EP0934040A1 - Method for treating dementia due to aids - Google Patents
Method for treating dementia due to aidsInfo
- Publication number
- EP0934040A1 EP0934040A1 EP97912879A EP97912879A EP0934040A1 EP 0934040 A1 EP0934040 A1 EP 0934040A1 EP 97912879 A EP97912879 A EP 97912879A EP 97912879 A EP97912879 A EP 97912879A EP 0934040 A1 EP0934040 A1 EP 0934040A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- dementia due
- effective amount
- hiv disease
- treating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 16
- 206010012289 Dementia Diseases 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 206010065040 AIDS dementia complex Diseases 0.000 claims abstract description 18
- 241000282412 Homo Species 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 230000037317 transdermal delivery Effects 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 208000020016 psychiatric disease Diseases 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 2
- 206010012218 Delirium Diseases 0.000 description 2
- 206010041243 Social avoidant behaviour Diseases 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- 239000000902 placebo Substances 0.000 description 2
- 229940068196 placebo Drugs 0.000 description 2
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- 208000000187 Abnormal Reflex Diseases 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 206010013496 Disturbance in attention Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 206010020852 Hypertonia Diseases 0.000 description 1
- 206010025280 Lymphocytosis Diseases 0.000 description 1
- 206010027951 Mood swings Diseases 0.000 description 1
- 206010053694 Saccadic eye movement Diseases 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 206010020745 hyperreflexia Diseases 0.000 description 1
- 230000035859 hyperreflexia Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000009017 pursuit movement Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000004434 saccadic eye movement Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- JOLJIIDDOBNFHW-UHFFFAOYSA-N xanomeline Chemical compound CCCCCCOC1=NSN=C1C1=CCCN(C)C1 JOLJIIDDOBNFHW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
Definitions
- This invention provides a method for treating or alleviating the symptoms of dementia due to AIDS, comprising administering an effective amount of 3- (4-hexyloxy-l, 2, 5- thiadiazol-3-yl) -1,2,5, 6-tetrahydro-l-methylpyridine .
- HIV disease Human immunodeficiency virus (HIV) disease may often result in the patient being further incapacitated due to the serious psychological disorder, Dementia Due to HIV Disease (characterized in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (American Psychiatric Association, 1994) DSM-IV as catagory 294.9). Such Dementia can result in hospitalization of the patient, stress for caretakers, and increased medical expense.
- HIV Human immunodeficiency virus
- the present invention relates to a method of treating Dementia Due to HIV Disease. More specifically, the invention provides a method of treating Dementia Due to HIV Disease in humans using 3- (4-hexyloxy-l, 2, 5-thiadiazol-3-yl) -1, 2, 5, 6- tetrahydro-1-methylpyridine .
- the compounds employed in the method of the present invention are known. Methods of preparing the compounds, as well as pharmaceutical formulations containing the compounds, are taught by Sauerberg in U.S. Pat. No. 5,043,345 herein incorporated by reference .
- the present invention provides a method for treating Dementia Due to HIV Disease in humans comprising administering to a human in need thereof, an effective amount of a compound of Formula I:
- the term "effective amount”, as used herein, represents an amount of compound necessary to prevent or treat a human susceptible to or suffering from Dementia due to HIV Disease following administration to such human.
- the active compound is effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.005 to about 500 mg/kg of body weight. In the treatment of adult humans, the range of about 0.05 to about 100 mg/kg, in single or divided doses, is preferred.
- the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
- the present compound may be administered orally to humans susceptible to or suffering from Dementia Due to HIV Disease, the compound is particularly well suited to be administered transdermally. When the compound is delivered transdermally, it is preferred that the effective amount is from about 50mg to about lOOmg per day delivery of base compound. It is especially preferred that such patch delivers an effective amount for about three to seven days.
- the compound may further be delivered by a variety of other pharmaceutically accepted routes including, but in no way limited to parenterally, subcutaneous, intranasal, intramuscular and intravenous routes.
- Such formulations may be designed to provide delayed or controlled release using formulation techniques which are known in the art.
- treating includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.
- the term "Dementia Due to HIV Disease” refers to a disorder that upon neuropathological examination may commonly involve diffuse multifocal destruction of the white matter and subcortical structures.
- the spinal fluid may show normal or slightly elevated protein and a mild lymphocytosis, and HIV can usually be isolated directly from the cerebrospinal fluid.
- Dementia associated with HIV is typically characterized by slowness, poor concentration, difficulties with problem solving, and forgetfulness .
- Behavioral manifestations most commonly include apathy and social withdrawal, and occasionally these may be accompanied by delirium, delusions, or hallucinations .
- Tremor, impaired rapid repetitive movements, imbalance, ataxia, hypertonia, generalized hyperreflexia, positive frontal release signs, and impaired pursuit and saccadic eye movements may be presented on physical examination.
- DSM-IV-R Diagnostic and Statistical Manual of Mental Disorders, Revised, 4th Ed. (1994) .
- the DSM-IV-R was prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric Association, and provides clear descriptions of diagnostic catagories. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for pathologic psychological conditions and that these systems evolve with medical scientific progress.
