IL118328A - Use of a combination of a selective antagonist for N-methyl-D-aspartate in the forebrain and an amplifier for re-stimulation to stimulate, in order to prepare a pharmaceutical preparation for the treatment of Parkinson's disease - Google Patents
Use of a combination of a selective antagonist for N-methyl-D-aspartate in the forebrain and an amplifier for re-stimulation to stimulate, in order to prepare a pharmaceutical preparation for the treatment of Parkinson's diseaseInfo
- Publication number
- IL118328A IL118328A IL11832896A IL11832896A IL118328A IL 118328 A IL118328 A IL 118328A IL 11832896 A IL11832896 A IL 11832896A IL 11832896 A IL11832896 A IL 11832896A IL 118328 A IL118328 A IL 118328A
- Authority
- IL
- Israel
- Prior art keywords
- mmol
- pharmaceutical composition
- hydroxy
- ethyl acetate
- hexane
- Prior art date
Links
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 89
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- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 55
- 230000002964 excitative effect Effects 0.000 title claims abstract description 54
- 208000018737 Parkinson disease Diseases 0.000 title claims abstract description 34
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 title claims description 66
- 230000002708 enhancing effect Effects 0.000 title claims description 44
- 239000005557 antagonist Substances 0.000 claims abstract description 29
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 claims abstract description 27
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- 230000001965 increasing effect Effects 0.000 claims abstract description 9
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- 150000001875 compounds Chemical class 0.000 claims description 96
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 60
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 50
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Classifications
-
- G—PHYSICS
- G10—MUSICAL INSTRUMENTS; ACOUSTICS
- G10H—ELECTROPHONIC MUSICAL INSTRUMENTS; INSTRUMENTS IN WHICH THE TONES ARE GENERATED BY ELECTROMECHANICAL MEANS OR ELECTRONIC GENERATORS, OR IN WHICH THE TONES ARE SYNTHESISED FROM A DATA STORE
- G10H5/00—Instruments in which the tones are generated by means of electronic generators
- G10H5/10—Instruments in which the tones are generated by means of electronic generators using generation of non-sinusoidal basic tones, e.g. saw-tooth
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB1995/000398 WO1996037226A2 (fr) | 1995-05-26 | 1995-05-26 | Combinaisons pour le traitement de la maladie de parkinson contenant des antagonistes de nmda |
| HU9601419A HUP9601419A3 (en) | 1995-05-26 | 1996-05-24 | Synergetic pharmaceutical compositions for treating parkinson-disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL118328A0 IL118328A0 (en) | 1996-09-12 |
| IL118328A true IL118328A (en) | 2001-06-14 |
Family
ID=89994003
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL11832896A IL118328A (en) | 1995-05-26 | 1996-05-20 | Use of a combination of a selective antagonist for N-methyl-D-aspartate in the forebrain and an amplifier for re-stimulation to stimulate, in order to prepare a pharmaceutical preparation for the treatment of Parkinson's disease |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US6258827B1 (fr) |
| EP (1) | EP0828513B1 (fr) |
| JP (1) | JPH11505828A (fr) |
| CN (1) | CN1159325A (fr) |
| AT (1) | ATE258067T1 (fr) |
| AU (1) | AU696258B2 (fr) |
| BR (1) | BR9602485A (fr) |
| CA (1) | CA2219911C (fr) |
| CO (1) | CO4700422A1 (fr) |
