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    • 专利摘要:
    Treatment of neurodegenerative diseases. Use of a composition comprising an aminosalicylate in the preparation of a medicament for the alleviation, improvement, prevention and/or treatment of diseases or disorders related to an aggregating protein, and specifically of parkinson's disease. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2650175A1
    申请号:ES201630475
    申请日:2016-04-15
    公开日:2018-01-17
    发明作者:Francisco ESCAMILLA SEVILLA
    申请人:Servicio Andaluz de Salud；
    IPC主号:
    专利说明:

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    DESCRIPTION
    Treatment of neurodegenerative diseases
    FIELD OF THE INVENTION
    The present invention is within the field of medicine and pharmacy, and refers to the use of aminosalicylates in the preparation of a medicament for the relief, improvement, prevention and / or treatment of diseases or disorders related to an aggregating protein, and specifically for the treatment of neurodegenerative diseases, more specifically those diseases related to synucleoinopathies with enteric onset Lewy bodies, and even more specifically Parkinson's disease. Preferably, the aminosalicylates used are: 5-ASA (salicylic acid), in combination with sulfapyridine or sulfasalazine, mesalazine, olsalazine and balsalazine.
    BACKGROUND OF THE INVENTION
    Parkinson's disease (PD) is currently conceived as a multisystemic process with early involvement of the peripheral autonomic nervous system and subsequent spread to the central nervous system (Goedert et al., 2012. Nature Publishing Group; 9: 13-24.1,2; Braak et al., 2003. NBA; 24: 197-211). After the description of deposits of alfasinuclein aggregates forming neurites or Lewy bodies in gastric myenteric and submucosal plexuses (Braak et al., 2003. J Neural Transm .; 110: 517-36), different clinical studies (Cersosimo et al., 2013. J. Neurol; 260: 1332-8; Abbott et al., 2001. Neurology; 57: 456-62) and experimental (Pan-Montojo et al. 2010. PLoS ONE; 5: e8762; Pan-Montojo et al. 2012. Sci. Rep. 2. DOI: 10.1038 / srep00898; Kelly et al., 2013. Movement Disorders; 29: 999-1009; Holmqvist et al., 2014. Acta Neuropathol 128: 805-20) consider the nervous system Enteric key in the pathogenesis of PD. Braak's hypothesis known as "dual hit" has been endorsed by works in which it is verified how alfasinuclein aggregates are propagated through a mechanism of transynaptic and axonal centripetal migration from neurons of the digestive system to brain stem structures such as the nucleus dorsal vagus (stage 2 of Braak; Pan-Montojo et al. 2010. PLoS ONE; 5: e8762; Pan-Montojo et al. 2012. Sci. Rep. 2. DOI: 10.1038 / srep00898; Kelly et al., 2013 Mov. Disord .; 29: 999-1009; Holmqvist et al., 2014. Acta Neuropathol 128: 805-20).
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    Numerous digestive symptoms, especially constipation, appear many years before the development of PD (prodromal or premotor stage of the disease; Cersosimo et al., 2013. J. Neurol; 260: 1332-8; Pont-Sunyer et al. 2015. The ONSET PDStudy. Mov Disord; 30 (2): 229-37.) On the other hand, recent studies find deposits of alfasinuclein aggregates at the intestinal level (Hilton et al., 2013. Acta Neuropathol. 127: 235-41) or in abdominal-pelvic plexuses (Mínguez-Castellanos et al., 2007. Neurology; 68: 2012-8) years before the onset of motor symptoms or as an expression of a condition of incidental Lewy bodies. However, such deposits could be found in the digestive tract in a high percentage of the general population at certain ages (Visanji et al., 2015. Neurology, 84: 609-16), in all its layers and especially in structures such as the appendix vermiform (Gray et al., 2013. Mov. Disord .; 29: 991-8). Certain authors find an increasing gradient of the cranio-cranial nerve in the distribution of phosphorylated alpha-synuclein deposits in the digestive tract of patients with PD (Beach et al., 2010. Acta Neuropathol; 119: 689-702; Pouclet et al., 2012
    Neurogastroenterol Motil 24: e202-5) and incidental Lewy bodies (Pouclet et al., 2012. Neurogastroenterol Motil 24: e202-5), without it being clear whether this distribution is related to distal axonopathy or hypothetical enteric neuronal loss , at the moment controversial.
    With regard to the etiologic agent, the possibility that it is related to the intestinal flora and certain bacteria whose toxins would generate an increase in intestinal permeability with bacterial translocation and inflammation, as well as accumulation of alpha-synuclein at the enteric level, has been considered, as it has recently been published (Kelly et al., 2013. Mov Disord; 29: 999-1009; Forsyth et al. 2011. PLoS ONE; 6: e28032-10). In fact, recent work relates certain types of intestinal flora with PD and its phenotype (Scheperjans et al. 2015. Mov Disord; 30: 350-8), and it has even been suggested that a type of “anti-inflammatory” flora is the “Responsible” for the protective role of tobacco and coffee in PD (Derkinderen et al. 2014. Mov Disord; 29: 976-9).
    In addition to the aforementioned, there are numerous questions still to be clarified about what happens at an enteric level in early phases of synucleinopathies with Lewy bodies: type and degree of inflammation (Forsyth et al. 2011. PLoS ONE; 6: e28032-10 ; Devos et al., 2013. Neurobiology of Disease; 50: 42-8), role of glial cells (Clairembault et al., 2015 Mov Disord; 30: 494-8), whether or not there is neuronal loss (Pouclet et al., 2012. Neurogastroenterol Motil 24: e202-5; Annerino et al., 2012. Acta Neuropathol; 124: 665-80), which neurons are most vulnerable, if at certain ages the accumulations of enteric alfasinuclein is present in almost all the population (Visanji et al., 2015. Neurology;
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    84: 609-16; Gray et al., 2013. Mov. Disord 29: 991-8), why in some subjects it does not spread to the central nervous system or what are the mechanisms of compensation or inhibition of such spread.
