WO1991018607A1 - Febarbamate for the treatment of cranial nervous disorders and encephalic circulation and metabolism disorders - Google Patents
Febarbamate for the treatment of cranial nervous disorders and encephalic circulation and metabolism disorders Download PDFInfo
- Publication number
- WO1991018607A1 WO1991018607A1 PCT/EP1991/000979 EP9100979W WO9118607A1 WO 1991018607 A1 WO1991018607 A1 WO 1991018607A1 EP 9100979 W EP9100979 W EP 9100979W WO 9118607 A1 WO9118607 A1 WO 9118607A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- disorders
- febarbamate
- pharmaceutically acceptable
- treatment
- acceptable salt
- Prior art date
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
Definitions
- This invention relates to a drug for the improvement and treatment of disorders and diseases originating in the breakdown or degeneration of cranial nerves and disorders in encephalic circulation and metabolism.
- Psychoneurotic diseases such as mania, depression, schizophrenia delirium and anxiety neurosis are psychoses to which an abnormality in the action system and metabolic system and the like of various neurotransmitters is considered to have principal relation, and pharmacotherapies using various psychopharmaceuticals are being widely carried out.
- 34912/1977 discloses a drug effective for diseases originating in disorders in neurostimulation transmission in the central nervous system and peripheral nervous system, which comprises a dispersion or solution of a ganglioside in a medium.
- gangliosides mixture is on the market under the name of cronassial ® in Italy.
- gangliosides are natural extracts derived from heterogenous animals and thus it is considered that there are problems of the antigenicity of themselves or impurities, and further it is fairly difficult to prescribe and prepare gangliosides as pharmaceutically uniform and stable substances.
- nerve growth factors NGF
- neurotrophic factors neurotrophic factors
- Japanese Patent Publication No. 28548/1984 discloses 2-isopropylaminopyrimidine orthophosphate and a drug containing it for the treatment of peripheral nervous diseases. Isaxonine
- phosphate was clinically studied but at present does not seem to have been placed on the market.
- mechobalamin a vitamin, in Japan.
- Japanese Laid-Open Patent Publication No. 144384/1979 (corresponding to Japanese Patent Publication No. 18553/1986 and British Patent No. 1581834) and Japanese Laid-Open Patent Publication No. 205370/1984.
- the former Japanese Laid-Open Patent Publication No. 144384/1979 discloses a series of com plexes comprising three kinds of malonylurea derivatives which have an ataractic action, more particularly, a useful action in the treatment of tremors. Further, there is a disclosure in the same publication saying "These
- malonylurea derivatives having abirritant and/or ataractic action(s) generally constitute a large class of psychopharmaceuticals which have widely uses ciincically for the treatment of many neural disorders, including anxiety states and psychomotor disturbances, whether of emotional, alcoholic, medicinal or mental origin.
- febarbamate is extremely helpful in the general care of geriatric patients. Such patients are prone to fits of excitation, agitation and aggressivity and frequently become extremely antisocial. In a series of clinical tests, we have found the administration of febarbamate to have a significant improving effect upon the mental well-being of geriatrics. This is not a consequence of any mild sedative action. Indeed febarbamate appears to be superior in its action to the best compounds currently in clinical use for the treat ment of irritable geriatrics.
- febarbamate In contrast to other psychotropic agents, febarbamate does not affect the personality and does not depress the patients' vigilance or other psychic reactions. This is an important quality of the product since elderly people are often quite psychically fragile. We have found febarbamate to produce a gentle and prolonged psychic stimulation which allows the patient to be more social, mentally alert and generally receptive.
- An object of this invention is to provide a drug for the improvement and treatment of disorders and diseases accompanying the breakdown and degeneration of nerves.
- a further aspect of the invention is to provide a drug for the improvement and treatment of disorders caused by degeneration of the blood vessels and neurons of a cerebrum and the like related to disorders in learning , memory and cognitive functions including cerebral aging , cerebrovascular dementia and Alzheimer type senile dementia .
