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WO1992001455A1 - Medicament contre les maladies degeneratives des fonctions cerebrales du type de la maladie d'alzheimer et troubles du systeme cholinergique - Google Patents

Medicament contre les maladies degeneratives des fonctions cerebrales du type de la maladie d'alzheimer et troubles du systeme cholinergique Download PDF

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Publication number
WO1992001455A1
WO1992001455A1 PCT/DE1990/000568 DE9000568W WO9201455A1 WO 1992001455 A1 WO1992001455 A1 WO 1992001455A1 DE 9000568 W DE9000568 W DE 9000568W WO 9201455 A1 WO9201455 A1 WO 9201455A1
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WIPO (PCT)
Prior art keywords
acetylcholine
alzheimer
diseases
boron
disorders
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Ceased
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PCT/DE1990/000568
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German (de)
English (en)
Inventor
Hans-Werner LÜDKE
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Individual
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Individual
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Priority to PCT/DE1990/000568 priority Critical patent/WO1992001455A1/fr
Publication of WO1992001455A1 publication Critical patent/WO1992001455A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/69—Boron compounds

Definitions

  • the invention relates to pharmaceutical preparations or containers that ect for the treatment of degenerative brain disorders such as poor memory, increasing loss of previous intellectual skills, personality changes, word finding disorders, disorders of spatial and temporal orientation, dizziness, weakening of the control of body functions. as well as for the treatment of Alzheimer's disease, senile dementias of the Alzheimer's type (SDAT), degenerative encephalopathies and disorders in the cholinergic system.
  • degenerative brain disorders such as poor memory, increasing loss of previous intellectual skills, personality changes, word finding disorders, disorders of spatial and temporal orientation, dizziness, weakening of the control of body functions.
  • ADAT senile dementias of the Alzheimer's type
  • degenerative encephalopathies disorders in the cholinergic system.
  • Nootropica are substances such as co-dergocrin melisate, pyritinol, piracetam and nicergoline, which increase the cerebral blood flow, oxygen and glucose sterilization. They have no special effect on the degenerative diseases of the Alzheimer's type. The fact that the treatment of dementia processes is unsatisfactory also results from the standard works. In H.G. Mertens and R.
  • Geriatric psychiatry edited by D.Cooper, p.192 states that there are no specific therapeutic measures available for this group of diseases.
  • NIA National Institute of Aging
  • Crapper also assumes such a compensatory mechanism between two elements, but between magnesium and aluminum (Crapper, DH.Quittcat S., Krishnan SS et al .: intranuclear aluminum content in Alzheimers disease, dialysis encephalopathy and experimental aluminum encephalopathy, Acta Neuropathologica 1980 , 50, pp. 19-24.
  • amyloid In the brain of Alzheimer's patients, increasing amounts of amyloid are found with increasing disease. The structure of this amyloid has only been elucidated by K.Beyreuther, Cologne (now Heidelberg) and C.Masters, Perth, since 1985. It is a 42-43 amino acid peptide called A4. This peptide is identical to the molecular part of a membrane receptor in the nerve cell (J.Kang: Nature 325; page 733-736, 1987). What does this receptor destruction of the nerve cell membrane have to do with a production disorder in acetylcholine metabolism?
  • Alzheimer's disease first damages short-term memory (STM). In contrast to long-term memory, which works with the construction of new protein structures in the nerve cells, it is believed that short-term memory has to do with the depolarization and hyperpolarization of the nerve cell membranes (G. Lynch, JLMcGaugh, NM Weinberger, Neurobiology of learning and memory, P.276, New York and London 1984; CDWoody, Memory, Learning and higher function, New York, Heidelberg, Berlin, 1982; M.Schwarz, physiological psychology, Weinheim and Basel 1980, page 399). 4. In the last book mentioned on page 380 ff. On "cholinergic processes".
  • the invention seeks to remedy this.
  • the electrophysiological approach is able to provide a model which shows the increased aluminum content, the appearance of cell wall amino acids in the deposits, the disorders in the cholinergic system in dementia disorders of the Alzheimer's type with the "electrical"
  • STM short-term memory
