WO2011053191A1 - Médicament pour le traitement de maladies et de troubles liés à des états de stress et affectant l'être humain et les animaux, et méthode de traitement et/ou de prophylaxie utilisant ce médicament - Google Patents

Médicament pour le traitement de maladies et de troubles liés à des états de stress et affectant l'être humain et les animaux, et méthode de traitement et/ou de prophylaxie utilisant ce médicament Download PDF

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WO2011053191A1
WO2011053191A1 PCT/RU2010/000615 RU2010000615W WO2011053191A1 WO 2011053191 A1 WO2011053191 A1 WO 2011053191A1 RU 2010000615 W RU2010000615 W RU 2010000615W WO 2011053191 A1 WO2011053191 A1 WO 2011053191A1
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knd
residue
amino acid
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configuration
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Russian (ru)
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Инэса Ивановна МИХАЛЕВА
Владислав Борисович ВОЙТЕНКОВ
Игорь Аркадьевич ПРУДЧЕНКО
Вадим Тихонович ИВАНОВ
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Общество С Ограниченной Ответственностью "Исследовательский Центр "Комкон"
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Publication of WO2011053191A1 publication Critical patent/WO2011053191A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides

Definitions

  • An agent for the treatment of stress-related diseases and disorders in humans and animals, as well as a method of treatment and / or prophylaxis using this agent is an agent for the treatment of stress-related diseases and disorders in humans and animals, as well as a method of treatment and / or prophylaxis using this agent.
  • This invention relates to oligopeptides with positive pharmacological properties and the use of these oligopeptides for the treatment and / or prevention of stress-related diseases and disorders in humans and animals.
  • the invention also encompasses the use of these peptides for the manufacture of pharmaceutical compositions.
  • the present invention relates to oligopeptides with pharmacological activity, which are suitable substances for the treatment and prevention of stress-related pathological changes that apply to the central nervous system (CNS), but are not limited to it.
  • CNS central nervous system
  • KND - KN-DSIP, ⁇ -DSIP (which corresponds to (Lys, Asn) -DSIP.
  • Lys is denoted by K
  • Asn is denoted by N
  • Peptides described in the general formula (I) are called analogues - see below, which differ from the peptide with the main claimed amino acid sequence by replacing some amino acid residues with others, including non-proteinogenic residues, or by converting peptides of the general formula (I) to the corresponding cyclic peptides or (retro-inverse) analogs or by replacing amide bonds between residues with the corresponding ⁇ -alkylamide or ester bonds (N-alkylated and depsipeptide analogues).
  • Derivatives of peptides of formula (I) are essentially also analogues of peptides of formula (I).
  • peptide derivatives are more chemically consistent with products of modification of the main peptide chain or side chains of amino acid residues, for example, by their ⁇ -acylation with fatty acid residues or by conversion of the C-terminal carboxyl groups of peptides to ester, amide or> T- alkyl (aryl) amide groups.
  • Multimers correspond to structures consisting of several identical peptide units combined by covalent bonds in one structure directly through functional groups of monomer units or by using various known branching or bridging agents.
  • Proteinogenic (protein) amino acids are called amino acids, which are the structural elements of the proteins of living organisms.
  • salts are salts described in the United States Pharmacopeia or any other accepted pharmacopeia. These salts include, but are not limited to, salts of mineral or organic acids such as carbonic, hydrochloric, sulfuric acid, phosphoric acid, as well as lactic, benzoic, citric, oxalic acids and other acids.
  • Appropriate carriers and auxiliary ingredients provide the possibility of medical use of the pharmaceutical composition and, if necessary, contribute to the preservation of the oligopeptide (s) protected by the patent during storage and production of finished dosage forms.
  • Such substances are well known in the art and can be found in standard literature. Suitable, but not limited to the following, are, for example, calcium carbonate / phosphate, various mono- and disaccharides, polysaccharides, fats, biopolymers such as human albumin, as well as biocompatible polymers, for example polyethylene glycol.
  • Stress is one of the main factors threatening human health. Stress is the physiological response of an organism to damaging factors of various origins or the threat of exposure to such factors. Stress can be caused by a number of factors, the so-called stressors: in addition to physical and mental injuries caused by severe accidents or infectious diseases, chemical irritations or radiation can also contribute to stress.
  • the given sources of information (1-26) illustrate both the nature of stress and are the previous level of knowledge regarding the claimed inventions.
