure is the god of delay Metabolic disorders of NMDA receptors that cause transcellular death, or quantitative and qualitative abnormalities It will always produce. Mediated by synaptically released glutamate Expression of epilepsy activates both NMDA and non-NMDA receptors And subsequently those receptors are acute or delayed chronic intracellular calcium Creates a neuropathological effect due to influx. Guru in patients with partially complex seizures Elevated levels of tamate both before and after rest and seizure activity are MRI of the brain. And it is the cause of cerebral atrophy (ie, hippocampal ridge) in autopsy observations. According to the present invention, in patients with complex seizures, even other agents are effective in seizure control. Even with the acute or chronic mechanism of NMDA receptor activity Glycine like fervamate to prevent degeneration and brain atrophy (neuroprotection) A site NMDA antagonist is administered. This antagonist is given to patients with seizure disorders Given and elevated glutamate disease expression occurs in the absence of clinical seizures Elevated resting level of glutamate at the time of seizures or epilepsy Prevents cell necrosis that occurs later in the future. This antagonist is NMDA Rece After epilepsy, even when triggered by a mechanism other than Putter's mechanism Has a neuroprotective effect (Chronopoulos, A., Epilepsy, 34 (2): 259-366, 1993 ). Fervamate administered at a dose of 3600 mg / day to normal adults Trough serum levels of 83 + 21 μg / ml were reached. Acute elevation of glutamate Hypoxia Causes In-Studies in Rats with Local Blood Deficiency 300 mg / kg reduced infarct volume and delayed cell necrosis (Wasterlain CG. , Neurology 43: 2303-2310,1993), at serum levels greater than 100 μg / ml Indicates maximum, but greater than 100 μg / ml to prevent apoptosis Key fervamate serum levels indicate that it was required for effective neuroprotection (Wasterlain, CG, Stroke 27: 1236-1240, 1996). Ferbamate The current method of administration of is added to the existing drug administration as a multi-treatment. Currently Felbami The serum therapeutic range for phosphates is unknown. For drug interactions , With substantially lower serum fervamine levels for the patient. In addition, Fe Individual reports of serum levels greater than 100 μg / ml for ruvamate monotherapy is there However, the patient has not been treated with fervamine monotherapy for more than a year. Patients who have maintained serum levels above 100 μg / ml for more than a year Not in. Chronically elevated levels of glutamate in the brain and development of acute disease onset For neuroprotection against both elevated glutamate levels before and after cropping, 1 Serum fervamine levels greater than 100 μg / ml over a period of more than a year is necessary. 100-15000 mg / day, preferably 1200-7200 mg / day (25) Long-term dosing Fel with caliber (serum levels in the range of ~ 300 μg / ml) Bamine reduces neuronal cell death due to a rapid rise in glutamate during seizures It is effective in doing so. More effectively, blood in the range of 100-300 μg / ml Epilepsy-delayed fine levels of Qing levels when given for long periods of time over a year It is effective in preventing cell death, apoptosis, atrophy, etc. Sepsis In systemic bloodborne diseases, coma and cardiac / respiratory dysfunction can lead to death There is sex. Coma and nervous system dysfunction increase toxin release as bacteria are killed It occurs after the administration of antibiotics that are thought to be. Elevated level of quinolinic acid Le causes nerve death due to NMDA receptor overstimulation. Toxins from bacteria are N Sites that cause nervous system symptoms and neuronal cell death due to MDA receptor overstimulation It is believed to increase the production of kainic acid and CSF quinolinic acid (Heyes) , M., Brain, 116: 1425-1450, 1993). Glycine site NMDA antagonists such as fervamate can be used to treat the pathological condition of the nervous system Reduces sepsis mortality. Ferbamate is intravenous at the time of diagnosis of sepsis Long-term administration by tract or oral administration, and oral administration within 6 months or more after recovery Is the most effective. 