| CZ (1) | CZ283979B6 (fr) |
| DE (1) | DE69532482T2 (fr) |
| DK (1) | DK0828513T3 (fr) |
| ES (1) | ES2211904T3 (fr) |
| FI (1) | FI974323A (fr) |
| HU (1) | HUP9601419A3 (fr) |
| IL (1) | IL118328A (fr) |
| MX (1) | MX9709112A (fr) |
| NO (1) | NO962130L (fr) |
| NZ (1) | NZ286656A (fr) |
| PL (1) | PL314413A1 (fr) |
| PT (1) | PT828513E (fr) |
| RU (1) | RU2176145C2 (fr) |
| SG (1) | SG45479A1 (fr) |
| TR (1) | TR199600436A2 (fr) |
| TW (1) | TW470740B (fr) |
| WO (1) | WO1996037226A2 (fr) |
Families Citing this family (42)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2321190B (en) * | 1997-01-16 | 2000-09-20 | Britannia Pharmaceuticals Ltd | Pharmaceutical composition |
| NZ502785A (en) * | 1997-10-24 | 2003-03-28 | Warner Lambert Co | Use of NR1A/2B site-selective NMDA receptor antagonist compounds for treating disease-related or drug-induced dyskinesias |
| US6291499B1 (en) | 1999-10-29 | 2001-09-18 | Merck & Co., Inc. | 2-cyclohexyl benzimidazole NMDA/NR2B antagonists |
| US6380205B1 (en) | 1999-10-29 | 2002-04-30 | Merck & Co., Inc. | 2-cyclohexyl quinazoline NMDA/NR2B antagonists |
| US6489477B1 (en) | 1999-10-29 | 2002-12-03 | Merck & Co., Inc. | 2-aza-bicyclo[2.2.2]octane NMDA/NR2B antigonists |
| US6476041B1 (en) | 1999-10-29 | 2002-11-05 | Merck & Co., Inc. | 1,4 substituted piperidinyl NMDA/NR2B antagonists |
| US6369076B1 (en) | 1999-10-29 | 2002-04-09 | Merck & Co. Inc. | 5-benzyl-octahydroindole and 6-benzyl-decahydroquinoline NMDA/NR2B antagonists |
| US6316474B1 (en) | 1999-10-29 | 2001-11-13 | Merck & Co., Inc. | 2-benzyl and 2-heteroaryl benzimidazole NMDA/NR2B antagonists |
| US6495561B2 (en) | 1999-10-29 | 2002-12-17 | Merck & Co., Inc. | 2-cyclohexyl imidazopyridine NMDA/NR2B antagonists |
| US6432976B1 (en) | 1999-10-29 | 2002-08-13 | Merck & Co., Inc. | 8-aza-bicyclo[3.2.1]octane NMDA/NR2B antagonists |
| JP2003512422A (ja) | 1999-10-29 | 2003-04-02 | メルク シャープ エンド ドーム リミテッド | ベンズイミダゾールｎｍｄａ／ｎｒ２ｂアンタゴニストを使用する疼痛の治療方法 |
| EP1186303A3 (fr) * | 2000-09-06 | 2003-12-10 | Pfizer Products Inc. | Combinaisons pharmaceutiques pour le traitement des accidents cerebrovasculaires, contenant un facteur inhibitant la neutrophile et un antagoniste selectif du NMDA-NR2B |
| EP1379520B2 (fr) | 2001-02-23 | 2014-04-09 | Merck Sharp & Dohme Corp. | Antagonistes nmda/nr2b nonaryl-heterocycliques n-substitues |
| WO2002069974A1 (fr) * | 2001-03-05 | 2002-09-12 | Andrew Holman | Administration d'agents restaurateurs de sommeil |
| US7375136B2 (en) | 2001-03-08 | 2008-05-20 | Emory University | pH-dependent NMDA receptor antagonists |
| AU2002338334B8 (en) | 2001-04-03 | 2008-09-18 | Merck & Co., Inc. | N-substituted nonaryl-heterocyclo amidyl NMDA/NR2B antagonists |
| US20030045449A1 (en) * | 2001-08-15 | 2003-03-06 | Pfizer, Inc. | Pharmaceutical combinations for the treatment of neurodegenerative diseases |
| DE10142176A1 (de) * | 2001-08-29 | 2003-03-27 | Eucro Europe Contract Res Gmbh | Verwendung einer Kombination aus ß-adrenergen Agonisten und NDMA-Antagonisten |
| WO2003062235A1 (fr) * | 2002-01-17 | 2003-07-31 | Eli Lilly And Company | Modulateurs de recepteurs de l'acetylcholine |
| US6743921B2 (en) * | 2002-01-24 | 2004-06-01 | Dsm Catalytica Pharmaceuticals, Inc. | Process for the preparation of nonracemic syn-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propanol compounds |
| PL376347A1 (en) * | 2002-10-08 | 2005-12-27 | Allergan, Inc. | Method of using (2-imidazolin-2-ylamino) qinoxalines in the treatment of dementia and parkinsons |
