WO2019238998A1 - Use of antioxidants for the treatment of depression in older patients - Google Patents

Use of antioxidants for the treatment of depression in older patients Download PDF

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Publication number
WO2019238998A1
WO2019238998A1 PCT/ES2019/070409 ES2019070409W WO2019238998A1 WO 2019238998 A1 WO2019238998 A1 WO 2019238998A1 ES 2019070409 W ES2019070409 W ES 2019070409W WO 2019238998 A1 WO2019238998 A1 WO 2019238998A1
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antioxidant
preparation according
vitamin
day
norepinephrine
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PCT/ES2019/070409
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Spanish (es)
French (fr)
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Lucía PÉREZ COSTILLAS
María José BANDERAS DONAIRE
Yolanda DE DIEGO OTERO
Yolanda CASADO MARTÍN
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Servicio Andaluz De Salud
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Publication of WO2019238998A1 publication Critical patent/WO2019238998A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention is within the field of medicine, and refers to the use of antioxidants such as ascorbic acid (Vitamin C) and Tocopherol (Vitamin E) for the treatment of depression in patients over 65 years.
  • antioxidants such as ascorbic acid (Vitamin C) and Tocopherol (Vitamin E) for the treatment of depression in patients over 65 years.
  • it refers to the use of the combination of said vitamins in therapeutic doses, in order to produce antidepressant effects, and the use of the combination of said antioxidants with antidepressants of the SSRI type to increase the effectiveness of the treatment of depression.
  • Some pathologies are found more frequently in the elderly, among them we can mention diseases of the circulatory system (heart failure, cerebrovascular diseases, arteriosclerosis, hypertension); metabolic, nutritional and endocrine disorders (palate disorders, periodontal diseases, osteoporosis, urinary incontinence, rheumatoid arthritis, diabetes mellitus), mental and behavioral disorders (Alzheimer's disease, Parkinson's disease, depression) which, in general, They need to be treated with medication.
  • Major Depressive Disorder is one of the most prevalent mental illnesses in the western world and will become, according to the World Health Organization (WHO), the second leading cause of disability in the world (after coronary heart disease) in the year 2020.
  • WHO World Health Organization
  • the most common mental and neurological disorders in the elderly are dementia and depression, which worldwide affect approximately 5% and 7%, respectively, of the elderly population. (WHO, 2017). Older people with depression have poor performance compared to those with chronic diseases such as lung diseases, high blood pressure or diabetes. This disorder also increases the perception of poor health, the use of medical services and the costs of healthcare.
  • Depression is a difficult disease to diagnose in the elderly, being ignored or confused with other conditions, since its symptoms such as fatigue, lack of appetite or sleeping problems can also be part of the aging process or of a physical condition, which leads to confuse it with aging itself, therefore, there is a greater risk that a specific treatment will not be applied.
  • the choice of the antidepressant is mainly based on the side effects; the compatibility of the treatment with other pathologies presented by the elderly; the reduced risk of interactions of antidepressants with drugs of continuous use, such as those used for the treatment of hypertension, diabetes mellitus and / or mental problems; physiological changes that occur with age, such as alterations in the absorption, distribution, metabolization and excretion of drugs.
  • hepatotoxicity effects can be cited as in monoamine oxidase inhibitors.
  • MAOIs monoamine oxidase inhibitors.
  • alterations of the cardiovascular system alterations in pressure values
  • alterations of the central nervous system sedation or excitatory behaviors
  • anticholinergic effects such as constipation, dry mouth, urinary retention, blurred vision and tachycardia
  • gastrointestinal reactions between others such as tricyclic antidepressants, (nortriptyline and desipramine), which have high efficacy in the treatment of depressive symptoms
  • side effects in the elderly may be a more relevant problem, since anticholinergic action can occur from cognitive alterations.
  • confusional conditions such as peripheral effects, dry mouth, constipation and retention urinary
  • the antidepressants of first choice in this age group due to their easy clinical management, their efficacy and good tolerance with few side effects, are selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors, such as venlafaxine, its mechanism of action is similar to tricyclics but without presenting the side effects of these, so a dose adjustment is not necessary due to age, and has few interactions with other drugs.
  • SSRIs serotonin reuptake inhibitors
  • norepinephrine reuptake inhibitors such as venlafaxine
  • its mechanism of action is similar to tricyclics but without presenting the side effects of these, so a dose adjustment is not necessary due to age, and has few interactions with other drugs.
  • the possible adverse effects must be taken into account in this group, are the appearance of nausea, sweating, vertigo and nervousness. In patients with arterial hypertension, it should be checked because there is a risk that it will increase.
  • Oxidative stress is the result of the imbalance between endogenous cellular defense systems.
  • ROS reactive oxygen species
  • RNS reactive nitrogen species
  • the authors of the present invention have developed an antioxidant composition, and a combined preparation, for use in the treatment of depression in a mammal, preferably in humans, more preferably over 65 years.
  • This solution has the advantage that simply adding a vitamin complex can improve antidepressant therapy, which in the elderly population is limited, and reduce toxicity, which translates into better disease control, making it possible to reduce the dose of antidepressant drug, and therefore, the adverse effects and drug interactions in these especially polymedicated elderly patients.
  • a first aspect of the invention relates to a combination composition or preparation comprising an antioxidant hydrophilic compound and an antioxidant lipophilic compound, wherein both the antioxidant hydrophilic compound and the antioxidant lipophilic compound are at a concentration of at least 200 mg each, for use in the treatment of depression in individuals over 60 years, more preferably 65 years.
  • hydrophilic compound or “hydrophilic molecule” or “polar” refers to any molecule that has an affinity for water. They are molecules that can form a transient bond with water (H20) by hydrogen bonding. This is thermodynamically favorable, and these molecules are not only soluble in water, but also in other polar solvents. On the contrary, they cannot diffuse through the plasma membrane and interact with cytosol or nucleus receptors; for example, but not limited to, peptides such as insulin, or proteins such as growth hormone and small charged molecules such as acetylcholine and others derived from some amino acids such as epinephrine, histamine, serotonin and dopamine, some of which work as hormones or neurotransmitters. In these cases, the effect of the cell surface bound molecule is almost immediate, but it persists only for a small period; However, the effect of some trophic factors can be extended for several days, since they can also regulate the gene expression patterns of the white cell.
  • lipophilic compound refers to any molecule that is soluble in lipids. They are able to diffuse through the plasma membrane and interact with cytosol or nucleus receptors; for example, but not limited to, steroid hormones, thyroxine and retinoic acid derivatives. After crossing the plasma membrane, these hormones interact with receptors intracellular, forming complexes capable of increasing or decreasing the transcription of specific genes; These complexes also contribute to the stability of certain messenger RNAs. Generally speaking, these compounds exert their effect for hours or days and contribute to the growth and differentiation of specific tissues.
  • lipophilic molecules have a water solubility of less than 2.5 pg / ml, more preferably less than 2 pg / ml, and even more preferably less than 1 pg / ml.
  • antioxidants refers to compounds capable of intercepting free radicals, giving them an active hydrogen atom or electrons, making them more stable compounds. They can be classified into two large groups, water soluble (hydrophilic) and fat soluble (hydrophobic). Among the hydrophilic antioxidants are vitamin C, alpha-lipoic acid (Ala), glutathione, uric acid, catechins, selenium, polyphenols, resveratol.
  • antioxidants are vitamin E or tocopherols, vitamin A, carotenoids (Beta-carotenes, Alpha-carotenes, Lycopene carotenoids, Lutein, Xanthines, Beta-cryptoxanthines), Lipoic acid, Coenzyme Q10 Ubiquinol, Astaxanthines.
  • the antioxidant hydrophilic compound employed is vitamin C and the lipophilic antioxidant compound employed is vitamin E.
  • antioxidant lipophilic compounds and the antioxidant hydrophilic compounds can be used separately or in combination, to achieve certain pharmacological effects that currently cannot be achieved with other medications. It is known that antioxidant vitamins such as Tocopherol and ascorbic acid enhance the antioxidant power of each other, several studies have shown their synergistic effect on the mechanisms of elimination of free radicals (Cederberg. Et al., 2001. Pediatr Res. 49 (6): 755-62.). The use of antioxidant combinations has also been used as a treatment for other diseases such as Fragile X SXF Syndrome, recognized as an orphan drug (Pérez Costillas L et al., 2011. Tox. 109 (S.3): 41-71). Antidepressant potency of vitamin C synergy with vitamin E has also been found (Maes et al, 2000. Neuropsychopharmacol Biol Psychiatry 35, 637-692).
  • 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 composition, in order to be available for separate or sequential application.
  • juxtaposed implies that it is not necessarily a combination true, in view of the physical separation of the components.
  • a combined preparation (hereinafter combined preparation of the invention) which comprises an antioxidant lipophilic compound, vitamin C and an antioxidant hydrophilic compound, vitamin E.
  • Ascorbic Acid or “Vitamin C” means the enantiomer L of ascorbic acid, of formula (I):
  • vitamin C is a potent antioxidant, acting to reduce oxidative stress; and is a substrate for ascorbate peroxidase. This Vitamin acts as a necessary cofactor in enzymatic reactions such as: enzymes involved in the hydroxylation of collagen.
  • vitamin C becomes an essential nutrient for the development and maintenance of scar tissue, blood vessels, and cartilage.
  • enzymes necessary for the synthesis of carnitine which works in the transport of fatty acids to the mitochondria for the generation of ATP.
  • Enzymes that participate in the biosynthesis of norepinephrine from dopamine through the enzyme dopamine-beta-hydroxylase.
  • Another enzyme adds amide groups to peptide hormones, greatly increasing its stability. It also acts as a cofactor in the metabolism of tyrosine.
  • the biological tissues that accumulate more than 100 times the blood level of vitamin C, are the adrenal glands, pituitary, thymus, corpus luteum, and the retina.
  • Vitamin C helps the development of teeth and gums, bones, cartilage, iron absorption, growth and repair of normal connective tissue (softer skin, by the union of cells that need this vitamin to join), to the Collagen production (acting as a cofactor in the hydroxylation of the amino acids lysine and proline), fat metabolization, wound healing. It has recently been described that part of the antioxidant activity of Vitamin C is due to the inhibition of NADPH oxidase activity in animal models.
  • the human being seems to be extremely efficient in the reuse of vitamin C, so its requirements are 50 times lower than in the rest of the apes. Being a water-soluble vitamin, its elimination by the kidney due to diuresis is extremely effective, so excesses can be eliminated in less than four hours.
