WO2003041701A2 - Preparation for improving the action of receptors - Google Patents

Preparation for improving the action of receptors Download PDF

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Publication number
WO2003041701A2
WO2003041701A2 PCT/NL2002/000731 NL0200731W WO03041701A2 WO 2003041701 A2 WO2003041701 A2 WO 2003041701A2 NL 0200731 W NL0200731 W NL 0200731W WO 03041701 A2 WO03041701 A2 WO 03041701A2
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WO
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Prior art keywords
vitamin
preparation
use according
receptors
acid
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PCT/NL2002/000731
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French (fr)
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WO2003041701A3 (en
Inventor
Amanda Johanne Kiliaan
Robert Johan Joseph Hageman
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N.V. Nutricia
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=19774312&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2003041701(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to AU2002343241A priority Critical patent/AU2002343241B2/en
Priority to EP02780164A priority patent/EP1443920B1/en
Priority to JP2003543588A priority patent/JP4290552B2/en
Priority to DK02780164.6T priority patent/DK1443920T3/en
Priority to ES02780164T priority patent/ES2378063T3/en
Priority to CA2467065A priority patent/CA2467065C/en
Priority to AT02780164T priority patent/ATE538783T1/en
Application filed by N.V. Nutricia filed Critical N.V. Nutricia
Priority to US10/495,341 priority patent/US7384981B2/en
Publication of WO2003041701A2 publication Critical patent/WO2003041701A2/en
Publication of WO2003041701A3 publication Critical patent/WO2003041701A3/en
Priority to HK04108352.1A priority patent/HK1065480A1/en
Priority to AU2006225161A priority patent/AU2006225161B8/en
Priority to AU2006225160A priority patent/AU2006225160B2/en
Priority to US12/045,112 priority patent/US7888391B2/en
Priority to US12/325,356 priority patent/US20090104283A1/en
Priority to US12/325,327 priority patent/US8362078B2/en
Priority to US14/455,726 priority patent/US20150037309A1/en
Priority to US14/634,368 priority patent/US9504712B2/en
Priority to US15/338,751 priority patent/US9844525B2/en

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
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    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a preparation for improving the action of receptors, in particular for improving the sensitivity of receptors to neurotransmitters.
  • Receptors can be present in the membranes of cells.
  • the receptor is activated under the influence of components present outside the cell (for example, neurotransmitters, neuromodulators or hormones) which bind to the receptor.
  • the receptor is then capable of transmitting signals, which can start a cascade of events.
  • Receptors can be present, inter alia, in or on nerve cells, muscle cells, endocrine cells, epithelial cells or other types of cells. Examples of substances which have an effect on receptors are neurotransmitters (see below), neuromodulators, neuropeptides and hormones such as insulin and steroids.
  • a specific class of receptors is, for example, constituted by receptors in nerve cells
  • neuroneurones which are controlled by neurotransmitters. These neurones consist of a cell body (soma) with several, frequently short fimbriae (dendrites) and one long fimbria, termed an axon. An electrical signal is transmitted from the soma via the axon. The axon branches into axon ends which can terminate next to the dendrites of adjacent nerve cells, onto another axon, next to the soma of nerve cells or in tissues or parts thereof. The so-called synaptic cleft is located between the axon of the one nerve cell and the dendrite (or also soma) of the other nerve cell.
  • neurotransmitters or neuromodulators are termed neurotransmitters or neuromodulators and which are able to activate another nerve cell.
  • the neuro- transmitters/neuromodulators are recognised by receptors in the postsynaptic membrane of the "receiving" nerve cell.
  • Examples of classic endogenous neurotransmitters are biogenic amines such as serotonin, dopamine, histamine, noradrenaline and adrenaline; amino acids such as GAB A (gamma- aminobutyric acid), glutamate, aspartate and glycine; cholinergic agents, such as acetylcholine; peptides, such as endorphins and other types of neurotransmitters such as nitrogen oxide and adenosine.
  • GAB A gamma- aminobutyric acid
  • cholinergic agents such as acetylcholine
  • peptides such as endorphins
  • other types of neurotransmitters such as nitrogen oxide and adenosine.
  • neurotransmitter receptors such as certain drugs (for example clenbuterol), which usually are prepared synthetically, but also substances from natural preparations (such as muscarine antagonists or ephedrine-rich plant extracts).
  • Receptors can be classified on the basis of their action. lonotropic receptors act rapidly and determine ion transport through the membrane. They consist of a large complex of multiple sub-units made up of five individual proteins which combine to establish an ion channel through the membrane. The sub-units have four transmembrane domains which form the pore. These ion channels are impermeable to ions in the absence of a neurotransmitter.
  • Metabotropic receptors constitute another class. These act relatively slowly and have a wide range of effects on the metabolism of the cell. Many comprise the seven trans- membrane domain receptors, which usually function via G proteins. These types of receptors play a role, inter alia, in the case of neurotransmitters which belong to the adrenergic agents (for example noradrenaline and adrenaline), in the case of dopamine, serotonin and in the case of neurotransmitters which belong to the cholinergic agents (such as acetylcholine or muscarine).
  • Other examples of seven transmembrane domain receptors are receptors which are activated by neuropeptides, such as by Substance P, Neuropeptide Y, Bombesine, Neurotensine, CCK and galanine.
  • tyrosine kinase receptor family growth factors, insulin
  • cytokine receptor family growth hormone, erythropoietin, leptin, prolactin
  • TGF-beta serine-threonine kinase receptor family
  • guanylyl cyclase receptor family atrial natriuretic peptides
  • a neurotransmitter functioning that is disturbed to a more or less severe extent can play a role in neurological disorders such as dementia, depression, Parkinson's disease, Huntington's chorea, epilepsy, schizophrenia, paranoia and ADHD, but also in other emotional disorders.
  • neurotransmitters such as dopamine or derivatives thereof have been administered to people suffering from Parkinson's disease in order to increase the amount of dopamine in the synapse.