100 ~ 15000mg / day, preferably 1200 ~ For oral administration of 7200 mg / day (serum levels in the range of 25-300 μg / ml) Ferbamate medication is effective in preventing neuronal cell death in sepsis .. Meningitis Both viral and bacterial meningitis increase CSF-quinolinic acid levels Known to be great (Heyes, M., Brain, 116: 1425-1450), on the other hand, excess CSF-glutamate levels are poorly present in patients with bacterial meningitis Shows floor results (Spranger, M., Arch. Neurol. 53: 922-966, 1996). Nervous system sickness Disease and death can be caused by excessive NMDA receptor stimulation. Glycine site NMDA antagonists prevent nervous system disease and death in meningitis .. Ferbamate is long-term by intravenous or oral administration at the time of diagnosis of meningitis It is most effective to administer to the drug and to administer it by mouth within 6 months or more after recovery. 1 00 ~ 15000mg / day, preferably 1200 ~ 7200mg / day (25 ~ 3) Dosing of fervamate by caliber administration (serum levels in the range of 00 μg / ml) Is effective in preventing nerve cell death in meningitis. Adrenal cerebral white matter atrophy Adrenal cerebral white matter atrophy (ADL) causes seizures and dementia in young men It is an X-linked recessive disease of metabolism. Pathologically, cytokinins and ki It has the characteristics of an inflammatory disease that suggests that nolin acid is associated with its cause. Gu Lysine site NMDA antagonists have anticonvulsant effects in addition to neuroprotective agents. Felbamine salt is 100 to 15000 mg / day, preferably 1200 to 72 Long-term oral administration of 00 mg / day (serum levels in the range of 25-300 μg / ml) Dosing with is effective in preventing neuronal cell death and seizures in ADL. CNS vasculitis CNS vasculitis, an inflammatory condition of the cerebral arteries, occurs in multiple autoimmune diseases. Rheumatoid arthritis). Sequelae of the nervous system include stroke, seizures, and dementia. Ki Nolin acid is elevated and is associated with the degree of brain damage by MRI and clinical dementia It is known that there is. Glycine site NMDA antagonists are a sequela of the nervous system of CNS vasculitis (stroke, seizures) , Dementia) has an effect. Ferbamate is 100-1500 0 mg / day, preferably 1200-7200 mg / day (25-300 μg / ml) of Long-term oral administration of (range of serum levels) degenerates the nervous system of CNS angiitis It is effective in preventing. Impotence The erection of the male genitalia is due to the NMDA receptor activity of nitric oxide in the paraventricular nucleus of the hypothalamus. Induced (Melis, MR, Neuro.Sci. Lett., 179: 9-12, 1994). NMDA Epileptic patients treated with fervamate, an antagonist of the glycine site of scepter There was an increase in ribido, the sexual instinctive energy. Efficacy of the intersection of fervamates The result is an increase in mental energy and arousal. Glycine site NMDA antagonists reduce stage 1 and stage impotence .. Felbamine salt is 100 to 15000 mg / day, preferably 1200 to 72 Long-term oral administration of 00 mg / day (serum levels in the range of 25-300 μg / ml) Dosing with is effective in increasing ribido, which is sexual energy. Schizophrenia Schizophrenia is caused by a metabolic disorder of the neurotransmitter dopamine in the brain. It is a chronic mental illness that is thought to occur. It has a genetic effect and also has brain atrophy It occurs in both schizophrenic patients and their asymptomatic identical twins. NMDA Seki It has been suggested that the ream glutamate hypothesis is included in the pathophysiology of schizophrenia. (Olney, JW, Arch.Gen.Psych., 52: 998-1007, 1995). NMDA D-cycloserine, a partial agonist of the glycine site of scepter, is a schizophrenia Reduced patient psychological symptoms (Cascella, NG, J. Neurol. Transm. Gen. Se ct., 95 (2): 