  • Vitamin E or alpha-tocopherol is a non-enzymatic fat-soluble antioxidant, which can function as an indicator of cellular oxidative state, limiting the spread of the lipid peroxidation chain reaction. It is the main lipophilic antioxidant of the brain and significantly prevents the oxidation of lipids, whose levels are high in the brain and must be protected by antioxidants. It has also been shown to show significant protection against cytotoxicity induced by L-buthionine-sulfoximine (BSO), which causes the decrease in intracellular glutathione. Vitamin E deficiency is generally characterized by neurological disorders due to poor conduction of nerve impulses.
  • antioxidants such as Vitamin E in the treatment of diseases related to oxidative stress, such as Alzheimer's disease, or in Parkinson's disease has shown that it is capable of delaying mental deterioration in patients with Alhzeimer's disease
  • vitamin E reduced lipid peroxidation and amyloid deposition in a transgenic mouse model for Alzheimer's disease.
  • Vitamin E develops antioxidant activity in cerebrospinal fluid lipoproteins (CSF) in the presence of physiologically relevant amounts of oxidants. Interestingly, vitamin E levels are decreased in CSF extracted from patients suffering from Alhzeimer disease and these levels are increased in patients who have been treated with vitamin E supplements.
  • CSF cerebrospinal fluid lipoproteins
  • the administration of the composition or the combined preparation is at least 200 mg / day, and more preferably 250 mg / day, 300 mg / day, 350 mg / day, 375 mg / day, and even more preferably 400 mg / day.
  • the dosage to obtain a therapeutically effective amount depends on a variety of factors, such as, for example, the age that in the present invention is over 60 years, weight, sex, tolerance, of the mammal.
  • the term "therapeutically effective amount” refers to the amount of antioxidant lipophilic compound and antioxidant hydrophilic compound that produce the desired effect and, in general, will be determined, among other causes, by the proper characteristics. of said active ingredients, prodrugs, derivatives or analogs and the therapeutic effect to be achieved.
  • the recommended daily intake of vitamin C is 80 mg and Vitamin E is 12 mg (Garc ⁇ a Gabarra et al. 2017. Nutr Hosp ; 34 (2): 490-498).
  • the United States Academy of Science recommends an intake of 60-95 milligrams of vitamin C per day to maintain health. According to this organism, 2000 milligrams per day should not be exceeded.
  • the half-life of vitamin C is 16 days, and its half-life decreases in people with elevated levels of this compound.
  • the amount of both the antioxidant lipophilic compound and the antioxidant hydrophilic compound is between 200 and 500 mg each, preferably at least 200 mg / day each, and even much more preferably 400 mg / day
  • excipient refers to a substance that aids the absorption, distribution or action of any of the active ingredients of the present invention, stabilizes said active substance or aids in the preparation of the medicament in the sense of giving it consistency or providing flavors. Make it more enjoyable.
  • the excipients could have the function of keeping the ingredients together such as starches, sugars or cellulose, sweetening function, dye function, drug protection function such as to isolate it from air and / or moisture, function filling a tablet, capsule or any other form of presentation such as dibasic calcium phosphate, a disintegrating function to facilitate the dissolution of the components and their absorption in the intestine, without excluding other types of excipients not mentioned in this paragraph.
  • pharmaceutically acceptable excipient refers to the excipient being allowed and evaluated so as not to cause damage to the organisms to which it is administered.
  • the excipient must be pharmaceutically suitable, that is, an excipient that allows the activity of the active ingredient or of the active ingredients, that is, that is compatible with the active ingredient, in this case, the active ingredient is any of the compounds of the present invention.
  • the combined preparation of the invention further comprises another active ingredient.
  • the other active ingredient is selected from the list consisting of: selective serotonin reuptake inhibitors (SSRIs), selective dopamine reuptake inhibitors (ISRD), selective norepinephrine (or norepinephrine) reuptake inhibitors (ISRN), selective serotonin and norepinephrine (or norepinephrine) reuptake inhibitors (IRSN), selective dopamine and norepinephrine (or norepinephrine) reuptake inhibitors (IRDN), tricyclic antidepressants (ATC), monoamine oxidase inhibitors (MAOIs) ), serotonin reuptake antagonists and inhibitors (AIRSs), noradrenergic and specific serotonergic antidepressants (NaASE), selective serotonin reuptake enhancers (PSRS), opioids or any combination thereof.
  • SSRIs selective serotonin reuptake
  • composition or the combined preparation, wherein the active ingredient is a selective serotonin reuptake inhibitor (SSRI).
  • SSRI selective serotonin reuptake inhibitor
  • the duration of the combined treatment of antioxidants and antidepressants is at least 24 days, preferably between 10 to 24 days, and even more preferably it is 12 days.
  • active substance 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.
  • compositions of the present invention can be formulated for administration to an animal, and more preferably to a mammal, including man, in a variety of ways known in the state of the art.
  • they can be, without limitation, in sterile aqueous solution or in biological fluids, such as serum.
  • Aqueous solutions may be buffered or unbuffered and have additional active or inactive components. Additional components include salts to modulate ionic strength, preservatives including, but not limited to, antimicrobial agents, antioxidants, chelators, and the like, and nutrients including glucose, dextrose, vitamins and minerals.
  • the compositions can be prepared for administration in solid form.
  • compositions may be combined with various inert vehicles or excipients, including but not limited to; binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid or corn starch; lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint or methyl salicylate.
  • binders such as microcrystalline cellulose, gum tragacanth, or gelatin
  • excipients such as starch or lactose
  • dispersing agents such as alginic acid or corn starch
  • lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin
  • flavoring agents such as peppermint or methyl salicylate.
  • compositions of the present invention can be formulated for administration in a variety of ways known in the state of the art. In each case the form of presentation of the pharmaceutical composition will adapt to the type of administration used, therefore, the composition of the present invention may be presented in the form of solutions or any other form of clinically permitted administration and in a therapeutically effective amount.
  • the pharmaceutical composition of the present invention may be associated, for example, but not limited to, with liposomes or micelles.
  • a liposome is a spherical vesicle with a phospholipid membrane.
  • the liposome contains a core of aqueous solution.
  • the micelle is a spherical lipid that contains non-aqueous material. Both liposomes and micelles can be used as carriers of various substances between the outside and inside of a cell.
  • the pharmaceutical composition of the present invention can be associated, for example, but not limited to, with microcapsules of soluble polysaccharides that form spherical vesicles with a hydrated polysaccharide shell and which can be used as carriers of various substances that cannot be mixed together, from the outside inside the organism and its organs.
  • the pharmaceutical compositions of the present invention can be used in a treatment method in isolation or in conjunction with other pharmaceutical compounds.
  • compositions or preparations and / or their formulations may be administered to an animal, including a mammal and, therefore, to man, in a variety of ways, including, but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intrathecal, intraventricular, oral, enteral, parenteral, intranasal or dermal.
  • EXAMPLE 1 The invention will now be illustrated by the test performed by the inventors. Randomized, double-blind, placebo-controlled clinical trial, one-way crossover to use vitamin C (ascorbic acid 400mg / day) and vitamin E (d-alpha tocopherol 400mg / day) for 29 weeks.
  • vitamin C ascorbic acid
  • vitamin E tocopherol
  • Age mean (d.s.) 66.80 64.54 1, 103 (42) .276
  • Phase II 12-week randomized double-blind period to be assigned to the treatment group of the combination of vitamin C (400mg of ascorbic acid / day) and vitamin E (d-alpha-tocopherol 400mg / day) or the placebo group.
  • Phase III 12-week period of open treatment of vitamin C (400mg of ascorbic acid / day) and vitamin E (d-alpha-tocopherol 400mg / day).
  • Phase IV One week without vitamin treatment.
  • EXAMPLE 2 To analyze the effect of the combination of antioxidants with antidepressants, the variable was analyzed if they took non-antidepressants of the selective serotonin reuptake inhibitor (SSRI) type. The results show, as shown in Table 3, that patients taking antidepressants with antioxidants reverse depressive symptoms in the first 12 weeks with a significantly statistical reduction in BDI values, however, those who only take antioxidants Depressive symptomatology takes longer to reverse, with a significant reduction in the evaluation observed at 24 weeks.
  • SSRI selective serotonin reuptake inhibitor
  • SSRI Selective serotonin reuptake inhibitor Table 3. Results of depressive symptomatology values in patients over 65 years according to the Beck Depression Inventory (BDI) efficacy of treatment with the combination of vitamins C and E, taking into account whether The population is under antidepressant treatment with a selective serotonin reuptake inhibitor.
  • BDI Beck Depression Inventory

Abstract

The invention relates to the use of antioxidants such as ascorbic acid (vitamin C) and tocopherol (vitamin E) to treat depression in patients aged over 65 years. Specifically, the invention relates to the use of said vitamins in specific therapeutic doses to maximise the amount of antioxidants in all the tissues of the body, in order to eliminate the excess free radicals produced in the cells and treat the disorder. Preferably, the antioxidants are combined with antidepressants of the selective serotonin reuptake inhibitor (SSRI) type to improve the efficacy of the treatment of depression.

Description

USO DE ANTIOXIDANTES PARA EL TRATAMIENTO DE LA DEPRESIÓN EN  USE OF ANTIOXIDANTS FOR THE TREATMENT OF DEPRESSION IN
PACIENTES MAYORES.  ELDERLY PATIENTS.
La presente invención se encuentra dentro del campo de la medicina, y se refiere al uso de antioxidantes como el ácido ascórbico (Vitamina C) y Tocoferol (Vitamina E) para tratamiento de la depresión en pacientes mayores de 65 años. En concreto se refiere al uso de la combinación de dichas vitaminas en dosis terapéuticas, con el fin de producir efectos antidepresivos, y del uso de la combinación de dichos antioxidante con antidepresivos del tipo ISRS para aumentar la eficacia del tratamiento de depresión. The present invention is within the field of medicine, and refers to the use of antioxidants such as ascorbic acid (Vitamin C) and Tocopherol (Vitamin E) for the treatment of depression in patients over 65 years. In particular, it refers to the use of the combination of said vitamins in therapeutic doses, in order to produce antidepressant effects, and the use of the combination of said antioxidants with antidepressants of the SSRI type to increase the effectiveness of the treatment of depression.