  • Substances have also been administered in order to reduce the reuptake of the neurotransmitter serotonin from the synaptic cleft into the dendrite.
  • Agents which inhibit a specific metabolic conversion of the neurotransmitter acetylcholine acetylcholinesterase inhibitors
  • acetylcholinesterase inhibitors as a result of which the concentrations of acetylcholine in the synaptic cleft (i.e. extracellular) remain high for a prolonged period.
  • Monoamine oxidase inhibitors partially prevent the conversion of monoamines such as dopamine.
  • the aim of the invention is to improve the action, and especially the sensitivity of receptors, in particular in nerve processes, but also in other physiological processes in which, for example, hormones play a role. What is meant by an improved action of receptors is that less agonist, in particular less neurotransmitter, is needed to achieve the same effect.
  • the present invention may advantageously be applied in patients who suffer from an imbalanced neurotransmitter functioning and/or neurodegenerative disorder.
  • the invention may be applied in healthy individuals to improve the concentration and/or learning ability of these individuals.
  • the invention relates to the use of polyunsaturated fatty acids and components which have a beneficial effect on methionine metabolism for improving the action of receptors.
  • the inventors have unexpectedly found that the combined application of polyunsaturated fatty acids and methionine metabolism stimulating compounds improves the action of receptors, but not as a result of the increased production of neurotransmitter or a reduced reuptake of neurotransmitter from the synaptic cleft.
  • the surprising effect of the active principles according to the invention may be explained from the improved arrangement and more fluid nature of the cell membranes, especially of the membranes of neurons, that results from the combined administration. Because of the improved arrangement and fluidity, in vivo membrane processes can proceed more effectively after receptor activation. This improvement is not only advantageous in individuals in whom these membrane processes are adversely affected by, for instance, a neurodegenerative disorder. The improvement is also beneficial to individuals who wish to improve their ability to learn and/or concentrate, e.g. for study or work.
  • WO 01/03696 The treatment of a variety of disorders, including neurodegenerative disorders such as Alzheimer disease and Parkinson's disease with polyunsaturated fatty acids and vitamin B6, B12 and/or folic acid is described in WO 01/03696.
  • a link is made between an elevated serum homocysteine concentration and the undesired oxidation of essential fatty acids, in particular of eicosapentenoic acid and arachidonic acid.
  • the administration of vitamin B6, folic acid and vitamin B12 is said to decrease the serum homocysteine concentration and consequently to diminish the oxidation of the aforementioned essential fatty acids, as a result of which, in combination with the administration of these same essential fatty acids, an increase in the serum concentration of these essential fatty acids is achieved.
  • an increase of the concentration of essential fatty acids can be advantageous in the treatment of (a) illnesses, (b) cardiovascular or cerebrovascular disorders, (c) diabetes, syndrome X and macro or microvascular complications of diabetes, (d) psychiatric disorders, (e) neurological or neurodegenerative disorders, (f) kidney disorders, (g) inflammatory or immunological disorders of the gastrointestinal tract, (h) eye or hearing disorders, (i) forms of obesity and (j) any form of cancer. Nowhere in the PCT-application reference is made to an effect of the preparations described therein on receptor action.
  • At least one substance is administered that increases the concentration of the neurotransmitters, neuromodulators or hormone in the synapse or at the receptor.
  • Polyunsaturated fatty acids are fatty acids containing at least two unsaturated bonds and having a chain length of at least 18. The unsaturated bond is located in the 3, 6 or 9 position relative to the terminal methyl group.
  • the preparation of the invention preferably contains ⁇ -3 polyunsaturated fatty acids.
  • the ⁇ -3 polyunsaturated fatty acids include ⁇ -linolenic acid, stearidonic acid, eicosapentaenoic acid and docosahexaenoic acid and arachidonic acid.
  • the preparation preferably contains at least docosahexaenoic acid.
  • cardiovascular-associated neurological disorders such as dementia eicosapentaenoic acid is also suitably present.
  • the daily dose of ⁇ -3 polyunsaturated fatty acids is preferably at least 120 mg, more preferentially at least 350 mg.
  • the total fat composition in the preparation must be such that the proportion of unsaturated fatty acids is relatively high, that is to say more than 50 % of the fat.
  • the unsaturated fatty acids preferably do not have a trans configuration, that is to say the proportion of unsaturated fatty acids having a trans configuration is less than 0.8 %, preferably less than 0.5 % based on the total amount of fat (weight).
  • the preparation contains as little linoleic acid as possible.
  • the proportion of ⁇ -3 polyunsaturated fatty acids relative to the proportion of ⁇ -6 polyunsaturated fatty acids must be relatively high. This means that the ratio between ⁇ -6 fatty acids and ⁇ -3 fatty acids is preferably less than 3, more preferentially less than 2, for example 1.4.
  • Cholesterol can be present in the fat composition, for example in an amount of 0.5 to 5 % (m/m) of the total amount of fat.
  • Such a fat composition ensures that the membrane of the cells, in particular nerve cells, has good arrangement and a fluid nature, so that in vivo membrane processes can take place efficiently after activation of the receptor.
  • the polyunsaturated fatty acids are preferably present in the form of bound fatty acids, for example fatty acids bound to glycerol, such as in the form of triglycerides, but also, and this is preferred, in the form of phospholipids.
  • TMM total methionine metabolism
  • components which have a beneficial effect on total methionine metabolism are understood to be the components as described in EP 0 891 719, which is included herein by reference. These components are selected from vitamin B12 and precursors thereof, vitamin B6 and derivatives thereof, folic acid, zinc and magnesium. Preferably these components are selected from vitamin B12 and precursors thereof, vitamin B6 and folic acid. More preferably a combination of folic acid, vitamin B6 and vitamin B12 is used.
  • Suitable forms of vitamin B 12 are cyanocobalamin, hydroxy-, adenosyl- or methyl- cobalamin or mixtures thereof, which may or may not be bound to binding proteins in such a way that these can be completely and easily absorbed in the small intestine. These substances are suitably incorporated in the preparation in an amount such that it contains at least 3 ⁇ g, preferably at least 10 ⁇ g and in particular 50 to 1000 ⁇ g cobalamin per daily dose of the product.