105-111, 1994). Dopaminergic mechanics associated with NMDA receptors in the limbic forebrain The selective interaction between Zum and glutamate is on the nucleus side of the rat, not on the nucleus beam. Selectively antagonize the stimulatory effect of d-amphetamine on dopamine synthesis in Has been demonstrated by the ability of glycine site antagonists for (Hutson, PH, Br.J.Ph) armacol., 103: 2037-2044, 1991). Haldle, the usual treatment for schizophrenia , NMDA receptor partial action on strychnine unresponsive glycine site medicine (Fletcher, EJ, Eur.J.Pharmacol., 235 (2-3): 291-295,1 993). Glycine site antagonists, including fervamate, cure schizophrenia and other psychoses Acts as an "atypical nerve relaxant" in medical treatment (Leeson, PD, J.Med.Chem., 3) 7 (24): 4053-4067, 1994). Glycine site such as fervamate NMDA antagonist Anti-drugs are therapeutic agents for glutamate-induced atrophy in patients with schizophrenia. Fu Elbamate is 100 to 15000 mg / day, preferably 1200 to 7200 By long-term oral administration of mg / day (serum levels in the range of 25-300 μg / ml) Medications are effective in preventing nervous system degeneration and brain atrophy in schizophrenia To. Drug addiction Paralytic withdrawal symptoms of drug addiction are partly due to the NMDA receptor complex in the beak bone marrow Is mediated. Ferbamate is naroki when administered to rats by the prescribed method. It has been reported to reduce the forbidden intensity of thin precipitation (Kosten, TA, Ne). uropsychopharm., 13: 323-333, 1995). Oral or IV administration, good tolerance Glycine site competition of NMDA receptor with properties such as low harmful empirical records Anti-drugs are therapeutic agents for drug addiction, tolerance, dependence, and withdrawal. Ferbamate is long-term by intravenous route or oral administration at the time of diagnosis of withdrawal symptoms It is most effective to administer the drug and administer it by mouth for at least 6 months after recovery. 100 ~ 15000mg / day, preferably 1200 ~ 7200mg / day (25 ~ Injection of fervamate by caliber administration (serum levels in the range of 300 μg / ml) The drug is effective in preventing the autonomic and psychologically detrimental experiences of drug addiction is there. Multiple sclerosis Cerebral cortex damage caused by acute onset of multiple sclerosis and chronic progressive multiple sclerosis Part of the wound is due to the prone to increased inflammation of cytokinins and quinolinic acid (Heyes, M) ., Brain, 116: 1425-1450, 1993). Brain atrophy and cognitive dysfunction are common in multiple sclerosis I am a connoisseur. Glycine site NMDA antagonist protects cerebral cortical nerves in multiple sclerosis (neuroprotection) ) Has an effect. Ferbamate is 100-15000 mg / day, preferably Is 1200-7200 mg / day (serum levels in the range 25-300 μg / ml) Long-term oral administration of the drug is effective in preventing the nervous system degeneration of multiple sclerosis. Is. fatigue Fatigue is a chronic illness (ie multiple sclerosis, postpolio syndrome, Parkinson's) It is common in Fatigue and chronic fatigue syndrome. Chronic Fatigue Syndrome Viral components in pro-inflammatory tendencies and potential causes associated with NMDA irritation It is believed to have. Glycine site NMDA antagonists provide nervous system protection in a variety of disease states In addition, reduce the symptoms of fatigue. Felbamine salt is 100 to 15000 mg / day , Desirably 1200-7200 mg / day (25-300 μg / ml blood range) Long-term oral administration of Qing level) is used to treat the cause of central nervous system fatigue. It is effective. Lead poisoning Chronic lead poisoning or acute lead poisoning is caused by overstimulation of NMDA receptors. Causes system symptoms and brain damage. Lead is the zinc binding site of the NMDA ion channel Require that it be combined in place. Long-term treatment of rats with lead is an adult forebrain It was shown that the density of NMDA receptors in the genenate increased slightly (Schu). lte, S., Neurotoxicology, 