    Recently a genetic relationship has been found between PD and Crohn's disease (CD) (Nalls et al. 2014. Hum. Mol. Genet .; 23: 831-41; Bialecka et al., 2007. Neurosci. Res. ; 57: 473-6), and it is striking that, as in PD, tobacco acts as a protective factor in ulcerative colitis (UC), although it may aggravate CD, the first circumstance that has also been related to the type of intestinal flora. More solidly than in PD, in inflammatory bowel diseases (IBD) there is multiple evidence of the role of certain bacteria and how they act as triggers of the inflammatory bowel response in predisposed subjects, in which inhibition mechanisms fail of said inflammation and therefore, the phenomenon of “tolerance” characteristic of a healthy intestine (Dalal et al., 2014. J. Clin. Invest. 124: 4190-6; West et al., 2015. J Allergy Clin Immunol; 135: 3-13-quiz14; Sheehan et al., 2015. J. Gastroenterol. 1-13; Ananthakrishnan et al., 2015. Dig. Dis. Sci. 60: 290-8).
    In summary, the neuropathic process that culminates with PD begins largely in the enteric nervous system according to the “dual hit” hypothesis. Intestinal inflammation and / or changes in bacterial flora could modify the risk of aggregation and / or spread of alfasinuclein.
    BRIEF DESCRIPTION OF THE INVENTION
    A first aspect of the invention relates to the use of a composition comprising or consisting of at least one aminosalicylate as an active ingredient, hereinafter referred to as the composition of the invention, in the preparation of a medicament for the relief, improvement, prevention and / or treatment of diseases or disorders related to an aggregating protein. Alternatively it refers to a composition comprising or consisting of at least one aminosalicylate as an active ingredient, hereinafter composition of the invention, for use in the relief, improvement, prevention and / or treatment of diseases or disorders related to a protein aggregator
    In a preferred embodiment of this aspect of the invention, the aminosalicylate is selected from the list consisting of: mesalazine (5-aminosalicylate), sulfasalazine, olsalazine, balsalazide, ipsalazide and bensalazide or any of its salts, esters, tautomers, solvates and hydrates Pharmaceutically acceptable, or any combination thereof.
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    More preferably, the use of the composition of the invention is preventive, that is, administration is performed before the diagnosis of the disease, or in the early stages.
    In another preferred embodiment of this aspect, the aminosalicylate is 5-ASA, of formula (I):
    image 1
    or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof.
    In another preferred embodiment of this aspect, the aminosalicylate is sulfasalazine, of formula (II):
    image2
    or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof.
    In another preferred embodiment of this aspect of the invention, the composition of the invention further comprises a pharmaceutically acceptable carrier or excipient.
    In another preferred embodiment of this aspect of the invention, the composition comprises an adjuvant.
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    In another preferred embodiment of this aspect of the invention, the composition further comprises another active ingredient.
    In another preferred embodiment of this aspect of the invention, the aggregator protein is selected from the list consisting of a-synuclein, huntingtin, beta-amyloid peptide, TDP-43, FUS, tau, Prion Protein, Fibronectin and SOD1, or any of their combinations.
    In another preferred embodiment of this aspect of the invention, the aggregating protein is α-synuclein, preferably intestinal phosphorylated α-synuclein.
    In another preferred embodiment of this aspect of the invention, the disease or disorder related to a-synuclein or a-synucleinopathy is selected from the list consisting of: Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, multisystem atrophy, Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis, frontotemporal dementia, Gaucher's disease, Huntington's disease, Type II diabetes. prion disease, Creutzfeldt Jakob disease, multiple sclerosis, Gerstmann-Straussler-Scheinker syndrome, Kuru, fatal familial insomnia, cerebrovascular amyloidosis, glaucoma, age-related macular degeneration, neurodegeneration due to protein aggregation related to age, psychiatric syndromes, schizophrenia and / or disorders similar to schizophrenia, or any combination thereof.
    In another preferred embodiment of this aspect of the invention, the disease or disorder is Parkinson's disease or any synucleinopathy with Lewy bodies.
    A second aspect of the invention relates to a combined preparation, hereafter combined preparation of the invention, comprising:
    a) a compound as described in the first aspect of the invention,
    b) a compound that is selected from: antibiotics, prebiotics, probiotics,
    neuroprotective drugs, MAOI-B, antiapoptotic agents, N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, glutamate release blockers, Q10 coezyme, vitamin E, antioxidants, anti-inflammatories, minocycline, Cox inhibitors -2 and / or agonists
    dopaminergic, or any of its combinations.
    A third aspect of the invention relates to the use of the combined preparation of the invention in the manufacture of a medicament.
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    A fourth aspect of the invention relates to the use of the combined preparation of the invention in the preparation of a medicament for the relief, improvement, prevention and / or treatment of diseases or disorders related to an aggregating protein, preferably Parkinson's disease.
    In a preferred embodiment of this aspect of the invention, the aggregating protein is intestinal phosphorylated a-synuclein.
    BRIEF DESCRIPTION OF THE FIGURES
    Figure 1. Prevalence by age groups of aminosalicylate treatment in patients> 50 years (dispensing in the Prescription XXI program in December 2014).
    Figure 2. Prevalence by age groups of treatment with antiparkinsonians in patients> 50 years (dispensing in the Prescription XXI program in December 2014).
    DETAILED DESCRIPTION OF THE INVENTION
    There is an apparent low association between PE and IBD, despite the important prevalence of both processes. Therefore, IBD and / or treatment of IBD could act as a protective factor by reducing the incidence of PD by preventing the spread of enteric alpha-synuclein as a result of the modification of a predisposing intestinal flora or a certain pro-inflammatory state or intestinal anti-inflammatory In the examples of the present invention it is shown how the authors have obtained a series of results from the clinical data of 2,020,868 individuals, which show the effect of aminosalicylates, and more specifically of mesalazine and sulfasalazine, on the risk of presenting an EP. From this analysis it is derived that such drugs exert an action on the aggregation and propagation of a-synuclein, key in the etiopathogenesis of PD.