  • Acute and chronic stress can disrupt or weaken the homeostasis of the body, which translates into a deterioration in the ability to maintain the physiological balance of vital functions, such as maintaining cardiac activity or respiration.
  • the loss of the body's ability to maintain homeostasis can lead to a permanent disruption of the functioning of major organs and systems, such as neuroendocrine and cardiovascular.
  • major organs and systems such as neuroendocrine and cardiovascular.
  • Typical consequences of impaired ability to adequately respond to prolonged stress can be: psychosomatic or immunological disorders, and even damage to organs, such as myocardial infarction and, for example, stress-induced stomach ulcers.
  • neuroregulatory factors - neurohormones, neuromodulators and neurotransmitters, which can be directly secreted by hypothalamic cells (1), as well as various secretory cells, including those outside the central nervous system, for example, in the thin intestines.
  • Neuroregulatory factors cause changes in the functioning of the mammalian organism, some of which contribute to the maintenance of homeostasis. Often, neuroregulatory factors have a peptide nature (2).
  • Nonapeptide ADH antidiuretic hormone, vasopressin
  • a “thirst hormone” endogenous regulatory peptides of the modulator type include the so-called delta-sleep inducing peptide (DSIP), which is the object of comparison closest to the present invention and differs from the molecules described in this patent, described below, by their primary structure, namely the nature of the two amino acid residues of the molecule .
  • DSIP delta-sleep inducing peptide
  • DSIP is described as a treatment and prophylaxis against stress-induced massive damage to nerve cells caused by stress-inducing factors such as radiation, infection or trauma.
  • DSIP stabilizes the basic functions of the central nervous system and as a result has a corrective effect on disorders of the homeostasis of the body as a whole.
  • DSIP various effects of DSIP on the endocrine regulation of the body are not limited to improving its resistance to stressors: more fundamental properties of the peptide are described, such as interaction with the corticotropin system, antioxidant, immunomodulating effects and membranotropic properties (13-15).
  • Patent EP 0065747 B1 which describes DSIP as an agent suitable for controlling the symptoms of withdrawal symptoms
  • patent RU 2099078 C1 which describes the medical use of an anti-stress agent
  • Patent EP 0065747 B1 which describes DSIP as an agent suitable for controlling the symptoms of withdrawal symptoms
  • patent RU 2099078 C1 which describes the medical use of an anti-stress agent
  • Patent RU 2115660 C1 25
  • analogues of DSIP as anti-stress and anticonvulsant agents.
  • the present invention was made taking into account the previous level of knowledge, with the aim of introducing a new family of peptides that regulate body functions, with preferably emerging therapeutic, especially stress-protective and adaptogenic properties.
  • inventive means - family of peptides - include analogues and derivatives of the main claimed peptide shown in the General formula (I), which is the acronym of the new family of peptides:
  • X H or an acyl residue of formic, acetic, propionic or other fatty acids (e.g. palmitic, stearic), as well as their alkyl or
  • Y 1 aromatic amino acid residue Tgr or Tug, Phe or their corresponding ⁇ -methyl derivative of the L- or D-configuration;
  • Y 2 amino acid residue of Lys or Arg, His, Orn or their ⁇ -methyl derivative of the L- or D-configuration;
  • Y 5 Asn or Gin residue, their ⁇ -alkylamide derivative, Asp, Glu, their ester derivative, or M a methyl derivative of the indicated residues of the L- or D-configuration;
  • Y 6 Ala residue or ⁇ -Ala, Gly, Ser, Thr, Phe, Val, L or D configuration;
  • Y 7 residue Ser or residue Thr, Asn, Gin L- or D-configuration
  • Y 8 Gly residue or Ala, Ser, Thr, Asn residue of the L or D configuration
  • Y 9 residue Glu, Asp, Asn, Gin L- or D-configuration
  • R —OH, —ORi, —NH 2 , —NHR], or —N (Rj) 2 (where Ri is alkyl or arylalkyl).
  • a new family of regulatory peptides related to DSIP but previously unknown structure that differ from the current level of knowledge (DSIP) by the nature of the two amino acid residues of the peptide chain corresponding to the known structure of DSIP is presented.
  • Such changes in the structure of 2 amino acid residues lead to an increase in the therapeutic effect, in particular, in prevention and therapy stress related diseases in humans and animals.