ESTADO DE LA TÉCNICA STATE OF THE TECHNIQUE
La proporción de personas mayores está aumentando rápidamente en todo el mundo. Según se calcula, entre 2015 y 2050 dicha proporción casi se duplicará, pasando de 12 a 22%. Más de un 20% de las personas que pasan de los 60 años de edad sufren algún trastorno mental o neural y el 6,6% de la discapacidad en ese grupo se atribuye a trastornos mentales y neurológicos. Concretamente en España, la esperanza de vida actual es de 82,87 años (80,08 años en varones y 85,58 años en mujeres), y se cifra que ei número de personas mayores de 65 años ya alcanza la cifra de 8,6 millones y representa el 18,5% de la población (datos del Instituto Nacional de Estadística INE, 2016). The proportion of older people is increasing rapidly worldwide. As calculated, between 2015 and 2050, this proportion will almost double, from 12 to 22%. More than 20% of people over 60 years of age suffer from a mental or neural disorder and 6.6% of the disability in that group is attributed to mental and neurological disorders. Specifically in Spain, the current life expectancy is 82.87 years (80.08 years in men and 85.58 years in women), and it is estimated that the number of people over 65 years already reaches the figure of 8, 6 million and represents 18.5% of the population (data from the National Statistics Institute INE, 2016).
Algunas patologías se encuentran con mayor frecuencia en los ancianos, entre ellas podemos citar las enfermedades del aparato circulatorio (insuficiencia cardíaca, enfermedades cerebro-vasculares, arteriesclerosis, hipertensión); los disturbios metabólicos, nutricionales y endocrinos (alteraciones del paladar, enfermedades periodontales, osteoporosis, incontinencia urinaria, artritis reumatoide, diabetes mellitus), trastornos mentales y de comportamiento (enfermedad de Alzheimer, enfermedad de Parkinson, depresión) que, de un modo general, necesitan ser tratadas con medicamentos. Some pathologies are found more frequently in the elderly, among them we can mention diseases of the circulatory system (heart failure, cerebrovascular diseases, arteriosclerosis, hypertension); metabolic, nutritional and endocrine disorders (palate disorders, periodontal diseases, osteoporosis, urinary incontinence, rheumatoid arthritis, diabetes mellitus), mental and behavioral disorders (Alzheimer's disease, Parkinson's disease, depression) which, in general, They need to be treated with medication.
Dentro de estas enfermedades, cabe destacar la depresión que es una de las principales causas de morbilidad a lo largo de la vida (Vos et al. 2010. Lancet 380, 2163-2196). El Trastorno Depresivo Mayor es una de las enfermedades mentales más prevalentes en el mundo occidental y se convertirá, según la Organización Mundial de la Salud (OMS), en la segunda causa de discapacidad en el mundo (después de la enfermedad coronaria) en el año 2020. Among these diseases, depression is one of the main causes of morbidity throughout life (Vos et al. 2010. Lancet 380, 2163-2196). Major Depressive Disorder is one of the most prevalent mental illnesses in the western world and will become, according to the World Health Organization (WHO), the second leading cause of disability in the world (after coronary heart disease) in the year 2020.
Los trastornos mentales y neurológicos más comunes en ancianos son la demencia y la depresión, que a escala mundial afectan aproximadamente al 5% y al 7%, respectivamente, de la población de adultos mayores. (OMS, 2017). Las personas mayores con depresión tienen un desempeño más deficiente en comparación con los que padecen enfermedades crónicas como las enfermedades pulmonares, la hipertensión arterial o la diabetes. Este trastorno también aumenta la percepción de tener mala salud, la utilización de los servicios médicos y los costos de la asistencia sanitaria. The most common mental and neurological disorders in the elderly are dementia and depression, which worldwide affect approximately 5% and 7%, respectively, of the elderly population. (WHO, 2017). Older people with depression have poor performance compared to those with chronic diseases such as lung diseases, high blood pressure or diabetes. This disorder also increases the perception of poor health, the use of medical services and the costs of healthcare.
La depresión es una enfermedad difícil de diagnosticar en ancianos, siendo ignorada o confundida con otras afecciones, ya que sus síntomas como la fatiga, la falta de apetito o los problemas para dormir también pueden ser parte del proceso de envejecimiento o de un padecimiento físico, lo que lleva a confundirla con el propio envejecimiento, por ello, existe un mayor riesgo de que no se aplique un tratamiento específico. Depression is a difficult disease to diagnose in the elderly, being ignored or confused with other conditions, since its symptoms such as fatigue, lack of appetite or sleeping problems can also be part of the aging process or of a physical condition, which leads to confuse it with aging itself, therefore, there is a greater risk that a specific treatment will not be applied.
En cuanto al tratamiento, para el uso de antidepresivos en ancianos hay que tener en cuenta algunas especificidades que no se tienen en otros grupos etaríos, la elección del antidepresivo se hace sobre todo en base a los efectos secundarios; la compatibilidad del tratamiento con otras patologías que presentara el anciano; el menor riesgo de interacciones de los antidepresivos con fármacos de uso continuo, como los usados para el tratamiento de hipertensión arterial, diabetes mellitus y/o problemas mentales; los cambios fisiológicos que ocurren con la edad, como las alteraciones en la absorción, distribución, metabolización y excreción de fármacos. As for the treatment, for the use of antidepressants in the elderly, some specificities that are not taken into account in other age groups must be taken into account, the choice of the antidepressant is mainly based on the side effects; the compatibility of the treatment with other pathologies presented by the elderly; the reduced risk of interactions of antidepressants with drugs of continuous use, such as those used for the treatment of hypertension, diabetes mellitus and / or mental problems; physiological changes that occur with age, such as alterations in the absorption, distribution, metabolization and excretion of drugs.
Respecto a los efectos secundarios de los antidepresivos, se pueden citar efectos de hepatotoxicidad como en los Inhibidores de la monoaminooxidasa. (IMAOs), alteraciones del Sistema cardiovascular (alteraciones en los valores de presión), alteraciones del sistema nervioso central ( sedación o conductas excitatorias), efectos anticolinérgicos (como constipación, sequedad bucal, retención urinaria, visión borrosa y taquicardia), reacciones gastrointestinales entre otros. En algunos casos como los antidepresivos triciclicos, (nortripilina y la desipramina), que tienen alta eficacia en el tratamiento de cuadros depresivos, los efectos secundarios en el anciano pueden constituir un problema más relevante, ya que, la acción anticolinérgica puede producir desde alteraciones cognitivas, con disminución de la memoria, hasta cuadros confusionales, como efectos periféricos, sequedad de boca, estreñimiento y retención urinaria. A pesar del correcto manejo de todos los antidepresivos, siempre hay que tener en cuenta sus posibles efectos adversos, ver siguiente tabla. Regarding the side effects of antidepressants, hepatotoxicity effects can be cited as in monoamine oxidase inhibitors. (MAOIs), alterations of the cardiovascular system (alterations in pressure values), alterations of the central nervous system (sedation or excitatory behaviors), anticholinergic effects (such as constipation, dry mouth, urinary retention, blurred vision and tachycardia), gastrointestinal reactions between others. In some cases, such as tricyclic antidepressants, (nortriptyline and desipramine), which have high efficacy in the treatment of depressive symptoms, side effects in the elderly may be a more relevant problem, since anticholinergic action can occur from cognitive alterations. , with decreased memory, to confusional conditions, such as peripheral effects, dry mouth, constipation and retention urinary In spite of the correct management of all antidepressants, its possible adverse effects must always be taken into account, see the following table.
Figure imgf000004_0001
Figure imgf000004_0001
En general, los antidepresivos de primera elección en este grupo etario, por su fácil manejo clínico, su eficacia y buena tolerancia con escasos efectos secundarios, son los Inhibidores selectivos de la recaptación de serotonina (ISRS) e inhibidores de la recaptación de noradrenalina, como la venlafaxina, su mecanismo de acción es similar a los tricíclicos pero sin presentar los efectos secundarios de éstos, por lo que no es necesario un ajuste de dosis por razones de edad, y tiene escasas interacciones con otros fármacos. Entre los posibles efectos adversos hay que tener en cuenta en este grupo, son la aparición de náuseas, sudoración, vértigo y nerviosismo. En pacientes con hipertensión arterial debe realizarse un control de la misma por existir riesgo de que se incremente. In general, the antidepressants of first choice in this age group, due to their easy clinical management, their efficacy and good tolerance with few side effects, are selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors, such as venlafaxine, its mechanism of action is similar to tricyclics but without presenting the side effects of these, so a dose adjustment is not necessary due to age, and has few interactions with other drugs. Among the possible adverse effects must be taken into account in this group, are the appearance of nausea, sweating, vertigo and nervousness. In patients with arterial hypertension, it should be checked because there is a risk that it will increase.
Como se ha expuesto, actualmente a pesar de todos los enfoques terapéuticos experimentales, los tratamientos farmacológicos de la depresión del anciano disponibles tienen un efecto limitado y tienen el inconveniente de dar lugar a efectos secundarios y frecuentes interacciones (Cooper y col, 2011. Am J Psychiatry. 168 (7):681-8.). Para este tipo de pacientes que suelen presentar pluripatología, se recomienda el uso de terapias alternativas y de baja intensidad (Kessler y cois, 2001 Am J Psychiatry. Feb; 158(2):289-94) por lo que es necesario desarrollar nuevos enfoques terapéuticos experimentales para mejorar la efectividad de los mismos. As stated above, despite all experimental therapeutic approaches, pharmacological treatments for elderly depression available have limited effect and have the disadvantage of giving rise to side effects and frequent interactions (Cooper et al, 2011. Am J Psychiatry. 168 (7): 681-8.). For this type of patients who usually present with pluripatology, the use of alternative and low-intensity therapies is recommended (Kessler and cois, 2001 Am J Psychiatry. Feb; 158 (2): 289-94) so it is necessary to develop new experimental therapeutic approaches to improve their effectiveness.