| AR044007A1 (es) * | 2003-04-11 | 2005-08-24 | Newron Pharmaceuticals Inc | Metodos para el tratamiento de la enfermedad de parkinson |
| US7763588B2 (en) * | 2003-06-13 | 2010-07-27 | The Salk Institute For Biological Studies | Method for increasing cognitive function and neurogenesis |
| WO2005025561A1 (fr) * | 2003-09-04 | 2005-03-24 | Synergia Pharma, Inc. | Compositions et methodes de traitement de l'intolerance orthostatique |
| EP1667630A4 (fr) * | 2003-09-04 | 2008-07-23 | Univ Texas | Methodes et compositions permettant de prevenir et de traiter les troubles genito-urinaires, en particulier, l'accouchement premature et les leiomyomes |
| EP1588704A1 (fr) * | 2004-04-22 | 2005-10-26 | Newron Pharmaceuticals S.p.A. | Dérivés d'alpha-aminoamides utiles dans le traitement de l'acroparesthésie nocturne et des troubles de toxicomanie |
| EP1799264A2 (fr) * | 2004-10-08 | 2007-06-27 | Neuromolecular Pharmaceuticals Inc | Methodes et compositions de traitement de la douleur de migraine |
| US7619007B2 (en) | 2004-11-23 | 2009-11-17 | Adamas Pharmaceuticals, Inc. | Method and composition for administering an NMDA receptor antagonist to a subject |
| WO2006075004A2 (fr) * | 2005-01-13 | 2006-07-20 | Neurosearch A/S | Nouveaux derives de 8-aza-bicyclo[3.2.1]octane et leur utilisation comme inhibiteurs du recaptage du neurotransmetteur monoamine |
| JP5666087B2 (ja) | 2005-04-06 | 2015-02-12 | アダマス・ファーマシューティカルズ・インコーポレーテッド | Ｃｎｓ関連疾患の治療のための方法及び組成物 |
| US20070118044A1 (en) * | 2005-07-18 | 2007-05-24 | Mega Elektroniikka Oy | Method and device for identifying; measuring and analyzing abnormal neurological responses |
| EP1870097A1 (fr) * | 2006-06-15 | 2007-12-26 | Newron Pharmaceuticals S.p.A. | Dérivés d'alpha-aminoamide pour le traitement de troubles cognitifs |
| RU2324492C1 (ru) * | 2006-12-04 | 2008-05-20 | Общество с ограниченной ответственностью "Березовый мир" | Средство для профилактики и лечения болезни паркинсона |
| US8420680B2 (en) * | 2007-06-29 | 2013-04-16 | Emory University | NMDA receptor antagonists for neuroprotection |
| RU2540470C9 (ru) * | 2008-06-06 | 2015-07-20 | Фарма Ту Б Лтд. | Фармацевтические композиции для лечения болезни паркинсона |
| US8648198B2 (en) | 2011-01-19 | 2014-02-11 | Cold Spring Harbor Laboratory | Phenylethanolamine-based NMDA receptor antagonists |
| JP6042968B2 (ja) * | 2012-04-20 | 2016-12-14 | ユセベ ファルマ ソシエテ アノニム | パーキンソン病の処置方法 |
| US10258585B2 (en) | 2014-03-13 | 2019-04-16 | Neuroderm, Ltd. | DOPA decarboxylase inhibitor compositions |
| ES2967693T3 (es) | 2014-03-13 | 2024-05-03 | Neuroderm Ltd | Composiciones del inhibidor de la dopa descarboxilasa |
| US11331293B1 (en) | 2020-11-17 | 2022-05-17 | Neuroderm, Ltd. | Method for treatment of Parkinson's disease |
| US11844754B2 (en) | 2020-11-17 | 2023-12-19 | Neuroderm, Ltd. | Methods for treatment of Parkinson's disease |
| US11213502B1 (en) | 2020-11-17 | 2022-01-04 | Neuroderm, Ltd. | Method for treatment of parkinson's disease |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5272160A (en) | 1989-05-17 | 1993-12-21 | Pfizer Inc | 2-piperidino-1-alkanol derivatives as antiischemic agents |
| RU2099339C1 (ru) | 1990-02-06 | 1997-12-20 | Пфайзер Инк. | Производные пиперидина |
| HUT65836A (en) | 1991-04-18 | 1994-07-28 | Pfizer | Process for producing phenol-esters of 1-(hydroxy-phenyl)-2-piperidino-1-alkanol derivatives and pharmaceutical compositions containing them |
| DE4118740A1 (de) | 1991-06-05 | 1992-12-10 | Schering Ag | Neue kombinationspraeparate zur behandlung des morbus parkinson |
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