  • the inventors show in an experiment with forced swimming in rats that the subject of the invention increases the stress resistance of animals when compared with DSIP.
  • the present invention relates to the prevention and treatment of pathological and stress-related disorders of homeostasis in humans and animals.
  • the inventors suggest that the peptides have a modulating effect on the level of excitatory and inhibitory neurotransmitters, including GABA, serotonin or glutamate.
  • the subject of the present invention can also modulate the activity of key membrane mitochondrial enzymes, as well as enzymes that control metabolism in the central nervous system and peripheral tissues, such as monoamine oxidase A, hexokinase, NADP-dependent malate dehydrogenase, creatine kinase, respiratory chain enzymes, hypothalamic glutamine superoxide dismutase (8, 9, 13). .
  • a computer search for amino acid sequences homologous to the subject of the invention using the BLAST search program revealed a 100% match to the human nuclear protein 1B site (called the “Jumonji domain containing 1B”) located on chromosome 5 human genome, and consisting of 1551 amino acid residues (17).
  • JMJD1B is a member of the family of histone demethylases type JHDM1 and JHDM2, including the JmjC domain.
  • JmjC-domain-containing histone demethylases capable of demethylating the lysine residues of histones are conserved in different species from yeast to humans.
  • Histone methylation-demethylation is an important mechanism of post-translational modifications and plays an exceptional role in the regulation of chromatin structure and gene transcription. These enzymes are ubiquitously present in various tissues.
  • the first studies of the JMJ base gene suggest its important role in the development of the nervous system and some organs, such as the liver, spleen, and thymus (18, 19).
  • EP 1950286A1 (22) closes the use of a mixture of Jumonji domain enzymes with demethylating properties, especially for the treatment of prostate cancer.
  • This invention is made taking into account the previous level of knowledge, in order to present a new family of peptides that regulate body functions, with preferably emerging therapeutic, especially stress-protective and adaptogenic properties.
  • a new family of oligopeptides with a peptide chain length of 4, 6 or 9 amino acid residues, as described above, corresponds to the following general formula:
  • X H or an acyl residue of formic, acetic, propionic or other fatty acids (e.g. palmitic, stearic), as well as their alkyl or
  • Y 1 aromatic amino acid residue Tgr or Tug, Phe or their corresponding ⁇ -methyl derivative of the L- or D-configuration;
  • Y is the amino acid residue of Lys or Arg, His, From or their ⁇ -methyl derivative of the L- or D-configuration;
  • Y 5 Asn or Gin residue, their ⁇ -alkylamide derivative, Asp, Glu, their ester derivative, or M a methyl derivative of the indicated residues of the L- or D-configuration;
  • Y 6 Ala residue or ⁇ -Ala, Gly, Ser, Thr, Phe, Val, L or D configuration;
  • Y 7 residue Ser or residue Thr, Asn, Gin L- or D-configuration
  • Y 8 Gly residue or Ala, Ser, Thr, Asn residue of the L or D configuration
  • Y 9 residue Glu, Asp, Asn, Gin L- or D-configuration
  • R -OH, -OR ⁇ , -NH 2 , -NHR 1? or -N (Ri) 2 (where -alkyl or arylalkyl).
  • the subject of the invention is the claimed K D peptide from the group of peptides of the general formula (I) has the following structure: TrpLysGlyGlyAsnAlaSerGlyGlu.
  • the peptides of the above general formula (I) can be synthesized by classical methods of peptide synthesis, both the traditional method of synthesis in solution and the solid-phase method of synthesis on a polymer carrier. Peptides are purified by chromatographic methods. Analysis of the structure and degree of individuality of synthetic peptides is carried out by modern physicochemical methods. These methods are well developed and described in the relevant literature (20, 21).
  • the group of the claimed peptides may also include the following analogues and derivatives of peptides of the family (I): 1. cyclic analogs formed using known methods for the synthesis of cyclopeptides by closing the (4-16)-membered ring through the N- and C-terminal or side functional groups, including when additional low molecular weight bridges weighing up to 500D are included in the cycle.
  • peptides attached (including adsorbed or encapsulated) to various pharmacologically acceptable polymer carriers for example, polyacrylates, polylactates, polysaccharides, gelatin, etc.
  • the general formula can be expanded by adding additional peptide fragments to one or both ends of the amino acid chain of type (I) nonapeptides, so that the extension fragments from the C- and / or N-terminus include from 1 to 5 protein amino acid residues each.
