EP1420772A2 - Utilisation d'agonistes de l'adrenocepteur beta pour traiter des affections neurodegeneratives - Google Patents

Utilisation d'agonistes de l'adrenocepteur beta pour traiter des affections neurodegeneratives

Info

Publication number
EP1420772A2
EP1420772A2 EP02797607A EP02797607A EP1420772A2 EP 1420772 A2 EP1420772 A2 EP 1420772A2 EP 02797607 A EP02797607 A EP 02797607A EP 02797607 A EP02797607 A EP 02797607A EP 1420772 A2 EP1420772 A2 EP 1420772A2
Authority
EP
European Patent Office
Prior art keywords
encephalopathy
use according
cells
disease
day
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Withdrawn
Application number
EP02797607A
Other languages
German (de)
English (en)
Inventor
Josef Krieglstein
Carsten Culmsee
Vera Junker
Helmut Blum
Wolfgang Greb
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
EUCRO European Contract Research GmbH and Co KG
Original Assignee
EUCRO European Contract Research GmbH and Co KG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE10142176A external-priority patent/DE10142176A1/de
Priority claimed from DE10142178A external-priority patent/DE10142178A1/de
Priority claimed from DE10142175A external-priority patent/DE10142175A1/de
Priority claimed from DE10149611A external-priority patent/DE10149611A1/de
Application filed by EUCRO European Contract Research GmbH and Co KG filed Critical EUCRO European Contract Research GmbH and Co KG
Publication of EP1420772A2 publication Critical patent/EP1420772A2/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0618—Cells of the nervous system
    • C12N5/0619—Neurons
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0618—Cells of the nervous system
    • C12N5/0622—Glial cells, e.g. astrocytes, oligodendrocytes; Schwann cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/999—Small molecules not provided for elsewhere

