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WO2012083034A1 - Modulation de facteurs neurotrophiques par des formulations d'acides gras oméga-3 - Google Patents

Modulation de facteurs neurotrophiques par des formulations d'acides gras oméga-3 Download PDF

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WO2012083034A1
WO2012083034A1 PCT/US2011/065189 US2011065189W WO2012083034A1 WO 2012083034 A1 WO2012083034 A1 WO 2012083034A1 US 2011065189 W US2011065189 W US 2011065189W WO 2012083034 A1 WO2012083034 A1 WO 2012083034A1
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omega
fatty acid
bdnf
treatment
disorders
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Louis Sanfilippo
Seth Feuerstein
Ann Coric
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • BDNF neurogenesis and synaptic plasticity in the brain. More specifically, the modulation of BDNF in the brain, and in particular the hippocampus, has special clinical relevance in the treatment of central nervous system disorders.
  • BDNF is a protein within the neurotrophin family of growth factors. It is genetically coded on chromosome 1 1 in humans and is associated with a number of polymorphisms, including Val66Met. Other known neurotrophins include neurotrophin-3 (NT-3), neurotrophin-4 (NT-4) and nerve growth factor (NGF). Neurotrophins exert important actions in both the central and peripheral nervous systems by enhancing neuronal growth, differentiation and synaptic plasticity. BDNF, among the most active neurotrophins, has significant neuronal actions in various areas of the brain, especially within the hippocampus and cortex (Altar, CA. 1999. Neurotrophins and depression. Trends Pharmacol Sci 20:59- 61).
  • BDNF may also play important roles in the human heart and vasculature, kidneys, and retina, among other body systems.
  • the hippocampus is an important region of the brain located in the medial temporal lobe and plays an integral role in memory and learning. It also has been shown to have a significant role in various CNS disorders including major depression and bipolar disorder (i.e., bipolar depression).
  • Omega-3 fatty acids are often referred to as "essential" fatty acids (EFAs) because they are needed for human health but are not sufficiently produced by the body alone.
  • EFAs essential fatty acids
  • the two major health promoting Omega-3 polyunsaturated fatty acids are eicosapentaenoic acid (EPA) and docosaliexaenoic acid (DHA).
  • EPA and DHA are naturally found in certain cold- water fatty fish, such as, salmon, tuna, and mackerel. They can also be derived in the body from alpha-linolenic acid (ALA), which is an Omega-3 fatty acid found in certain seeds and plant-based oils.
  • ALA alpha-linolenic acid
  • the body is very inefficient at converting ALA into EPA and DHA.
  • the invention provides methods of using Omega-3s fatty acids to modulate, or in preferred embodiments, to upregulate or increase, BDNF in a mammal and to treat a range of CNS disorders wherein BDNF modulation is important to the pathophysiology of the disorder and its treatment.
  • the BDNF gene encodes a precursor peptide, proBDNF that derives from a precursor protein preproBDNF that is synthesized in the endoplasmic reticulum. Any of these BDNF precursors can also be utilized as a biomarker target selected for modulation with omega-3 fatty acid formulations.
  • High purity Omega-3 fatty acid formulations including formulations which are disclosed in US Patent Nos. 8,071,646 and 7,652,068, can provide higher doses of EPA and DHA, in a safer and clinically optimal manner, than is capable through the ingestion of fish or low purity omega-3 fish oils.
  • the quality of products and the Omega-3 concentration is highly variable across the range of available products, from the prescription drug Lovaza (greater than 90% Omega-3 concentration and greater than 80% EPA plus DHA); to Epanova (a high purity mixture of free fatty acid forms of EPA and DHA), to supplements, such as, OMAX3 (greater than 90% Omega-3 concentration; EPA + DHA concentration >84%); to less optimal products that are less than 30% Omega-3 purity (and low EPA + DHA concentrations) and may carry large amounts of saturated fats or other unhealthy ingredients.
  • the products may vary in ratios of EPA to DHA, from pure EPA to pure DHA, such ratios in turn impact the efficacy of the Omega-3s against certain therapeutic targets.
  • the disclosure provides methods of using Omega-3 fatty acid formulations for the modulation of BDNF, in the hippocampus, serum, and cerebrospinal fluid. Also disclosed are methods for the treatment of various neurologic and psychiatric disorders with Omega-3 formulations wherein BDNF is therapeutically modulated , including but not limited to depressive disorders, bipolar disorders, schizophrenia and related psychotic disorders, Attention Deficit Hyerpactivity Disorder (ADHD), Alzheimer's Disease, learning disorders, autism, anxiety disorders, mild cognitive impairment, amnestic syndromes, stroke,
  • ADHD Attention Deficit Hyerpactivity Disorder
  • Huntington's Disease various learning disorders, and multiple sclerosis.
  • BDNF may also have beneficial effects in the periphery where such growth factors may play important intermediary roles in a number of conditions including cardiovascular diseases, endocrine disorders, inflammatory disorders, skin function, hematopoetic or immune function.