16 (2): 309-317, 1995). Glycine site NMDA antagonists are both NMDA function and the amount in such condition Acute neuroprotection and prophylactic neuroprotection are performed by controlling the direction. Felva Minate is administered long-term by intravenous route or oral administration at the time of diagnosis of acute lead poisoning. However, it is most effective to administer by mouth for at least 6 months after recovery. Felva Minate is 100-15000 mg / day, preferably 1200-7200 mg / day Daily (serum levels in the range of 25-300 μg / ml) long-term oral dosing Is effective in preventing degeneration of the nervous system from lead poisoning. Mitochondrial dysfunction Mitochondrial dysfunction is a mitochondrial abnormality (energy for cells) (Intracellular structure that produces) and other congenital or acquired biochemical abnormalities Attached (Beal, MF, Ann. Neurol. 31: 119-130, 1992). As a disease or medical condition MELAS Syndrome, MERF Syndrome, Liver Disease, Wernicke Brain Disease, Rett syndrome, homocystinuria, hyperprol inemia), nonketotic hyperglycinemia , Hydroxybutyric aminoaciduria, Sulfur There is hydrochloride oxidase deficiency and comorbidities (B12 deficiency). Glycine site NMDA antagonists protect nerve cells in these pathologies. Ferbamate is most beneficially administered at diagnosis by the venous route or by administration. Given, and in the long term administered by oral administration for 6 months or longer after recovery can do. Long term 100-15,000 mg / day, preferably 120 Oral administration of 0 to 7200 mg / day (serum level is 25 μg to 300 μg / ml) Felvamineate administered by Nerve Cells in Mitochondrial Muscle Disease Has the effect of preventing denaturation. HIV dementia Patients with HIV (+) have early preliminary clinical cranial nerve details on NMR spectroscopy Shows degeneration of vesicles. When HIV (+) patients transition to AIDS, dementia due to their relationship with the brain Is generally fatal. The mechanism of degeneration of the brain is a neurotoxic substance (su That is, it seems to be involved in the production of quinolinic acid). This substance is NMDA Activates the receptor and causes intracellular Ca⁺⁺Death of nerve cells by inducing overload Destroy (Giulian, D., Science 250: 1593-1596, 1990, Heeyes, MP, An n. Neurol., 29: 202-209, 1991a). Blocking NMDA receptors at the glycine site is a neuronal protection And function to prevent the death of nerve cells. 100 ~ 15,000mg / day in the long term Preferably 1200-7200 mg / day (serum levels 25 μg-300 μg / day) ml)) Felvaminetate administered by oral administration is a nerve in HIV dementia It is effective in preventing cell degeneration. pain The center of pain transmission structure in a given layer of the spinal cord, thalamus, and cerebral cortex is NMD Contains A receptor. Hard-to-heal facial spasms douloureux (Chesir) e, WP, Clin.J.Pain, 11: 139-142,1995) is a dose of 1200-2400 mg / day Effectively treated with fervamate. Zhou that is difficult to cure with current drug treatment Ferbamic acid is a condition of end cancer pain and poor prognosis surgery such as perineuropathy. Benefit from salt treatment. In the formalin-injected animal pain model, Glish Site antagonists (Millan, MJ, Neurosci. Lett., 178 (1): 139-143, 1994, Vaoca rino, AL, Brain Res., 615 (2): 331-334,1993) reduced late-stage pain response Reduced. Ferbamate in a rat model of painful peripheral neuropathy However, a large reduction was manifested in all pain measurements (Imamura, I., J. Phar). m.Exp.The.,275 (1): 177-182, 1995). In particular, the action of fervamate It was an anti-hyperalgesic and anti-allodynic rather than an analgesic. Blocking the NMDA receptor at the glycine site is on the central nervous system side Prevents chronic pain transmission and provides symptom relief without affecting. Long term 100 to 15,000 mg / day, preferably 1200 to 7200 mg / day ( Serum level is 25 μg ~ 300 μg / ml)) Fel administered by oral administration Bamineate is effective in relieving chronic pain. Depression