ZA200409147B - A combination of an NMDA-antagonist and acetylcholine esterase inhibitors for the treatment of alzheimer's disease - Google Patents
A combination of an NMDA-antagonist and acetylcholine esterase inhibitors for the treatment of alzheimer's disease Download PDFInfo
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- ZA200409147B ZA200409147B ZA200409147A ZA200409147A ZA200409147B ZA 200409147 B ZA200409147 B ZA 200409147B ZA 200409147 A ZA200409147 A ZA 200409147A ZA 200409147 A ZA200409147 A ZA 200409147A ZA 200409147 B ZA200409147 B ZA 200409147B
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- disease
- treatment
- alzheimer
- antagonist
- dementia
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- 206010012289 Dementia Diseases 0.000 claims description 14
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 9
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 8
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 claims description 8
- 229960004640 memantine Drugs 0.000 claims description 8
- 229960003530 donepezil Drugs 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims description 5
- 208000010877 cognitive disease Diseases 0.000 claims description 5
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 5
- 229960004136 rivastigmine Drugs 0.000 claims description 5
- 229960001685 tacrine Drugs 0.000 claims description 5
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 5
- 229960003980 galantamine Drugs 0.000 claims description 4
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims 1
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- 230000006872 improvement Effects 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 2
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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- 231100000868 delusion Toxicity 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 150000002334 glycols Chemical class 0.000 description 1
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
A combination of an NMDA-antagonist and acetylcholine esterase inhibitors for the treatment of Alzheimer’s disease.
The present invention provides a treatment for mild cognitive impairment (MCI) and for dementia of different types such as dementia of Alzheimer’s type, vascular dementia, Lewy body dementia, AIDS dementia and frontotemporal dementia by administration of medicaments having dual mechanisme of action.
Dementia of different origin are a growing problem in the world. Among the elderly,
Alzheimer’s disease is the most common type of dementia. The prevalence of the disease raises from 2% of the people aged 65-70 to as high as 20% of the people aged 80 and older. Though perhaps not the only contributing factor, the increased life expectancy and the increased elderly population explains the raise in the frequency of the disease.
Alzheimer’s disease is a slowly progressing neurodegencrative disease characterised by significant loss of function in more than one cognitive domain. Associated diseases such as psychiatric illness and change in behaviour or personality are common.
Presently, the disease cannot be cured. Current treatment gives for some patients a delay in the symptoms, for others a modest cognitive improvement and a dramatic improvement in only a small number of patients. A slower progression of the disease is also desirable for improving the life quality for the patient and the patient’s relatives. However, experience with the current treatment with Alzheimer’s therapy, still 30% of the patients do not respond to the treatment. Consequently, a great need for improvement in the treatment of Alzheimer’s disease exists.
The mechanisms behind the different types of dementia, including Alzheimer’s . 30 disease, are not fully understood. Of medicaments available for treatment, which presently is only slowing the progression of the disease, they represent different mechanism of action in the central nervous system.
SUBSTITUTE SHEET
One group of medicaments are represented by the acetylcholinesterase inhibitors, of which medicaments like Donepezil, Rivastigmine, Galantamine and Tacrine are - pharmaceuticals having this particular activity. The acetylcholinesterase inhibitors are i presently approved in many countries for treatment of mild to moderate Alzheimer’s disease.
Another group of medicaments are the NMDA antagonist of which Memantine is a representative. Memantine was recently approved in the EU for treatment of moderate severe to severe Alzheimer’s disease.
Though of very different mechanisms of action, both types of medicaments are useful in the treatment of Alzheimer’s disease, though in different stages of the disease progression.
The invention thus provides the combined treatment of a patient suffering from a dementia syndrome with a first component which is an acetylcholinesterase inhibitor(s) and a second component which is an NMDA antagonist.
The invention also provides a pharmaceutical composition which comprises a first component which is an acetylcholinesterase inhibitor(s) and a second component which is an NMDA antagonist.
The acetylcholinesterase inhibitors include, but are not limited to: Donepezil, a known compound described in EP 296560 and US 4895841.
Galantamines use in the treatment of Alzheimer’s disease is described in EP236684 . and US 4663318. . 30 Rivastigmine as described in national applications corresponding to US 5602176 and
GB 2203040.
SUBSTITUTE SHEET
:
Tacrine as used in the treatment of cholinergic deficit state, such as Alzheimer’s disease, is described in EP 328535 and US 4816456. - Similarly, when the invention is regarded in its broadest sense, the second component ] is a compound which functions as an NMDA antagonist or partial antagonist of which assays like Ebert et. al European Journal of Pharmacology 1997, 333 , 99-104 exists for determining this activity. Other compounds than the compounds mentioned here have the desired effect. It is intended to include compounds which show antagonisme in the assay described above.