Definitions

  • ß-adrenoceptor agonists for the treatment of neurodegenerative diseases
  • the present invention relates to the use of ⁇ -adrenoceptor agonists for the treatment of neurodegenerative diseases.
  • the brain is the central organ of the conscious and unconscious processing of the stimuli acting on the human body, of thinking and feeling, of purposeful action, learning and memory.
  • One of the most important services of the human brain is information processing in speech; also the control center for a large number of organ functions as well as breathing, heart rate and temperature control.
  • Examples of such clinical pictures are Alzheimer's disease, cerebrovascular dementias,
  • Parkinson's disease Pick's disease, Huntington's chorus, amyotrophic lateral sclerosis, Lewy
  • Body dementia stroke and brain trauma, such as contusio and commotio cerebri as well as brain and spinal cord injuries or cross-sectional injuries, spina bifida, as well as diseases of the inner ear, for example diseases associated with the occurrence of tinnitus, such as subacute or chronic tinitus, hearing loss, Crohn's
  • the goal of causal therapy is to prevent the destruction of nerve cells.
  • the object of the present invention was to find drugs which protect nerve cells from damage and which can at least partially restore the function of partially or completely degenerated cells.
  • the present invention accordingly relates to the use of ⁇ -adrenergic agonists for restoring and / or maintaining the function of partially or completely damaged cells of the central nervous system and / or other nerve cells.
  • damaged cell means that the cell has been damaged by external influences or is partially or completely destroyed in the sense of degeneration by processes taking place in the cell, which can be associated with an impairment of bodily functions.
  • the expression “damage to the cell” includes both the damage to individual cells or cell types and the damage to the strands or pathways of nerve cells.
  • the nerve cells also include the cells of the spinal cord and all other nerve cells in the body.
  • ⁇ -adrenoceptors respond in particular to adrenergic drugs.
  • ⁇ -adrenergic agonists which are preferably used in the present invention because of their good activity are clenbuterol, formoterol, fenoterol, salbutamol, orciprenaline, isoetharine, cimaterol, ractopamine, reproterol, salmeterol, terbutaline, their isomers, acid addition salts, Analogues and any mixtures of the above.
  • ⁇ -adrenergic agonists mentioned above are in part known medicinal substances.
  • clenbuterol is known from the prior art as a branch agent.
  • the lipophilic ß-adrenoceptor agonists can permeate into the brain and stimulate the ß-adrenoceptors of the astrocytes there.
  • the stimulation of these receptors in turn leads to activation of the astrocytes and, as a result, to an increased release of growth factors, such as NGF, which can protect nerve cells from damage.
  • the beta-adrenoceptor agonists are administered for therapy in the amounts customary for these medicaments, in particular in an amount of 0.01 to 100 mg / day, preferred ranges of amounts also being able to depend on the particular beta-adrenoceptor agonist.
  • substances such as clenbuterol, formoterol, fenoterol and salmeterol, a particularly good neuroprotective effect is obtained if they are administered in an amount of 0.01 to 5 mg / day.
  • Terbutaline is preferably applied in an amount of 1.0 to 30 mg / day, salbutamol in an amount of 1.0 to 50 mg / day, and orciprenaline and reproterol in an amount of 1.0 to 100 mg / day.
  • ⁇ 1-adrenoceptor agonists such as Dobuta in
  • the ⁇ -adrenoceptor agonists used according to the invention are used in combination with the ⁇ 1 and / or ⁇ 2 adrenoceptor agonists.
  • the ⁇ -adrenergic agonists are used in combination with NMDA antagonists, as a result of which a supplementary or further principle of action is used.
  • the NMDA antagonists e.g. the adamantane derivatives are known compounds which are often used for the treatment of various diseases.
  • the dopaminergic influence of amantadine (1-adamantanamine) is known.
  • European patent application EP-392 059 describes the use of adamantane derivatives for the prevention and treatment of cerebral ischemia. According to this publication, the use of the adamantane derivatives prevents the destruction of brain cells after ischemia by using the adamantane derivatives as antagonists for the NMDA receptor channels of the nerve cells in the brain.
  • R 1 and R 2 are the same or different and represent hydrogen or a straight-chain or branched CC 6 alkyl group or together with the N atom can represent a heterocyclic group with 5 or 6 ring atoms
  • R 3 and R 4 are the same or different are and represent hydrogen, a straight-chain or branched CC 6 alkyl group or a C 5 -C 6 cycloalkyl group or a vinyl group
  • R 1 and R 2 are the same or different and represent hydrogen or a straight-chain or branched CC 6 alkyl group or together with the N atom can represent a heterocyclic group with 5 or 6 ring atoms
