Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/27—Growth hormone [GH] (Somatotropin)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/30—Insulin-like growth factors (Somatomedins), e.g. IGF-1, IGF-2
• • 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

Definitions

• a present invention relates to medicine, in particular to methods of therapy and/or prophylaxis of multiple sclerosis (MS) by introducing growth hormone (somatotropin) and/or somatomedin C (IGF-1) or their physiological inducers to a subject who needs it.
• MS multiple sclerosis
• Myelin is a multi-layered plasma membrane that forms the myelin sheath around nerve fibers, in particular around oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system, around neuronal axons, which acts as an electrical isolator, which increases the speed of a nerve impulse.
• the destruction of the myelin sheath consisting of lipids for approximately 70% and of proteins for approximately 30%, leads to the occurrence of sclerosis and autoimmune diseases.
• MS Multiple sclerosis
• MS is a chronic autoimmune disease that affects the myelin sheath of nerve fibers due to the immune system attack on the Central nervous system.
• myelin damage lesion formation (demyelination) of the white matter of the brain and spinal cord, the conductivity of signals between nerve cells is disturbed.
• MS is a multifactorial disease, in the pathogenesis of which both external factors, such as viral infections, and internal, namely genetic predisposition, can be involved.
• the etiology of MS is still not clear, which is an obstacle to the development of etiotropic treatment.
• Clinical manifestations of MS are evaluated using the subject’s condition scales, assessing the severity of symptoms of lesions of brain various conductive systems and the degree of disability, such as the functional systems state (FSS) scale and the expanded disability status scale (EDSS) (Kurtzke JF (1983). "Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS)". Neurology 33 (11): 1444-1452; Collins et al. A comparative analysis of Patient-Reported Expanded Disability Status Scale tools. Mult Scler. 2016 Sep; 22(10): 1349–1358).
• FSS functional systems state
• EDSS expanded disability status scale
• RS remittent-relapsing
• SPMS secondary progressive
• PPMS primary progressive
• PRMS progressive recurrent
• Symptoms of MS are diverse and manifest during periods of relapse with a gradual progressive depletion of neurological functions. Symptoms can be expressed by muscle weakness, a violation of the coherence of muscle movements (ataxia) of the body and limbs, paresis, tremor, and abnormality of vision functions. Often, a decrease in sensitivity is observed, including without clear localization, dysfunction of the pelvic organs, decreased intelligence, depression, and behavioral disorders. The first clinical symptoms of multiple sclerosis usually appear in patients between the ages of 18 and 45, although the debut of MS is described for both children and the elderly.
• WO 2010/128035 discloses the use of GM-CSF (granulocyte macrophage colony-stimulating factor) antibody or its receptor in the treatment or prophylaxis of multiple sclerosis.
• GM-CSF granulocyte macrophage colony-stimulating factor
• the introduction of antibodies to GM-CSF to the patient leads to a decrease in the proliferation of T-cells, the release of IL-17 (interleukin-17) from them.
• WO 2010/147665 discloses a method of reducing the frequency of relapses and reducing the development of physical disability in remittent-relapsing MS (RRMS) by daily oral administration of 0.6 mg of laquinimod, which is a derivative of phenylquinolone.
• WO 2017165367 describes a method for inducing remyelination for the treatment of RRMS using a composition containing siRNA (small interfering RNA) that inhibits the activity, synthesis or expression of a protein associated with low density lipoprotein 1 (LRP1).
• siRNA small interfering RNA
• Betaferon from Bayer Pharma AG for the treatment of multiple sclerosis is known containing recombinant human interferon- ⁇ -1b.
• a fairly low efficiency of its use is the disadvantage of this drug – only 30% decrease in the frequency of exacerbations of the disease and their severity is observed, as well as the presence of such side effects as the increase of depressive symptomatology (Sokolova E. S., Totolyan N. A., Klimenko V. M. Psycho-emotional changes in patients with multiple sclerosis after the treatment by Betaferon // "Stress and behavior", VII Interdisciplinary conference on biological psychiatry, Novosibirsk, 2003).
• Copaxone immunomodulatory drug from Teva is known containing glatiramer acetate as the active substance, which is a polymer of four sinistrorotatory isomers of acetates of synthetic polypeptides glutamine, lysine, alanine and tyrosine. Copaxon does not show advantages in the treatment of primary progressive and secondary progressive multiple sclerosis.