  • Folic acid must be present in an amount of at least 250 ⁇ g, in particular 300 to 1500 ⁇ g, per daily dose of the product. Suitable forms are folinic acid, folic acid and methyl derivates thereof, in the non-oxidised or oxidised form.
  • Pyridoxine or derivatives thereof, such as pyridoxamine or pyridoxal, can be used in the product as suitable sources of vitamin B6. At least 1 mg vitamin B6, preferably 2 to 20 mg vitamin B6, per daily dose is contained in the product.
  • the preparation according to the invention can also contain phospholipids.
  • phospholipids are preferably phosphatidylserine, phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine.
  • a mixture of two or more of these phospholipids is used, in particular a mixture that contains at least phosphatidylcholine and phosphatidylserine.
  • the daily dose of phospholipids is preferably at least 0.2 g, more preferentially at least 1 g.
  • Another characteristic of the phospholipids is the fatty acid group of the phospholipids. These preferably have a composition corresponding to the ⁇ -3 polyunsaturated fatty acids as described above. This can be achieved by using known interesterif ⁇ cation techniques using crude phospholipid mixtures and ingredients rich in the suitable fatty acids as the starting materials.
  • phospholipid fraction obtained from their eggs has a fatty acid composition that is as similar as possible to the desired composition.
  • Narieties of plants can also be genetically modified so that they contain the active compounds in the correct amounts.
  • An example of this is genetically modified soya where the phospholipid fraction contains additional EPA and/or DHA.
  • Phospholipids can be obtained from egg yolk or soya and can be isolated using known techniques, for example by acetone extraction and subsequent chromatographic techniques or adsorption methods. If required, synthetic phospholipid fractions can also be used, but this is not preferred.
  • Other substances which are preferably present in the preparation are components selected from thiamine, pantothenic acid, camitine, vitamin C, vitamin E, carotenoids, coenzyme Q10 and flavinoids.
  • camitine is a preferred compound. This also includes functional equivalents of camitine, such as salts thereof or alkanoyl- and acyl-carnitines (acetyl-L- camitine).
  • Camitine can be incorporated in an amount of 0.1 to 3 g, preferably 0.2 to 1 g per daily dose.
  • Coenzyme Q10 can be incorporated in an amount of 0.8 to 200 mg, preferably 5 to 70 mg per daily dose.
  • the components are preferably combined with existing agents which increase the amount of neurotransmitter in the synapse.
  • These can be the neurotransmitters themselves, but also derivates thereof, precursors of the neurotransmitters and drugs that are used for this purpose, such as drugs that inhibit the reuptake of the neurotransmitters released in the synapse, such as the so-called serotonin-reuptake inhibitors, or substances that inhibit the metabolic conversion of the neurotransmitters, such as the cholinesterase inhibitors, monoamine oxidase inhibitors and decarboxylation inhibitors. Certain nucleotides or precursors thereof also stimulate the formation of neurotransmitters.
  • neurotransmitters themselves are, for example, dopamine and the known analogues thereof which are already widely used in combating the symptoms of Parkinson's disease. These substances are obtainable in synthetic form. When the preparation of the invention is used, the dosage of these substances can be reduced by as much as 50 %.
  • Known drugs that increase the levels of neurotransmitters for example serotonin agonists or serotonin reuptake inhibitors, which can be combined with the preparation of the invention are Prozac, Zoloft, Luvox, Redux, Pondimin, Maxalt, Imitrex, Almogram, Zelapar, Selegiline, Mirapex, Permax, Exelon, Remilnyl, Aricept, Cognex, Tasaclidine, Ergoset and many other similar drugs. Insulin is also used to stimulate the insulin receptor.
  • neurotransmitters are serotonin, adrenaline, noradrenaline, glutamate, acetylcholine and gamma-aminobutyric acid. These can also be incorporated in the preparation.
  • precursors of neurotransmitters are the amino acids L-tryptophan, L-phenyl- alanine and L-tyrosine.
  • serotonin can be formed from L- tryptophan in the body of the animal.
  • dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine) can be formed under certain conditions from L-phenylalanine and/or L-tyrosine.
  • Functional equivalents of these amino acids can also be used as precursor for neurotransmitters, such as, for example, N-alkylated forms or esterified forms and salts.
  • An example of a suitable derivative of tryptophan is 5-hydroxytryptophan.
  • proteins or hydrolysed products thereof or peptides Preferably, the proteins used contain a relatively high concentration of the relevant amino acids. Enriched proteins can also be used, for example obtained by dialysis and membrane filtration techniques.
  • An example of a protein enriched in tryptophan is ⁇ -lactalbumin.
  • the amounts of neurotransmitters or agents which increase the concentration of neurotransmitters in the synapse are dependent on the nutritional status of the patient and his or her diet.
  • Per daily dose at least 14 mg/kg body weight phenylalanine + tyrosine, that is to say on average 1 g/day, must be consumed via the complete diet.
  • the product according to the invention preferably contributes at least 50 % to this, that is to say at least 0.5 g/day and preferably 0.7 - 3 g/day.
  • the diet must also provide at least 3.5 mg/kg body weight tryptophan.
  • the product according to the invention preferably contributes at least 50 % of this, that is to say at least 130 mg/day.
  • the preparation contains 200 - 2200 mg tryptophan per daily dose.
  • acetylcholine can be formed from choline and betaine. Choline can also originate from phosphatidylcholine. It is advantageous that the product contains at least 0.4 g choline equivalents per daily dose, preferably in the form of 0.4 to 2 g betaine or in the form of 3.5 to 18 g phosphatidylcholine, in particular obtained from lecithins with rapeseed, egg or soya as possible source.