En esta línea, diversos estudios han planteado la hipótesis de que el aumento del estrés oxidativo y el envejecimiento celular están implicados en la fisiopatología de la depresión (Maes y cois, 2011. Neuropsychopharmacol Biol Psychiatry 35, 637-692) e implican el deterioro físico de los sujetos depresivos (Wolkowitz et al, 2011 Dialogues Clin Neurosci. 13, 25-39). En un reciente metanálisis se encontró que en la depresión hay un aumento del estrés oxidativo que mejora hasta cierto punto con el tratamiento antidepresivo (Jiménez-Fernández et al, 2015. J Clin Psychiatry. 2015;76 (12): 1658- 67). El estrés oxidativo es el resultado del desequilibrio entre los sistemas endógenos de defensa celular. Las especies reactivas de oxígeno (ROS) y las especies reactivas de nitrógenos (RNS) se producen en el funcionamiento celular normal y están imbricados en los mecanismos de defensa celular ante toxinas externas e internas. No obstante, en altas proporciones estas especies reactivas pueden actuar dañando el DNA, proteínas y lípidos celulares. Para evitarlo, el organismo está produciendo continuamente radicales libres en forma de oxígeno, superóxido, óxido nítrico, etc. Este equilibrio también está mediado por antioxidantes enzimáticos (superoxido dismutasa, catalasa y glutatión peroxidasa) y no enzimáticos (bilirrubina, ácido úrico, glutatión, vitaminas A, C y E, etc.). Along these lines, several studies have hypothesized that increased oxidative stress and cellular aging are involved in the pathophysiology of depression (Maes and cois, 2011. Neuropsychopharmacol Biol Psychiatry 35, 637-692) and involve physical deterioration of depressive subjects (Wolkowitz et al, 2011 Dialogues Clin Neurosci. 13, 25-39). In a recent meta-analysis it was found that in depression there is an increase in oxidative stress that improves to some extent with antidepressant treatment (Jiménez-Fernández et al, 2015. J Clin Psychiatry. 2015; 76 (12): 1658-67). Oxidative stress is the result of the imbalance between endogenous cellular defense systems. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) occur in normal cellular functioning and are embedded in cellular defense mechanisms against external and internal toxins. However, in high proportions these reactive species can act by damaging the DNA, proteins and cellular lipids. To avoid this, the body is continuously producing free radicals in the form of oxygen, superoxide, nitric oxide, etc. This balance is also mediated by enzymatic antioxidants (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymatic (bilirubin, uric acid, glutathione, vitamins A, C and E, etc.).
Experimentos recientes en modelos animales, llevan a concluir, por el test de supresión de la cola ( tail suspensión test, TST) y el test de natación forzado ( torced swim test ,FST) (Lobato et al., 2010. Behav Brain Res. 2010 Jun 19; 209 (2):249-59.), que el tratamiento con L-tocoferol mejora la respuesta antidepresiva. También se ha encontrado una asociación entre síntomas depresivos y el déficit vitamina C, (Gariballa et al, 2014. Int J Vitam Nutr Res. 84(1 -2): 12-17). Y se ha postulado su efecto terapéutico (Amr 2013 Nutrition J, 12-31.). Recent experiments in animal models lead to the conclusion of the tail suspension test (TST) and the forced swim test (FST) (Lobato et al., 2010. Behav Brain Res. 2010 Jun 19; 209 (2): 249-59.), That treatment with L-tocopherol improves the antidepressant response. An association has also been found between depressive symptoms and vitamin C deficiency, (Gariballa et al, 2014. Int J Vitam Nutr Res. 84 (1-2): 12-17). And its therapeutic effect has been postulated (Amr 2013 Nutrition J, 12-31.).
DESCRIPCIÓN DE LA INVENCIÓN DESCRIPTION OF THE INVENTION
Los autores de la presente invención han desarrollado una composición de antioxidantes, y una preparación combinada, para su uso en el tratamiento de la depresión en un mamífero, preferiblemente en humanos, más preferiblemente mayores de 65 años. Esta solución presenta la ventaja de que simplemente añadiendo un complejo vitamínico se puede mejorar la terapéutica antidepresiva, que en población anciana es limitada, y disminuir la toxicidad, lo cual se traduce en un mejor control de la enfermedad, posibilitando la reducción de la dosis de fármaco antidepresivo, y por tanto, los efectos adversos y las interacciones medicamentosas en estos pacientes de avanzada edad especialmente polimedicados.  The authors of the present invention have developed an antioxidant composition, and a combined preparation, for use in the treatment of depression in a mammal, preferably in humans, more preferably over 65 years. This solution has the advantage that simply adding a vitamin complex can improve antidepressant therapy, which in the elderly population is limited, and reduce toxicity, which translates into better disease control, making it possible to reduce the dose of antidepressant drug, and therefore, the adverse effects and drug interactions in these especially polymedicated elderly patients.
Por tanto, un primer aspecto de la invención se refiere a una composición o una preparación combinada que comprende un compuesto hidrofílico antioxidante y un compuesto lipofílico antioxidante, donde tanto el compuesto hidrofílico antioxidante como el compuesto lipofílico antioxidante se encuentran en una concentración de al menos 200 mg cada uno, para su uso en el tratamiento de la depresión en individuos mayores de 60 años, más preferiblemente de 65 años. Thus, a first aspect of the invention relates to a combination composition or preparation comprising an antioxidant hydrophilic compound and an antioxidant lipophilic compound, wherein both the antioxidant hydrophilic compound and the antioxidant lipophilic compound are at a concentration of at least 200 mg each, for use in the treatment of depression in individuals over 60 years, more preferably 65 years.
El término“compuesto hidrofílico” o“molécula hidrofílica” o“polar”, se refiere a toda molécula que tiene afinidad por el agua. Son moléculas que pueden formar un enlace transitorio con el agua (H20) por vinculación del hidrógeno. Esto es termodinámicamente favorable, y estas moléculas no sólo son solubles en agua, sino también en otros solventes polares. Por el contrario, no pueden difundirse a través de la membrana plasmática e interaccionan con receptores del citosol o del núcleo; por ejemplo, pero sin limitarnos, péptidos como la insulina, o proteínas como la hormona del crecimiento y pequeñas moléculas cargadas como la acetilcolina y otras derivadas de algunos aminoácidos como la epinefrina, la histamina, la serotonina y la dopamina, algunas de las cuales funcionan como hormonas o neurotransmisores. En estos casos, el efecto de la molécula ligada a la superficie celular es casi inmediato, pero persiste sólo por un periodo pequeño; sin embargo, el efecto de algunos factores tróficos se pueden extender por varios días, pues también pueden regular los patrones de expresión genética de la célula blanco. The term "hydrophilic compound" or "hydrophilic molecule" or "polar" refers to any molecule that has an affinity for water. They are molecules that can form a transient bond with water (H20) by hydrogen bonding. This is thermodynamically favorable, and these molecules are not only soluble in water, but also in other polar solvents. On the contrary, they cannot diffuse through the plasma membrane and interact with cytosol or nucleus receptors; for example, but not limited to, peptides such as insulin, or proteins such as growth hormone and small charged molecules such as acetylcholine and others derived from some amino acids such as epinephrine, histamine, serotonin and dopamine, some of which work as hormones or neurotransmitters. In these cases, the effect of the cell surface bound molecule is almost immediate, but it persists only for a small period; However, the effect of some trophic factors can be extended for several days, since they can also regulate the gene expression patterns of the white cell.
El término“compuesto lipofílico” o“molécula lipofílica”, se refiere a toda molécula que es soluble en lípidos. Son capaces de difundirse a través de la membrana plasmática e interaccionan con receptores del citosol o del núcleo; por ejemplo, pero sin limitarnos, las hormonas esteroideas, la tiroxina y los derivados del ácido retinoico. Después de atravesar la membrana plasmática, estas hormonas interactúan con receptores intracelulares, formando complejos capaces de incrementar o disminuir la trnscripción de genes específicos; estos complejos también contribuyen a la estabilidad de ciertos RNA mensajeros. Generalizando, estos compuestos ejercen su efecto por horas o días y contribuyen al crecimiento y diferenciación de tejidos específicos. Preferiblemente, las moléculas lipófilas tienen una solubilidad en agua inferior a 2,5 pg/ml, más preferiblemente inferior a 2 pg/ml, y aún más preferiblemente inferior a 1 pg/ml. The term "lipophilic compound" or "lipophilic molecule" refers to any molecule that is soluble in lipids. They are able to diffuse through the plasma membrane and interact with cytosol or nucleus receptors; for example, but not limited to, steroid hormones, thyroxine and retinoic acid derivatives. After crossing the plasma membrane, these hormones interact with receptors intracellular, forming complexes capable of increasing or decreasing the transcription of specific genes; These complexes also contribute to the stability of certain messenger RNAs. Generally speaking, these compounds exert their effect for hours or days and contribute to the growth and differentiation of specific tissues. Preferably, lipophilic molecules have a water solubility of less than 2.5 pg / ml, more preferably less than 2 pg / ml, and even more preferably less than 1 pg / ml.
El término“antioxidantes” se refiere a compuestos capaces de interceptar radicales libres, dándoles un átomo de hidrógeno activo o electrones, convirtiéndolos en compuestos más estables. Se pueden clasificar en dos grandes grupos, los solubles en agua (hidrofílicos) y los solubles en grasa (hidrofobicos). Dentro de los antioxidantes hidrofílicos están la vitamina C, ácido alfa-lipoico (Ala), glutatión, ácido úrico, catequinas, el Selenio, polifenoles, resveratol. Y dentro de los antioxidantes hidrofobicos están la vitamina E o tocoferoles, la vitamina A, los carotenoides (Beta- carotenos, Alfa-carotenos, Licopenos carotenoides, Luteina, Xantinas, Beta- criptoxantinas), Acido lipoico, Coenzima Q10 Ubiquinol, Astaxantinas. En una realización preferida de la presente invención el compuesto hidrofílico antioxidante empleado es la vitamina C y el compuesto lipofílico antioxidante empleado es la vitamina E. The term "antioxidants" refers to compounds capable of intercepting free radicals, giving them an active hydrogen atom or electrons, making them more stable compounds. They can be classified into two large groups, water soluble (hydrophilic) and fat soluble (hydrophobic). Among the hydrophilic antioxidants are vitamin C, alpha-lipoic acid (Ala), glutathione, uric acid, catechins, selenium, polyphenols, resveratol. And among the hydrophobic antioxidants are vitamin E or tocopherols, vitamin A, carotenoids (Beta-carotenes, Alpha-carotenes, Lycopene carotenoids, Lutein, Xanthines, Beta-cryptoxanthines), Lipoic acid, Coenzyme Q10 Ubiquinol, Astaxanthines. In a preferred embodiment of the present invention the antioxidant hydrophilic compound employed is vitamin C and the lipophilic antioxidant compound employed is vitamin E.
