WO2019238998A1 - Utilisation d'antioxydants pour le traitement de la dépression chez des patients adultes - Google Patents

Utilisation d'antioxydants pour le traitement de la dépression chez des patients adultes 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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Prior art keywords
antioxidant
preparation according
vitamin
day
norepinephrine
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PCT/ES2019/070409
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English (en)
Spanish (es)
Inventor
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/fr

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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

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Abstract

La présente invention porte sur l'utilisation d'antioxydants pour le traitement de la dépression chez des patients adultes de 65 ans. L'utilisation d'antioxydants comme l'acide ascorbique (Vitamine C) et le tocophérol (Vitamine E) pour le traitement de la dépression chez des patients adultes de 65 ans. Concrètement, l'invention porte sur l'utilisation desdites vitamines suivant des posologies thérapeutiques déterminées, afin d'avoir la meilleure quantité possible d'antioxydants dans tous les tissus de l'organisme pour éliminer l'excès de radicaux libres produits dans des cellules et traiter ledit trouble. De préférence, on combine lesdits antioxydants à des antidépresseurs du type ISRS pour augmenter l'efficacité du traitement de la dépression.
PCT/ES2019/070409 2018-06-13 2019-06-12 Utilisation d'antioxydants pour le traitement de la dépression chez des patients adultes WO2019238998A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998048788A1 (fr) * 1997-04-29 1998-11-05 Scotia Holdings Plc Traitement de la depression et de l'anxiete au moyen d'acide docosahexaenoique ou d'antioxydants naturels
WO1999017612A1 (fr) * 1997-10-08 1999-04-15 Serotoen, Incorporated Procede d'elaboration d'une preparation orale contenant de la serotonine, et methodes d'utilisation associees
WO2006119589A2 (fr) * 2005-05-11 2006-11-16 Ramaekers, Vincent Prevention et traitement de la carence en folates cerebraux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998048788A1 (fr) * 1997-04-29 1998-11-05 Scotia Holdings Plc Traitement de la depression et de l'anxiete au moyen d'acide docosahexaenoique ou d'antioxydants naturels
WO1999017612A1 (fr) * 1997-10-08 1999-04-15 Serotoen, Incorporated Procede d'elaboration d'une preparation orale contenant de la serotonine, et methodes d'utilisation associees
WO2006119589A2 (fr) * 2005-05-11 2006-11-16 Ramaekers, Vincent Prevention et traitement de la carence en folates cerebraux

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
AMR M ET AL.: "Efficacy of vitamin C as an adjunct to fluoxetine therapy in pediatric major depressive disorder: a randomized, double-blind, placebo- controlled pilot study", NUTRITION JOURNAL, vol. 12, no. 31, 2013, pages 1 - 8, XP021141838, Retrieved from the Internet <URL:http://www.nutritionj.com/content/12/1/31> [retrieved on 20190826] *
SCAPAGNINI G ET AL.: "Antioxidants as Antidepressants Fact or Fiction?", CNS DRUGS, vol. 26, no. 6, 2012, pages 477 - 490, XP55662659, Retrieved from the Internet <URL:https://www.researchgate.net/publication/225271908> [retrieved on 20190827], DOI: 10.2165/11633190 *

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