- febarbamate has a novel drug action other than its so far known pharmacological actions , namely an activity to make overgrow the neurites of neurocytes , particularly the neuroblastoma cells of mouse , Homo sapiens , etc . and an antagonistic activity against triethyl-tin-induced brain edema
- a yet further feature of this invent ion comprises febarbamate in a form adapted for the treatment of disorders and diseases accompanying the breakdown and degeneration of nerves , and disorders caused by the degeneration of the blood vessels and neurons of a cerebrum and the like related to disorders in learning , memory and cognitive functions including cerebral
- Such a form may comprise a pharmaceutically acceptable composition comprising febarbamate in admixture with a pharmaceutically acceptable excipient, diluent or carrier.
- the above aspects and advantages of the inventicri can be attained by the use of a drug for the improvement and treatment of disorders and diseases accompanying the breakdown and degeneration of nerves or disorders in encephalic circulation and metabolism.
- the drug of the invention is a substance having the drug of the invention.
- disorders and diseases related to the central nervous system include cerebrovascular disorders due to, for example, head injury, brain ischemia, brain infarction, brain bleeding, brain arteriosclerosis, brain venous thrombus and the like; functional breakdowns of the brain due to these cerebrovascular disorders and lowering of the intellectual functions and other symptoms accompanying them; and various mental that follow.
- multiple sclerosis amyotrophic lateral sclerosis, acute sporadic encephalomyelitis, postvaccinal encephalitis, SMON, dementia, Alzheimers syndrome, etc. are also included.
- peripheral nervous disorders accompanied by kinetic, sensory and/or objective reflex retardation, including nerve root lesions due to traumatic, inflammatory or immunological causes; alcoholic, pharmaceutical, metabolic such as diabetic, and idiopathic peripheral nervous disorders; and the like. More specifically mentioned are facial paralysis, sciatic paralysis, spinal amyotrophy, muscular dystrophy, myasthenia gravis, Guillan-Barre syndrome, rheumatism, etc.
- Febarbamate as an effective ingredient of the improvement and treatment agent of the invention may be provided for the treatment as it is, i.e. as a free base, or otherwise as an alkali salt or acid addition salt thereof.
- Suitable alkali salts thereof include its potassium salt, sodium salt, lithium salt, calcium salt, magnesium salt, zinc salt and aluminum salt and so on.
- Suitable acid addition salts thereof include its hydrochloride, acetate, tosylate, methanesulfonate, succinate, lactate, benzoate, maleate, tartrate, citrate, fumarate and naphthalenesulfonate salts and so on.
- neurocytes used as neurocytes were murine neuroblastoma cells such as a neuro-2a strain (given from the Second Biochemical classroom, the Medical Department, Tokyo University) and an NS-2OYS strain, human neuroblastoma cells such as a GOTO strain and an NB-1 strain (similarly, given from the Biochemical Classroom, Tokyo University), and so on.
- murine neuroblastoma cells such as a neuro-2a strain (given from the Second Biochemical classroom, the Medical Department, Tokyo University) and an NS-2OYS strain
- human neuroblastoma cells such as a GOTO strain and an NB-1 strain (similarly, given from the Biochemical Classroom, Tokyo University), and so on.
- DMEM Dulbecco's modified Eagle's medium
- models with central nerve disorders were prepared using rats, mice, etc. and the drug actions of febarbamate of the invention were tested. Namely, rats, mice, etc. having neuropathies caused by mercury poisoning were prepared and the activity of febarbamate of the invention was tested. As a result, it was revealed that febarbamate has a promoting effect and a therapeutic effect about the improvement of the symptoms and recovery to the normal state.
- nigral dopamine cells of the rat brain were chemically destroyed by injecting a very small amount of 6-hydroxydopamine to induce motor imbalance.
- dopamine cells of fetal brain v/ere transplanted in the caudate nucleus into the lesioned side of the rat brain and an attempt was made to improve the motor trouble.
- febarbamate of the invention was intraperitoneally administered every day over 2 weeks, and the activity of febarbamate on the improvement of the motor imbalance and the growth of the transplanted cells was examined. It was found that febarbamate of the invention has a promoting effect on the improvement, etc. of the motor trouble.
- febarbamate has a promoting effect on the recovery to the normal values of parameters of function, such as the distance between the hindlegs of the crush side and twitch tension, and the weight of the musculi extensor digitorum longus of the hindlegs and musculi soleus, and the like.