Los compuestos lipofílicos antioxidantes y los compuestos hidrofílicos antioxidantes se pueden emplear de forma separada o combinada, para alcanzar determinados efectos farmacológicos que actualmente no se pueden alcanzar con otros medicamentos. Es conocido que las vitaminas antioxidantes como el Tocoferol y el ácido ascórbico se potencian el poder antioxidante entre sí, diversos estudios han demostrado su efecto sinérgico, en los mecanismos de eliminación de los radicales libres (Cederberg. y col., 2001. Pediatr Res. 49(6):755-62.). El uso de combinación de antioxidantes se ha utilizado también como tratamiento de otras patologías como el Síndrome X Frágil SXF reconociéndose como medicamento huérfano (Pérez Costillas L y col., 2011. Tox. 109 (S.3): 41-71). También se ha encontrado potencia antidepresiva de la sinergia vitamina C con vitamina E (Maes y col, 2000. Neuropsychopharmacol Biol Psychiatry 35, 637-692). The antioxidant lipophilic compounds and the antioxidant hydrophilic compounds can be used separately or in combination, to achieve certain pharmacological effects that currently cannot be achieved with other medications. It is known that antioxidant vitamins such as Tocopherol and ascorbic acid enhance the antioxidant power of each other, several studies have shown their synergistic effect on the mechanisms of elimination of free radicals (Cederberg. Et al., 2001. Pediatr Res. 49 (6): 755-62.). The use of antioxidant combinations has also been used as a treatment for other diseases such as Fragile X SXF Syndrome, recognized as an orphan drug (Pérez Costillas L et al., 2011. Tox. 109 (S.3): 41-71). Antidepressant potency of vitamin C synergy with vitamin E has also been found (Maes et al, 2000. Neuropsychopharmacol Biol Psychiatry 35, 637-692).
El término“preparación combinada” o también denominada“yuxtaposición”, en esta memoria, significa que los componentes de la preparación combinada no necesitan encontrarse presentes como unión, por ejemplo en una composición, para poder encontrarse disponibles para su aplicación separada o secuencial. De esta manera, la expresión “yuxtapuesta” implica que no resulta necesariamente una combinación verdadera, a la vista de la separación física de los componentes. 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 composition, in order to be available for separate or sequential application. In this way, the expression "juxtaposed" implies that it is not necessarily a combination true, in view of the physical separation of the components.
En otro aspecto de la invención se describe una preparación combinada (de ahora en adelante preparación combinada de la invención) que comprende, un compuesto lipofílico antioxidante, la vitamina C y un compuesto hidrofílico antioxidante, la vitamina E. In another aspect of the invention a combined preparation (hereinafter combined preparation of the invention) is described which comprises an antioxidant lipophilic compound, vitamin C and an antioxidant hydrophilic compound, vitamin E.
En esta memoria se entiende por“Acido Ascórbico” o“Vitamina C” al enantiómero L del ácido ascórbico, de fórmula (I):  In this specification, "Ascorbic Acid" or "Vitamin C" means the enantiomer L of ascorbic acid, of formula (I):
Figure imgf000008_0001
Figure imgf000008_0001
Es un nutriente esencial para los humanos y un pequeño número de otras especies. La presencia de esta vitamina es requerida para un cierto número de reacciones metabólicas en todos los animales y plantas y es creada internamente por casi todos los organismos, siendo los humanos una notable excepción. Su deficiencia causa escorbuto en humanos, de ahí el nombre de ascórbico que se le da al ácido. En organismos vivos, el ascorbato es un antioxidante, pues protege el cuerpo contra la oxidación, y es un cofactor en varias reacciones enzimáticas vitales. En humanos, la vitamina C es un potente antioxidante, actuando para disminuir el estrés oxidativo; y es un substrato para la ascorbato-peroxidasa. Esta Vitamina actúa como cofactor necesario en reacciones enzimáticas como por ejemplo: enzimas participantes en la hidroxilación del colágeno. De esta manera la vitamina C se convierte en un nutriente esencial para el desarrollo y mantenimiento de tejido de cicatrización, vasos sanguíneos, y cartílago. También de enzimas necesarias para la síntesis de carnitina, que funciona en el transporte de ácidos grasos hacia la mitocondria para la generación de ATP. Enzimas que participan en la biosíntesis de norepinefrina a partir de dopamina a través de la enzima dopamina-beta-hidroxilasa. Otra enzima adiciona grupos amida a hormonas peptídicas, incrementando enormemente su estabilidad. También actúa como cofactor en el metabolismo de la tirosina. Los tejidos biológicos que acumulan más de 100 veces el nivel sanguíneo de vitamina C, son las glándulas adrenales, pituitaria, timo, cuerpo lúteo, y la retina. Aquellos con 10 a 50 veces la concentración presente en el plasma incluyen el cerebro, bazo, pulmón, testículos, nodulos linfáticos, mucosa del intestino delgado, leucocitos, páncreas, riñón y glándulas salivares. La vitamina C ayuda al desarrollo de dientes y encías, huesos, cartílagos, a la absorción del hierro, al crecimiento y reparación del tejido conectivo normal (piel más suave, por la unión de las células que necesitan esta vitamina para unirse), a la producción de colágeno (actuando como cofactor en la hidroxilación de los aminoácidos lisina y prolina), metabolización de grasas, la cicatrización de heridas. Se ha descrito recientemente que parte de la actividad antioxidante de la Vitamina C se debería a la inhibición de la actividad de la NADPH oxidasa en modelos animales. It is an essential nutrient for humans and a small number of other species. The presence of this vitamin is required for a certain number of metabolic reactions in all animals and plants and is created internally by almost all organisms, with humans being a notable exception. Its deficiency causes scurvy in humans, hence the name of ascorbic acid is given. In living organisms, ascorbate is an antioxidant, as it protects the body against oxidation, and is a cofactor in several vital enzymatic reactions. In humans, vitamin C is a potent antioxidant, acting to reduce oxidative stress; and is a substrate for ascorbate peroxidase. This Vitamin acts as a necessary cofactor in enzymatic reactions such as: enzymes involved in the hydroxylation of collagen. In this way, vitamin C becomes an essential nutrient for the development and maintenance of scar tissue, blood vessels, and cartilage. Also of enzymes necessary for the synthesis of carnitine, which works in the transport of fatty acids to the mitochondria for the generation of ATP. Enzymes that participate in the biosynthesis of norepinephrine from dopamine through the enzyme dopamine-beta-hydroxylase. Another enzyme adds amide groups to peptide hormones, greatly increasing its stability. It also acts as a cofactor in the metabolism of tyrosine. The biological tissues that accumulate more than 100 times the blood level of vitamin C, are the adrenal glands, pituitary, thymus, corpus luteum, and the retina. Those with 10 to 50 times the concentration present in the plasma include the brain, spleen, lung, testicles, lymph nodes, small intestine mucosa, leukocytes, pancreas, kidney and salivary glands. Vitamin C helps the development of teeth and gums, bones, cartilage, iron absorption, growth and repair of normal connective tissue (softer skin, by the union of cells that need this vitamin to join), to the Collagen production (acting as a cofactor in the hydroxylation of the amino acids lysine and proline), fat metabolization, wound healing. It has recently been described that part of the antioxidant activity of Vitamin C is due to the inhibition of NADPH oxidase activity in animal models.
El ser humano parece ser extremadamente eficiente en la reutilización de la vitamina C, por lo que sus requerimientos son 50 veces menores que en el resto de los simios. Al ser una vitamina hidrosoluble su eliminación por el riñón por diuresis es extremadamente eficaz, por lo que los excesos se pueden eliminar en menos de cuatro horas. The human being seems to be extremely efficient in the reuse of vitamin C, so its requirements are 50 times lower than in the rest of the apes. Being a water-soluble vitamin, its elimination by the kidney due to diuresis is extremely effective, so excesses can be eliminated in less than four hours.
En esta memoria se entiende por alfa-Tocoferol (Vitamina E), un compuesto de fórmula (II): Herein is understood as alpha-Tocopherol (Vitamin E), a compound of formula (II):
Figure imgf000009_0001
Figure imgf000009_0001
La vitamina E o alfa-tocoferol es un antioxidante liposoluble no enzimático, que puede funcionar como un indicador del estado oxidativo celular, limitando la propagación de la reacción en cadena de la peroxidación de lípidos. Es el antioxidante lipofílico principal del cerebro y previene significativamente la oxidación de lípidos, cuyos niveles son altos en cerebro y deben ser protegidos por antioxidantes. También se ha visto que muestra una protección significativa contra la citotoxicidad inducida por L- buthionine-sulfoximine (BSO), la cual causa la disminución del glutatión intracelular. La deficiencia en vitamina E se caracteriza generalmente por trastornos neurológicos debidos a una mala conducción de los impulsos nerviosos. El uso de antioxidantes como la Vitamina E en el tratamiento de enfermedades relacionadas con el estrés oxidativo, tales como la enfermedad de Alzheimer, o en la enfermedad de Parkinson ha mostrado que es capaz de retrasar el deterioro mental en pacientes con enfermedad de Alhzeimer. Además, la vitamina E redujo la peroxidación lipídica y la deposición amiloide en un modelo de ratón transgénico para la enfermedad de Alzheimer. Vitamin E or alpha-tocopherol is a non-enzymatic fat-soluble antioxidant, which can function as an indicator of cellular oxidative state, limiting the spread of the lipid peroxidation chain reaction. It is the main lipophilic antioxidant of the brain and significantly prevents the oxidation of lipids, whose levels are high in the brain and must be protected by antioxidants. It has also been shown to show significant protection against cytotoxicity induced by L-buthionine-sulfoximine (BSO), which causes the decrease in intracellular glutathione. Vitamin E deficiency is generally characterized by neurological disorders due to poor conduction of nerve impulses. The use of antioxidants such as Vitamin E in the treatment of diseases related to oxidative stress, such as Alzheimer's disease, or in Parkinson's disease has shown that it is capable of delaying mental deterioration in patients with Alhzeimer's disease In addition, vitamin E reduced lipid peroxidation and amyloid deposition in a transgenic mouse model for Alzheimer's disease.
La vitamina E desarrolla actividad antioxidante en lipoproteínas del líquido cefalorraquídeo (LCR) en presencia de cantidades fisiológicamente relevantes de oxidantes. Interesantemente, los niveles de vitamina E están disminuidos en LCR extraído de pacientes que sufren enfermedad de Alhzeimer y estos niveles se ven incrementados en pacientes que han sido tratados con suplementos con vitamina E. Vitamin E develops antioxidant activity in cerebrospinal fluid lipoproteins (CSF) in the presence of physiologically relevant amounts of oxidants. Interestingly, vitamin E levels are decreased in CSF extracted from patients suffering from Alhzeimer disease and these levels are increased in patients who have been treated with vitamin E supplements.