    MEDICAL USE OF THE INVENTION
    Therefore, a first aspect of the invention relates to the use of a composition, hereinafter the composition of the invention, which comprises or consists of at least one aminosalicylate as an active ingredient in the preparation of a medicament for the relief, improvement, prevention and / or treatment of diseases or disorders related to an aggregating protein.
    In a preferred embodiment of this aspect, the composition of the invention comprises only as an active ingredient an aminosalicylate, although additionally it can
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    comprise at least one pharmaceutically acceptable carrier and / or excipients and / or at least one adjuvant.
    In this specification, "aminosalicylate" means derivatives of acetylsalicylic acid. They are commonly used as anti-inflammatories, and more specifically for the treatment of inflammatory bowel disease. Among the best known are mesalazine, also known as 5-aminosalicylate or 5-ASA, sulfasalazine, olsalazine, balsalazide, ipsalazide and bensalazide.
    "Mesalazine is 5 aminosalicylic acid or 5-amino-2-hydroxybenzoic acid", which is why it is also known with the anagram of 5-ASA, and has formula (I):
    image3
    Mesalazine is one of the two components of another aminosalicylate: sulfasalazine. "Sulfasalazine or 2-hydroxy-5 - [(E) -2- {4 - [(pyridin-2-yl) sulfamoyl] phenyl} diazen-1-yl] benzoic acid" is composed of mesalazine and sulfapyridine, and has formula (II):
    image4
    Sulfasalazine belongs to the group of sulfonamides, containing sulfur, and is a derivative of mesalazine (5-aminosalicylic acid, 5-ASA). It is mainly used as an anti-inflammatory agent in the treatment of IBD and rheumatoid arthritis, thanks to its immunomodulatory effect on the immune system.
    "Osalazine or acid 5 - [(2Z) -2- (3-carboxy-4-oxocycloesa-2,5-dien-1-ylidene) idrazino] -2- hydroxybenzoic acid" is another aminosalicylate of formula (III):
    image5
    5 "Balsalazide, E) -5 - ([4- (2-carboxyethylcarbamoyl) phenyl] diacenyl) -2-hydroxybenzoic acid or 4- aminobenzoylalanine" is an anti-inflammatory drug used in IBD of formula (IV):
    image6
    Balsalazide is usually given as the disodium salt. Balsalazide releases 5-ASA 10 in the large intestine. This drug improves the delivery of the active substance to the large intestine, improving the treatment of ulcerative colitis.
    "Ipsalazide or 4-aminobenzoyl glycine" is an anti-inflammatory drug that has formula
    (V):
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    "Bensalazide or para-aminobenzoic acid" is an anti-inflammatory drug that has formula (VI):
    COOH
    image8
    Formula (VI)
    In a preferred embodiment of this aspect of the invention, the aminosalicylate is selected from the list comprising or consisting of: mesalazine (5-aminosalicylate), sulfasalazine, olsalazine, balsalazide, ipsalazide and bensalazide or any of its salts, esters, tautomers, pharmaceutically acceptable solvates and hydrates, or any combination thereof.
    In another preferred embodiment of this aspect, the aminosalicylate is 5-ASA, of formula (I), or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof.
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    In another preferred embodiment of this aspect, the aminosalicylate is sulfasalazine, of formula (II), or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof.
    The compounds of the present invention represented by formulas (I-VI) may include isomers, depending on the presence of multiple bonds, including optical or enantiomeric isomers, depending on the presence of chiral centers. The individual isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention, that is, the term isomer also refers to any mixture of isomers, such as diastereomers, racemic, etc., even their optically isomers. assets or mixtures in different proportions thereof. The individual enantiomers or diastereoisomers, as well as mixtures thereof, can be separated by conventional techniques.
    Also, within the scope of this invention are the prodrugs of the compounds of the formulas (I-VI). The term "prodrug" or "prodrug" as used herein includes any derivative of the compounds of formulas (I-VI) - for example and not limited to: esters (including esters of carboxylic acids, amino acid esters, phosphate esters, sulphonate esters of metal salts, etc.), carbamates, amides, etc. - which when administered to an individual can be transformed directly or indirectly into said compounds of formulas (I-VI) in said individual. Advantageously, said derivative is a compound that increases the bioavailability of the compounds of formulas (I-VI) when administered to an individual or that enhances the release of the compounds of formulas (I-VI) in a biological compartment. The nature of said derivative is not critical as long as it can be administered to an individual and provides the compounds of formulas (I) in a biological compartment of an individual. The preparation of said prodrug can be carried out by conventional methods known to those skilled in the art.
    As used herein, the term "derivative" includes both pharmaceutically acceptable compounds, that is, derivatives of the compounds of formulas (I-VI) that can be used in the manufacture of a medicament or food compositions, such as pharmaceutically derived derivatives. acceptable, since these may be useful in the preparation of pharmaceutically acceptable derivatives.
    The compounds of the invention may be in crystalline form as free compounds or as solvates. In this sense, the term "solvate", as used herein, includes both pharmaceutically acceptable solvates, that is, solvates of the compounds of formulas (I-
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    VI) that can be used in the preparation of a medicament, such as pharmaceutically acceptable solvates, which may be useful in the preparation of solvates or pharmaceutically acceptable salts. The nature of the pharmaceutically acceptable solvate is not critical as long as it is pharmaceutically acceptable. In a particular embodiment, the solvate is a hydrate. Solvates can be obtained by conventional solvation methods known to those skilled in the art.
    For their application in therapy, the compounds of formulas (I-VI), their salts, prodrugs or solvates, will preferably be found in a pharmaceutically acceptable or substantially pure form, that is, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and not including material considered toxic at normal dosage levels. The purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, and still more preferably greater than 90%. In a preferred embodiment, they are greater than 95% of compounds of formulas (I-III), or of their salts, solvates or prodrugs.