• the author of a present invention has unexpectedly discovered that active substances such as somatotropin and immunoglobulin growth factor 1 (IGF-1, also referred to as somatomedin C) can be used to effectively treat multiple sclerosis, and in quantities that exceed the amount of these substances that were considered acceptable for administration to patients.
• IGF-1 immunoglobulin growth factor 1
• the author has found that the task of the invention is solved in the same way when using physiological inducers of somatotropin and/or IGF-1.
• the relief of symptoms, reducing the frequency of recurrence and stimulation of regeneration of neuronal myelin membranes is understood here as the treatment of multiple sclerosis, i.e., all that has beneficial effects on the course of the disease in a subject.
• the present invention makes it possible to carry out the treatment of multiple sclerosis effectively, but at the same time providing the necessary safety in terms of the occurrence and/or severity of side effects.
• Somatotropin also called somatotropic hormone or growth hormone
• Somatotropin is a pituitary growth hormone with a molecular weight of about 22 kDa and 191 amino acid residues. Somatotropin is necessary for postnatal growth and for the normalization of carbohydrate, lipid, nitrogen and mineral metabolism.
• somatotropin secretion of somatotropin is affected by a number of substances, including protein food, some amino acids, such as arginine, lysine, ornithine and glutamine, clofelin, moxonidine, baclofen, estrogens, dopamine, intestinal hormones, such as releasing growth hormone peptides (GHRP) and ghrelin, serotonin, amphetamine, propranolol, glucagon, thyroid hormones, vasopressin and others.
• GHRP growth hormone peptides
• IGF-1 a protein similar to insulin.
• IGF-1 consists of 70 amino acid residues, has a molecular mass of 7.6 kDa and enters the blood mainly from the liver, and its secretion is stimulated by somatotropin. It is known that IGF-1 has a direct regulating effect on hematopoiesis, especially lymphopoiesis and the functioning of the immune system (Clark P., 1997), stimulates the differentiation and transition of pro-B-to pre-B cells (Landgreth K.
• IGF-1 secretion is affected by substances such as glutamine, arginine, angiotensin-II, baclofen, ghrelin, thyroid hormones, somatotropin, sterilglucosides (SG), such as acylated steril- ⁇ -glucosides (ASG) and others.
• substances such as glutamine, arginine, angiotensin-II, baclofen, ghrelin, thyroid hormones, somatotropin, sterilglucosides (SG), such as acylated steril- ⁇ -glucosides (ASG) and others.
• a method of treating multiple sclerosis comprising administering of somatotropin to a subject who needs it in a therapeutically effective amount.
• a method for treating multiple sclerosis including the introduction of insulin-like growth factor 1 (IGF-1) in a therapeutically effective amount to a subject who needs it.
• IGF-1 insulin-like growth factor 1
• a method of treating multiple sclerosis comprising administering a physiological inducer of somatotropin and/or of IGF-1 in therapeutically effective amount to a subject who needs it.
• the invention encompasses the use of somatotropin as a medication for treating multiple sclerosis in a subject, the use of IGF-1 as a medication for treating multiple sclerosis in a subject, and finally the use of a physiological inducer of somatotropin and/or IGF-1 as a medication for the treatment of multiple sclerosis in a subject.
• the invention relates to the use of somatotropin and/or IGF-1 and/or their physiological inducers for the manufacture of a medication for the treatment and/or prophylaxis of multiple sclerosis or its selected symptoms.
• the applied amount of somatotropin according to the invention may be, for example, from 0.05 to 0.5 IU/kg of the body weight of a subject.
• the applied amount of IGF-1 according to the invention may be, for example, from 50 to 500 ⁇ g/kg of the body weight of a subject.
• the preferred regimen of administration of somatotropin, IGF-1, as well as their physiological inducers may be one or two times a day for 10-60 days. It should be noted that, depending on the therapeutic advisability, other doses and regimen of administration can be chosen.
• the active substances according to the invention are administered, as a rule, in the form of a pharmaceutical composition having a dosage form suitable for the desired administration.
• the methods and active substances of the invention can be used in combination to treat the same subject, for example, somatotropin, IGF-1, and one or more of their physiological inducers can be administered to the subject in any combination as one combined composition or in several compositions separately.