  • the acetylcholine is stored in the presynaptic vesicle, and is now not simply given off according to the concentration gradient, but rather to certain signals; the control can take place either by changing the electrical resistance in the cell membrane - that is to say by changing the potential difference between outside and inside - or by switching on carriers.
  • Alzheimer's disease is at least partly a transport problem through the cell membrane.
  • triarylcyanoborate and other tetraarylborates play an important role in choline and acetylcholine research as cation-binding and lipophilic anions.
  • Sodium tetraphenylborate Na (B (C6H5) 4 ) is an excellent precipitant for choline and choline esters (HWSpier, Biochem. Z.322 (1952) 467-470).
  • PTCarroll and others have also carried out in vivo experiments to determine acetylcholine turnover in the brain (Biochem. Pharmakol. 26 (1977) 397-402).
  • Sodium tetraphenylborate is also used by official pharmacopoeias as a reagent for qualitative and quantitative studies.
  • a 0.02 M volumetric sodium tetraphenylborate solution was included for the first time as a pharmaceutical reagent.
  • TPB is also a very effective anion for inhibiting the
  • TPB central nervous system
  • TPB does not act directly like acetylcholine through depolarization of the postjunctional endplate membrane, but through an increased acetylcholine release from the motor nerve endings and weak anti-acetylcholinesterase activity (IGMarshall, Eur.J. Pharmacol. 13, 1970, pp. 51-54). TPB also attacks the postsynaptic membrane, where it reacts with cationic sites, and possibly causes the local change in membrane permeability. On the basis of the test results, activation of cholinergic receptors by a change in the occupation of cationic and anionic binding sites is also discussed (G. Guideri, E. Seifter, J. Seifter, Eur.J. Pharmakol. 17, 1972, pp. 253-258).
  • TPB also affects the autonomic nervous system. It was not the release of cholinergic transmitter substances or the prevention of their degradation that was responsible for the effect, but rather the change in the measure of activity and the in fl uence.
  • the membrane or receptor effect of the TPB - instead of an indirect effect via acetylcholine release or acetylcholinesterase inhibition - corresponds to the results on the skeletal and cardiac muscle of the frog (G.Guideri, J.Seifter, Arch. Intern.Pharmaco.Dyn.
  • Alzheimer's type was produced. The answer is two
  • a 0.1% sodium tetraphenylborate solution, which is isotized with NaCl in bidistilled water, is given as an example.
  • This solution is slowly infused intravenously until a total of 0.5 mg sodium tetraphenylborate per 1 kg body weight is reached. This dose should be increased to a maximum of 1 mg per kg body weight.
  • the example is based on the t o x i k o l o g i s c h e n information in the literature.
  • side effects in healthy people after injection of a sodium tetraphenylborate solution that was less than 4.5% concentrated were not observed at all (H.W. Spier, G.Wagner, Klin.Wochenschrift 30 (1952) p.757-759).
  • the intravenous injection of 1 mg per kg body weight caused a temporary drop in blood pressure; 10 mg per kg body weight led to cardiac arrhythmias (A.H. Soloway in: Steinberg, A.L.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Les maladies du type de la maladie d'Alzheimer se caractérisent par différentes perturbations des fonctions cérébrales et du système cholinergique causées par des dépôts de chaînes d'acides aminés ou d'aluminium. On établit un lien entre les résultats de la recherche en notant la similarité électrophysiologique entre le bore et l'aluminium, ainsi que les propriétés cationiques de l'acétylcholine, et en considérant les maladies d'Alzheimer comme un problème de transport de cations, ce qui entraîne la recherche d'une substance porteuse anionique. On met en oeuvre le principe thérapeutique qui consiste à utiliser des substances porteuses de l'acétylcholine à charge négative au moyen de composés organiques de bore, par exemple de tétraphénylborate de sodium. Cette substance peut accroître de deux à huit fois l'écoulement d'acétylcholine dans la cellule. Des tests thérapeutiques préliminaires incitent à effectuer des tests cliniques systématiques. On peut toutefois mettre en oeuvre le principe de l'utilisation d'une substance porteuse anionique de l'acétylcholine au moyen d'autres composés.
PCT/DE1990/000568 1990-07-25 1990-07-25 Medicament contre les maladies degeneratives des fonctions cerebrales du type de la maladie d'alzheimer et troubles du systeme cholinergique Ceased WO1992001455A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/DE1990/000568 WO1992001455A1 (fr) 1990-07-25 1990-07-25 Medicament contre les maladies degeneratives des fonctions cerebrales du type de la maladie d'alzheimer et troubles du systeme cholinergique