Recognized that fervamate and glycine site antagonists are given to patients with epilepsy Improve function and mood. Autonomic depression can lead to depression, excessive drowsiness, and obesity More characterized. Autonomic depression is uplifted by the NMDA mechanism Reacts to glycine antagonists by causing, with stimulating effects, and weight loss (Ke) tter, TA, Epilpsey Res., 23 (2): 129-137, 1996). In addition, NMDA reception The activity of ter is partly located at serotonergic nerve endings in the cerebral cortex. Serotonin induces the release of major neurotransmitters in depression (Fink, k., N) aumym Schmiedebargs Arch.Pharmacol., 352 (4): 394-401, 1995). Long term 100-15,000 mg / day, preferably 1200-7200 mg / day (serum level 25 μ) g ~ 300 μg / ml)) Fervamate administered by oral administration suppresses autonomic nerves Effective in treating depression. Late stage hardening of muscular atrophy Amyotrophic Lateral Sclerosis (ALS) is the brain stem and A progressive disease of the motor area of the spinal cord that causes muscle weakness, wasting and death. .. Excessive glutamate stimulation may be associated with the onset of the disease (Rothatein) , JD, Ann. Neurol., 28: 18-25, 1990). NMDA receptors in the spinal cord Number decreases in patients with ALS (Shaw, PJ, Brain Res., 637: 297-302,1994) ). Abnormal metabolism of glycine and glutamate is due to the NMDA mechanism Causes neurotoxins (Virgo, L., Brain Res., 676: 196-204). Glycine site antagonists prevent these NMDA receptors from being overstimulated Prevent and prevent weakening and death in ALS. 100 ~ 15,000mg in the long term / Day, preferably 1200-7200 mg / day (serum levels 25 μg-300) μg / ml) Felbaminetate administered by oral administration is effective in preventing ALS There is. Parkinson's disease Parkinson's disease (PD) is predominantly in the substantia nigra (the motor region of the basal ganglion) D₂Selective degeneration of dopaminergic neurons, sclerosis and bradykinesia (slow movement) ) Onset of progressive motor signs. NMDA stimulation mechanism for early nerve cell death Nism is included in the cause of PD (Beal, MF, Ann. Neurol., 31: 119-130, 19) 2, Beal, MF, FASEBJ., 6: 3338-3344, 1992). Ferbamate is weak D in the animal model of the work₂Showed to neutralize (dopamine receptors) (Kretehmer, SD, Neuroscl. Lett., 179 (1-2): 115-118, 1994). NMDA glycine site that suppresses overstimulation of NMDA receptors Antagonists prevent the weakening and degeneration of progressive motor areas in PD (nerve cells) protection). Long term 100-15,000 mg / day, preferably 1200-720 0 mg / day (serum level is 25 μg to 300 μg / ml) Administered by oral administration Ferbamate is effective in preventing nerve cell death in PD. Attention loss abnormality Attention Deficit Disorder (ADD) is impulsive, excessive exercise A brain abnormality characterized as signs and cognitive impairment. The current treatment is the brain There is the use of amphetamines to stimulate. Felvamine simple acid German treatment had a stimulant-like effect on patients with epilepsy (Ketter, TA, Epilpsey Res., 23 (2): 129-137, 1996). Glycine site NMDA antagonists are recognized It has strength-enhancing and psychostimulatory properties, such as amphetamine addiction and growth inhibition. No side effects. Glycine site NMDA antagonists are a useful therapeutic tool for ADD. 10 in the long run 0 to 15,000 mg / day, preferably 1200 to 7200 mg / day (serum level) Lu is 25 μg ~ 300 μg / ml)) Felvamic acid administered by oral administration Salt is effective in treating ADD. Narcolepsy Narcolepsy is a dyssomnia that causes the patient to suddenly fall into REM (dreaming) sleep To. Glycine site NMDA antagonists have cognitive enhancement properties and psychostimulatory properties To. Glycine site NMDA antagonists are useful in the treatment of narcolepsy. Fel Glycine site NMDA antagonists such as bamate are 100 to 15,000 in the long term mg / day, preferably 1200-7200 mg / day (serum levels 25 μg-3 00 μg / ml)) Effective in treating narcolepsy when administered