• the introduction of somatotropin, IGF-1 or their physiological inducers may be accompanied by the additional introduction of interferon- ⁇ -1b, in particular recombinant human interferon- ⁇ -1b.
• recombinant human interferon- ⁇ -1b is administered in amounts of from 33 to 330 mg/kg of the body weight of a subject; the regimen of administration may correspond with the regimen of introduction of somatotropin, IGF-1 and their physiological inducers, preferably once or twice a day for 10-60 days.
• inducer refers to a molecule that stimulates the expression of genes that are in an inactive state. Inducers can also function by binding to activators. In the absence of an inducer, activators, as a rule, weakly bind to DNA, whereas during the formation of the complex of activator and inducer, the activity of the latter increases many times, after which such complex binds to the activated sequence and triggers the transcription of the target gene.
• GHRP growth hormone
• SG sterilglucosides
• ASG acylated steril- ⁇ -glucosides
• peptide refers to a polymer of amino acids, regardless of the length of the polymer; thus, protein fragments, oligopeptides and proteins are included in the definition of a peptide or polypeptide.
• This term also does not define or does not exclude post-expression modifications of polypeptides, for example, polypeptides, which include the covalent attachment of glycosyl groups, acetyl groups, phosphate groups, lipid groups and the like are uniquely covered by the term “polypeptide”.
• This definition also includes polypeptides that contain one or more amino acid analogs (including, for example, non-naturally occurring amino acids, amino acids that are found in nature only outside an unrelated biological system, modified amino acids from mammalian systems, etc.), polypeptides with substituted bonds, as well as other modifications known in this field, both natural and non-natural.
• amino acid analogs including, for example, non-naturally occurring amino acids, amino acids that are found in nature only outside an unrelated biological system, modified amino acids from mammalian systems, etc.
• treatment refers to therapeutic treatment, prophylactic or preventative measures for research and diagnostic applications.
• treatment refers to reversion, alleviating, inhibiting the progression or preventing a disorder or a state in relation to which the term is used, or one or more symptoms of such a disorder or a state.
• the term covers a full range of therapies for the specific state from which a subject suffers, e.g., the introduction of active substance or composition containing it, to alleviate or relieve symptoms or complications; the delay of the state progression, partial relief of disease or disorder clinical implications; cure or elimination of a state, disease or disorder and/or prevention or reduction of the risk of developing a state, disease or disorder.
• prevention or “prophylaxis” mean a system of measures and patient care to prevent the development of a state, disease or disorder and imply the administration of active compounds to prevent or reduce the risk of the appearance of symptoms or complications.
• administration when applied to biological objects, such as an animal, human, experimental subject, cell, tissue, organ or biological fluid, refers to bringing into contact an exogenous pharmaceutical, therapeutic agent, diagnostic agent or composition with a biological object, including an animal, a human, a subject, a cell, a tissue, an organ or a biological fluid.
• administration may refer, for example, to therapeutic, pharmacokinetic, diagnostic, research and experimental methods.
• Treatment of cells involves bringing the reagent into contact with the cell, as well as bringing the reagent into contact with the fluid medium where the fluid medium is in contact with the cell.
• administration also means methods of cells treatment in vitro and ex vivo, for example, by reagent, diagnostic means, binding compound or other cell.
• autoimmune disease is understood in its usual meaning, and refers to a disease developed as a result of an immune response against one's own tissues or tissue components, including both humoral immune response and cell-mediated responses.
• subject refers to any mammal, including rodents, such as a mouse or rat, guinea pigs and primates, such as the Javanese macaque (Masas fascicularis), the rhesus monkey (Masas mulatta) or humans (Homo sapiens).
• rodents such as a mouse or rat
• guinea pigs and primates such as the Javanese macaque (Masas fascicularis), the rhesus monkey (Masas mulatta) or humans (Homo sapiens).
• rodents such as a mouse or rat
• guinea pigs and primates such as the Javanese macaque (Masas fascicularis), the rhesus monkey (Masas mulatta) or humans (Homo sapiens).
• a subject is a primate, most preferably a human.
• terapéuticaally effective dose or “therapeutically effective amount” or “pharmaceutically effective dose” or “pharmaceutically effective amount” means the dose that has the effects for which it is administered.