In the present invention, the combination of one compound of the group of acetylcholinesterase inhibitors with one compound of the group of NMDA antagonist 1s included. Likewise, the combination of two compounds of the first group with one or two or the compounds selected from the second group is also within the present invention and vice versa.
While all combinations of first and second group compounds are useful the following combinations are considered as the preferred combinations:
Memantine/Donepezil, Memantine/Galantamine, Memantine/Rivastigmine and
Memantine/Tacrine.
Where the compounds exists as different polymorphs, isomers, enantiomers or tautomers the present invention also embraces these variations as well as different salts or solvates etc.
Active metabolites of the compounds described are also embraced by the invention.
Alzheimer’s Disease . 30
Characteristics of Alzheimer’s Disease are some of the following symptoms occuring: eo Dementia
SUBSTITUTE SHEET e Deficits in cognition (such as language, memory, motor skills and perception ie. aphasia, apraxia, agnosia) ) e Progressive worsening of memory and cognitive functions
Some of the following associated symptoms often occur:
Depression, insomnia, incontinence, delusions, illusion, hallucinations, emotional or physical outbursts, shouting, wandering , aggression, agitation, apathy, abnormal eating, sexual disorders and weight loss.
Increased motor tone, myoclonus or gait disorder in the late stages of the disease progression.
Since Alzheimer’s disease is not curable at present, the complexity of the disease progression and the associated symptoms often gives rise to a multiplicity of diseases, which all need medical treatment. Such treatment regimens and side-effects are difficult to administerable for the patient as well as for the health carer.
Consequently, a positive outcome of an Alzheimer’s treatment is an improved cognitive function. A slower progression of the disease, or a delay in the normal disease progression is a positive outcome of a treatment.
Improvements could also be measured in the secondary or associated symptoms of more psychiatric character. Diminished intake or complete stop in the intake of for example antipsychotic, antidepressive, tranquilising or sedative medication will also be signs of a positive response to the treatment of the underlying cause of the dementia, ie. the Alzheimer’s Disease.
When combination treatment is evaluated a synergistic effect of the combined . 30 administration could be evaluated and the total dose of the combination treatment of individual compounds relative to the doses used for single compound administration could be lowered.
SUBSTITUTE SHEET
The present invention covers treatment of mild cognitive impairment and dementia regardless of the underlying cause. For example the dementia can be Alzheimer’s © disease, vascular dementia, Lewy body dementia, AIDS dementia or frontotemporal } dementia. 5
In the context of this invention, Alzheimer’s disease includes all stages of the disease, 1e. mild, moderate and severe Alzheimer’s disease.
In the context of this invention, mild cognitive impairment are characterised by symptoms defined by Petersen et. al.
Pharmaceutical compositions: 1s To prepare the pharmaceutical compositions of this invention, an effective amount of the active ingredients, in acid or base addition salt form or base form, is combined in intimate admixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form of preparation desired for administration.
These pharmaceutical compositions are desirably in unitary dosage form suitable, for administration orally, nasal, rectally, percutaneously or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage.
SUBSTITUTE SHEET
Dosage unit form as used in the specification and claims herein refer to physically discrete units suitable as unitary dosages, each unit containing a predetermined oo quantity of active ingredient calculated to produce the desired therapeutic effect, in . association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
The NMDA antagonist may be administered before, during or after the administration of the acetylcholinesterase inhibitor provided that the time between the administration of the acetylcholinesterase inhibitor and the administration of the acetylcholinesterase inhibitor is such that ingredients are allowed to act synergistically on the CNS.
When simultaneous administration of NMDA antagonist and an acetylcholinesterase inhibitor is envisaged, a composition containing both an acetylcholinesterase inhibitor and an NMDA antagonist may be particularly convenient. The compositions may be prepared as described herein above.
Simultaneous administration may also be accomplished by administration of the active ingredients in two separate unit dosage forms.
When sequential administration of the NMDA antagonist is envisaged, the pharmaceutical composition may comprise, for example, a kit including discrete unit dosage forms containing the NMDA antagonist and discrete unit dosage forms containing an acetylcholinesterase inhibitor, all contained in the same container or pack, e.g. a blister pack.
Dose Ranges
The selection of dosage of the first and second component is that which gives the patient relief of the symptoms of the disease. The dosage depends on several factors such as the potency of the selected compounds, the mode of administration, the age
SUBSTITUTE SHEET and weight of the patient, the severity of the condition to be treated and the like. This is considered to be the skill of the artisan and suitable literature can be consulted for © the dosages recommended for each compound. oF 5 The dosage ranges for the NMDA antagonist, Memantine are 0.1mg —500mg of active ingredient pr. dosage. More preferred are 1- 50 mg and most preferred are 2 - 25 mg.