  • UMP uridine monophosphate
  • a pentose such as D-ribose, xylitol, L-arabinose or an oligosaccharide or polysaccharide that contains these sugars can also be incorporated in the product instead of or in addition to nucleotides. Oligosaccharides that contain D-ribose and arabans are most preferred. At least 0.5 g of the pentose, preferably 1 to 20 g, is administered per daily dose.
  • the preparations according to the invention can be used for improving the action of receptors in cells of the central nervous system, in particular for improving the sensitivity of receptors to neurotransmitters.
  • Specific receptors that can be influenced by the preparation of the invention are metabotropic receptors, preferably G protein coupled receptors.
  • metabotropic receptors are the seven transmembrane domain receptors which usually function via G proteins, but also single transmembrane domain receptors such as the tyrosine kinase receptor family (growth factors, insulin), the cytokine receptor family (growth hormone, erythropoietin, leptin, prolactin), the serine-threonine kinase receptor family (TGF-beta), the guanylyl cyclase receptor family (atrial natriuretic peptides) and the phosphotyrosine phosphatase family.
  • the tyrosine kinase receptor family growth factors, insulin
  • the cytokine receptor family growth hormone, erythropoietin, leptin, prolactin
  • TGF-beta serine-threonine kinase receptor family
  • guanylyl cyclase receptor family atrial natriuretic peptides
  • disorders of which the severity can be reduced by increasing the action of the receptor are, in particular, disorders associated with disturbed neurotransmitter functioning. Specific examples of these are Parkinson's disease, Huntington's chorea, epilepsy, schizophrenia, paranoia, depression, sleep disorders, impaired memory function, psychoses, dementia and ADHD and motor disorders such as can arise after, for example, a trauma, stroke and ALS and chronic fatigue syndrome.
  • the preparation of the invention can be used both for humans and animals, preferably for humans.
  • the preparation can be brought into a suitable form and administered either as a pharmaceutical preparation or as a nutritional preparation. Suitable additives and excipients for such preparations are known to those skilled in the art.
  • the chronic dietary intake of essential polyunsaturated fatty acids can modulate learning and memory processes by being incorporated into neuronal and glial plasma membranes.
  • hippocampal neurotransmitter receptor densities after chronic administration of diets enriched in docosahexaenoic/eicosapentaenoic acid and methionine metabolism stimulating components in a brain hypoperfusion model which mimics decreased cerebral perfusion as it occurs in ageing and dementia.
  • muscarinic 1, serotonergic 1 A and the glutaminergic ⁇ MDA receptors were labelled in hippocampal slices by autoradiographic methods.
  • the increased ratio of n-3 fatty acids in combination with additional dietary supplements (table 1) enhanced the density of the serotonergic 1 A and muscarinic 1 receptors (Table 2), but no major effects were found on the ⁇ MDA receptors. Since the examined receptor types reacted differently to the dietary supplementation, it can be concluded that besides changes in membrane fluidity, the biochemical regulation of receptor sensitivity may also play a role in increasing hippocampal receptor density.
  • the ⁇ MDA receptor differs from the here investigated Mi and 5-HTl A receptors in that the ⁇ MDA receptor is an ion channel receptor versus the other two G protein-coupled, metabotropic receptors.
  • ⁇ MDA receptors are ionotropic receptors which need no major conformational changes like the metabotropic receptors during binding.
  • Metabotropic receptors like the muscarinic 1 acetylcholine receptor and the serotonergic 5-HTl receptor bind transmitter and through a series of conformational changes bind to G proteins and activate them. These conformations are facilitated when membranes are fluid. Table 1

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Abstract

The present invention relates to the use of polyunsaturated fatty acids in particular docosa hexaenoic acid and one or more components which have a beneficial effect on total methionine metabolism selected from the group consisting of vitamin B12 and precursors thereof, vitamin B6 and derivatives thereof, folic acid, zinc and magnesium, in the manufacture of a preparation for improving the action of receptors. This preparation is advantageously applied in patients suffering from Parkinson's disease, Huntington's chorea, epilepsy, schizophrenia, paranoia, depression, sleep disorders, impaired memory function, psychoses, dementia and ADHD.

Description

Preparation for improving the action of receptors
The present invention relates to a preparation for improving the action of receptors, in particular for improving the sensitivity of receptors to neurotransmitters.
Receptors can be present in the membranes of cells. The receptor is activated under the influence of components present outside the cell (for example, neurotransmitters, neuromodulators or hormones) which bind to the receptor. The receptor is then capable of transmitting signals, which can start a cascade of events. Receptors can be present, inter alia, in or on nerve cells, muscle cells, endocrine cells, epithelial cells or other types of cells. Examples of substances which have an effect on receptors are neurotransmitters (see below), neuromodulators, neuropeptides and hormones such as insulin and steroids.
A specific class of receptors is, for example, constituted by receptors in nerve cells
(neurones) which are controlled by neurotransmitters. These neurones consist of a cell body (soma) with several, frequently short fimbriae (dendrites) and one long fimbria, termed an axon. An electrical signal is transmitted from the soma via the axon. The axon branches into axon ends which can terminate next to the dendrites of adjacent nerve cells, onto another axon, next to the soma of nerve cells or in tissues or parts thereof. The so-called synaptic cleft is located between the axon of the one nerve cell and the dendrite (or also soma) of the other nerve cell.
If a nerve cell is stimulated, substances can be released which are termed neurotransmitters or neuromodulators and which are able to activate another nerve cell. The neuro- transmitters/neuromodulators are recognised by receptors in the postsynaptic membrane of the "receiving" nerve cell.
Examples of classic endogenous neurotransmitters are biogenic amines such as serotonin, dopamine, histamine, noradrenaline and adrenaline; amino acids such as GAB A (gamma- aminobutyric acid), glutamate, aspartate and glycine; cholinergic agents, such as acetylcholine; peptides, such as endorphins and other types of neurotransmitters such as nitrogen oxide and adenosine. In addition, many substances have been found which are recognised by the neurotransmitter receptors, such as certain drugs (for example clenbuterol), which usually are prepared synthetically, but also substances from natural preparations (such as muscarine antagonists or ephedrine-rich plant extracts).