• a therapeutic agent is administered in an amount effective to alleviate one or more disease or state of a patient or population to be treated, either by inducing regressions of these diseases or states, or by inhibiting the progression of such diseases or states in any clinically measurable degree.
• composition refers to a mixture containing one or more active substances in accordance with the present invention together with other components, in particular physiologically/pharmaceutically acceptable excipients.
• the pharmaceutical composition should have a compound optimized for the desired route of administration of the active ingredient into the body and, ultimately, demonstration of the biological action.
• “Pharmaceutical” or “pharmaceutically acceptable” refers to chemical compounds and compositions that do not lead to nect side, allergic or other adverse reaction when administered to a mammal, in particular a human, or such reactions are minimized.
• a pharmaceutically acceptable excipient is a non-toxic solid, soft or liquid filler, diluent, capsule material or other additive substance of any type.
• pharmaceutically acceptable salt refers to the salt formed by the compounds used in the present invention, and an acid or base, which is suitable for inclusion in the composition of the drug.
• Pharmaceutically acceptable salts include inorganic and organic salts.
• the preferred types of salts are salts formed by the compounds according to the present invention and an acid.
• Suitable salt-forming acids include: inorganic acids, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and the like, but are not limited to.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, ni
• salts formed by the compounds of the present invention and bases for example, alkali metal salts (for example, sodium or potassium salts), alkaline earth metal salts (for example, calcium or magnesium salts), ammonium salts (for example, ammonium salts lower alkanols or other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylene diamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts and amine salts formed with morpholine, piperazine and lysine.
• alkali metal salts for example, sodium or potassium salts
• alkaline earth metal salts for example, calcium or magnesium salts
• ammonium salts for example, ammonium salts lower alkanols or other pharmaceutically
• “Pharmaceutically acceptable carrier” means one or more compatible solid, semi-solid or liquid excipients that are suitable for administration to a subject and must have sufficient purity and sufficiently low toxicity. "Compatibility” in this document means that the components of the composition can be mixed with compounds according to the invention or with each other, and they will not significantly reduce the effectiveness of compounds.
• Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), a humectant (such as sodium dodecyl sulfate), dyes and flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
• cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
• gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose
• prodrug refers to peptides that are rapidly transformed in vivo to form the basic compound of the above formulas, for example, by hydrolysis in the blood or by metabolism in cells, such as, for example, cells of the basal ganglia.
• prodrugs include pharmaceutically acceptable nontoxic esters of compounds of the present invention.
• Compound esters of the present invention can be obtained by usual methods: «March's Advanced Organic Chemistry, 5th Edition» M. B. Smith & J. March, John Wiley & Sons, 2001.
• Somatotropin, IGF-1 or their inducers are administered usually in the form of a pharmaceutical composition.
• the invention also relates to a pharmaceutical composition for the treatment and/or prophylaxis of multiple sclerosis, containing somatotropin.
• the invention relates to a pharmaceutical composition for the treatment and /or prophylaxis of multiple sclerosis containing IGF-1.
• the invention also relates to a composition comprising one or more physiological inducers of somatotropin and/or IGF-1.
• Pharmaceutical compositions or substances according to the invention may contain pharmaceutically acceptable excipients, including carriers, diluents, adjuvants, etc. Examples of excipients are well known in the art and, for example, are described in Remington: The Science procurement Practice of Pharmacy, 20th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 2000.
• compositions of the invention can be produced in various ways, in accordance with techniques well known to a person skilled in the art, for example, from Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins; Twenty first Edition, 2005), WO 1993025222, WO 1990011070, EU 1991462959.
• Pharmaceutically acceptable excipients that can be used are, in particular, described in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association (Pharmaceutical Press; 6th revised edition, 2009).
• the pharmaceutical composition of the invention contains somatotropin and/or IGF-1 and/or one or more physiological inducers of somatotropin and/or IGF-1 in an amount effective to provide therapy of multiple sclerosis (MS), in particular, to reduce and/or slow down the rate of disability in MS.
• the composition according to the invention further comprises a recombinant human interferon- ⁇ -1b in a therapeutically effective amount.
• composition according to the invention can be carried out in various ways, including, without limitation, the oral, subcutaneous, intravenous, parenteral, intranasal, intraortical, intraocular, rectal, vaginal, transdermal, intraperitoneal, intramuscular, intrapulmonary, or intrathecal route of administration.