En otro aspecto de la invención la administración de la composición o la preparación combinada la dosis tanto del compuesto hidrofílico antioxidante como del hidrofílico antioxidante es de al menos 200 mg/día, y más preferiblemente de 250 mg/día, 300 mg/día, 350 mg/día, 375 mg/día, y aún mucho más preferiblemente de 400 mg/día. In another aspect of the invention the administration of the composition or the combined preparation the dose of both the antioxidant hydrophilic compound and the antioxidant hydrophilic is at least 200 mg / day, and more preferably 250 mg / day, 300 mg / day, 350 mg / day, 375 mg / day, and even more preferably 400 mg / day.
La dosificación para obtener una cantidad terapéuticamente efectiva depende de una variedad de factores, como por ejemplo, la edad que en la presente invención es de mayores de 60 años, peso, sexo, tolerancia, del mamífero. En el sentido utilizado en esta descripción, la expresión "cantidad terapéuticamente efectiva" se refiere a la cantidad de compuesto lipofílico antioxidante y de compuesto hidrofílico antioxidante que produzcan el efecto deseado y, en general, vendrá determinada, entre otras causas, por las características propias de dichos principios activos, profármacos, derivados o análogos y el efecto terapéutico a conseguir. The dosage to obtain a therapeutically effective amount depends on a variety of factors, such as, for example, the age that in the present invention is over 60 years, weight, sex, tolerance, of the mammal. In the sense used in this description, the term "therapeutically effective amount" refers to the amount of antioxidant lipophilic compound and antioxidant hydrophilic compound that produce the desired effect and, in general, will be determined, among other causes, by the proper characteristics. of said active ingredients, prodrugs, derivatives or analogs and the therapeutic effect to be achieved.
De acuerdo con las recomendaciones de Ingestas de energía y nutrientes recomendadas en la Unión Europea: 2008-2016, la ingesta diaria recomendada de vitamina C es de 80 mg y de la Vitamina E es de12 mg (García Gabarra et al. 2017. Nutr Hosp; 34(2):490-498). La academia de ciencia de estados Unidos recomienda una ingesta de 60-95 miligramos de vitamina C por día para mantener la salud. Según este organismo no se deben exceder los 2000 miligramos por día. La vida media de la vitamina C es de 16 días, y disminuye su vida media en personas con niveles elevados de este compuesto. According to the recommendations of energy and nutrient intakes recommended in the European Union: 2008-2016, the recommended daily intake of vitamin C is 80 mg and Vitamin E is 12 mg (García Gabarra et al. 2017. Nutr Hosp ; 34 (2): 490-498). The United States Academy of Science recommends an intake of 60-95 milligrams of vitamin C per day to maintain health. According to this organism, 2000 milligrams per day should not be exceeded. The half-life of vitamin C is 16 days, and its half-life decreases in people with elevated levels of this compound.
En una realización preferida de este aspecto de la invención, la cantidad tanto del compuesto lipofílico antioxidante, como compuesto hidrofílico antioxidante es de entre 200 y 500 mg, cada uno, preferiblemente al menos 200mg/día, cada uno, y aún mucho más preferiblemente 400 mg/día. En otra realización preferida se refiere a la composición farmacéutica que comprende, además, un excipiente farmacéuticamente aceptable. El término “excipiente” hace referencia a una sustancia que ayuda a la absorción, distribución o acción de cualquiera de los principios activos de la presente invención, estabiliza dicha sustancia activa o ayuda a la preparación del medicamento en el sentido de darle consistencia o aportar sabores que lo hagan más agradable. Así pues, los excipientes podrían tener la función de mantener los ingredientes unidos como por ejemplo almidones, azúcares o celulosas, función de endulzar, función de colorante, función de protección del medicamento como por ejemplo para aislarlo del aire y/o la humedad, función de relleno de una pastilla, cápsula o cualquier otra forma de presentación como por ejemplo el fosfato de calcio dibásico, función desintegradora para facilitar la disolución de los componentes y su absorción en el intestino, sin excluir otro tipo de excipientes no mencionados en este párrafo. In a preferred embodiment of this aspect of the invention, the amount of both the antioxidant lipophilic compound and the antioxidant hydrophilic compound is between 200 and 500 mg each, preferably at least 200 mg / day each, and even much more preferably 400 mg / day In another preferred embodiment it refers to the pharmaceutical composition which further comprises a pharmaceutically acceptable excipient. The term "excipient" refers to a substance that aids the absorption, distribution or action of any of the active ingredients of the present invention, stabilizes said active substance or aids in the preparation of the medicament in the sense of giving it consistency or providing flavors. Make it more enjoyable. Thus, the excipients could have the function of keeping the ingredients together such as starches, sugars or cellulose, sweetening function, dye function, drug protection function such as to isolate it from air and / or moisture, function filling a tablet, capsule or any other form of presentation such as dibasic calcium phosphate, a disintegrating function to facilitate the dissolution of the components and their absorption in the intestine, without excluding other types of excipients not mentioned in this paragraph.
El término excipiente “farmacéuticamente aceptable” hace referencia a que el excipiente esté permitido y evaluado de modo que no cause daño a los organismos a los que se administra. The term "pharmaceutically acceptable" excipient refers to the excipient being allowed and evaluated so as not to cause damage to the organisms to which it is administered.
Además, el excipiente debe ser farmacéuticamente adecuado, es decir, un excipiente que permita la actividad del principio activo o de los principios activos, es decir, que sea compatible con el principio activo, en este caso, el principio activo es cualquiera de los compuestos de la presente invención. In addition, the excipient must be pharmaceutically suitable, that is, an excipient that allows the activity of the active ingredient or of the active ingredients, that is, that is compatible with the active ingredient, in this case, the active ingredient is any of the compounds of the present invention.
En otro aspecto de la invención, la preparación combinada de la invención además comprende otro principio activo. En una realización preferida el otro principio activo se selecciona de la lista que consiste en: inhibidores selectivos de la recaptación de serotonina (ISRS), inhibidores selectivos de la recaptación de dopamina (ISRD), inhibidores selectivos de la recaptación de noradrenalina (o norepinefrina) (ISRN), inhibidores selectivos de la recaptación de serotonina y noradrenalina (o norepinefrina) (IRSN), inhibidores selectivos de la recaptación de dopamina y noradrenalina (o norepinefrina) (IRDN), antidepresivos tricíclicos (ATC), inhibidores de la monoaminooxidasa (IMAO), antagonistas e inhibidores de la recaptación de serotonina (AIRSs), noradrenérgicos y antidepresivos serotoninérgicos específicos (NaASE), potenciadores selectivos de la recaptación de serotonina (PSRS), opioides o cualquiera de sus combinaciones. En una realización aún más preferida la composición o la preparación combinada, donde el principio activo es un inhibidor selectivo de la recaptación de serotonina (ISRS). Los inventores de la presente invención han demostrado que la unión de los antioxidantes con antidepresivos ISRS son una opción terapéutica mejor que los antioxidantes o los antidepresivos individualmente. In another aspect of the invention, the combined preparation of the invention further comprises another active ingredient. In a preferred embodiment, the other active ingredient is selected from the list consisting of: selective serotonin reuptake inhibitors (SSRIs), selective dopamine reuptake inhibitors (ISRD), selective norepinephrine (or norepinephrine) reuptake inhibitors (ISRN), selective serotonin and norepinephrine (or norepinephrine) reuptake inhibitors (IRSN), selective dopamine and norepinephrine (or norepinephrine) reuptake inhibitors (IRDN), tricyclic antidepressants (ATC), monoamine oxidase inhibitors (MAOIs) ), serotonin reuptake antagonists and inhibitors (AIRSs), noradrenergic and specific serotonergic antidepressants (NaASE), selective serotonin reuptake enhancers (PSRS), opioids or any combination thereof. In an even more preferred embodiment the composition or the combined preparation, wherein the active ingredient is a selective serotonin reuptake inhibitor (SSRI). The inventors of the present invention have shown that the binding of antioxidants with SSRI antidepressants is a better therapeutic option than antioxidants or antidepressants individually.
Por tanto en otro aspecto de la invención la duración del tratamiento combinado de antioxidantes y antidepresivos es de al menos 24 días, preferiblemente entre 10 a 24 días, y aún más preferiblemente es de 12 días. Therefore in another aspect of the invention the duration of the combined treatment of antioxidants and antidepressants is at least 24 days, preferably between 10 to 24 days, and even more preferably it is 12 days.
Como se emplea aquí, el término“principio activo”,“substancia activa”,“substancia farmacéuticamente activa”, “ingrediente activo” ó “ingrediente farmacéuticamente activo” significa cualquier componente que potencialmente proporcione una actividad farmacológica u otro efecto diferente en el diagnóstico, cura, mitigación, tratamiento, o prevención de una enfermedad, o que afecta a la estructura o función del cuerpo del hombre u otros animales. El término incluye aquellos componentes que promueven un cambio químico en la elaboración del fármaco y están presentes en el mismo de una forma modificada prevista que proporciona la actividad específica o el efecto. 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.
Tanto las composiciones de la presente invención, así como la preparación combinada pueden formularse para su administración a un animal, y más preferiblemente a un mamífero, incluyendo al hombre, en una variedad de formas conocidas en el estado de la técnica. Así, pueden estar, sin limitarse, en disolución acuosa estéril o en fluidos biológicos, tal como suero. Las disoluciones acuosas pueden estar tamponadas o no tamponadas y tienen componentes activos o inactivos adicionales. Los componentes adicionales incluyen sales para modular la fuerza iónica, conservantes incluyendo, pero sin limitarse a, agentes antimicrobianos, antioxidantes, quelantes, y similares, y nutrientes incluyendo glucosa, dextrosa, vitaminas y minerales. Alternativamente, las composiciones pueden prepararse para su administración en forma sólida. Las composiciones pueden combinarse con varios vehículos o excipientes inertes, incluyendo pero sin limitarse a; aglutinantes tales como celulosa microcristalina, goma tragacanto, o gelatina; excipientes tales como almidón o lactosa; agentes dispersantes tales como ácido algínico o almidón de maíz; lubricantes tales como estearato de magnesio, deslizantes tales como dióxido de silicio coloidal; agentes edulcorantes tales como sacarosa o sacarina; o agentes aromatizantes tales como menta o salicilato de metilo. Both the compositions of the present invention, as well as the combined preparation can be formulated for administration to an animal, and more preferably to a mammal, including man, in a variety of ways known in the state of the art. Thus, they can be, without limitation, in sterile aqueous solution or in biological fluids, such as serum. Aqueous solutions may be buffered or unbuffered and have additional active or inactive components. Additional components include salts to modulate ionic strength, preservatives including, but not limited to, antimicrobial agents, antioxidants, chelators, and the like, and nutrients including glucose, dextrose, vitamins and minerals. Alternatively, the compositions can be prepared for administration in solid form. The compositions may be combined with various inert vehicles or excipients, including but not limited to; binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid or corn starch; lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint or methyl salicylate.