    The compounds described in the present invention, their salts, prodrugs and / or solvates as well as the pharmaceutical compositions containing them can be used together with other drugs, or additional active ingredients, to provide a combination therapy. Said additional drugs may be part of the same pharmaceutical composition or, alternatively, they may be provided in the form of a separate composition for simultaneous or non-simultaneous administration to the pharmaceutical composition comprising a compound of formula (I-VI), or a salt, prodrug or solvate thereof.
    In another preferred embodiment of this aspect of the invention, the composition of the invention comprises a pharmaceutically acceptable carrier.
    Pharmaceutical vehicles suitable for the administration of the compositions provided herein include any of the vehicles known to those skilled in the art that are considered suitable for the particular mode of administration. Accordingly, a further aspect of the present invention includes pharmaceutical compositions comprising one or more compounds of the invention described above together with a pharmaceutically acceptable carrier. For administration, the compounds are normally combined with one or more adjuvants appropriate for the indicated route of administration. The compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, acid
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    Stearic, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol. Alternatively, the compounds of this invention can be dissolved in saline, water, polyethylene glycol, propylene glycol, colloidal solutions of carboxymethyl cells, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and / or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include temporary delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
    In another preferred embodiment of this aspect of the invention, the composition of the invention comprises an adjuvant.
    The pharmaceutically acceptable adjuvants and vehicles that can be used in said compositions are the adjuvants and vehicles known to those skilled in the art and commonly used in the elaboration of therapeutic compositions.
    In another preferred embodiment of this aspect of the invention, the composition of the invention further comprises another active ingredient. Preferably, this additional active ingredient is selected from the list comprising or consisting of: antibiotics, prebiotics, probiotics, neuroprotective drugs, IMAO-B, antiapoptotic agents, N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, blockers of the release of glutamate, coezyme Q10, vitamin E, antioxidants, anti-inflammatories, minocycline, Cox-2 inhibitors and / or dopamine agonists, or any combination thereof.
    The active ingredient can be administered at once, or it can be divided into several smaller doses to be administered at time intervals. It is understood that the dosage and precise duration of treatment are a function of the disease being treated and can be determined empirically using known assay protocols or by extrapolation from in vivo or in vitro test data. It should be noted that concentrations and dosage values may also vary with the severity of the condition to be relieved. In addition, it should be understood that for any particular subject, specific dosage regimens must be adjusted over time according to the individual need and professional judgment of the person administering or supervising the administration of the compositions, and that the intervals of Concentrations set forth herein are illustrative only and are not intended to limit the scope or practice of the claimed compositions.
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    As used herein, the term "active substance", "active substance", "pharmaceutically active substance", "active ingredient" or "pharmaceutically active ingredient" means any component that potentially provides a pharmacological activity or other different effect on the diagnosis, cure, mitigation, treatment, or prevention of a disease, or that affects the structure or function of the body of man or other animals. The term includes those components that promote a chemical change in the preparation of the drug and are present therein in a modified form intended to provide the specific activity or effect.
    Another aspect of the invention relates to a pharmaceutical form, hereinafter pharmaceutical form of the invention, comprising the compound of the invention or the composition of the invention.
    In this specification, "pharmaceutical form" means the mixture of one or more active ingredients with or without additives that have physical characteristics for proper dosage, preservation, administration and bioavailability.
    In another preferred embodiment of the present invention, the compositions and pharmaceutical forms of the invention are suitable for oral administration, in solid or liquid form. Possible forms for oral administration are tablets, capsules, syrups or solutions and may contain conventional excipients known in the pharmaceutical field, as aggregating agents (eg syrup, acacia, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone), fillers (eg lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine), disintegrants (eg starch, polyvinyl pyrrolidone or microcrystalline cellulose) or a pharmaceutically acceptable surfactant such as sodium lauryl sulfate. Other pharmaceutical forms may be colloidal systems, which include nanoemulsions, nanocapsules and polymeric nanoparticles. Preferably, the composition of the invention is administered orally and / or rectally.
    Compositions for oral administration can be prepared by conventional methods of Galenic Pharmacy, as mixing and dispersion. The tablets can be coated following methods known in the pharmaceutical industry.
    The compositions and pharmaceutical forms can be adapted for parenteral administration, such as sterile solutions, suspensions, or lyophilisates of the products of the invention, using the appropriate dose. Suitable excipients, such as pH buffering agents or surfactants, can be used.
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    The aforementioned formulations can be prepared using conventional methods, such as those described in the Pharmacopoeias of different countries and in other reference texts.
    Administration of the compounds, compositions or pharmaceutical forms of the present invention can be accomplished by any suitable method, such as intravenous infusion and oral and / or straight, topical or parenteral routes. Preferably, the administration is performed orally and / or rectally.
    The amount administered of a compound of the present invention will depend on the relative efficacy of the compound chosen, the severity of the disease to be treated and the weight of the patient. However, the compounds of this invention will be administered one or more times a day, for example 1, 2, 3 or 4 times daily, preferably 1 or 2 times a day, with a total dose between 1 and 5000 mg / kg / day. , and more preferably between 500-5000 mg / day. It is important to keep in mind that it may be necessary to introduce variations in the dose, depending on the age and condition of the patient, as well as modifications in the route of administration.
    In the sense used in this description, the term "therapeutically effective amount" refers to the amount of the agent or compound capable of developing the therapeutic action determined by its pharmacological properties, calculated to produce the desired effect and, in general, will be determined, among other causes, due to the characteristics of the compounds, including the age, condition of the patient, the severity of the alteration or disorder, and the route and frequency of administration.
    The compounds and compositions of the present invention can be used together with other medicaments in combination therapies. The other drugs may be part of the same composition or of a different composition, for administration at the same time or at different times.