- the compounds employed in the invention are not believed to act via the GABA/benzodiazepine, 5HT1A, or Dl receptor systems in humans. Rather, the activity of the present compound as a treatment for Dementia Due to HIV Disease is believed to be based upon modulation of muscarinic cholinergic receptors. However, the mechanism by which the present compounds function is not necessarily the mechanism stated supra . , and the present invention is not limited by any mode of operation. The following Examples are studies to establish the usefulness of the named compounds for treating Dementia Due to HIV Disease.
- Treatment groups are compared with respect to the number and percent of patients who ever had the symptom during the double-blind portion of the study (visits 5 through 33) , at a severity that was worse than during the baseline visits (1 through 4) .
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Tropical Medicine & Parasitology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- AIDS & HIV (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a method for treating Dementia Due to HIV Disease using a compound of the Formula (I).
Description
METHOD FOR TREATING DEMENTIA DUE TO AIDS
This invention provides a method for treating or alleviating the symptoms of dementia due to AIDS, comprising administering an effective amount of 3- (4-hexyloxy-l, 2, 5- thiadiazol-3-yl) -1,2,5, 6-tetrahydro-l-methylpyridine .
Human immunodeficiency virus (HIV) disease may often result in the patient being further incapacitated due to the serious psychological disorder, Dementia Due to HIV Disease (characterized in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (American Psychiatric Association, 1994) DSM-IV as catagory 294.9). Such Dementia can result in hospitalization of the patient, stress for caretakers, and increased medical expense.
Sauerberg et al . in U.S. Patent 5,043,345 ('345) disclose the 3- (4-hexyloxy-l, 2, 5-thiadiazol-3-yl) -1, 2, 5, 6- tetrahydro-1-methylpyridine compound which Applicants have discovered is useful for treating Dementia due to HIV Disease. The compounds in the '345 patent are taught to be useful in treating Alzheimer's disease, severe painful conditions, and glaucoma. There is no disclosure in the patent of using the compounds to treat Dementia due to HIV Disease.
Surprisingly, we have discovered that 3- (4- hexyloxy-1, 2, 5-thiadiazol-3-yl) -1, 2, 5, 6-tetrahydro-l- methylpyridine, thought to be a muscarinic agonist, can be useful for treating Dementia Due to HIV Disease. The present invention relates to a method of treating Dementia Due to HIV Disease. More specifically, the invention provides a method of treating Dementia Due to HIV Disease in humans using 3- (4-hexyloxy-l, 2, 5-thiadiazol-3-yl) -1, 2, 5, 6- tetrahydro-1-methylpyridine . As noted hereinbefore, the compounds employed in the method of the present invention are known. Methods of preparing the compounds, as well as pharmaceutical
formulations containing the compounds, are taught by Sauerberg in U.S. Pat. No. 5,043,345 herein incorporated by reference .
The present invention provides a method for treating Dementia Due to HIV Disease in humans comprising administering to a human in need thereof, an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt or solvate thereof.
It is to be understood that the invention extends to the use of each of the stereoisomeric forms of the compound of the present invention as well as any pure diastereomeric, pure enantiomeric, and racemic forms of the named compounds .
The term "effective amount", as used herein, represents an amount of compound necessary to prevent or treat a human susceptible to or suffering from Dementia due to HIV Disease following administration to such human. The active compound is effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.005 to about 500 mg/kg of body weight. In the treatment of adult humans, the range of about 0.05 to about 100 mg/kg, in single or divided doses, is preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances
including the condition to be treated, the choice of compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. While the present compound may be administered orally to humans susceptible to or suffering from Dementia Due to HIV Disease, the compound is particularly well suited to be administered transdermally. When the compound is delivered transdermally, it is preferred that the effective amount is from about 50mg to about lOOmg per day delivery of base compound. It is especially preferred that such patch delivers an effective amount for about three to seven days. The compound may further be delivered by a variety of other pharmaceutically accepted routes including, but in no way limited to parenterally, subcutaneous, intranasal, intramuscular and intravenous routes. Such formulations may be designed to provide delayed or controlled release using formulation techniques which are known in the art.
As used herein the term "treating" includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.
As used herein the term "Dementia Due to HIV Disease" refers to a disorder that upon neuropathological examination may commonly involve diffuse multifocal destruction of the white matter and subcortical structures. The spinal fluid may show normal or slightly elevated protein and a mild lymphocytosis, and HIV can usually be isolated directly from the cerebrospinal fluid. Dementia associated with HIV is typically characterized by slowness, poor concentration, difficulties with problem solving, and forgetfulness . Behavioral manifestations most commonly include apathy and social withdrawal, and occasionally these may be accompanied by delirium, delusions, or
hallucinations . Tremor, impaired rapid repetitive movements, imbalance, ataxia, hypertonia, generalized hyperreflexia, positive frontal release signs, and impaired pursuit and saccadic eye movements may be presented on physical examination.