Las composiciones farmacéuticas de la presente invención pueden formularse para su administración en una variedad de formas conocidas en el estado de la técnica. En cada caso la forma de presentación de la composición farmacéutica se adaptará al tipo de administración utilizada, por ello, la composición de la presente invención se puede presentar bajo la forma de soluciones o cualquier otra forma de administración clínicamente permitida y en una cantidad terapéuticamente efectiva. The pharmaceutical compositions of the present invention can be formulated for administration in a variety of ways known in the state of the art. In each case the form of presentation of the pharmaceutical composition will adapt to the type of administration used, therefore, the composition of the present invention may be presented in the form of solutions or any other form of clinically permitted administration and in a therapeutically effective amount.
La composición farmacéutica de la presente invención puede ir asociada, por ejemplo, pero sin limitarse, con liposomas o micelas. Un liposoma es una vesícula esférica con una membrana fosfolipídica. El liposoma contiene un núcleo de solución acuosa. La micela es un lípido esférico que contiene material no acuoso. Tanto los liposomas como las micelas pueden utilizarse como transportadores de diversas sustancias entre el exterior y el interior de una célula. La composición farmacéutica de la presente invención puede ir asociada, por ejemplo, pero sin limitarse, con microcapsulas de polisacaridos solubles que forman vesículas esféricas con una envoltura de polisacárido hidratado y que pueden utilizarse como transportadores de diversas sustancias que no pueden mezclarse entre si, desde el exterior al interior del organismo y de sus órganos. Las composiciones farmacéuticas de la presente invención pueden utilizarse en un método de tratamiento de forma aislada o conjuntamente con otros compuestos farmacéuticos. Tales composiciones o preparaciones combinadas y/o sus formulaciones pueden administrarse a un animal, incluyendo un mamífero y, por tanto, al hombre, en una variedad de formas, incluyendo, pero sin limitarse a, intraperitoneal, intravenoso, intramuscular, subcutáneo, intratecal, intraventricular, oral, enteral, parenteral, intranasal o dérmico. The pharmaceutical composition of the present invention may be associated, for example, but not limited to, with liposomes or micelles. A liposome is a spherical vesicle with a phospholipid membrane. The liposome contains a core of aqueous solution. The micelle is a spherical lipid that contains non-aqueous material. Both liposomes and micelles can be used as carriers of various substances between the outside and inside of a cell. The pharmaceutical composition of the present invention can be associated, for example, but not limited to, with microcapsules of soluble polysaccharides that form spherical vesicles with a hydrated polysaccharide shell and which can be used as carriers of various substances that cannot be mixed together, from the outside inside the organism and its organs. The pharmaceutical compositions of the present invention can be used in a treatment method in isolation or in conjunction with other pharmaceutical compounds. Such combined compositions or preparations and / or their formulations may be administered to an animal, including a mammal and, therefore, to man, in a variety of ways, including, but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intrathecal, intraventricular, oral, enteral, parenteral, intranasal or dermal.
EJEMPLOS EXAMPLES
EJEMPLO 1 A continuación se ilustrará la invención mediante el ensayo realizado por los inventores. Ensayo clínico aletorizado, doble ciego controlado con placebo, cruzado de una vía para utilizar vitamina C (ácido ascórbico 400mg/día) y vitamina E (d-alfa tocoferol 400mg/día) durante 29 semanas. EXAMPLE 1 The invention will now be illustrated by the test performed by the inventors. Randomized, double-blind, placebo-controlled clinical trial, one-way crossover to use vitamin C (ascorbic acid 400mg / day) and vitamin E (d-alpha tocopherol 400mg / day) for 29 weeks.
Para evaluar el efecto de la combinación de una dosis terapéutica de dos conocidos antioxidantes el ácido ascórbico (vitamina C) y el tocoferol (vitamina E) para el tratamiento de depresión menor y la depresión leve en ancianos. To evaluate the effect of the combination of a therapeutic dose of two known antioxidants, ascorbic acid (vitamin C) and tocopherol (vitamin E) for the treatment of minor depression and mild depression in the elderly.
Se incluyeron en el estudio 44 participantes con rasgos sociodemográficos similares (Tabla 1), de las consultas de atención primaria de varios centros de salud del distrito sanitario de Málaga. El tamaño de la muestra se realizó utilizando el poder estadístico de la prueba 0,8 (1-a), con un nivel de significancia 0,05. Para asegurar el tamaño mínimo de la muestra con poder estadístico. The study included 44 participants with similar sociodemographic features (Table 1), of the primary care consultations of several health centers in the health district of Malaga. The sample size was performed using the statistical power of the test 0.8 (1-a), with a 0.05 level of significance. To ensure the minimum sample size with statistical power.
Placebo Vitaminas X2 (df) Z T (df) p (n = 20) (n = 24) Placebo Vitamins X2 (df) Z T (df) p (n = 20) (n = 24)
Edad: media (d.s.) 66,80 64,54 1 ,103(42) .276  Age: mean (d.s.) 66.80 64.54 1, 103 (42) .276
(6,26) (7,14)  (6.26) (7.14)
Mujeres: n (%) 19 (95%) 22 (91 ,7%) .191 (1) .662 Women: n (%) 19 (95%) 22 (91, 7%) .191 (1) .662
Estado Civil 1 (5%) 1 (4,2%) 4.204(4) .379Marital Status 1 (5%) 1 (4.2%) 4,204 (4) .379
Soltero 15 (75%) 18 (75%) Single 15 (75%) 18 (75%)
Casado 1 (5%) 2 (8,3%)  Married 1 (5%) 2 (8.3%)
Separado o divorciado 3 (15%) 3 (12,5%)  Separated or divorced 3 (15%) 3 (12.5%)
Viuda Widow
Nivel Educativo 3 (15%) 3 (12,5%) .776 (4) .942 Sin estudios primarios 14 (70%) 16 (66,6%)  Educational Level 3 (15%) 3 (12.5%) .776 (4) .942 Without primary studies 14 (70%) 16 (66.6%)
Estudios Primario 2 (10%) 2 (8,4%)  Primary Studies 2 (10%) 2 (8.4%)
Estudios Secundarios 1 (5%) 3 (12,5%)  Secondary Studies 1 (5%) 3 (12.5%)
Estudios Universitarios  University Studies
Ansiedad rasgo: mediana (IQR) 25,5 (15) 37 (19) -2,44 .015 Trait anxiety: median (IQR) 25.5 (15) 37 (19) -2.44 .015
Anxiety estado: mediana (IQR) 32 (17) 32 (15) -0,49 .623 Anxiety state: median (IQR) 32 (17) 32 (15) -0.49.623
Depresión: median (IQR) 19 (8) 22 (1 1) 0,22 .830 Depression: medium (IQR) 19 (8) 22 (1 1) 0.22 .830
Whodas: median (IQR) 10 (10) 13 (9) -1 ,51 .131Whodas: median (IQR) 10 (10) 13 (9) -1, 51 .131
Tabla 1. Datos sociodemográficos Placebo/Control (edad, sexo, comorbilidad, Medicación, efectos adversos) Los criterios de selección para mantener condiciones de doble ciego, se asignaron aleatoriamente al grupo de tratamiento o de placebo, a través de un programa informático de asignación al azar (Figura 1). Los criterios de inclusión de los pacientes reclutados, fueron diagnostico de depresión leve o moderada, de acuerdo con Mini Internacional Neuropsychiatric Interview (MINI), mayores de 65 años y firma del consentimiento. Los criterios de exclusión fueron Cualquier enfermedad avanzada grave o inestable. Diagnóstico previo y / o presencia de trastorno mental grave. Riesgo de comportamiento suicida. Cualquier régimen de tratamiento, incluido el tratamiento con fármacos psicotrópicos y / o terapia anticonvulsiva que no haya sido estable durante un período ³ 4 semanas antes de la asignación al azar. Tratamiento actual con más de dos medicamentos psicoactivos, incluyendo medicamentos para el control de las convulsiones. Ingerir más de 100 mg de vitamina E o C al día en los últimos 4 meses. Hipoprotrombinemia secundaria a deficiencia de vitamina K. Sensibilidad a la tartrazina o a los sulfitos. Deficiencia de G-6-PD. Tratamiento con anticoagulantes orales. Alergia a los componentes de la fórmula o excipiente utilizado. Table 1. Placebo / Control sociodemographic data (age, sex, comorbidity, Medication, adverse effects) The selection criteria for maintaining double-blind conditions were randomly assigned to the treatment or placebo group, through a randomization software (Figure 1). The inclusion criteria of the recruited patients were diagnosed with mild or moderate depression, according to Mini International Neuropsychiatric Interview (MINI), over 65 years old and signing of consent. The exclusion criteria were any serious or unstable advanced disease. Previous diagnosis and / or presence of serious mental disorder. Risk of suicidal behavior. Any treatment regimen, including treatment with psychotropic drugs and / or anticonvulsant therapy that has not been stable for a period ³ 4 weeks before randomization. Current treatment with more than two psychoactive medications, including seizure control medications. Ingest more than 100 mg of vitamin E or C daily in the last 4 months. Hypoprothrombinemia secondary to vitamin K deficiency. Sensitivity to tartrazine or sulphites. G-6-PD deficiency. Treatment with oral anticoagulants. Allergy to the components of the formula or excipient used.
Figure imgf000015_0001
Figure imgf000015_0001
3 ÍB^gD p!azo  3 ÍB ^ gD p! Azo
Fig. 1. Diagrama de flujo de ensayo Descripción y Duración del tratamiento: 29 semanas con diferentes fases: Fig. 1. Test flow diagram Description and Duration of treatment: 29 weeks with different phases:
Fase I. Periodo de 4 semanas de simple ciego placebo. Phase I. 4-week period of simple placebo blind.
Fase II: Periodo de 12 semanas de doble ciego Aleatorizado para asignarlo al grupo de tratamiento de la combinación de vitamina C (400mg de ácido ascórbico/día) y la vitamina E (d-alfa-tocoferol 400mg/día) o al grupo placebo. Phase II: 12-week randomized double-blind period to be assigned to the treatment group of the combination of vitamin C (400mg of ascorbic acid / day) and vitamin E (d-alpha-tocopherol 400mg / day) or the placebo group.
Fase III: Periodo de 12 semanas de tratamiento abierto de vitamina C (400mg de ácido ascórbico/día) y la vitamina E (d-alfa-tocoferol 400mg/día). Phase III: 12-week period of open treatment of vitamin C (400mg of ascorbic acid / day) and vitamin E (d-alpha-tocopherol 400mg / day).
