D-Serine, D-Alanine, And N-Methylglycine For Neuropsychiatric Disorders

Introduction

The subject matter of the parent application was restricted to use of D-alanine and D-serine and pharmaceutical compositions comprising D-alanine and D-serine for treating neuropsychiatric disorders. The subject matter of this divisional application is directed to use of N-methylglycine and pharmaceutical compositions comprising N-methylglycine for treating neuropsychiatric disorders. However, it should be understood that the expression "the invention" and the like when used herein encompasses the subject matter of both the parent and this divisional application. Neuropsychiatric disordersDiseases which are include in neuropsychiatric disorders are Schizophrenia, Alzheimer's disease, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder.

Alzheimer's disease typically is treated by acetylcholine esterase inhibitors such as tacrine hydrochloride or donepezil Attention Deficit Disorder is associated with increased motor activity and a decreased attention span and is treated by administration of psycho stimulants such as Ritalin TM or Dexedrin. Depression is treated by conventional therapeutics such as serotonin uptake inhibitors (PROZACTM), monoamine oxidase inhibitors, and tricyclic antidepressants. The term schizophrenia represents a group of neuropsychiatric disorders characterized by dysfunctions of the thinking process. Conventional antipsychotic drugs and the new atypical antipsychotic drugs, which act on the dopamine D2 and 5HT2 serotonin receptor, can be used to treat the positive symptoms of schizophrenia, such as delusion and hallucination but they could not treat negative symptoms such as affect blunting (i. e. , lack of facial expressions), anergia, and social withdrawal.

Summary

The invention derives from the discovery that neuropsychiatric disorders characterized by a deficit in neurotransmission when glycine is up taken by NMDA receptors. Partial agonist (D-cycloserine), full agonist (D-serine or D-alanine) or glycine uptake inhibitor (N-methylglycine) are used to cure neuropsychiatric disorders. The invention provides methods for treating a patient diagnosed as suffering from a neuropsychiatric disorder. First the patients are diagnosed by using various diagnostic methods such as clinical psychiatry. Once the disorder is diagnosed the patient undergo process of treatment. Treatment includes administering a therapeutically effective amount of pharmaceutical composition containing D-alanine, D-serine and N-methylglycine is given to a patient suffering from neuropsychiatric disorder at a dosage of 10 mg to 100 g for at least several weeks to several years. In an alternative method pharmaceutical composition containing D-cycloserine in an amount equivalent to a dosage of 105 to 500 mg/day is administered to a patient in need of such treatment for at least one week and can continue for several.

In all of the methods, different concentration and different modified forms of D-alanine, D-serine, and D-cycloserine and/or N-methylglycine such as a salt, ester, alkylated form, or a precursor of the amino acid are used. Appropriate dosage of amino acids is determined by monitoring patients for signs of disease by increasing or decreasing the dosage and frequency of treatment as desired. The drug-based compositions can be given to the patient by any, or combination of routes, such as oral, into a vein, trans-mucosal (e. g. , nasal, vaginal, etc. ), lung-related, through the skin, eye-related, buccal, under the tongue, intraperitoneal or in the muscle. Inject able compositions may contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol and polyols. Tablet binders that may be used include, without limitation, acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, sucrose, starch, and ethyl cellulose. Solid compositions for oral administration can contain suitable carriers such as corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginic acid, or ingredients for controlled slow release.

Examples

The following example shows that neuropsychiatric disorders can be treated by D-alanine, D-serine, and N-methylglycine. PatientsThis study was employed to 37 patients who were suffering from schizophrenia. All of the patients also fulfilled the criteria of primary deficit syndrome, with a SANS score of more than 40, they were poorly responsive to treatment by other antipsychotic drugs as they were kept on a stable dose of an antipsychotic drug for at least 3 months prior to enrollment in this study.

Analysis

A few scales were utilized for analysis of disease in every patient. The PANSS, SANS, and Global Assessment Scales were used at the start of the examination. The Wisconsin Card Sort Test was utilized to give an intellectual rating of the patients. The Wisconsin Card Sort Test was controlled just at the start and at the end of the 6-week study. The Simpson-Angus Scale was utilized to measure additional pyramidal indications and for dyskinesia, Abnormal Involuntary Movement Scale was utilized. The symptoms of D-serine, D-alanine, and N-methylglycine medicines were analyzed every other week as indicated by the UKU reactions rating scale.

Treatment

Patients were provided with fruit juices, D-alanine (60-100mg/day), D-serine (30mg/day), or N-methylglycine (30mg/day) for a month.

Results

Treatment with D-serine, D-alanine, or N-methylglycine improved the schizophrenic symptoms and cognitive deficit of the patients. 1. 17% reduction of the positive symptoms (on the PANSS-positive subscale) and 21% reduction of the negative symptoms resulted by treatment with D-serine (on the SANS scale). 2. 11% reduction of the negative symptoms and 12% reduction of the positive symptoms resulted by treatment with D-alanine. 3. 20% reduction of the negative symptoms and 15% reduction of the positive symptoms resulted by treatment with N-methylglycine. These reductions in the negative and positive symptoms represented clinically significant improvement.

Conclusion

These outcomes show that D-serine, D-alanine, and N-methylglycine are successful in treating schizophrenia even in patients who are inadequately receptive to treatment by ordinary drugs that fight mental illness. UKU scale for rating reactions noted no side effects after treatment with D-serine, D-alanine, or N-methylglycine. No signs of recently tardive dyskinesia or worsening of extra pyramidal or akathesia were seen. Along these lines, D-serine, D-alanine, and N-methylglycine offer advantage over numerous ordinary medications for treating schizophrenia and other mental disorders and also they do not have any side effects. (Page 1 of 3)