• composition according to the invention can be administered in parallel with other therapeutic agents, i.e., therapeutic agents described herein can be administered in parallel, simultaneously or sequentially with other pharmacotherapeutic agents or in the setting of other therapeutic effects on the body, such as radiation therapy, physiotherapy, surgery, etc.
• Any of the active substances included in the compositions according to the invention can be administered indirectly by introducing exogenous nucleic acid, for example DNA or RNA encoding the corresponding active substance, which results in the introduced nucleic acid expression.
• compositions of the invention are given a drug form suitable for the desired route of administration.
• the composition of the invention is in a solid form, including capsules, tablets, pills, powders, and granules.
• the active compounds are mixed with at least one conventional inert excipient, for example, with any of the following components: (a) a filler or agent that improves compatibility, such as starch, lactose, sucrose, glucose, mannitol or salicylic acid: (b) binders, for example hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) a humectant, such as glycerin; (d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain mixed silicates and sodium carbonate; (e) dissolution retardants, such as paraffin; (e) absorption accelerators, for example, quaternary ammonium compounds; (g) plasticizers, such as cetyl alcohol
• Solid dosage forms such as tablets, capsules, pills and granules may contain coatings and shells such as intestinal-soluble coatings and any other materials known in the field. They can contain an opaque agent. The release of active compounds or compounds from compositions may be delayed in a certain part of the digestive tract. Examples of encapsulants include polymers and waxes. If necessary, the active compounds and one or more of the above excipients can form microcapsules.
• a solid pharmaceutical composition according to the invention can be made in the form of a lyophilizate suitable for obtaining a liquid preparation for injection (intramuscular, subcutaneous, etc.) or oral administration.
• Liquid dosage forms may, for example, be a solution or suspension of one or more of these compounds and optionally be the pharmaceutical adjuvants in a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like.
• a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like.
• the pharmaceutical composition for administration may also contain other non-toxic excipients such as wetting or emulsifying agents, pH buffering agents, etc. Typical examples of such excipients are sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, etc.
• solutions of peptides according to the present invention are used in a sterile aqueous solution, in aqueous propylene glycol or in sesame or peanut oil.
• Aqueous solutions should be suitably buffered when appropriate, and the liquid diluent must be made isotonic, for example, using an appropriate saline solution or glucose.
• Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All used sterile water mediums can be easily obtained by standard methods known to experts in the field.
• Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
• solid carriers are lactose, magnesia, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
• liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene, and water.
• the carrier or diluent may include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with wax.
• the pharmaceutical compositions obtained by combining the compounds used in the present invention and pharmaceutically acceptable carriers can then be easily administered in various dosage forms suitable for the described routes of administration. Preparations may, for convenience, be provided in a standard dosage form using methods known in the pharmaceutical field.
• the active substances of the invention formulated into a pharmaceutical composition can be enclosed in microcapsules, for example, from the poly(lactic-co-glycolic acid) (PLGA), as well as in liposomes or virus-like particles, etc.
• PLGA poly(lactic-co-glycolic acid)
• Somatotropin for use in the invention can be obtained by any known method; may be of natural or synthetic origin. The most convenient way is the use of recombinant somatotropin (rhGH), methods for producing which are well known, for example from US 8178108.
• rhGH recombinant somatotropin
• Somatotropin can be presented in any modification, in which the activity of the hormone is preserved and at the same time the preferential properties are given.
• somatotropin can be in the form of complexes, in particular, in a complex with zinc.
• Another modification includes somatotropin conjugates with polymers, such as with polyethylene glycol.
• hybrid somatotropin containing additional domains can be used, for example, facilitating the delivery of protein to the target, for example, somatotropin-transferrin fusion protein.
• various somatotropin isoforms may be used. In the present description and in the claims, all of these options are covered by the term "somatotropin", "growth hormone", etc..
• IGF-1 can also be a protein of natural or synthetic origin, for example, recombinant IGF-1, the production method of which is known, for example, from US5262308.
• IGF-1 can be a complex, conjugate, hybrid, isomorph, in which case the activity is preserved and additional preferential properties appear. In this description and in the claims of the invention, all these options are covered by the term "IGF-1", "somatomedin C", etc.