    The term "treatment" as understood in the present invention refers to combating the effects caused as a result of a disease or pathological condition of interest in a subject (preferably mammal, and more preferably a human) that includes:
    (i) inhibit the disease or pathological condition, that is, stop its development;
    (ii) alleviate the disease or the pathological condition, that is, cause the regression of the disease or the pathological condition or its symptomatology;
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    (iii) stabilize the disease or pathological condition.
    The term "prevention" as understood in the present invention is to prevent the onset of the disease, that is, to prevent the disease or pathological condition from occurring in a subject (preferably mammal, and more preferably a human), in particularly, when said subject has a predisposition for the pathological condition.
    In this specification, "aggregating peptide" and / or "aggregating protein" means peptides, polypeptides or proteins that are commonly found forming aggregates in neurodegenerative diseases. Among these proteins are, but not limited to, a-synuclein (SEQ ID NO: 1).
    In another preferred embodiment of this aspect of the invention, the aggregator protein is selected from the list comprising or consisting of a-synuclein, huntingtin, beta-amyloid peptide, TDP-43, FUS, tau, Prion Protein, Fibronectin and SOD1.
    In another preferred embodiment of this aspect of the invention, the aggregating protein is α-synuclein, preferably intestinal phosphorylated α-synuclein.
    In this specification, "a-synuclein or alfasinuclein" means (SNCA, NACP, PARK1, PARK4, PD1, alpha-synuclein; non A-beta component of AD amyloid; synuclein alpha-140) is a member of the synuclein family, which also includes beta- and gamma-synuclein. Synucleins are abundantly expressed in the brain and alpha- and betasinuclein D2 selectively inhibit phospholipase. A-synuclein can serve to integrate signaling and presynaptic membrane traffic. A-synuclein defects have been implicated in the pathogenesis of Parkinson's disease. A-synuclein is a major component of amyloid plaques in the brains of patients with Alzheimer's disease. Two different isoforms have been identified for this gene. Its amino acid sequence corresponds to SEQ ID NO: 1.
    In the context of the present invention, the a-synuclein gene is also defined by a nucleotide or polynucleotide sequence, which constitutes the coding sequence of the protein collected in SEQ ID NO: 1, and which would comprise various variants from:
    a) nucleic acid molecules encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 1,
    b) nucleic acid molecules whose complementary hybrid chain with the polynucleotide sequence of a),
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    c) nucleic acid molecules whose sequence differs from a) and / or b) due to the degeneracy of the genetic code,
    d) nucleic acid molecules encoding a polypeptide comprising the amino acid sequence with an identity of at least 80%, 90%, 95%, 98% or 99% with SEQ ID NO: 1, and in which the polypeptide encoded by said nucleic acids possesses the activity and structural characteristics of the a-synuclein protein.
    Several amino acid sequences are available in the databases for the peptide and protein of the invention, which differ in one or more amino acids from the amino acid sequence in SEQ ID NO: 1. These peptide variants and proteins are composed of the present invention, provided they have an activity and structural behavior of said proteins. As used herein, the protein variants of SEQ ID NO: 1, are proteins with an amino acid sequence that differs from the amino acid sequence of the protein of SEQ ID NO: 1, may be substituted for another. amino acid, provided that the variant of the resulting protein exhibits an activity and the structural behavior of said proteins. The determination of the activity and structural behavior of said proteins can be performed, by methods known in the state of the art. In particular, protein variants that differ from the amino acid sequence shown in SEQ ID NO: 1 are included.
    It is preferred that the substitutions be conservative substitutions, that is, substitutions of an amino acid residue for another amino acid of a similar polarity, which acts as a functional equivalent. Preferably, the amino acid residue used as a substitute is selected from the same group of amino acids as the amino acid residue to be substituted. For example, a hydrophobic residue can be substituted with another hydrophobic residue, or a polar residue can be substituted with another polar residue having the same charge. Functionally homologous amino acids that can be used for conservative substitution comprise, for example, non-polar amino acids such as glycine, valine, alanine, isoleucine, leucine, methionine, proline, phenylalanine and tryptophan. Examples of uncharged polar amino acids include serine, threonine, glutamine, asparagine, tyrosine and cysteine. Examples of charged (basic) polar amino acids include histidine, arginine and lysine. Examples of charged polar amino acids (acids) include aspartic acid and glutamic acid. Also included by the term "variant" are protein sequences that include more amino acids than the sequence of SEQ ID NO: 1.
    The sequence SEQ ID NO: 1 is as follows:
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    Met Asp Val Phe Met Lys Gly Leu Ser Lys Wing Lys Glu Gly Val Val Wing Wing Glu Lys Thr Lys Gln Gly Val Glu Wing Wing Wing Gly Lys Thr Lys Glu Gly Val Leu Tyr Val Gly Ser Lys Thr Lys Glu Gly Val Val His Gly Val Wing Thr Val Wing Glu Lys Thr Lys Glu Gln Val Thr Asn Val Gly Gly Wing Val Wing Val Thr Gly Val Thr Wing Val Wing Gln Lys Thr Val Glu Gly Wing Gly Ser Wing Wing Wing Wing Thr Gly Phe Val Lys Lys Asp Gln Leu Gly Lys Asn Glu Glu Gly Ala Pro Gln Glu Gly Ile Leu Glu Asp Met Pro Val Asp Pro Asp Asn Glu Ala Tyr Glu Met Pro Ser Glu Glu Gly Tyr Gln Asp Tyr Glu Pro Glu Ala
    In the present invention "a-synuclein" refers both to the unfolded and soluble native form and to that with conformational and post-translational modifications. In addition, native a-synuclein can be modified by, for example but not limited to, the replacement of Ser / Ala by Cys, for example, through site-directed mutagenesis. An example of this type is set forth by Chang, USA. 2006/0018918 A1.