by oral administration There is. Alzheimer's disease Alzheimer's disease (DAT) is a progressive dementia disease, amylois in the brain. Due to the abnormal formation of amyloid deposits. Excessive amyloid deposition is NMDA Induces glutamate toxicity of scepters (Koh, JY. Brain res., 533: 315-320) , 1990, Mattson, MP, J. of Neurosci., 12: 376-388,1992), resulting in the ocean NMs such as horse circulation and cerebral cortex (the area where most nerve cells die in DAT) Nerve cells die in areas of the brain where DA receptors are dense. DAT visual cortex Decreased NMDA receptor binding in NMDA receptors correlates with increased nerve fiber entanglement There was (Carlson, MD, Neurobiol.Aging, 14 (4): 343-352, 1993). To animals Studies have shown that glycine antagonists improve learning ability and scopala. mine) Showed to reduce memory loss (Fishkin, JE, Behav. Neuro. Biol. , 59 (2): 150-157,1993, Finkelstein, JE, Pharmacol.Biochem.Behav., 49 (3): 707-710,1994, Baxter, MG, Neurobiol.Aging, 15 (2): 207-213,1994) .. Glycine site NMDA antagonists with cognitive enhancement properties and neuronal protection properties Useful for the treatment of DAT. Felbamine salt is 100 to 15,000 in the long term mg / day, preferably 1200-7200 mg / day (serum levels 25 μg-3 00 μg / ml)) Degeneration of nerve cells in DAT when administered by oral administration Is effective in preventing. birth All births carry the risk of complications, including preterm birth, late birth and hypoxia. this In addition to the risk of cerebral ischemic injury and cerebral palsy in the fetal There is a risk of seizures after childbirth, hypotension, hypoxia, etc. Glycine site NMDA antagonists with excessive placental permeability are teratogenic to the foetation It is neither sexual nor toxic, so it is a useful preventative measure for all mothers during childbirth. Ferbamate is most preferably normal as expected from the vein or oral cavity. Administered within 24 hours of delivery. In mothers with known prenatal abnormalities, Erbamine salt is administered for several months before the expected date of delivery and is taken orally for a long time after delivery. Administer for 6 months or longer. Children also take long-term fervamate It may be taken by cavity for 6 months or longer. Ferbamate is a long-term 100 to 15,000 mg / day, preferably 1200 to 7200 mg / day (blood) Qing level is 25 μg ~ 300 μg / ml)) When administered by oral administration, childbirth It has the effect of preventing nerve cell damage to both the mother and the child at times. Surgical anesthesia All patients who receive normal anesthesia for any surgical procedure are hypoxic, absent Risk of oxygenation, cerebral embolism (eg, due to lipids, air), hypotension, hypoglycemia, etc. They are sexual and can cause permanent damage to the brain. Glycine site NMDA antagonists with neuroprotective properties are all anesthetized It is a useful preventive measure in patients with. Ferbamate is most preferably static Administered from the pulse or oral cavity within minutes to 24 hours of surgery, in the long term Is taken orally for 6 months or longer. Ferbamate is a long-term 100 to 15,000 mg / day, preferably 1200 to 7200 mg / day (blood) Qing level is 25 μg ~ 300 μg / ml)) When administered by oral administration, surgery It has the effect of preventing damage to nerve cells during surgical anesthesia. Traumatic head and spinal cord injuries In a rat SDH (acute subdural hematoma) model, with a glycine site antagonist Greatly reduces hemispheric ischemic injury, both pre- and post-treatment (Tsuchida) , E., J. Neurotrauma, 12 (3): 279-288, 1995). The role of the NMDA receptor is Traumatic brain injury (Faden, AI, Sciende, 244: 798-800, 1989) and spinal cord due to bruise Possible cause of injury (Wrathall, JR, Brain Res., 586: 140-143, 1992) I came. Ferbamate is a CA1 parahippocampal gyrus in an animal model of traumatic head injury It has been shown to have a neuroprotective effect on neurons (Wallis, RA, Eu). rJPharmacol., 294: 475-482, 1995). Patients with head