• Physiological inducers of somatotropin and/or IGF-1 can be obtained by known methods, chemical or microbiological, and equally can be obtained from natural sources, which also applies to amino acids, in particular lysine, arginine and glutamine, acylated steril- ⁇ -glucosides and other inducers.
• the present invention relates to a method of treating, preventing and/or prophylaxis of multiple sclerosis and/or one or more of its symptoms, which comprises administering to a subject an active substance that is somatotropin and/or insulin-like growth factor 1 (IGF-1) and/or their physiological inducers selected from the group consisting of arginine, lysine, glutamine and an acylated steril- ⁇ -glucoside, or a composition containing the specified active substance, in a therapeutically effective amount.
• IGF-1 insulin-like growth factor 1
• a composition comprising one or more active substances according to the invention is administered to the subject.
• several compositions are administered to the subject comprising the selected active substances of the invention. However, they can be introduced simultaneously, sequentially or separately.
• Treatment of a subject suffering from multiple sclerosis is not necessarily limited to the administration of the active substances or compositions of the invention; any other therapeutic treatment known to specialists can be used, including other active substances, in particular interferon- ⁇ -1b.
• This substance may be included in the compositions described above or administered separately, in particular as part of another pharmaceutical composition, simultaneously, sequentially or separately in relation to the active substances or compositions according to the invention.
• the amount of active substances administered by the invention is determined, as a rule, according to the body weight of a subject.
• Somatotropin is preferably used in an amount of from about 100 to 600 ⁇ g/kg of the body weight of a subject.
• this amount may be from 100, 125, 150, 175, 200, 225, 250, 275 or 300 ⁇ g/kg of the body weight of a subject and up to 600, 575, 550, 500, 475, 450, 425, 400, 375, 350 or 325 ⁇ g/kg of the body weight of a subject.
• the amount of somatotropin can be expressed in international units and range from 0.05 to 0.5 IU/kg of the body weight of a subject.
• this amount may be between 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 or 0.2 IU/kg of the body weight of a subject; and up to 0.49, 0.48, 0.47, 0.46, 0.45, 0.44, 0.43, 0.42, 0.41, 0.4, 0.39, 0.38, 0.37, 0.36, 0.35, 0.34, 0.33, 0.32, 0.31 or 0.3 IU/kg of the body weight of a subject, including, in particular, the mentioned values.
• IGF-1 is preferably used in an amount of from 50 to 500 ⁇ g/kg of the body weight of a subject.
• this amount may be between 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160 , 165, 170, 175, 180, 185, 190, 195 or 200 ⁇ g/kg of the body weight of a subject; and up to 495, 490, 485, 480, 475, 470, 465, 460, 455, 450, 445, 440, 435, 430, 425, 420, 415, 410, 405, 400, 395, 390, 385, 380, 375, 370, 365, 360, 355, 350, 345, 340, 335, 330, 325, 320, 315, 310, 305 or 300 ⁇ g/kg of a subject’s body weight, including, in particular, the
• Physiological inducers are preferably used in an amount of from 1 ng/kg to 50 g/kg of the subject's body weight, depending on the type of inducer used. For example, this number can range from 1, 5, 10, 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 , 950 or 1000 ng/kg of the subject's body weight and up to 10000, 9000, 8000, 7000, 6000, 5000, 4000, 3000 or 2000 ng/kg of the subject's body weight, including, in particular, the mentioned values.
• the number of a physiological inducer can range from 1, 5, 10, 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 ⁇ g/kg of the body weight of a subject and up to 10000, 9000, 8000, 7000, 6000, 5000, 4000, 3000 or 2000 ⁇ g/kg of the body weight of a subject, including, in particular, the mentioned values.
• the number can range from 1, 5, 10, 20, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg/kg of the body weight of a subject and up to 10000, 9000, 8000, 7000, 6000, 5000, 4000, 3000 or 2000 mg/kg of the body weight of a subject.
• the number can be from 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4 or 2.5 g/kg of the body weight of a subject, and up to 5, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1 or 3.0 g/kg of the subject's body weight, including, in particular, the mentioned values.
• the number can range from 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 or 40 and up to 50, 40, 30, 25, 20, 15, 10, 9, 8, 7 or 6 g/kg of the body weight of a subject, including, in particular, the mentioned values.