Receptors can be classified on the basis of their action. lonotropic receptors act rapidly and determine ion transport through the membrane. They consist of a large complex of multiple sub-units made up of five individual proteins which combine to establish an ion channel through the membrane. The sub-units have four transmembrane domains which form the pore. These ion channels are impermeable to ions in the absence of a neurotransmitter.
Metabotropic receptors constitute another class. These act relatively slowly and have a wide range of effects on the metabolism of the cell. Many comprise the seven trans- membrane domain receptors, which usually function via G proteins. These types of receptors play a role, inter alia, in the case of neurotransmitters which belong to the adrenergic agents (for example noradrenaline and adrenaline), in the case of dopamine, serotonin and in the case of neurotransmitters which belong to the cholinergic agents (such as acetylcholine or muscarine). Other examples of seven transmembrane domain receptors are receptors which are activated by neuropeptides, such as by Substance P, Neuropeptide Y, Bombesine, Neurotensine, CCK and galanine.
Others include single transmembrane domain receptors such as the tyrosine kinase receptor family (growth factors, insulin), the cytokine receptor family (growth hormone, erythropoietin, leptin, prolactin), the serine-threonine kinase receptor family (TGF-beta), the guanylyl cyclase receptor family (atrial natriuretic peptides) and the phosphotyrosine phosphatase family.
Many medical disorders are associated with disturbed signal transmission. This can be due to a reduced concentration of hormones and/or neurotransmitters and/or neuromodulators, but also to a reduced sensitivity of the receptor towards the specific substance.
A neurotransmitter functioning that is disturbed to a more or less severe extent can play a role in neurological disorders such as dementia, depression, Parkinson's disease, Huntington's chorea, epilepsy, schizophrenia, paranoia and ADHD, but also in other emotional disorders.
Various ways for improving the functioning of the nerve processes have been conceived in the past. For example, neurotransmitters such as dopamine or derivatives thereof have been administered to people suffering from Parkinson's disease in order to increase the amount of dopamine in the synapse. Substances have also been administered in order to reduce the reuptake of the neurotransmitter serotonin from the synaptic cleft into the dendrite. Agents which inhibit a specific metabolic conversion of the neurotransmitter acetylcholine (acetylcholinesterase inhibitors), as a result of which the concentrations of acetylcholine in the synaptic cleft (i.e. extracellular) remain high for a prolonged period, have also been described. Monoamine oxidase inhibitors partially prevent the conversion of monoamines such as dopamine.
In contrast with the aforementioned approaches, the aim of the invention is to improve the action, and especially the sensitivity of receptors, in particular in nerve processes, but also in other physiological processes in which, for example, hormones play a role. What is meant by an improved action of receptors is that less agonist, in particular less neurotransmitter, is needed to achieve the same effect. The present invention may advantageously be applied in patients who suffer from an imbalanced neurotransmitter functioning and/or neurodegenerative disorder. In addition, the invention may be applied in healthy individuals to improve the concentration and/or learning ability of these individuals.
The invention relates to the use of polyunsaturated fatty acids and components which have a beneficial effect on methionine metabolism for improving the action of receptors.
The inventors have unexpectedly found that the combined application of polyunsaturated fatty acids and methionine metabolism stimulating compounds improves the action of receptors, but not as a result of the increased production of neurotransmitter or a reduced reuptake of neurotransmitter from the synaptic cleft. According to the inventors, the surprising effect of the active principles according to the invention may be explained from the improved arrangement and more fluid nature of the cell membranes, especially of the membranes of neurons, that results from the combined administration. Because of the improved arrangement and fluidity, in vivo membrane processes can proceed more effectively after receptor activation. This improvement is not only advantageous in individuals in whom these membrane processes are adversely affected by, for instance, a neurodegenerative disorder. The improvement is also beneficial to individuals who wish to improve their ability to learn and/or concentrate, e.g. for study or work.
The treatment of a variety of disorders, including neurodegenerative disorders such as Alzheimer disease and Parkinson's disease with polyunsaturated fatty acids and vitamin B6, B12 and/or folic acid is described in WO 01/03696. In this PCT-application a link is made between an elevated serum homocysteine concentration and the undesired oxidation of essential fatty acids, in particular of eicosapentenoic acid and arachidonic acid. The administration of vitamin B6, folic acid and vitamin B12 is said to decrease the serum homocysteine concentration and consequently to diminish the oxidation of the aforementioned essential fatty acids, as a result of which, in combination with the administration of these same essential fatty acids, an increase in the serum concentration of these essential fatty acids is achieved. According to the PCT-application an increase of the concentration of essential fatty acids can be advantageous in the treatment of (a) illnesses, (b) cardiovascular or cerebrovascular disorders, (c) diabetes, syndrome X and macro or microvascular complications of diabetes, (d) psychiatric disorders, (e) neurological or neurodegenerative disorders, (f) kidney disorders, (g) inflammatory or immunological disorders of the gastrointestinal tract, (h) eye or hearing disorders, (i) forms of obesity and (j) any form of cancer. Nowhere in the PCT-application reference is made to an effect of the preparations described therein on receptor action.
Suppletion with the preparation according to the invention is beneficial in those situations where the endogenous production of neurotransmitters is marginal but the receptor is still functional, as is the case for minor manifestations of neurological disorders.
In persons suffering from serious forms of neurological disorders it is advantageous that, in addition to the aforementioned components, at least one substance is administered that increases the concentration of the neurotransmitters, neuromodulators or hormone in the synapse or at the receptor.
Polyunsaturated fatty acids are fatty acids containing at least two unsaturated bonds and having a chain length of at least 18. The unsaturated bond is located in the 3, 6 or 9 position relative to the terminal methyl group.