    In another preferred embodiment of this aspect of the invention, the disease or disorder related to a-synuclein or a-synucleinopathy is selected from the list consisting of: Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, multisystem atrophy, Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis, frontotemporal dementia, Gaucher's disease, Huntington's disease, Type II diabetes. prion disease, Creutzfeldt Jakob disease, multiple sclerosis, Gerstmann-Straussler-Scheinker syndrome, Kuru, fatal familial insomnia, cerebrovascular amyloidosis, glaucoma, age-related macular degeneration, neurodegeneration due to protein aggregation related to age, psychiatric syndromes, schizophrenia and / or disorders similar to schizophrenia, or any combination thereof.
    In another preferred embodiment of this aspect of the invention, the disease or disorder is Parkinson's disease or any synucleinopathy with Lewy bodies.
    Within this activity is also the immunogenic activity. In addition to using the recombinant protein or synthetic peptides, a-synuclein can be derived directly from the Lewy bodies present at the post mortem autopsy of human brain tissue in cases with a-synucleinopathies. Both soluble (i.e., soluble preparations in Tris buffered saline) and insoluble (i.e., insoluble preparations in Tris buffered saline) the a-synuclein fractions are purified. These sample preparations can be injected into animals as such, or fractionated by chromatographic methods before injection. The generated antibodies can be
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    used for the treatment of patients in a passive vaccination scheme or in diagnostic immunoassays.
    In a preferred embodiment of this aspect of the invention, the composition of the invention is administered to groups of individuals or subjects with a greater potential to develop Parkinson's disease. The risk groups can be: subjects with idiopathic hyposmia, chronic constipation, chronic depression, REM sleep behavior disorder, genetic parkinsonism or any pathology related to Parkinson's disease.
    Here the terms "Parkinson's", "Parkinson's disease", "Parkinson's disease", "idiopathic parkinsonism", "agitating paralysis" are used interchangeably and refer to a chronic neurodegenerative disorder that leads to progressive disability. within movement disorders and also produces alterations of cognitive function, autonomous function and expression of emotions.
    Parkinson's patients usually present with any of these signs: resting tremor (approximately 85% of cases), muscle hypertonia or muscle stiffness, bradykinesia, loss of postural reflexes and / or segmental head tremor. Not all symptoms appear in all patients and the evolution and progression of the disease varies widely depending on the case. Symptoms gradually get worse over time.
    The scales to determine the severity of Pakinson are: On the one hand, the Hoehn and Yahr scale where movement symptoms are assessed in severity on a scale of 1 to 5. On this scale, depending on a person's difficulties in performing its activities, a score of 1 and 2 (levere to moderate) is assigned to represent the early- scenario of the table, score of 2 and 3 (moderate to severe) in the average evolution chart and score of 4 and 5 the advanced chart ( severe to disabling). On the other hand, there is the scale of evaluation of Parkinson's Disease UPDRS (Unified Parkinson Disease Rating Scale) that takes into account difficulties, ability to perform daily activities, behavior, humor, and cognitive complications of treatment along with movement symptoms.
    The term "identity", as used herein, refers to the proportion of identical amino acids between two amino acid sequences that are compared.
    The term "homology", as used herein, refers to the similarity between two structures due to a common evolutionary ancestry, and more specifically, to the similarity between the amino acids of two or more proteins or amino acid sequences.
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    COMBINED PREPARATION OF THE INVENTION AND USES
    A second aspect of the invention relates to a combined preparation, hereafter combined preparation of the invention, comprising:
    a) A COMPONENT A which is a compound as described in the first aspect of the invention,
    b) A COMPONENT B which is a compound that is selected from: antibiotics, prebiotics, probiotics, neuroprotective drugs, MAOI-B, antiapoptotic agents, N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, blockers the release of glutamate, coefficient Q10, vitamin E, antioxidants, anti-inflammatories, minocycline, Cox-2 inhibitors and / or dopamine agonists, or any combination thereof.
    It should be emphasized that the term "combined preparation" or also called "juxtaposition", herein, means that the components of the combined preparation need not be present as a joint, for example in a true composition, in order to be available for combined application. , separate or sequential. In this way, the expression "juxtaposed" implies that it is not necessarily a true combination, in view of the physical separation of the components
    A third aspect of the invention relates to the separate, simultaneous or sequential use of the active ingredients of the combined preparation of the invention (or of component A and component B of the combined preparation) for the preparation of a medicament.
    A fourth aspect of the invention relates to the separate, simultaneous or sequential use of the active ingredients of the combined preparation of the invention in the preparation of a medicament for the relief, improvement, prevention and / or treatment of diseases or disorders related to an aggregating protein, preferably Parkinson's disease.
    In a preferred embodiment of this aspect of the invention, the aggregating protein is intestinal phosphorylated a-synuclein.
    In another preferred embodiment of this aspect of the invention, the disease or disorder
    Related to a-synuclein or a-synucleinopathy is selected from the list consisting of:
    Parkinson's disease, dementia with Lewy bodies, the variant of Lewy bodies
    of Alzheimer's disease, multisystem atrophy, Alzheimer's disease,
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    Down, amyotrophic lateral sclerosis, frontotemporal dementia, Gaucher's disease, Huntington's disease, Type II diabetes. prion disease, Creutzfeldt Jakob disease, multiple sclerosis, Gerstmann-Straussler-Scheinker syndrome, Kuru, fatal familial insomnia, cerebrovascular amyloidosis, glaucoma, age-related macular degeneration, neurodegeneration due to protein aggregation related to age, psychiatric syndromes, schizophrenia and / or disorders similar to schizophrenia.
    In another preferred embodiment of this aspect of the invention, the disease or disorder is Parkinson's disease or any synucleinopathy with Lewy bodies.
    The term "medication", as used herein, refers to any substance used for prevention, diagnosis, relief, treatment or cure of diseases in man and animals. In the context of the present invention, it also refers to a composition capable of generating a response to a given aggregating protein that is causing or can cause disease in man or animals.
    Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and figures are provided by way of illustration, and are not intended to be limiting of the present invention.
    EXAMPLES OF THE INVENTION
    Study Methodology
    1. - Type of study.
    Cross-sectional observational study (prevalence or section).
    2. - Subjects of study.