  • the N and C ends of any elongated peptides as well as all peptides of formula (I) may be free and have no substituents at the N and C ends of the amino acid chain, or be blocked by X and / or R.
  • peptides that exist in whole or in part in the form of compositions with pharmaceutically acceptable carriers.
  • This invention also relates to mixtures of the peptides of the present invention with other neuropeptides, for example DSIP, its analogs and their pharmaceutically acceptable salts and pharmaceutically acceptable solvents and / or solutions and / or excipients, for example, distilled water, physiological solution, suitable buffers, calcium carbonate / phosphate, various mono- and disaccharides, polysaccharides, fats, etc.
  • the present invention also relates to mixtures with other known neuroprotective agents, such as, for example, piracetam. It can be assumed that the combined use of the peptides of this invention with piracetam will enhance the protective effect of each component separately, as described previously for a mixture of DSIP and piracetam (26).
  • These mixtures can be used in the manufacture of pharmaceutical compositions in the preparation of dosage forms suitable for the treatment and / or prevention of diseases, especially those associated with stress-induced diseases and disorders of the body in humans and animals.
  • compositions of peptides of the KND family specified in the above general formula (I) and other synergistically active components such as protein amino acids (e.g. neurotransmitters glycine, arginine and other amino acids), natural antioxidants, e.g. carnitine, carnosine, homocarnosine or their precursors, for example, acetyl derivatives.
  • protein amino acids e.g. neurotransmitters glycine, arginine and other amino acids
  • natural antioxidants e.g. carnitine, carnosine, homocarnosine or their precursors, for example, acetyl derivatives.
  • the ratio of the main components of the above pharmaceutical compositions by weight is as follows: peptide component: amino acid component: natural antioxidant component 1: (0-250): (0-250).
  • compositions may also include various other neuroprotective metabolically active substances (one or more), such as phospholipids (lecithin), unsaturated fatty acids, choline and its derivatives, trimethyl glycine, vitamin C, vitamin A and / or its precursors, nicotinamide, vitamin E , B vitamins, folic acid, lipoic acid, eicosapentenoic and docosahexaenoic acids, bioflavonoids, coenzyme Q 10, taurine, terpenes, polyphenols, extracts of plant origin (garlic, onion, green tea, gingko beluba, female nya, licorice, ginger, gotu kola, conifers), succinic acid, riboxin, macro and trace elements (magnesium, calcium, potassium, chromium, selenium), etc.
  • phospholipids lecithin
  • unsaturated fatty acids choline and its derivatives
  • trimethyl glycine vitamin C
  • compositions may include other acceptable ingredients commonly used in the preparation of medicaments such as fillers, flavoring and flavoring agents, sweeteners, preservatives, etc.
  • the present compositions are based on natural substances, which can also be included in parapharmaceutical biologically active additives, homeopathic remedies and baby food.
  • a subject of the invention includes a therapeutically effective amount of the peptides of the invention for use in a dose range from a few ⁇ g / kg to 1-10 mg / kg or in homeopathic doses in the case of homeopathic dosage forms.
  • the inventive tool can be administered intranasally in the form of nasal drops, in the form of a spray, nebulized powder, aerosol, sublingually in the form of absorbable tablets, capsules and powders; in the form of various injections (intravenous, intramuscular, subcutaneous and intradermal); intralumbally and intracisternally (intraventricularly), percutaneously using devices for therapeutic electrophoresis; in the form of suppositories, ointments, creams, lotions, and also be included in baby food.
  • the subject of the invention also relates to the use of oligopeptides of the KND family as peptide antigens for the production of specific anti-antibodies for medical purposes, the introduction of which into the body can lead to the same effects as the use of the basic starting substance.
  • the present invention relates to agents that have pharmacological activity and are substances suitable for the treatment and prevention of stress-induced pathological changes. These changes relate mainly to the central nervous system, but are not limited to it. Exogenous and endogenous factors, such as intoxication, trauma, serious illnesses, cause stress and can provoke a violation of the homeostasis of the body as a whole. If the body is not able to cope with these disorders of homeostasis, due to various diseases or chronic disorders, both functional and organic, so-called stress-induced diseases and disorders can develop.