The preparation of the invention preferably contains Ω-3 polyunsaturated fatty acids. The Ω-3 polyunsaturated fatty acids include α-linolenic acid, stearidonic acid, eicosapentaenoic acid and docosahexaenoic acid and arachidonic acid. The preparation preferably contains at least docosahexaenoic acid. For cardiovascular-associated neurological disorders such as dementia eicosapentaenoic acid is also suitably present. The daily dose of Ω-3 polyunsaturated fatty acids is preferably at least 120 mg, more preferentially at least 350 mg.
The total fat composition in the preparation must be such that the proportion of unsaturated fatty acids is relatively high, that is to say more than 50 % of the fat. The unsaturated fatty acids preferably do not have a trans configuration, that is to say the proportion of unsaturated fatty acids having a trans configuration is less than 0.8 %, preferably less than 0.5 % based on the total amount of fat (weight). In addition, the preparation contains as little linoleic acid as possible.
The proportion of Ω-3 polyunsaturated fatty acids relative to the proportion of Ω-6 polyunsaturated fatty acids must be relatively high. This means that the ratio between Ω-6 fatty acids and Ω-3 fatty acids is preferably less than 3, more preferentially less than 2, for example 1.4.
Cholesterol can be present in the fat composition, for example in an amount of 0.5 to 5 % (m/m) of the total amount of fat.
Such a fat composition ensures that the membrane of the cells, in particular nerve cells, has good arrangement and a fluid nature, so that in vivo membrane processes can take place efficiently after activation of the receptor. The polyunsaturated fatty acids are preferably present in the form of bound fatty acids, for example fatty acids bound to glycerol, such as in the form of triglycerides, but also, and this is preferred, in the form of phospholipids.
Components which have a beneficial effect on total methionine metabolism (TMM) are understood to be the components as described in EP 0 891 719, which is included herein by reference. These components are selected from vitamin B12 and precursors thereof, vitamin B6 and derivatives thereof, folic acid, zinc and magnesium. Preferably these components are selected from vitamin B12 and precursors thereof, vitamin B6 and folic acid. More preferably a combination of folic acid, vitamin B6 and vitamin B12 is used.
Suitable forms of vitamin B 12 are cyanocobalamin, hydroxy-, adenosyl- or methyl- cobalamin or mixtures thereof, which may or may not be bound to binding proteins in such a way that these can be completely and easily absorbed in the small intestine. These substances are suitably incorporated in the preparation in an amount such that it contains at least 3 μg, preferably at least 10 μg and in particular 50 to 1000 μg cobalamin per daily dose of the product.
Folic acid must be present in an amount of at least 250 μg, in particular 300 to 1500 μg, per daily dose of the product. Suitable forms are folinic acid, folic acid and methyl derivates thereof, in the non-oxidised or oxidised form.
Pyridoxine or derivatives thereof, such as pyridoxamine or pyridoxal, can be used in the product as suitable sources of vitamin B6. At least 1 mg vitamin B6, preferably 2 to 20 mg vitamin B6, per daily dose is contained in the product.
In addition to Ω-3 polyunsaturated fatty acids and components which have a beneficial effect on methionine metabolism, the preparation according to the invention can also contain phospholipids. These are preferably phosphatidylserine, phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine. Preferably a mixture of two or more of these phospholipids is used, in particular a mixture that contains at least phosphatidylcholine and phosphatidylserine. The daily dose of phospholipids is preferably at least 0.2 g, more preferentially at least 1 g. Another characteristic of the phospholipids is the fatty acid group of the phospholipids. These preferably have a composition corresponding to the Ω-3 polyunsaturated fatty acids as described above. This can be achieved by using known interesterifϊcation techniques using crude phospholipid mixtures and ingredients rich in the suitable fatty acids as the starting materials.
This can also be achieved by feeding birds with special fats, so that the phospholipid fraction obtained from their eggs has a fatty acid composition that is as similar as possible to the desired composition. Narieties of plants can also be genetically modified so that they contain the active compounds in the correct amounts. An example of this is genetically modified soya where the phospholipid fraction contains additional EPA and/or DHA.
Phospholipids can be obtained from egg yolk or soya and can be isolated using known techniques, for example by acetone extraction and subsequent chromatographic techniques or adsorption methods. If required, synthetic phospholipid fractions can also be used, but this is not preferred.
Other substances which are preferably present in the preparation are components selected from thiamine, pantothenic acid, camitine, vitamin C, vitamin E, carotenoids, coenzyme Q10 and flavinoids.
Amongst these, camitine is a preferred compound. This also includes functional equivalents of camitine, such as salts thereof or alkanoyl- and acyl-carnitines (acetyl-L- camitine). Camitine can be incorporated in an amount of 0.1 to 3 g, preferably 0.2 to 1 g per daily dose. Coenzyme Q10 can be incorporated in an amount of 0.8 to 200 mg, preferably 5 to 70 mg per daily dose.
In the preparation of the invention the components are preferably combined with existing agents which increase the amount of neurotransmitter in the synapse. These can be the neurotransmitters themselves, but also derivates thereof, precursors of the neurotransmitters and drugs that are used for this purpose, such as drugs that inhibit the reuptake of the neurotransmitters released in the synapse, such as the so-called serotonin-reuptake inhibitors, or substances that inhibit the metabolic conversion of the neurotransmitters, such as the cholinesterase inhibitors, monoamine oxidase inhibitors and decarboxylation inhibitors. Certain nucleotides or precursors thereof also stimulate the formation of neurotransmitters.
Examples of the neurotransmitters themselves are, for example, dopamine and the known analogues thereof which are already widely used in combating the symptoms of Parkinson's disease. These substances are obtainable in synthetic form. When the preparation of the invention is used, the dosage of these substances can be reduced by as much as 50 %.
Known drugs that increase the levels of neurotransmitters, for example serotonin agonists or serotonin reuptake inhibitors, which can be combined with the preparation of the invention are Prozac, Zoloft, Luvox, Redux, Pondimin, Maxalt, Imitrex, Almogram, Zelapar, Selegiline, Mirapex, Permax, Exelon, Remilnyl, Aricept, Cognex, Tasaclidine, Ergoset and many other similar drugs. Insulin is also used to stimulate the insulin receptor.