Presently the preferred dosage administered is 20mg.
The dosage of the second component, the acetylcholinesterase inhibitor, will depend on the dosage of the NMDA antagonist administered or vice versa. The average daily dosage of the acetylcholinesterase inhibitor are from 0.1mg -500mg of active ingredient pr. dosage. More preferred are 1- 50 mg and most preferred are 2 - 25 mg.
Presently, the dosage regime for the available acetylcholinesterase inhibitor are the following:
Tacrine 10-40 mg four times a day
Donepezil 5-10 mg per day
Rivastigmine 3-12 mg per day
Galantamine 4-24 mg per day
SUBSTITUTE SHEET
Claims (4)
1. The use of a composition comprising: (a) an effective amount of one or more acetylcholinesterase inhibitor(s) or a pharmaceutically acceptable salt thereof and (b) an effective amount of one or more NMDA -antagonist(s) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of mild cognitive impairment of dementia in connection with moderate to severe Alzheimer’s.
2. The use according to claim 1 wherein component (a) is selected from the group consisting of Tacrine, Donepezil, Rivastigmine and Galantamine and mixtures thereof.
3. The use according to claim 1 or claim 2 wherein component (a) is Donepezil.
4. The use according to any one of claims 1-3 wherein component (b) is Memantine. Amended sheet 27/06/2006
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200200844 | 2002-05-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200409147B true ZA200409147B (en) | 2006-06-28 |
Family
ID=28051666
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200409147A ZA200409147B (en) | 2002-05-31 | 2004-11-11 | A combination of an NMDA-antagonist and acetylcholine esterase inhibitors for the treatment of alzheimer's disease |
Country Status (9)
| Country | Link |
|---|---|
| KR (1) | KR101016927B1 (en) |
| CN (1) | CN1655793A (en) |
| AR (1) | AR040121A1 (en) |
| CA (1) | CA2426492C (en) |
| EA (1) | EA007632B1 (en) |
| IS (1) | IS7558A (en) |
| PE (1) | PE20040623A1 (en) |
| UA (1) | UA82480C2 (en) |
| ZA (1) | ZA200409147B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA107653U (en) | 2012-10-01 | 2016-06-24 | Общєство С Огранічєнной Отвєтствєнностью "Валєнта-Інтєллєкт" | COMPOSITION OF MEDICINAL PRODUCTS FOR TREATMENT AND PREVENTION OF BEHAVIORAL, MENTAL, AND COGNITIVE DISORDERS |
| CN105294450B (en) * | 2014-05-29 | 2024-05-17 | 广州喜鹊医药有限公司 | Amantadine nitrate compound with neuroprotection effect, preparation and medical application thereof |
| WO2018062941A1 (en) * | 2016-09-30 | 2018-04-05 | 주식회사 바이오파마티스 | Pharmaceutical composition for preventing or treating dementia and cognitive dysfunction, containing donepezil or pharmaceutically acceptable salt thereof and memantine or pharmaceutically acceptable salt thereof, and preparation method therefor |
| KR20210072569A (en) | 2019-12-09 | 2021-06-17 | 주식회사 종근당 | Complex formulation comprising donepezil and memantine |
-
2003
- 2003-05-08 CA CA002426492A patent/CA2426492C/en not_active Expired - Fee Related
- 2003-05-22 EA EA200401617A patent/EA007632B1/en not_active IP Right Cessation
- 2003-05-22 CN CNA038121611A patent/CN1655793A/en active Pending
- 2003-05-22 KR KR1020047019333A patent/KR101016927B1/en not_active IP Right Cessation
- 2003-05-22 UA UA20041109789A patent/UA82480C2/en unknown
- 2003-05-27 AR ARP030101849A patent/AR040121A1/en unknown
- 2003-05-29 PE PE2003000527A patent/PE20040623A1/en not_active Application Discontinuation
-
2004
- 2004-11-11 ZA ZA200409147A patent/ZA200409147B/en unknown
- 2004-11-26 IS IS7558A patent/IS7558A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| UA82480C2 (en) | 2008-04-25 |
| EA007632B1 (en) | 2006-12-29 |
| IS7558A (en) | 2004-11-26 |
| PE20040623A1 (en) | 2004-09-11 |
| CN1655793A (en) | 2005-08-17 |
| KR20050024296A (en) | 2005-03-10 |
| CA2426492A1 (en) | 2003-09-16 |
| AR040121A1 (en) | 2005-03-16 |
| KR101016927B1 (en) | 2011-02-28 |
| EA200401617A1 (en) | 2005-06-30 |
| CA2426492C (en) | 2006-10-03 |
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