  • R 3 and R 4 are the same or different are and represent hydrogen, a straight-chain or branched CC 6 alkyl group or a C 5 -C 6 cycloalkyl group or a vinyl group
  • R 5 represents hydrogen or a straight-chain or branched CrCe alkyl group.
  • adamantane derivatives with the formula I can be used in the form of the compounds described by the formula I or in the form of their pharmaceutically acceptable salts.
  • Preferred pharmaceutically acceptable salts include the acid addition salts, such as the hydrochlorides, hydrobromides, sulfates, acetates, succinates, tartrates, the hydrochlorides being preferred.
  • Preferred compounds with the formula I are those in which R 1 , R 2 and R 4 are hydrogen and R 3 and R 5 are a methyl and / or ethyl group.
  • R 1 , R 2 and R 4 are hydrogen and R 3 and R 5 are a methyl radical, or their hydrochloride. This connection is known as the INN Memantine.
  • the ß-adrenoceptor agonists used according to the invention and, if appropriate, other customary medicinal substances which do not negatively influence or support the therapy and usual ingredients, can be present in pharmaceutical dosage forms, in particular as a solution, suspension, emulsion, tablets, suppository, etc. it can be used in special formulations such as liposomes, nanosomes, slow-release pellets, etc.
  • the mode of administration is preferably selected such that the impaired cells can be reached as quickly as possible by the drug according to the invention.
  • the ⁇ -adrenoceptor agonists used according to the invention are particularly suitable for the production of medicaments for the treatment of neurodegenerative diseases.
  • diseases are Alzheimer's disease, cerebrovascular dementias, Parkinson's disease, Pick's disease, Huntington's chorea, amyotrophic lateral sclerosis, Lewy-body dementia, stroke and brain trauma such as contusion and cerebral sprain, as well as brain and spinal cord injuries or cross-sectional injuries, spina bifida , as well as diseases of the inner ear, for example diseases that are associated with the occurrence of tinnitus, such as subacute or chronic tinitus, sudden hearing loss, Meniere's disease, and diseases that are associated with impaired hearing or impaired vision, etc.
  • the ⁇ -adrenergic agonists are used to restore and / or maintain the function of cells of the central nervous system and / or other nerve cells which have been partially or completely damaged by encephalopathy.
  • Encephalopathy is one of the pathological non-inflammatory brain changes with variable neurological and / or psychological symptoms.
  • encephalopathies that can be treated according to the invention with ⁇ -adrenergic agonists are toxic encephalopathy, encephalopathia diabetica, encephalopathia hepatica, encephalopathia hypertensive, metabolic encephalopathy, such as encephalopathy caused by metabolic disorders, eg endogenous, renal encephalopathy, eg in case of enzyme disorders, enzymatic disorders, endogenous enzymes Liver diseases, disturbances in the water-electrolyte or acid-base balance, myclonic infantile encephalopathy (Kinsboorne syndrome), encephalopathia postictereca infantum (bilirubin encephalopathy), post-combinatory encephalopathy, encephalopathy caused by heavy metals, especially organic compounds, such as inorganic and organic compounds, especially from inorganic and organic compounds, especially from inorganic and organic compounds, especially from inorganic and organic compounds , especially from inorganic and organic compounds , Mercury and
  • the compounds used according to the invention are used as additive (s) for culture media to promote the growth and / or differentiation and / or protection of mammalian cells and human cells.
  • astrocytes Primary cultures of astrocytes were obtained from the cerebral cortex tissue of newborn Fischer 344 rats within 24 hours after birth. The brains were dissected out of the skull cap under sterile conditions, the bark tissue (cortex) was isolated and the cells were dissociated by a close-meshed wire network. The cells were placed in cell culture bottles and cultured in serum-containing DMEM solution (containing fetal calf serum and a penicillin-streptomycin mixture) until the cells confluent. Oligodendrocytes and microglia were removed by washing with cold buffer solution.
  • serum-containing DMEM solution containing fetal calf serum and a penicillin-streptomycin mixture
  • the confluent astrocytes were then detached from the bottom of the culture flasks with a trypsin solution and sown at a density of 20,000 cells / cm 2 in petri dishes on coverslips and cultivated in serum-containing medium until the cells re-confluent.
  • the medium was changed with serum-free medium and after 24 hours another medium change, also with serum-free medium.
  • Twenty-four hours after the second medium change salmeterol was added.
  • the astrocytes were photographed in 200x microscopic magnification to document the morphological changes (Fig. 1/7). The figure shows the astrocytes 6 hours after the start of treatment.
  • the changes from the polygonal, flat and light-refractive cells in the controls compared to the activated, star-shaped and light-refracting astrocytes in the groups treated with salmeterol can be clearly seen.