- febarbamate significantly inhibited the formation of brain edema, as is the case with vinpocetine, a brain circulation and metabolism-improving drug. This is
- febarbamate The action of febarbamate was investigated on brain edema formed by orally administering triethyl-tin (2 mg/kg) to rats every morning (at 9 am) once a day every day over 5 days. Drugs were orally administered twice a day (9 am and 3 pm) every day over 4 days and on the fifth day once a day (9 am). At 3 pm on the fifth day the rats were sacrificed and the water amount of the brains was measured.
- Brain edema by triethyl-tin is a cell-impairing brain edema. It is verification of the usefulness of febarbamate as a brain circulation and metabolism- improving drug that febarbamate inhibited this brain edema in comparison with the brain circulation and metabolism-improving drug vinpocetine.
- LD 50 mg/kg
- Febarbamate of the invention has a promoting effect on the formation and overgrowth of the neurites of neurocytes, and has even on rats, mice, etc. having neuropathies a neurotization effect, a motor function recovery effect, a learing and memory improvement and recovery effect, and an anti-brain edema effect, and thus can suitably be used for the improvement and treatment of central nervous and cerebrovascular disorders, dementia, and nervous system diseases such as peripheric nervous disorders. Further, it is expected that febarbamate can also suitably be used for the recovery, improvement and treatment of nervous system diseases caused by the disorders of nervous tissues and cells related to sensory functions and autonomic functions.
- Febarbamate used as an effective ingredient in the invention is used usually in the form of a pharmaceutical composition, and administered through various routes such as oral, subcutaneous, intramuscular, intraveous, intranasal, transcutaneous and rectal routes.
- a yet further feature of this invention is the use of febarbamate or a salt thereof for the preparation of a medicament for the treatment of the diseases and disorders hereinbefore listed.
- composition of the invention can be made into forms such as, for example, tablets, capsules, powders, granules, lozenges, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols, ointments, sterile injections, molded cataplasmas, tape preparations, soft and hard gelatin capsuls, suppositories and sterilely packaged powders.
- pharmaceutically acceptable carriers are lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, gam arabic, calcium phosphate, alginates, calcium
- silicate finely crystalline cellulose, polyvinylpyrrolidone, tragacanth gum, gelatin, syrup, methylcellulose, carboxymethylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium
- Both solid and liquid compositions can contain fillers, binders, lubricants, wetting agents, disintegrants, emulsifying and suspending agents, preservatives, sweeteners, aromatic agents, etc. as above mentioned.
- the present composition can be formulated so that, after administration to patients, the active ingredient is released rapidly, lastingly or with delay.
- febarbamate is mixed with carriers and diluents, and the mixture is made into forms such as tablets and capsules.
- parenteral administration the active ingredient is dissolved in a 10 % aqueous glucose solution, isotonic saline, sterile water or a similar liquid, and sealed into vials or ampules for administration into veins by drip or injection or into muscles by injection.
- solubilizing agents, local anesthetics, preservatives and buffering agents can also be used.
- parenteral administration there are formulations to be administered transcutaneously such as ointments and cataplasmas. In this connection shaped cataplasmas and tape preparations are advantageous.
- compositions of the invention may contain from 0.1 to 2000 mg, more generally 0.5 to 1000 mg of the active ingredient per unit dose shape.
- Febarbamate is effective over a wide dose range. For example, its dose per day falls usually within the range of 0.003 to 100 mg/kg.
- the amount of the compound actually administered is determined by the doctor, actual compound to be administered, the age, weight and response of individual patients, the degree of the symptom of patients, administration routes, etc.
- Proper dosage number can be 1 to 6, usually 1 to 4 per day.
- febarbamate itself is an effective central nervous and cerebrovascular disorder-improving and treating drug and a peripheral nervous disorder- treating drug
- dosage can also be made, if necessary, by combination with one or more other drugs having the same effect.
- Tablets containing 200 mg of an active ingredient are prepared as follows.
- the above components were passed through a 80 mesh sieve and then completely mixed.
- the obtained powder was compression molded to prepare tablets each having a weight of 300 mg.