Other examples of neurotransmitters are serotonin, adrenaline, noradrenaline, glutamate, acetylcholine and gamma-aminobutyric acid. These can also be incorporated in the preparation.
Examples of precursors of neurotransmitters are the amino acids L-tryptophan, L-phenyl- alanine and L-tyrosine. Under certain conditions, serotonin can be formed from L- tryptophan in the body of the animal. Also, for example, dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine) can be formed under certain conditions from L-phenylalanine and/or L-tyrosine.
Functional equivalents of these amino acids can also be used as precursor for neurotransmitters, such as, for example, N-alkylated forms or esterified forms and salts. An example of a suitable derivative of tryptophan is 5-hydroxytryptophan. However, it is preferable to use proteins or hydrolysed products thereof or peptides. Preferably, the proteins used contain a relatively high concentration of the relevant amino acids. Enriched proteins can also be used, for example obtained by dialysis and membrane filtration techniques. An example of a protein enriched in tryptophan is α-lactalbumin.
The amounts of neurotransmitters or agents which increase the concentration of neurotransmitters in the synapse are dependent on the nutritional status of the patient and his or her diet. Per daily dose, at least 14 mg/kg body weight phenylalanine + tyrosine, that is to say on average 1 g/day, must be consumed via the complete diet. The product according to the invention preferably contributes at least 50 % to this, that is to say at least 0.5 g/day and preferably 0.7 - 3 g/day. The diet must also provide at least 3.5 mg/kg body weight tryptophan. The product according to the invention preferably contributes at least 50 % of this, that is to say at least 130 mg/day. Preferably the preparation contains 200 - 2200 mg tryptophan per daily dose.
Under certain conditions, acetylcholine can be formed from choline and betaine. Choline can also originate from phosphatidylcholine. It is advantageous that the product contains at least 0.4 g choline equivalents per daily dose, preferably in the form of 0.4 to 2 g betaine or in the form of 3.5 to 18 g phosphatidylcholine, in particular obtained from lecithins with rapeseed, egg or soya as possible source.
Nucleotides play an important role in the formation of acetylcholine. It is preferable to incorporate nucleotides in the preparation, in particular in the form of ribonucleic acids such as, for example, are present in yeast or extracts thereof. Preferably the product contains at least 50 mg nucleobases, including uridine or cytidine, per daily dose. This corresponds to, for example, at least 2.5 g crude brewer's yeast. Instead of the bases it is also possible to use the phosphates thereof, such as the mono-, di- or tri-phosphate (for example uridine monophosphate (UMP)).
A pentose, such as D-ribose, xylitol, L-arabinose or an oligosaccharide or polysaccharide that contains these sugars can also be incorporated in the product instead of or in addition to nucleotides. Oligosaccharides that contain D-ribose and arabans are most preferred. At least 0.5 g of the pentose, preferably 1 to 20 g, is administered per daily dose.
The preparations according to the invention can be used for improving the action of receptors in cells of the central nervous system, in particular for improving the sensitivity of receptors to neurotransmitters. Specific receptors that can be influenced by the preparation of the invention are metabotropic receptors, preferably G protein coupled receptors.
Examples of metabotropic receptors are the seven transmembrane domain receptors which usually function via G proteins, but also single transmembrane domain receptors such as the tyrosine kinase receptor family (growth factors, insulin), the cytokine receptor family (growth hormone, erythropoietin, leptin, prolactin), the serine-threonine kinase receptor family (TGF-beta), the guanylyl cyclase receptor family (atrial natriuretic peptides) and the phosphotyrosine phosphatase family.
Disorders of which the severity can be reduced by increasing the action of the receptor are, in particular, disorders associated with disturbed neurotransmitter functioning. Specific examples of these are Parkinson's disease, Huntington's chorea, epilepsy, schizophrenia, paranoia, depression, sleep disorders, impaired memory function, psychoses, dementia and ADHD and motor disorders such as can arise after, for example, a trauma, stroke and ALS and chronic fatigue syndrome.
In view of the general nature of the improvement in receptor function, in a number of cases it is desirable to add an antagonist. This is, for example, the case when aiming for weight loss. A more rapid effect is obtained if an antagonist for the α-2 receptor is given.
The preparation of the invention can be used both for humans and animals, preferably for humans.
The preparation can be brought into a suitable form and administered either as a pharmaceutical preparation or as a nutritional preparation. Suitable additives and excipients for such preparations are known to those skilled in the art.
Experimental
The chronic dietary intake of essential polyunsaturated fatty acids can modulate learning and memory processes by being incorporated into neuronal and glial plasma membranes. Representatives of the two important polyunsaturated fatty acid families, the n-3 and n-6 types become integrated into membrane phospholipids, where the actual (n-6)/(n-3) ratio can determine membrane fluidity. In the present experiment we studied hippocampal neurotransmitter receptor densities after chronic administration of diets enriched in docosahexaenoic/eicosapentaenoic acid and methionine metabolism stimulating components in a brain hypoperfusion model which mimics decreased cerebral perfusion as it occurs in ageing and dementia.
Sixty 30-day-old Wistar rats were randomly divided into 3 groups of 20. Each group was given a specific diet, the first ordinary chow (placebo), the second group chow of a specific composition SI and the third group the same feed as Group 2 with additional components (S2); see Table 1. The diets contained identical quantities of proteins, carbohydrates, minerals and energy. At the age of 4 months, two of the four carotid arteries of half of each group of animals were occluded (2NO animals). The other half was subjected to a similar operation without occlusion of the arteries. At the age of 7 months the animals were sacrificed for further investigation. Inter alia, the receptor density in specific parts of the brain was determined with the aid of labelling using a radioactive marker substance.