  • the culture medium was collected four hours after the start of the Clenbuterol incubation.
  • the NGF content in the medium was determined using a standardized enzyme-linked immune reaction (ELISA).
  • ELISA enzyme-linked immune reaction
  • the chambers of a multiwell plate were coated with an NGF antibody and then incubated in the individual chambers with the medium of the different groups. The NGF thus bound in the chambers from the medium was then incubated with a beta-galactosidase : conjugated NGF antibody.
  • beta-galactosidase catalyzed conversion of chlorophenol red beta-galactopyranoside to a red dye which was measured photometrically.
  • standard dilutions of NGF were also measured to create a standard curve. The NGF content in the samples was determined using the standard curve (Fig. 2/7).
  • the medium was changed and the cells were incubated for 1 hour with L-glutamate (1mM) in serum-free medium. The medium was then changed again with serum-free medium in order to remove the glutamate from the cultures. Propranolol and clenbuterol were added freshly with each change of medium and were thus present in the medium during the glutamate treatment and up to 18 hours afterwards. Eighteen hours after the damage to glutamate, the cells were incubated with a trypan blue solution, fixed, and the damaged, blue-stained neurons were quantified under 200 ⁇ microscopic magnification (Fig. 3/7).
  • the body temperature of the rats was regulated to 37 + 0.5 ° C during the operation and kept stable for 2 hours after the procedure with the help of a heat lamp at an ambient temperature of 30 ° C.
  • Physiological parameters blood pressure, plasma glucose level, arterial pH, CO 2 and O 2 partial pressures
  • coronal sections (20 ⁇ M) of the brains were made at defined intervals of 0.5 mm. The brain sections were then stained with cresyl violet, whereby the area of the infarct showed only a weak color and could thus be distinguished from the healthy tissue.
  • Salmeterol was added fresh each time the medium was changed and was thus present in the medium during the glutamate treatment and up to 18 hours afterwards. Eighteen hours after the damage to glutamate, the cells were incubated with a trypan blue solution, fixed, and the damaged, blue-stained neurons were quantified under a 200-fold microscopic magnification (Fig. 5/7). The values given are mean values and standard deviation from 5-6 cultures per group. * P ⁇ 0.05; ** p ⁇ 0.01; and * * * * p ⁇ 0.001 compared to the control treated with glutamate (analysis of variance, Scheffe test). 6) Neuroprotective effect of salmeterol in vivo
  • Focal cerebral ischemia of the mouse was produced by ligating the cerebral artery.
  • Male NMRI mice (26-31 g, 10-12 animals per group) were used for the experiments.
  • the animals were anesthetized by an intraperitoneal injection of tribromoethanol (600 mg / kg).
  • the surgical field was then opened through a 2 cm incision between the left eye and ear, the temporalis muscle was removed with a thermocauter and the bone was removed with a fine bur to expose the cerebral artery.
  • This artery and its two distal branches were permanently occluded.
  • the body temperature of the mouse was measured and kept constant at 37 +/- 1 ° C by an infrared heat lamp.
  • mice were anesthetized again with tribromoethanol 48 hours after occlusion of the cerebral artery and perfused with a 1.5% neutral red solution (0.5 ml intraperitoneally). As a result, the perfused brain tissue turned red and the infarcted area remained bright.
  • the isolated brains were fixed with 4% formaldehyde buffer (pH 7.4) for at least 24 hours and then the unstained area on the brain surface (infarct area) became a computer -supported (NIH image software) measured.
  • the salmeterol dissolved in 0.9% NaCI was injected interperitoneally 5 hours before the operation.
  • the animals in the control group received only 0.9% NaCI solution (Fig. 6/7). The values are mean values and standard deviation of 15-16 animals per group. * p ⁇ 0.05 compared to the control (analysis of variance, Duncan's test)
  • the body temperature of the mouse was measured and kept constant at 37 +/- 1 ° C by an infrared heat lamp. After the preparation, the animals were left for an additional two hours at an ambient temperature of 30 ° C. To determine the infarct area, the mice were again treated with tribromoethanol 48 hours after occlusion of the cerebral artery anesthetized and perfused with a 1.5% neutral red solution (0.5 ml intraperitoneally). As a result, the perfused brain tissue turned red and the infarcted area remained bright.
  • the isolated brains were fixed with 4% formaldehyde buffer (pH 7.4) for at least 24 hours and then the unstained area on the brain surface (infarct area) became a computer -supported (NIH image software) measured.
  • the two pharmaceuticals to be investigated Memantine and Clenbuterol, were dissolved in 0.9% NaCl for injection. Memantine (20 mg / kg) was injected interperitoneally 30 minutes before surgery and clenbuterol 2 hours after surgery. The animals in the control group received only 0.9% NaCI solution (Fig. 7/7).