    All individuals of the Andalusian registry Prescription XXI with at least one pharmacological dispensation during December 2014. We identified the following groups:
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    - Suggestive of PD (SEP): patients with dispensing of antiparkinsonian drugs (levodopa in its different presentations and / or dopaminergic agonists and / or IMAOs-B).
    - Suggestive of IBD (SEII): patients with dispensing aminosalicylates in their different commercial presentations (mesalazine or mesalamine, sulfasalazine or 5- ASA).
    - Suggestive of PE and IBD (SEII_SEP): patients with both dispensations (antiparkinsonians and aminosalicylates).
    Other dispensations, suggestive of other pathologies or group not suggestive of PD or IBD (NO SEII_NO SEP).
    3. - Selection criteria.
    Subjects of both sexes with an age> 50 years. Subjects with exclusive dispensations of a low-dose dopamine agonist (ropinirole <1 mg; rotigotine <2 mg; pramipexole LP <1.0 mg; pramipezole L <0.7 mg; pergolide <1 mg; cabergoline <1 mg) are excluded as SEP.
    4. - Sample size.
    The entire population with dispensation in the referred period with elimination of duplicate cases (records with multiple dispensations will be eliminated maintaining a primary record encoded with an antiparkinsonian drug or an aminosalicylate or both).
    5. - Study variables:
    Variable result or dependent:
    - Main variable: SEP STUDY GROUP.
    Independent or predictive variables:
    - Main variable: SEII STUDY GROUP.
    - Secondary variable: sex, age, Andalusian province of dispensation, codified medical history number.
    6. - Data collection.
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    The data were obtained by the computer services of the Department of Pharmacy and Benefits (Support Services of the Andalusian Health Service) from the dispensing record of the Prescription XXI program during the month of December 2014. The clinical history numbers (NUHSA) were masked.
    7.- Data analysis.
    A descriptive study of all the variables collected was carried out. Measures of central tendency and dispersion (mean, standard deviation, median and quartiles) were calculated for the quantitative ones; absolute and relative frequencies for qualitative ones; as well as the corresponding graphic representations. To contrast the main qualitative variables, the Pearson chi-square test or with Yates continuity correction, or Fisher's test will be used if the applicability criteria are not met and the quantitative variables will be compared between the groups using the test of Student t, including variables. Prior to this bivariate analysis, the normality hypothesis will be checked using the Shapiro-Wilks test. To analyze the strength of the association between the groups, after controlling for confounding factors (age and sex), a multiple logistic regression model was made in order to estimate odds ratios (OR) and their 95% confidence interval.
    A p value <0.05 was considered significant for all tests. The statistical software used is R.
    Results
    2,020,868 subjects (68 ± 11 years, 56% women) were registered, of whom 19966 were identified as "possible PD" (75 ± 9 years, 53% women) and 7485 as "possible EN" (64 ± 10 years , 47% women). Only 56 were included in both groups (76 ± 8 years; 32 men / 24 women). Prevalence of PD in IBD = 0.7% and in those without IBD = 1% (OR = 0.75; 95% CI = 0.57-0.98; p = 0.036). OR adjusted for age and sex 0.28 (95% CI = 0.10-0.74; p = 0.01) in subjects <65 years and 1.17 (95% CI = 0.89-1.54; p = 0.257) in> 65 years.
    Our study suggests a protective role of IBD and / or aminosalicylates for the development of PD, especially in children under 65 years. Given the important scientific and therapeutic implications, new longitudinal studies on this association are needed. With regard to the aforementioned, it has been suggested that IBD and / or treatment with aminosalicylates acts as a protective factor reducing the incidence of PD, by preventing the spread of enteric alfasinuclein, a consequence of the modification of a flora
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    intestinal predisposing or of a certain pro-inflammatory or anti-inflammatory intestinal state. If this hypothesis is verified and it is verified that the aminosalicylates modify the risk of developing PD, we would have for the first time a preventive or neuroprotective treatment to be applied in the risk groups that are increasingly defined, all subject to a correct experimental development (including murine models) of our idea.
    Although it is primarily a descriptive study without other claims than to know the feasibility of an analytical longitudinal study of retrospective cohorts, we have not wanted to renounce the analytical facet of the project with knowledge of the multiple biases of these types of designs and derivatives of managing a database of patients (drug dispensing) with seasonal influences. Main expected biases:
    - Selection bias: It is a database of patients not representative of the general population. Being a database of patients, the prevalence of both diseases will be higher than in the general population, with a possible overestimation of the resulting OR. It is a record of dispensation: despite the over-representation of pathologies only those who withdraw at least one recipe are included, so it is likely that there are more cases of intersection or on the contrary, those that do not withdraw prescriptions are not included and They do it in other periods. For future studies it will be necessary to select subjects in whom such a dispensation is ensured for a long period, to also avoid seasonal peak influences. Patients with PD are likely to have more dispensations than those with IBD, as they are usually more polymedicated patients. When selecting patients treated with amino salicylates, ulcerative colitis is likely to be the most prevalent disease in the sample. Not all patients with IBD, especially Crohn's disease, are treated with salicylates, as many pass prolonged phases without treatment, others are only treated with salicylates in their early stages and then do so with monoclonal antibodies, immunosuppressants, etc.
    - Information bias due to poor classification of the variables: There is an error related to the way of relating the treatment with the presumed diagnosis of both categories. For future studies, subjects with dispensations maintained for a period of more than 6 months will be selected. It is unlikely in punctual consumption of aminosalicylates; With respect to subjects with possible PD, there is a possibility that they are classified as such patients with secondary parkinsonism (vascular, pharmacological, etc.), atypical parkinsonisms and even some case of restless legs syndrome. Cases with both diseases that only remove one of the pharmacological groups from the pharmacy.
    Results Tables:
    Table 1. 2x2 contigence table with the prevalence of possible Parkinson's disease (PD +) and inflammatory bowel disease (IBD) recorded in the Prescription XXI dispensing database in December 2014.