Dementia Due to HIV Disease has been characterized in the DSM-IV-R. Diagnostic and Statistical Manual of Mental Disorders, Revised, 4th Ed. (1994) . The DSM-IV-R was prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric Association, and provides clear descriptions of diagnostic catagories. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for pathologic psychological conditions and that these systems evolve with medical scientific progress.
The compounds employed in the invention are not believed to act via the GABA/benzodiazepine, 5HT1A, or Dl receptor systems in humans. Rather, the activity of the present compound as a treatment for Dementia Due to HIV Disease is believed to be based upon modulation of muscarinic cholinergic receptors. However, the mechanism by which the present compounds function is not necessarily the mechanism stated supra . , and the present invention is not limited by any mode of operation. The following Examples are studies to establish the usefulness of the named compounds for treating Dementia Due to HIV Disease.
Example 1 Human Clinical Trials
Finally, the activity of 3- (4-hexyloxy-l, 2, 5- thiadiazol-3-yl) -1,2,5, 6-tetrahydro-l-methylpyridine for treating or alleviating Dementia Due to HIV Disease can be demonstrated by human clinical trials. The study was designed as a double-blind, parallel, placebo-controlled multicenter trial. The patients were randomized into four groups, placebo and 25, 50, and 75 mg tid of test compound.
The dosages were administered orally with food. Patients were observed at four visits to provide baseline measurements. Visits 5-33 served as the treatment phase for the study. During the visits, patients and their caregivers are questioned and observed for signs of agitation, mood swings, tremor, delirium, social withdrawal, and concentration abilities. Each of these behaviors are indicative of the effect of the test compound on Dementia Due to HIV Disease. Additionally, patients are asked a series of questions designed to assess ability to solve problems and slowness.
Treatment groups are compared with respect to the number and percent of patients who ever had the symptom during the double-blind portion of the study (visits 5 through 33) , at a severity that was worse than during the baseline visits (1 through 4) .
Claims
1. A method for treating Dementia Due to HIV
Disease in humans comprising administering to a human in need thereof, an effective amount of a compound of Formula
I:
a pharmaceutically acceptable salt thereof.
2. A method of Claim 1 wherein the effective amount is from 1 mg/kg to about 100 mg/kg per day.
3. A method of Claim 2 wherein the effective amount is from about 50 mg/kg to about 100 mg/kg per day,
4. A method of Claim 1 wherein the effective amount is delivered using a transdermal patch.
5. A method of Claim 4 wherein the transdermal patch delivers from about 50 to about 100 mg of base compound per day.
6. A method of Claim 5 wherein the transdermal patch delivers an effective amount for three (3) to seven (7) days.
7. A compound of Formula I:
I
CH3 j or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of Dementia Due to HIV Disease.
8.A compound of Claim 7 wherein the compound is administered using a transdermal delivery formulation.
9. A compound of Claim 7 wherein the compound is administered using a transdermal delivery system that delivers and effective amount of compound from about three (3) to about seven (7) days.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2973696P | 1996-10-23 | 1996-10-23 | |
| US29736P | 1996-10-23 | ||
| PCT/US1997/019184 WO1998017214A1 (en) | 1996-10-23 | 1997-10-23 | Method for treating dementia due to aids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0934040A1 true EP0934040A1 (en) | 1999-08-11 |
Family
ID=21850604
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP97912879A Withdrawn EP0934040A1 (en) | 1996-10-23 | 1997-10-23 | Method for treating dementia due to aids |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0934040A1 (en) |
| JP (1) | JP2001502696A (en) |
| AU (1) | AU4995797A (en) |
| CA (1) | CA2269506A1 (en) |
| WO (1) | WO1998017214A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE59904564D1 (en) * | 1998-11-27 | 2003-04-17 | Sanochemia Pharmazeutika Ag Wi | USE OF ACETYLCHOLINESTERASE INHIBITORS FOR THE TREATMENT OF DELIRIA |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4826843A (en) * | 1985-07-08 | 1989-05-02 | Bristol-Myers | Cerebral function enhancing diazinylpiperidine derivatives |
| US5043345A (en) * | 1989-02-22 | 1991-08-27 | Novo Nordisk A/S | Piperidine compounds and their preparation and use |
| US5232929A (en) * | 1990-11-28 | 1993-08-03 | Pfizer Inc. | 3-aminopiperidine derivatives and related nitrogen containing heterocycles and pharmaceutical compositions and use |
-
1997
- 1997-10-23 CA CA002269506A patent/CA2269506A1/en not_active Abandoned
- 1997-10-23 AU AU49957/97A patent/AU4995797A/en not_active Abandoned
- 1997-10-23 JP JP10519635A patent/JP2001502696A/en active Pending
- 1997-10-23 EP EP97912879A patent/EP0934040A1/en not_active Withdrawn
- 1997-10-23 WO PCT/US1997/019184 patent/WO1998017214A1/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9817214A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1998017214A1 (en) | 1998-04-30 |
| AU4995797A (en) | 1998-05-15 |
| JP2001502696A (en) | 2001-02-27 |
| CA2269506A1 (en) | 1998-04-30 |
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