Fase IV: Una semana sin tratamiento de vitaminas. Phase IV: One week without vitamin treatment.
Para evaluar la eficacia del ensayo del tratamiento se utilizaron las pruebas estadísticas, prueba T de Student o U Mann-Whitney para analizar las puntuaciones de homogeneidad entre los grupos (placebo vs tratamiento) y prueba Z de Wilconson para los análisis comparativos de la evolución pre y post del tratamiento. (Tabla 2). To evaluate the efficacy of the treatment trial, statistical tests, Student's T test or Mann-Whitney U test were used to analyze the homogeneity scores between the groups (placebo vs treatment) and Wilconson's Z test for comparative analyzes of pre-evolution and post treatment. (Table 2).
Median Median Median Median
N M (SD) (IQR) N M (SD) (IQR) p  N M (SD) (IQR) N M (SD) (IQR) p
Figure imgf000016_0001
Figure imgf000016_0001
Tabla 2. Comparación grupos Placebo/Control todas las evaluaciones de depresión.  Table 2. Placebo / Control groups comparison all depression evaluations.
Tras el análisis estadístico se demuestra la efectividad del tratamiento con una dosis terapéutica de la combinación de dos vitaminas (Vitamina C y E), 400mg/día de Vitamina C (ácido ascórbico) y 400mg/día de vitamina E (d-alfa-tocoferol) en personas mayores de 65 años con una combinación de tocoferol y ácido ascórbico ya que mejora a las 12 semanas de tratamiento los trastornos de ánimo y cognitivos en el grupo tratado comparado con el grupo placebo (P=0.013). After the statistical analysis the effectiveness of the treatment with a therapeutic dose of the combination of two vitamins (Vitamin C and E), 400mg / day of Vitamin C (ascorbic acid) and 400mg / day of vitamin E (d-alpha-tocopherol) is demonstrated ) In person over 65 years with a combination of tocopherol and ascorbic acid as it improves mood and cognitive disorders within 12 weeks of treatment in the treated group compared to the placebo group (P = 0.013).
EJEMPLO 2 Para analizar el efecto de la combinación de los antioxidantes con los antidepresivos, se analizo la variable si tomaban a no antidepresivos del tipo Inhibidor selectivo de la recaptación de la serotonina (ISRS). Los resultados demuestran, tal como se muestra en la tabla 3, que los pacientes que toman antidepresivos junto a los antioxidantes revierten la sintomatología depresiva en las primeras 12 semanas con una reducción significativamente estadística de los valores del BDI, sin embargo los que solo toman antioxidantes la sintomatología depresiva tarda más tiempo en revertir observándose una reducción significativa en la evaluación a las 24 semanas. EXAMPLE 2 To analyze the effect of the combination of antioxidants with antidepressants, the variable was analyzed if they took non-antidepressants of the selective serotonin reuptake inhibitor (SSRI) type. The results show, as shown in Table 3, that patients taking antidepressants with antioxidants reverse depressive symptoms in the first 12 weeks with a significantly statistical reduction in BDI values, however, those who only take antioxidants Depressive symptomatology takes longer to reverse, with a significant reduction in the evaluation observed at 24 weeks.
Figure imgf000017_0001
Figure imgf000017_0001
ISRS= Inhibidor selectivo de la recaptación de serotonina Tabla 3. Resultados de los valores de sintomatología depresiva en mayores de 65 años según el Inventario de Depresión de Beck (BDI) eficacia del tratamiento con la combinación de vitaminas C y E, teniendo en cuenta si la población está en tratamiento antidepresivo con un inhibidor selectivo de la recaptación de serotonina.  SSRI = Selective serotonin reuptake inhibitor Table 3. Results of depressive symptomatology values in patients over 65 years according to the Beck Depression Inventory (BDI) efficacy of treatment with the combination of vitamins C and E, taking into account whether The population is under antidepressant treatment with a selective serotonin reuptake inhibitor.
En conclusión la unión de los antioxidantes + antidepresivos ISRS es una opción terapéutica más eficaz que los antioxidantes o los antidepresivos individualmente en población de mayores de 65 años. In conclusion, the union of antioxidants + SSRI antidepressants is a more effective therapeutic option than antioxidants or antidepressants individually in a population over 65 years of age.

Claims

REIVINDICACIONES
1.- Una composición o una preparación combinada que comprende un compuesto hidrofílico antioxidante y un compuesto lipofílico antioxidante, donde tanto el compuesto hidrofílico antioxidante como el compuesto lipofílico antioxidante se encuentran en una concentración de al menos 200 mg cada uno, para su uso en el tratamiento de la depresión en individuos mayores de 60 años, más preferiblemente de 65 años. 1. A combined composition or preparation comprising an antioxidant hydrophilic compound and an antioxidant lipophilic compound, where both the antioxidant hydrophilic compound and the antioxidant lipophilic compound are in a concentration of at least 200 mg each, for use in the Depression treatment in individuals over 60 years, more preferably 65 years.
2.- La composición o la preparación combinada según la reivindicación 1 , donde la dosis tanto del compuesto hidrofílico antioxidante como del hidrofílico antioxidante es de al menos 200 mg/día, y más preferiblemente de 250 mg/día, 300 mg/día, 350 mg/día, 375 mg/día, y aún mucho más preferiblemente de 400 mg/día. 2. The combined composition or preparation according to claim 1, wherein the dose of both the antioxidant hydrophilic compound and the antioxidant hydrophilic compound is at least 200 mg / day, and more preferably 250 mg / day, 300 mg / day, 350 mg / day, 375 mg / day, and even more preferably 400 mg / day.
3.- La composición o la preparación combinada según cualquiera de las reivindicaciones 1-2, donde el compuesto hidrofílico antioxidante es el ácido ascórbico (Vitamina C) y donde el compuesto lipofílico antioxidante es el Tocoferol (Vitamina E). 3. The combined composition or preparation according to any of claims 1-2, wherein the antioxidant hydrophilic compound is ascorbic acid (Vitamin C) and wherein the antioxidant lipophilic compound is Tocopherol (Vitamin E).
4 La composición o la preparación combinada según cualquiera de las reivindicaciones 1-3, donde el tiempo de administración para es de al menos 20 días, más preferiblemente de al menos 29 días. The combined composition or preparation according to any one of claims 1-3, wherein the administration time for is at least 20 days, more preferably at least 29 days.
5.- La composición o la preparación combinada según cualquiera de las reivindicaciones 1-4, que además comprende un vehículo farmacéuticamente aceptable. 5. The combined composition or preparation according to any of claims 1-4, further comprising a pharmaceutically acceptable carrier.
6.- El uso de preparación combinada según cualquiera de las reivindicaciones 1-5, donde la administración del compuesto lipofílico antioxidante y del compuesto hidrofílico antioxidante se realiza de forma separada, simultánea ó secuencial. 6. The use of combined preparation according to any of claims 1-5, wherein the administration of the antioxidant lipophilic compound and the antioxidant hydrophilic compound is carried out separately, simultaneously or sequentially.
7.- La composición o la preparación combinada según cualquiera de las reivindicaciones 1-6, que además comprende otro principio activo. 7. The combined composition or preparation according to any of claims 1-6, which further comprises another active ingredient.
8.- La composición o la preparación combinada según la reivindicación 7, donde el otro principio activo es un antidepresivo. 8. The composition or the combined preparation according to claim 7, wherein the other active ingredient is an antidepressant.
9.- La composición o la preparación combinada según cualquiera de las reivindicación 8, donde el principio activo se selecciona de la lista que consiste en: inhibidores selectivos de la recaptación de serotonina (ISRS), inhibidores selectivos de la recaptación de dopamina (ISRD), inhibidores selectivos de la recaptación de noradrenalina (o norepinefrina) (ISRN), inhibidores selectivos de la recaptación de serotonina y noradrenalina (o norepinefrina) (IRSN), inhibidores selectivos de la recaptación de dopamina y noradrenalina (o norepinefrina) (IRDN), antidepresivos tricíclicos (ATC), inhibidores de la monoaminooxidasa (IMAO), antagonistas e inhibidores de la recaptación de serotonina (AIRSs), noradrenérgicos y antidepresivos serotoninérgicos específicos (NaASE), potenciadores selectivos de la recaptación de serotonina (PSRS), opioides o cualquiera de sus combinaciones. 9. The combined composition or preparation according to any of claims 8, wherein the active ingredient is selected from the list consisting of: inhibitors selective serotonin reuptake (SSRIs), selective dopamine reuptake inhibitors (ISRD), selective norepinephrine (or norepinephrine) (ISRN) reuptake inhibitors, selective serotonin and norepinephrine (or norepinephrine) reuptake inhibitors (or norepinephrine) ( IRSN), selective reuptake inhibitors of dopamine and norepinephrine (or norepinephrine) (IRDN), tricyclic antidepressants (ATC), monoamine oxidase inhibitors (MAOIs), serotonin reuptake inhibitors and serotonin reuptake inhibitors and serine reuptake inhibitors specific (NaASE), selective serotonin reuptake enhancers (PSRS), opioids or any combination thereof.
10.- La composición o la preparación combinada según cualquiera de las reivindicaciones 8-9, donde el principio activo es un inhibidor selectivo de la recaptación de serotonina (ISRS), 10. The combined composition or preparation according to any of claims 8-9, wherein the active ingredient is a selective serotonin reuptake inhibitor (SSRI),
11.- La composición o la preparación combinada según cualquiera de las reivindicaciones 8-10, donde el tiempo de administración es de entre 10 a 20 días, y más preferiblemente es de 12 días. 11. The combined composition or preparation according to any of claims 8-10, wherein the administration time is between 10 to 20 days, and more preferably is 12 days.
12.- El uso de preparación combinada según cualquiera de las reivindicaciones 8-11 , donde la administración del compuesto lipofílico antioxidante y del compuesto hidrofílico antioxidante y del inhibidor selectivo de la recaptación de serotonina (ISRS), se realiza de forma separada, simultánea ó secuencial. 12. The use of combined preparation according to any of claims 8-11, wherein the administration of the antioxidant lipophilic compound and the antioxidant hydrophilic compound and the selective serotonin reuptake inhibitor (SSRI), is carried out separately, simultaneously or sequential.
PCT/ES2019/070409 2018-06-13 2019-06-12 Use of antioxidants for the treatment of depression in older patients WO2019238998A1 (en)

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Citations (3)

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