     EP + EP-
     IBD +  56 7429
     IBD-  19910 1993473
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    Table 2. Defining statistics of the strength of association (odds ratio) resulting from the previous table (table 1).
     Odds ratio  0.7547
     95% CI  0.55800 to 0.9821
     Z statistic  2,095
     Level of significance  P = 0.0362
    Table 3. Logistic regression model of patients with age <65 years.
     Predictor    OR P OR (95% CI) P
     Possible IBD  -1.32 0.26 0.008 -1.28 0.28 (0.10-0.74) 0.0103
     Age  0.07 1.07 <0.0001 0.07 1.074 (1.0661.083) <0.0001
     Gender (Female)  -0.23 0.80 <0.0001 -0.22 0.80 (0.75-0.86) <0.0001
     Intercept = -9.74 ± 0.24 (B0 ± standard error)
    Logit possible EP (y) = -9.74 -1.28 * possible IBD + 0.07 * Age-0.22 * Sex (Female)
    权利要求:
    Claims (16)
    [1]
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    1. - Use of a composition comprising at least one aminosalicylate as an active ingredient in the preparation of a medicament for the relief, improvement, prevention and / or treatment of diseases or disorders related to an aggregating protein.
    [2]
    2. - Use of a composition consisting of at least one aminosalicylate as an active ingredient in the preparation of a medicament for the relief, improvement, prevention and / or treatment of diseases or disorders related to an aggregating protein.
    [3]
    3. - The use of a composition according to any of claims 1-2, wherein the aminosalicylate is selected from the list comprising or consisting of: mesalazine (5- aminosalicylate), sulfasalazine, olsalazine, balsalazide, ipsalazide and bensalazide or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof.
    [4]
    4. - The use of a composition according to any of claims 1-3, wherein the aminosalicylate is 5-ASA, a compound of formula (I):
    image 1
    or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof.
    [5]
    5. The use of a composition according to any of claims 1-3, wherein the aminosalicylate is sulfasalazine, a compound of formula (II):
    image2
    Formula (II)
    or any of its pharmaceutically acceptable salts, esters, tautomers, solvates and hydrates, or any combination thereof.
    [6]
    6. - The use of a composition according to any of claims 1-5, wherein the composition comprises a pharmaceutically acceptable carrier.
    [7]
    7. - The use of a composition according to any of claims 1-6, wherein the composition comprises an adjuvant.
    The use of a composition according to any of claims 1-7, wherein the
    composition also comprises another active ingredient.
    [9]
    9. The use of a composition according to any of claims 1-8, wherein the aggregating protein is selected from the list comprising or consisting of a-synuclein, huntingtin, beta-amyloid peptide, TDP-43, FUS, tau, Prion Protein, Fibronectin and SOD1.
    The use of a composition according to any of claims 1-9, wherein the
    Aggregating protein is a-synuclein, preferably intestinal phosphorylated a-synuclein.
    [11]
    11. The use of a composition according to any of claims 1-10, wherein the disease or disorder related to a-synuclein or a-synucleinopathy is selected from the list consisting of: Parkinson's disease, dementia with Lewy bodies , the 20 Lewy body variant of Alzheimer's disease, multisystem atrophy, Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis, frontotemporal dementia, Gaucher disease, Huntington's disease, Type II diabetes, prion disease, Creutzfeldt Jakob disease, multiple sclerosis, Gerstmann-Straussler-Scheinker syndrome, Kuru, fatal familial insomnia, cerebrovascular amyloidosis, glaucoma, age-related macular degeneration,
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    neurodegeneration due to aggregation of proteins related to age, psychiatric syndromes, schizophrenia and / or disorders similar to schizophrenia, or any combination thereof.
    [12]
    12. - The use of a composition according to any of claims 1-11, wherein the disease or disorder is Parkinson's disease or any synucleinopathy with Lewy bodies.
    [13]
    13. - A combined preparation comprising two components:
    a) a component A, which is a compound as described in any of claims 1-5,
    b) a component B, which is a compound that is selected from: antibiotics, prebiotics and probiotics to modify the intestinal flora, or other drugs with presumable neuroprotective action such as MAOI-B, antiapoptotic agents, N-glutamate receptor antagonists methyl-D-aspartate (NMDA) and blockers of the release of glutamate, coezyme Q10, vitamin E and other antioxidants, and even anti-inflammatories (minocycline, Cox-2 inhibitors, etc.) and dopamine agonists, or any combination thereof .
    [14]
    14. - The separate, simultaneous or sequential use of components A and B of the combined preparation according to the preceding claim, in the preparation of a medicament.
    [15]
    15. - The separate, simultaneous or sequential use of components A and B of the combined preparation according to claim 13, in the preparation of a medicament for the relief, improvement, prevention and / or treatment of diseases or disorders related to a aggregating protein
    [16]
    16. - The use of the combined preparation according to the preceding claim, wherein the aggregating protein is a-synuclein, preferably intestinal phosphorylated a-synuclein.
    [17]
    17. - The use of the combined preparation according to the preceding claim, wherein the a-synuclein causes an a-synucleinopathy.
    [18]
    18. - The use of the combined preparation according to the preceding claim, wherein the atynucleinopathy is Parkinson's disease.
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    同族专利:
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    WO2017178685A1|2017-10-19|
    ES2650175B1|2019-02-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    KR20070030488A|2005-09-13|2007-03-16|윤성화|New aminosalicylic acid analogs, it's pharmaceutically acceptable salts and their preparations|
    CN102245180A|2008-11-14|2011-11-16|帕金森氏病研究院|Compositions and methods for the treatment of altered alpha-synuclein function|
    CA2899032A1|2013-02-01|2014-08-07|Glialogix, Inc.|Compositions and methods for the treatment of neurodegenerative and other diseases|MX2019009117A|2017-02-17|2019-09-13|Squibb Bristol Myers Co|Antibodies to alpha-synuclein and uses thereof.|
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