  • the described agent and in particular the preferred formula, as well as its derivatives, analogues and physiologically acceptable salts, is able to prevent the development of deficiency of endogenous regulatory peptides, for example, DSIP and others, which can occur in case of severe or chronic stressful situations.
  • Animal experiments showed a similar focus of DSIP and KND, with KD even superior to DSIP in terms of effectiveness in some respects.
  • 270 Wistar male rats at the age of 3 months were divided into 18 groups and received in each group 5 rats subcutaneously for 2 periods of administration for 4 days for 2 weeks, doses of 100 ⁇ g / kg of peptides of the family, except for two cases (see below) in which peptides of the KND family were administered at higher dosages (250 and 400 ⁇ g / kg); 100 ⁇ g / kg DSIP dissolved in water for injection in a volume of 0.2 ml, or water for injection in a volume of 0.2 ml per rat. The introduction was carried out in the morning.
  • KND-1 a substance with an amino acid sequence
  • KND-2 a substance with an amino acid sequence
  • KND-3 a substance with an amino acid sequence
  • TrpMeLysGlyGlyAsnAlaSerGly Glu
  • KND-4 a substance with an amino acid sequence
  • KND-5 substance with amino acid sequence
  • KND-6 substance with amino acid sequence
  • TrpLysGlyGlyAspAlaSerGly Glu, KND-7 substance with amino acid sequence
  • TrpLysGlyGlyGluAlaSerGly Glu
  • KND-8 substance with amino acid sequence
  • KND-9 substance with amino acid sequence
  • KND-10 substance with amino acid sequence
  • KND-11 a substance with an amino acid sequence
  • KND-12 a substance with an amino acid sequence
  • TrpLysGlyGlyAsnAlaSerGlyGlu in a mixture with the synergistically active amino acid glycine
  • KND-13 a substance with an amino acid sequence
  • TrpLysGlyGlyAsnAlaSerGlyGlu in a mixture with the synergistically active amino acid glycine and the natural antioxidant carnosine in a ratio of 1: 25: 30,
  • TrpLysGlyGlyAsnAlaSerGlyGlu in a mixture with the synergistically active amino acid glycine and the natural antioxidant carnosine in a ratio of 1: 50: 50,
  • KND-15 substance with amino acid sequence
  • TrpLysGlyGlyAsnAlaSerGlyGlu in a mixture with the synergistically active amino acid glycine and the natural antioxidant carnosine in a ratio of 1: 100: 100,
  • KND-16 substance with amino acid sequence
  • TrpLysGlyGlyAsnAlaSerGlyGlu in a mixture with the additional neuroprotective metabolically active component riboxin
  • KND-17 substance with amino acid sequence
  • TrpLysGlyGlyAsnAlaSerGlyGlu administered at a dose of 250 ⁇ g / kg
  • KND-18 a substance with an amino acid sequence
  • TrpLysGlyGlyAsnAlaSerGlyGlu administered at a dose of 400 mcg / kg.
  • Toxicity study The body mass of adult rodents is a common parameter for studying the toxicity of various substances. The increase in body weight between the days of the first and last injections was comparable in all groups (table 1).
  • the test was carried out in a pool of water, the temperature of which was controlled by a thermometer and was 30 ⁇ 1 ° ⁇ throughout the experiment.
  • a weight consisting of metal elements, which was calculated based on the weight of the rat, was always attached to the neck of the rats on a soft, not restricting the animal’s movements and not obstructing the air flow collar, which was always 20% of it, the rat was weighed and the weight of the metal elements were calculated immediately before the animal was immersed in water.
  • the swimming duration was estimated, which was recorded by a stopwatch and measured in seconds. At the end of the swimming time, the moment was taken when the rat stopped swimming, sank to the bottom of the pool and for at least 10 seconds made no further attempts to surface. At this point, the animal was removed from the water for further research.
  • KND-12 Duration of control of the KND-12 DSIP of swimming, with an average of 356.21 344.40 418.04 standard 100.21 132.12 88.86 deviation
  • KND-15 Duration of control KND-15 DSIP of swimming, with an average of 299.12 292.20 319.03 standard 91.31 127.99 77.73 deviation;
  • rats treated with 100 ⁇ g / kg of the drug most often had greater endurance in terms of swimming in water than control animals. This indicates greater physical strength, as well as better stress resistance.