• the amount can be expressed in international units and range from 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 25 IU/kg of subject’s body weight to 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3 or 2 IU/kg of the body weight of a subject.
• arginine is administered in an amount of from 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250, 300, 350, 400 or 450 mg/kg of the body weight of a subject and up to 500, 450, 400, 350, 300, 250, 200, 175, 150, 125, 100, 90, 80, 70 or 60 mg/kg of the body weight of a subject, including, in particular, the mentioned values.
• arginine is administered in an amount of from 5, 6, 7, 8, 9, 10, 15, 20, 25, 30 or 40 to 50, 40, 30, 25, 20, 15, 10, 9, 8, 7 or 6 g/kg of the body weight of a subject, including, in particular, the mentioned values.
• glutamine or lysine is administered in an amount of from 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 250 or 300 mg/kg of the body weight of a subject and up to 350, 300, 250, 200, 175, 150, 125, 100, 90, 80, 70 or 60 mg/kg of the body weight of a subject, including, in particular, the mentioned values.
• acylated steril- ⁇ -glucoside is administered in an amount of from 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, or 1.5 mg/kg of the body weight of a subject, and up to 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2 or 0.1 mg/kg of the body weight of a subject, including, in particular, the mentioned values.
• the frequency of administration can be both reduced and increased.
• the frequency of administration can be reduced to 1 time in 2 days, 1 time in 3 days, 1 time in 4 days, 1 time in 5 days, 1 time in 6 days or 1 time in a week.
• the frequency can be increased to more than twice a day, for example 3, 4 or 5 times a day.
• the duration of administration of the active substances or compositions according to the invention is preferably from 10 to 60 days, for example from 10, 14, 21, 28 days and/or up to 56, 49, 42, 35, 30 days. Of course, depending on the severity of the therapeutic effect and possible side effects, the duration of treatment can be either reduced or increased relative to the mentioned values.
• the treatment may include several courses of administration of the active substances or compositions according to the invention or their essentially permanent administration.
• the exact dosage will depend on the purpose of the treatment and should be determined by the attending doctor with the help of well-known recommendations.
• the amount of therapeutic agent that is effective in alleviating a particular disease or condition may change according to several factors, such as the status of the disease, the age and weight of the patient, and others.
• the dosage may, if necessary, be corrected directly during treatment, depending on the severity of the therapeutic effect and side effects.
• the amount of somatotropin and/or IGF-1, and/or their physiological inducers in the compositions for use according to the invention can vary widely depending on the desired dosage form.
• the content of active substances in the compositions of the invention can be selected based on the approximate doses specified above, so that the finished dosage form ensures the easiest adherence of the patient to the prescribed treatment regimen.
• EAE Experimental allergic encephalomyelitis
• an encephalitogenic emulsion is obtained (homogenate of homologous brain of animals in a complete Freund's adjuvant), which is injected into the pads of hind paws of Guinea pigs (Abdurasulova I.N., Serdyuk S. ⁇ ., Gmiro V.E. 2007. // Neuroimmunology. V, N 1. P.4-10).
• the neurological status of the animals was evaluated daily. The time of the disease onset, the severity of neurological disorders, which was scored according to the clinical index, and lethal cases were recorded.
• the clinical index was determined by the intensity and prevalence of neurological manifestations: muscular weakness of one limb – 0.5 point, paresis - 1 point, paralysis – 1.5. If several limbs were affected, points were summed up. If there were additional symptoms (paresis of the sphincters), one point was added for every symptom. The absence of visible disorders was taken as 0 points, in the case of death – 6 points.
• somatotropin Four IU of somatotropin were administered to 16 subjects with an average weight of 70 kg, suffering from multiple sclerosis. The composition was administered daily in the morning 1 hour before meals. Before treatment and throughout the study period subjects were surveyed, assessing subjective symptoms on a 10-point scale, when a score of 10 is corresponding to the strongest symptom manifestation, and a score of 1 – the least weak symptom manifestation.
• somatotropin As can be seen from the results of the study, the introduction of somatotropin at a dose of approximately 0.05 IU/kg/day significantly reduced the degree of disease symptoms manifestations, starting from the first week of treatment; by the end of the fifth week of treatment, manifestations of dizziness, irritability, depression, numbness of the limbs were reduced to a minimum, the symptoms associated with fatigue and walking were significantly reduced.

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