Three receptor types, the muscarinic 1, serotonergic 1 A and the glutaminergic ΝMDA receptors were labelled in hippocampal slices by autoradiographic methods. The increased ratio of n-3 fatty acids in combination with additional dietary supplements (table 1) enhanced the density of the serotonergic 1 A and muscarinic 1 receptors (Table 2), but no major effects were found on the ΝMDA receptors. Since the examined receptor types reacted differently to the dietary supplementation, it can be concluded that besides changes in membrane fluidity, the biochemical regulation of receptor sensitivity may also play a role in increasing hippocampal receptor density. The ΝMDA receptor differs from the here investigated Mi and 5-HTl A receptors in that the ΝMDA receptor is an ion channel receptor versus the other two G protein-coupled, metabotropic receptors. ΝMDA receptors are ionotropic receptors which need no major conformational changes like the metabotropic receptors during binding. Metabotropic receptors like the muscarinic 1 acetylcholine receptor and the serotonergic 5-HTl receptor bind transmitter and through a series of conformational changes bind to G proteins and activate them. These conformations are facilitated when membranes are fluid. Table 1
Figure imgf000013_0001
Table 2 (nCi/mg tissue)
Figure imgf000013_0002

Claims

Claims
1. Use of polyunsaturated fatty acids and one or more components which have a beneficial effect on total methionine metabolism selected from the group consisting of vitamin B12 and precursors thereof, vitamin B6 and derivatives thereof, folic acid, zinc and magnesium, in the manufacture of a preparation for improving the action of receptors.
2. Use according to Claim 1, for improving the sensitivity of receptors for neutrotransmitters and or neuromodulators.
3. Use according to claim 1 or 2, wherein the method comprises the administration of Ω-3 polyunsaturated fatty acids, preferably in a daily dose of at least 120 mg, more preferably of at least 350 mg.
4. Use according to any one of the preceding Claims, wherein the preparation contains at least docosahexaenoic acid (DHA) as Ω-3 polyunsaturated fatty acid.
5. Use according to any one of the preceding Claims, wherein the components which have a beneficial effect on total methionine metabolism are selected from vitamin B12, vitamin B6, folic acid, precursors, derivatives and mixtures thereof.
6. Use according to Claim 5, wherein the preparation contains a combination of vitamin B12, vitamin B6 and folic acid or precursors or derivatives thereof as components which have a beneficial effect on total methionine metabolism.
7. Use according to any one of the preceding claims, wherein the method comprises the administration of phospholipids, preferably in a daily dose of at least 0.2 g, more preferably of at least 1 g.
8. Use according to any one of the preceding claims, wherein the method comprises the administration of camitine or functional derivatives thereof, preferably in a daily dose of
0.1 to 3 g, more preferably of 0.2 to 1 g.
9. Use according to any one of the preceding claims for improving the action of metabotropic receptors.
10. Use according to any one of the preceding claims for improving the action of receptors with a transmembrane structure, in particular G protein coupled receptors.
11. Use according to any one of the preceding claims for the treatment and/or prevention of disorders related to a disturbed neurotransmitter functioning.
12. Use according to Claim 11 for the treatment and/or prevention of Parkinson's disease, Huntington's chorea, epilepsy, schizophrenia, paranoia, depression, sleep disorders, impaired memory function, psychoses, dementia and ADHD.
13. Use according to any one of the preceding claims for the treatment of dementia, wherein the preparation contains a combination of docosahexaenoic acid and eicosapentenoic acid as polyunsaturated fatty acids.
14. Use according to any one of the preceding claims, wherein the preparation also contains an agent that increases the quantity of neurotransmitter in the synapse.
15. Use according to Claim 14, wherein the agent that increases the quantity of neurotransmitter in the synapse is selected from neurotransmitters themselves, such as dopamine or analogues thereof, serotonin, adrenaline, noradrenaline, glutamate, acetylcholine and gamma-aminobutyric acid.
16. Use according to Claim 15, wherein the agent that increases the quantity of neurotransmitter in the synapse is selected from precursors of neurotransmitters, such as tryptophan, phenylalanine or tyrosine or functional equivalents thereof.
17. Preparation that contains: polyunsaturated fatty acids, one or more components that have a beneficial effect on total methionine metabolism selected from the group consisting of vitamin B12 and precursors thereof, vitamin B6 and derivatives thereof, folic acid, zinc and magnesium, and an agent that increases the quantity of neurotransmitter in the synapse.
18. Preparation according to Claim 17, wherein the polyunsaturated fatty acids are Ω-3 polyunsaturated fatty acids, preferably present in an amount of at least 120 mg, more preferably of at least 350 mg.
19. Preparation according to Claim 18, which contains at least docosahexaenoic acid (DHA) as Ω-3 polyunsaturated fatty acid.
20. Preparation according to any one of Claims 17 to 19, wherein the components which have a beneficial effect on total methionine metabolism are selected from vitamin B12, vitamin B6, folic acid, precursors, derivatives and mixtures thereof.
21. Preparation according to Claim 20, which contains a combination of vitamin B 12, vitamin B6 and folic acid or precursors or derivatives thereof as components which have a beneficial effect on total methionine metabolism.
22. Preparation according to any one of Claims 17 to 21, which contains phospholipids, preferably in an amount of at least 0.2 g, more preferably of at least 1 g.
23. Preparation according to any one of Claims 17 to 22, which also contains camitine or functional equivalents thereof, preferably in an amount of 0.1 -3 g, more preferably of 0.2- 1 g-
24. Preparation according to any one of Claims 17 to 23, wherein the agent that increases the quantity of neurotransmitter in the synapse is selected from neurotransmitters themselves, such as dopamine or analogues thereof, serotonin, adrenaline, noradrenaline, glutamate, acetylcholine and gamma-aminobutyric acid.
25. Preparation according to Claim 24, wherein the agent that increases the quantity of neurotransmitter in the synapse is selected from precursors of neurotransmitters, such as tryptophan, phenylalanine or tyrosine or functional equivalents thereof.
PCT/NL2002/000731 2001-11-14 2002-11-14 Preparation for improving the action of receptors WO2003041701A2 (en)

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US12/045,112 US7888391B2 (en) 2001-11-14 2008-03-10 Method for reducing the severity of neurological disorders
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