  • the experiment was carried out on white rats of both sexes weighing 150-200 g. Hypokinetic stress was caused by placing rats in special chambers restricting the mobility of animals for a period of 6 hours. 1 hour before the onset of stress, KND was administered in various dosages, either in a mixture with glycine or saline.
  • K D was administered intraperitoneally in a single dose of 60 ⁇ g / kg or 120 ⁇ g / kg 24 hours before and after administration of the cytostatic agent.
  • Cytostatic cisplatin was administered once intravenously in a single dose of 15 mg / kg, causing 50% death of animals. Studies were performed on 50 mice, BDF1 hybrids, and females.
  • the results indicate that the claimed agent can affect the ratio of excitatory and inhibitory neurotransmitters in the body, such as GABA, glutamic acid, aspartic acid and serotonin, and also exhibits antioxidant and antitoxic effects.
  • excitatory and inhibitory neurotransmitters such as GABA, glutamic acid, aspartic acid and serotonin
  • mitochondrial enzymes that control the metabolism of the central nervous system and peripheral nerve tissues, e.g. MAO A, hexokinase, NADP-dependent malate dehydrogenase, creatine kinase, as well as respiratory chain enzymes, hypothalamic glutamine synthetase, SOD, catalase, etc.
  • Means - a family of peptides - is therefore suitable for the treatment of a wide range of stress-related, especially neurological pathological processes. Therefore, CKND can be used for diseases both in the form of monotherapy, and in combination with various medications, herbal preparations, food additives, as well as for the treatment of various manifestations and consequences of impaired homeostasis.
  • neurohumoral and endocrine disorders caused by external and internal disorders.
  • the mechanism of action of the proposed peptides can be described, for example, as stress-protective, adaptogenic, neuroprotective, immunomodulating, geroprotective, antioxidant, anticonvulsant, antitoxic.
  • KND is also obviously suitable for the treatment and prevention of primary drug cravings, withdrawal symptoms, sleep disturbances, encephalopathies, neurosis, autonomic disorders, cognitive impairment, attention deficit disorder, episodes of depression, cardiovascular disease, cerebrovascular disease, autoimmune and endocrinological diseases.
  • the agent may be administered by any of the administration routes.
  • the conviction of the inventors is that the substance, like DSIP, can easily cross the BBB.
  • DSIP Delta sleep inducing peptide
  • Prudchenko I.A. Stashevskaya L.V., Shepel E.N., Mikhaleva I.I., Ivanov V.T., Shmalko Yu.P., Chaly A.P., Umansky V.Yu., Grzhevskaya S .N. Synthesis and biological properties of delta-sleep peptide analogues (DSIP).
  • DSIP delta-sleep peptide analogues
  • Mikhaleva 1. Rikhireva, G. T., Prudchenko, I. A., Golubev, I. N. Interaction of delta sleep-inducing peptide and its analog with cellular membranes: A structure-function analysis. Russian Journal of Bioorganic Chemistry, 32, 160-165 (2006).
  • Prudchenko, I.I. Mikhaleva The endogenous problem of the delta sleep peptide. Advances in Modern Biology Vol. 114, pp. 728-740, (1994).

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Abstract

L'invention concerne le domaine de la médecine, et notamment un médicament pour le traitement et la prophylaxie de maladies et de troubles liés à des états de stress et affectant l'être humain et les animaux, ce médicament correspondant à un nonapeptide KND de la formule suivante : ТrрLуsGIуGlуАsnАlаSеrGlуGlu. Le médicament pour le traitement et la prophylaxie de maladies et de troubles liés à des états de stress et affectant l'être humain et les animaux comprend une famille d'oligopeptides comprenant des analogues et des dérivés du nonapeptide KND. Les méthodes de traitement au moyen des médicaments précités se caractérisent en ce qu'elles utilisent lesdits médicaments en tant que tels ou comme antigènes pour la production d'anticorps et pour leur application en médecine.
PCT/RU2010/000615 2009-10-26 2010-10-18 Médicament pour le traitement de maladies et de troubles liés à des états de stress et affectant l'être humain et les animaux, et méthode de traitement et/ou de prophylaxie utilisant ce médicament WO2011053191A1 (fr)

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RU2009140209/15A RU2450823C2 (ru) 2009-10-26 2009-10-26 Средство для лечения связанных со стрессовыми условиями заболеваний и расстройств у человека и животных, а также способ лечения и/или профилактики с использованием этого средства

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