and spinal cord injuries Elevated cerebrospinal fluid levels of nolinic acid are the cause of nerve cell death N Suggests MDA receptor. Glycine site NMDA antagonists with neuroprotective properties can be used for head and spinal cord injuries In all patients with hypoxia and NMDA receptor glutamate stings It is a useful preventive measure by protecting against severeness. Ferbamate is the best Also preferably a few minutes or more of the diagnosis of traumatic head or spinal cord injury by vein or oral cavity It is administered orally for 6 months or longer, both internally and in the long term. Fel Bamineate is 100-15,000 mg / day, preferably 1200- 7200 mg / day (serum level is 25 μg to 300 μg / ml) by oral administration When administered, it has the effect of preventing the death of nerve cells in brain or spinal cord injuries. is there. Hypoglycemia Patients with acute hypoglycemia are associated with AMPA and NMDA receptors There is a risk of cerebral damage due to the mechanism. Glutamic acid toxicity causes hypoglycemia Suggested for neuronal damage in the area (Kaupinen, RA, Neurosci., 27: 175-182,1988, Zeevalk, GD, J.Pharmacol.Exp.Ther., 253: 1285-1292,1 990). Glycine site NMDA antagonists with neuroprotective properties can prevent hypoglycemia Or useful for emergency treatment. Ferbamate is most preferably intravenous or Within minutes of diagnosis of hypoglycemia by oral cavity, and in the long term, 6 months with oral administration Or more. Felbamine salt is 100 ~ 15,00 in the long term 0 mg / day, preferably 1200-7200 mg / day (serum level 25 μg ~ 300 μg / ml)) Nerve cells in hypoglycemia when administered by oral administration It has the effect of preventing the death of. Tourette's Syndrome Tourette's syndrome is an abnormality of the basal ganglion that causes spontaneous movement and vocalization. .. Damage to the basal ganglion is transmitted via the NMDA receptor It is thought to be due to toxic substances in the form of phosphate or glutamate. Glycine site NMDA antagonists with neuroprotective properties are associated with Tourette's syndrome Useful for treatment. Felbamine salt is 100 to 15,000 mg / in the long term Daily, preferably 1200-7200 mg / day (serum levels 25 μg-300 μ) g / ml)) Nerve cells in Tourette's syndrome when administered by oral administration It has the effect of preventing the death of. Liver brain damage Hepatic brain damage is a neurological disorder that includes secondary seizures, cognitive impairment and excessive exercise. Characterized by fulminant liver disease that causes the condition. NMDA receptors are these It is associated with the development of three symptoms. Glycine site NMDA antagonists with neuroprotective properties are available in all patients with liver damage It is useful as a preventive measure in. Ferbamate is 100 to 1 in the long term 5,000 mg / day, preferably 1200-7200 mg / day (serum level 2) 5 μg ~ 300 μg / ml)) When administered by oral administration, it causes hepatic brain damage Effective in preventing nerve cell death in the treatment of seizures and nerve cell degeneration is there. Abnormal movement The NMDA receptor is located in the subdural region of the brain, which is involved in motor control. In a mouse model of clonic (central nervous system hyperexcitability) after hypoxia Ferbamate was found to have anti-clonic properties. Ferbamate is Shivering (Edwards, KR, Neurology, 45) in humans at doses of 1800-2800 mg / day : 1951, 1995) and hemifacial spasm (Mellick, GA, J. Pain and Symptom Manageme) It was effective in controlling nt, 10: 392-295, 1995). Glycine site NMDA antagonists are useful in the treatment of all motor abnormalities. Fel Bamineate is 100-15,000 mg / day, preferably 1200- 7200 mg / day (serum level is 25 μg to 300 μg / ml) by oral administration When administered, it prevents the death of nerve cells in the treatment of dyskinesia and causes dyskinesia. It has the effect of preventing the degeneration of nerve cells. Strengthening awareness in normal old people Glutamate activation of the NMDA