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Genetics & Genomics (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • General Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Addiction (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cardiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Endocrinology (AREA)
  • Hospice & Palliative Care (AREA)

Abstract

L'invention concerne l'utilisation d'agonistes de l'adrénocepteur β pour rétablir et/ou maintenir la fonction de cellules partiellement ou entièrement endommagées/dégénérées du système nerveux central et/ou d'autres cellules nerveuses. L'utilisation d'agonistes de l'adrénocepteur β permet d'activer des astrocytes et de lancer des processus endogènes de neuroprotection, ce qui permet de réduire l'altération ou la destruction de cellules nerveuses, voire dans certains cas même les empêcher.
EP02797607A 2001-08-29 2002-08-22 Utilisation d'agonistes de l'adrenocepteur beta pour traiter des affections neurodegeneratives Withdrawn EP1420772A2 (fr)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
DE10142178 2001-08-29
DE10142176A DE10142176A1 (de) 2001-08-29 2001-08-29 Verwendung einer Kombination aus ß-adrenergen Agonisten und NDMA-Antagonisten
DE10142176 2001-08-29
DE10142178A DE10142178A1 (de) 2001-08-29 2001-08-29 Verwendung von Clenbuterol zur Behandlung von neurodegenerativen Erkrankungen
DE10142175A DE10142175A1 (de) 2001-10-09 2001-08-29 Verwendung von ß-Adrenozeptor-Agonisten zur Behandlung von neurodegenerativen Erkrankungen
DE10142175 2001-08-29
DE10149611 2001-10-09
DE10149611A DE10149611A1 (de) 2001-08-29 2001-10-09 Verwendung von ß-Adrenozeptor Agonisten zur Behandlung von neurodegenerativen Erkrankungen
PCT/EP2002/009369 WO2003020257A2 (fr) 2001-08-29 2002-08-22 Utilisation d'agonistes de l'adrenocepteur $g(b) pour traiter des affections neurodegeneratives

Publications (1)

Publication Number Publication Date
EP1420772A2 true EP1420772A2 (fr) 2004-05-26

Family

ID=27438007

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02797607A Withdrawn EP1420772A2 (fr) 2001-08-29 2002-08-22 Utilisation d'agonistes de l'adrenocepteur beta pour traiter des affections neurodegeneratives

Country Status (5)

Country Link
EP (1) EP1420772A2 (fr)
JP (1) JP2005505548A (fr)
AU (1) AU2002333510A1 (fr)
PL (1) PL373490A1 (fr)
WO (1) WO2003020257A2 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1754474A1 (fr) * 2005-02-02 2007-02-21 Eucro European Contract Research GmbH & Co. KG Utilisation du S-Clenbutérol
GB0519274D0 (en) * 2005-09-21 2005-11-02 Arakis Ltd The treatment of neurodegenerative diseases
EP2007206A4 (fr) * 2006-03-16 2010-12-08 Yeda Res & Dev Procede et composition pour la protection du tissu neuronal de degats induits par des niveaux eleves de glutamate
CN101915841B (zh) * 2010-07-26 2013-01-02 河南省科学院生物研究所有限责任公司 β-兴奋剂沙丁胺醇、盐酸克伦特罗、莱克多巴胺三元检测测试条制备方法
US9265735B2 (en) 2010-11-30 2016-02-23 New York University Methods for screening to identify therapeutic agents for Alzheimer's disease and use thereof
US20140249180A1 (en) * 2011-10-03 2014-09-04 National Center For Geriatrics And Gerontology Tau aggregation inhibitor
EP2962687B1 (fr) 2013-04-02 2019-06-05 The Doshisha Inhibiteur de l'agrégation des protéines tau
CN115531368A (zh) * 2021-06-14 2022-12-30 谭文 R-氨基甲酸酯-β-苯乙醇胺类化合物治疗学习和记忆缺陷以及神经退行性疾病的应用
CN116236467B (zh) * 2023-02-07 2023-10-27 中国人民解放军总医院 西马特罗或其衍生物的新用途

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5334618A (en) * 1991-04-04 1994-08-02 The Children's Medical Center Corporation Method of preventing NMDA receptor-mediated neuronal damage
ES2059602T3 (es) 1989-04-14 1994-11-16 Merz & Co Gmbh & Co Uso de derivados de adamantano para la prevencion y tratamiento de isquemia cerebral.
US5281607B1 (en) * 1992-10-08 1998-05-19 Univ New York Method of using alpha 2-antagonists for the treatment of neurodegenerative diseases
US5958919A (en) * 1996-09-20 1999-09-28 Washington University Treatment of presymptomatic alzheimer's disease to prevent neuronal degeneration
CN1344168A (zh) * 1999-12-07 2002-04-10 老笃制药株式会社 眼用组合物
JP2003534385A (ja) * 2000-06-01 2003-11-18 チルドレンズ メディカル センター コーポレーション 被験者の神経に有益な効果をもたらす方法および組成物
US7135497B1 (en) * 2000-07-07 2006-11-14 New York Medical College Treating neural conditions resulting from spinal cord contusions and other causes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03020257A2 *