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/DE1990/000568 WO1992001455A1 (fr) 1990-07-25 1990-07-25 Medicament contre les maladies degeneratives des fonctions cerebrales du type de la maladie d'alzheimer et troubles du systeme cholinergique

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WO1992001455A1 true WO1992001455A1 (fr) 1992-02-06

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996015798A3 (fr) * 1994-11-22 1996-08-08 Gsf Forschungszentrum Umwelt Utilisation de composes bioassimilables de bore pour la lutte contre des agents pathogenes
EP1609794A3 (fr) * 2004-06-22 2007-03-14 Mitsui Chemicals, Inc. Composé ionique, composition de résine et leur utilisation
US7395980B2 (en) 2003-03-21 2008-07-08 Oliver Haack Device for separating and transporting away raw materials
EP2413696A4 (fr) * 2009-04-03 2012-10-24 Sinai School Medicine Compositions pour le traitement de la maladie d'alzheimer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2104079A (en) * 1981-08-14 1983-03-02 London Polytech >New aminoacid isomers, their production and their medicinal use
GB2104078A (en) * 1981-08-14 1983-03-02 London Polytech New amino acid isomers, their production and their medicinal use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2104079A (en) * 1981-08-14 1983-03-02 London Polytech >New aminoacid isomers, their production and their medicinal use
GB2104078A (en) * 1981-08-14 1983-03-02 London Polytech New amino acid isomers, their production and their medicinal use

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, Band 69, Nr. 13, 23. September 1968, (Columbus, Ohio, US), J. Seifter et al.: "Effect of tetraphenyl-boron (Ph4B), a negative quaternary, on muscle contraction and enzyme cation: a new vieuw of activation and blockade of cholinergic receptors", siehe Seite 4731 *
Chemical Abstracts, Band 76, Nr. 21, 22. Mai 1972, (Columbus, Ohio, US), F. Herz et al.: "Inactivation of erythrocyte membrane acetylcholinesterase by tetraphenyl-boron", siehe Seite 110 *
Chemical Abstracts, Band 84, Nr. 7, 16. Februar 1976, (Columbus, Ohio, US), G. Guideri et al.: "Effects of tetraphenyl-boron on frog skeletal and cardiac muscle", siehe Seite 24 *
Harrison's Principles of Internal Medicine, 9. Auflage, 1980, McGraw-Hill Kogakusha, Ltd, (Tokyo, JP), siehe Seiten1992,1993 *
Martindale, The Extra Pharmacopoeia, 29. Auflage, 1989, The Pharmaceutical Press, (London, GB), siehe Seite 1549 *
The Merck Index, 11. Auflage, 1989, Merck & Co., Inc., (Rahway, N.J., US), siehe Seite 1369 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996015798A3 (fr) * 1994-11-22 1996-08-08 Gsf Forschungszentrum Umwelt Utilisation de composes bioassimilables de bore pour la lutte contre des agents pathogenes
AU716511B2 (en) * 1994-11-22 2000-02-24 Gsf - Forschungszentrum Fur Umwelt Und Gesundheit Gmbh Use of bioassimilable boron compounds for the control of subviral pathogenic agents
US7395980B2 (en) 2003-03-21 2008-07-08 Oliver Haack Device for separating and transporting away raw materials
EP1609794A3 (fr) * 2004-06-22 2007-03-14 Mitsui Chemicals, Inc. Composé ionique, composition de résine et leur utilisation
EP2413696A4 (fr) * 2009-04-03 2012-10-24 Sinai School Medicine Compositions pour le traitement de la maladie d'alzheimer

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