receptor results in neuronal flexibility and long-term It has been hypothesized to be involved in the process of memory (Monaghan, DT, Annu. Rev. Pha) rmacol.Tosicol., 29: 365-402, 1989). May be related to learning and memory recovery Strychnine insensitive glycine binding age-related reduction in older animals Occurs in (Miyoshi, R., Synapse, 6: 338-343, 1990). Lenox Gustau The effects of the behavior of fervamine in G syndrome are intellectual and motor functions. , Attention and concentration, as well as significant improvement in memory (Gay, PE, Psvch.Rep., 77 (3): 1208-1210, 1995). These are cognitive It was also strengthened. Glycine site NMDA antagonists such as fervamate are 100 to 15 in the long term 000 mg / day, preferably 1200-7200 mg / day (serum level 25 μg ~ 300μg / ml)) When administered by oral administration, it is a normal old man's recognition machine. It has the effect of preventing deterioration of ability. Down Syndrome (Trisomy 21) Down's syndrome is a chromosomal syndrome with a frequency of 1 in 700. A slight delay in wisdom Common, after age 40, Alz with nerve fiber entanglement and nerve cell plaques Progress to Heimer's disease. Do Glycine Site NMDA Antagonists, such as Ferbamate, Enhance Cognitive Ability? It is possible to prevent the outbreak of Alzheimer's disease in Down's syndrome. 10 in the long run 0 to 15,000 mg / day, preferably 1200 to 7200 mg / day (serum level) Lu is 25 μg ~ 300 μg / ml)) Felvamic acid administered by oral administration The salt has the effect of preventing the degeneration of nerve cells in Down's syndrome. Electroconvulsive therapy (ECT) Patients undergoing electroconvulsive therapy (ECT) have cognitive confusion, including memory loss I have something to do. ECT is an artificially induced seizure that causes nerve cell damage , Similar to that of chronic seizures. The mechanism of cognitive dysfunction is the parahippocampal gyrus and spinal cord Damage to the NMDA receptor. ECT is an NMDA receptor in animals It was shown to promote the conversion of. Glycine site NMDA antagonists such as fervamates are available from ECT therapy to NMDA Prevents damage to attracted nerve cells. Ferbamate is most preferably ECT Administered intravenously or orally before rinsing, and for 6 months or longer in the long term It is administered by oral administration. 100-15,000 mg / day in the long term, preferably 1200-7200 mg / day (serum level is 25 μg-300 μg / ml) mouth Felbamines administered by cavity dosing are nerve cells as a result of ECT therapy It has the effect of preventing damage to cells and preventing cell death. Brain tumor Brain tumors increase quinolinic acid levels, which can lead to seizures, nerve cell degeneration and And causes atrophy of the brain. Glycine site NMDA antagonists such as fervamate are 100 to 15 in the long term 000 mg / day, preferably 1200-7200 mg / day (serum level 25 μg ~ 300 μg / ml)) Seizures from brain tumors when administered by oral administration , Has the effect of preventing nerve cell degeneration and brain atrophy. Degeneration of the cerebellum NMDA receptors in the cerebellum have glutamate and glycine sites compared to the forebrain Has different denaturation patterns in. Therefore, glycine is an NMDA machine in the cerebellum. Plays a more important role in controlling Noh (Widdowson, PS, J. Neurochem., 64 (2): 651-61, 1995). Atrophy is common in cerebellar degeneration. Glycine site NMDA antagonists such as fervamate are 100 to 15 in the long term 000 mg / day, preferably 1200-7200 mg / day (serum level 25 μg ~ 300 μg / ml)) Prevents cerebellar degeneration when administered by oral administration Has the effect. As described above, the present invention has been fully disclosed, but those skilled in the art can use the present invention or its responsibilities. A wide range of compositions, conditions and administration methods without departing from the gist and scope of the intended examples. It will be obvious that the present invention can be carried out with equivalent parameters in the range.