- Capsules containing 100 mg of an active ingredient are prepared as follows. per capsule
- the above components are mixed, passed through a 80 mesh sieve and completely mixed.
- the obtained powder was charged in 150 mg portions into capsules.
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO92920387A NO920387L (en) | 1990-05-30 | 1992-01-29 | FEBARBAMATE FOR TREATMENT OF CRANICAL NERVOUS DISEASES AND ENCEPHALIC CIRCULATION AND METABOLISM DISORDERS |
FI920397A FI920397A0 (en) | 1990-05-30 | 1992-01-29 | FEBRUARY FOR THE MANUFACTURE OF FISHING PRODUCTS IN THE METABOLISM AND THE METABOLISM OF THE FARMING. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2138547A JPH0436236A (en) | 1990-05-30 | 1990-05-30 | Agent for amelioration and therapy of cerebral nerve disorder and cerebral circulation and metabolism disorder |
JP2/138547 | 1990-05-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1991018607A1 true WO1991018607A1 (en) | 1991-12-12 |
Family
ID=15224706
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1991/000979 WO1991018607A1 (en) | 1990-05-30 | 1991-05-25 | Febarbamate for the treatment of cranial nervous disorders and encephalic circulation and metabolism disorders |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0484497A1 (en) |
JP (1) | JPH0436236A (en) |
AU (1) | AU7899391A (en) |
CA (1) | CA2063736A1 (en) |
FI (1) | FI920397A0 (en) |
HU (1) | HUT60434A (en) |
IE (1) | IE911833A1 (en) |
WO (1) | WO1991018607A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011136700A3 (en) * | 2010-04-30 | 2012-02-23 | Клевер Фарм, Общество С Ограниченной Ответственностью | Agent exhibiting the properties of a cognitive function promoter (embodiments) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0125046A1 (en) * | 1983-04-12 | 1984-11-14 | Sapos S.A. | Process for preparing pyrimidinetrione derivatives |
-
1990
- 1990-05-30 JP JP2138547A patent/JPH0436236A/en active Pending
-
1991
- 1991-05-25 HU HU92672Q patent/HUT60434A/en unknown
- 1991-05-25 EP EP91910092A patent/EP0484497A1/en not_active Withdrawn
- 1991-05-25 AU AU78993/91A patent/AU7899391A/en not_active Abandoned
- 1991-05-25 WO PCT/EP1991/000979 patent/WO1991018607A1/en not_active Application Discontinuation
- 1991-05-25 CA CA002063736A patent/CA2063736A1/en not_active Abandoned
- 1991-05-29 IE IE183391A patent/IE911833A1/en unknown
-
1992
- 1992-01-29 FI FI920397A patent/FI920397A0/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0125046A1 (en) * | 1983-04-12 | 1984-11-14 | Sapos S.A. | Process for preparing pyrimidinetrione derivatives |
Non-Patent Citations (1)
Title |
---|
Neuropsychobiology, volume 11, no. 3, 1984, S. Karger AG (Basel, CH) H.D. Brenner et al: "Pharmacotherapy of agitational states in psychiatric gerontology: double-blind study: febarbamat-pipamperon", pages 187-190, see the whole article * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011136700A3 (en) * | 2010-04-30 | 2012-02-23 | Клевер Фарм, Общество С Ограниченной Ответственностью | Agent exhibiting the properties of a cognitive function promoter (embodiments) |
US8476433B2 (en) | 2010-04-30 | 2013-07-02 | Unikorm | Agent exhibiting the properties of a cognitive function promoter (embodiments) |
EA021482B1 (en) * | 2010-04-30 | 2015-06-30 | Общество С Ограниченной Ответственностью "Уникорм" (Ооо "Уникорм") | Agent exhibiting the properties of a cognitive function promoter (embodiments) |
Also Published As
Publication number | Publication date |
---|---|
IE911833A1 (en) | 1991-12-04 |
AU7899391A (en) | 1991-12-31 |
EP0484497A1 (en) | 1992-05-13 |
HUT60434A (en) | 1992-09-28 |
JPH0436236A (en) | 1992-02-06 |
CA2063736A1 (en) | 1991-12-01 |
HU9200672D0 (en) | 1992-08-28 |
FI920397A0 (en) | 1992-01-29 |
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