Also Published As

Publication number Publication date
WO2003020257A2 (fr) 2003-03-13
WO2003020257A3 (fr) 2004-01-08
JP2005505548A (ja) 2005-02-24
AU2002333510A1 (en) 2003-03-18
PL373490A1 (en) 2005-09-05

Similar Documents

Publication Publication Date Title
DE69621756T2 (de) Betahydroxybuttersäure oder Acetoessigsäure oder deren Salze oder Ester zur Verwendung zur Verbesserung der Gehirnfunktion
DE69937198T2 (de) Behandlung der alzheimer-krankheit durch erhöhung des cytidin-spiegels in vivo
DE69730330T2 (de) Verwendung von l-acetylcarnitin, l-isovalerylcarnitin oder l-propionyl-carnitin zur steigerung des igf-spiegels
EP0857065A2 (fr) Utilisation de 4-amino-4-(4-fluorobenzylamino)-1-ethoxy-carbonylaminobenzene pour la prophylaxie et le traitement des sequelles d'une insuffisance de vascularisation cerebrale aigüe et chronique et de maladies neurodegeneratives
DE60220043T2 (de) Carbamatverbindungen zur vorbeugung oder behandlung von neurodegenerativen störungen
EP0659408A1 (fr) Utilisation de R(+)alpha acide loique, R(-)-acide dihydrolipoique et leurs metabolites pour le traitement de diabète et ses désordres secondaires
DE68913756T2 (de) In vivo cytoprotektiv wirkende neurotrope alkohole.
DE69926804T2 (de) Vorrichtungen zur behandlung und diagnose des restless leg syndroms
DE3805744C2 (de) Phenylcarbamate zur Hemmung der Acetylcholinesterase
DE60111025T2 (de) Verwendung von Topiramat zur Behandlung und Diagnostizierung von Atemstörungen während des Schlafens und Mittel zur Durchführung der Behandlung und Diagnose
EP1420772A2 (fr) Utilisation d'agonistes de l'adrenocepteur beta pour traiter des affections neurodegeneratives
US20040248984A1 (en) Use of $g(b)-adrenoceptor agonists for the treatment of neurodegenerative diseases
DE60019914T2 (de) Verwendung von Sibutramin oder dessem Derivat zur Behandlung von Schlafstörungen
EP1207878B1 (fr) Traitement de la migraine par administration d'acide alpha-lipoique ou de derives de cet acide
DE60216776T2 (de) Neue piperidin-2,6-dion bisulfatsalze und deren verwendung für die behandlung stressbezogener gemütserkrankungen
US20100240764A1 (en) Use of S-Clenbuterol
EP0912177B1 (fr) Utilisation de flupirtine pour la therapie et prevention de l'infarctus du myocarde, poumon de choc et rein de choc
EP0774961B1 (fr) Utilisation de selegiline dans le traitement d'affections epileptiques
EP0669826B1 (fr) Medicament contenant du (-)-metrifonate
DE10142178A1 (de) Verwendung von Clenbuterol zur Behandlung von neurodegenerativen Erkrankungen
DE60203895T2 (de) Verwendung von n-acetyl-d-glucosamin bei der herstellung eines arzneimittels zur unterdrückung der nebenwirkungen von strahlentherapie und chemotherapie
EP0845264A1 (fr) Extrait partiel ou total de Camellia sinensis L. non fermenté
Roy et al. Role of Moringa oleifera on brain electrical activity in colchicine induced experimental rat model of Alzheimer’s disease: possible involvement of antioxidants
DE10142175A1 (de) Verwendung von ß-Adrenozeptor-Agonisten zur Behandlung von neurodegenerativen Erkrankungen
AT402691B (de) Verwendung von galanthamin zum herstellen von arzneimitteln zur behandlung von trisomie 21 oder verwandter trisomie-syndrome

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040309

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LI LU MC NL PT SE SK TR

AX Request for extension of the european patent

Extension state: RO SI

RIN1 Information on inventor provided before grant (corrected)

Inventor name: GREB, WOLFGANG

Inventor name: BLUM, HELMUT

Inventor name: JUNKER, VERA

Inventor name: CULMSEE, CARSTEN

Inventor name: KRIEGLSTEIN, JOSEF

17Q First examination report despatched

Effective date: 20090409

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20130209