  • the present invention also provides for the modulation of BDNF, in the brain, in blood and in peripheral tissues to target disorders that may arise from the dysregulation of these growth factors. Identification and selection of patients for treatment with Omega-3 fatty acid formulations on the basis of serum BDNF levels are also disclosed in the invention.
  • the invention also provides for a novel form of modulating one or more of the family of tryrosine protein kinase receptors (trk).
  • Neurotropins including BDNF mediate their effects through two distinct families of receptors: the tyrosine kinase family of receptors (trk's) or p75 NTR .
  • the trks A-C are tyrosine protein kinases and activation of these receptors by neurotrophins can lead to cell proliferation, survival, chemotaxis and various responses to injury. TrkB is most closely linked to BDNF and may have special relevance in the pathophysiology of disease states and response to treatment within the central nervous and cardiovascular systems.
  • BDNF central nervous system
  • depressed subjects have been shown to have reduced levels of BDNF in the cortex and hippocampus.
  • Serum and plasma levels of BDNF have also been shown to be significantly reduced in depressed patients, and normalize after effective antidepressant treatment.
  • stress and depression may lead to strong downregulation of BDNF and mRNA BDNF in the hippocampus, which in turn may lead to hippocampal atrophy and cell loss, a finding seen in animal models of chronic stress or depression.
  • the direct infusion of BDNF into animal brains has demonstrated antidepressant effects.
  • BDNF and neurotrophic factors produced by antidepressant medications may play an important role in the cellular proliferation, enhanced synaptic activity and neurogenesis believed to play an important role in the treatment of chronic depression.
  • the modulation of BDNF in the central nervous system, especially in the hippocampus, may confer important therapeutic actions for the treatment of psychiatric and central nervous system disorders.
  • novel features of this invention provide for the modulation of neurotrophic factors including BDNF previously ascribed to non-omega-3 drugs and products, elucidating a mechanism of action whereby omega-3 formulations, and more preferably high purity omega-3 fatty acid formulations, may be used to modify important biomarkers implicated in psychiatric and central nervous system disorders, as well as other kinds of illness including cardiovascular diseases, inflammatory disorders, endocrine disorders, skin disorders, hematopoetic disorders or immune disorders.
  • the hippocampus structure consists of multiple layers of cells in essentially two basic fields, the dentate gyrus and the cornu ammonis (designated "CA", and including CA 1 , CA2, CA3).
  • the dentate gyrus consists of a layer of granule cells leading into a series of CA areas including CA1 , CA2, and CA3.
  • the dentate gyrus is one region of the brain currently known to exhibit high rates of neurogenesis in adult persons. In various animal models, chronic treatment with antidepressants in rodents has been shown to increase neurogenesis in the dentate gyrus while stress and depression have been shown to inhibit neurgogenesis.
  • the modulation of neurogenesis in the dentate gyrus is believed to play an important functional role in modulating symptoms of both depression and stress, and may have significant clinical and treatment implications in a range of other CNS disorders.
  • the hippocampal region CA3 receives input from the dentate gyrus and from the entorhinal cortex and has output to various brain regions including CA2 and CA1 in the hippocampal circuit.
  • CA1 consisting of pyramidal cells, receives input from the entorhinal cortex and has significant output pathways including to the entoirhinal cortex.
  • Disorders, such as, depression and Alzheimer's disease have been associated with reduced levels of BDNF and other growth nerve factors.
  • BDNF can be measured or assessed by various methods, known to one of ordinary skill in the art. BDNF can be detected and quantified through serum, plasma or blood analysis, CSF analysis, or measured in other tissues, such as the brain or heart. In obtaining a human patient's blood, serum BDNF can be measured by standard assays and is characteristically measured in units of ⁇ g/mL. The gene product, or BDNF protein, can be the basis of measurement for analytical determinations, as would occur in a blood test in human subject wherein serum or plasma BDNF levels is determined by standard assays for measuring serum or plasma BDNF levels. BDNF can also be calculated with regard to messenger RNA expression of the BDNF protein as well by in situ hybridization analysis using standard procedures.
  • mRNA analysis can provide information about the specific transcription patterns of the BDNF gene including the multiple transcripts that contribute to total BDNF mRNA expression or total BDNF protein production.
  • analyses are typically utilized post-mortem in animal or human subjects, though novel technologies are in development for determining BDNF in living mammals.
  • BDNF expression in various parts of the body, including the brain, the hippocampus of the brain, the blood or serum or plasma, the cerebrospinal fluid, or cells in the periphery, carry potential benefit in a range of disorders.
  • the present invention provides methods of treatment with Omega-3s fatty acids to modulate, or more specifically upregulate or increase BDNF in a mammal, and in particular a human patient, and to treat a range of CNS disorders wherein BDNF plays an important pathophysiologic role in the disorder.
  • BDNF or other neurotrophic factors can be used as biomarkers for identification, selection, monitoring, or modification, wherein the biomarker is utilized before treatment with Omega-3 fatty acid formulations as a target for modulation, and can be measured or monitored for such purposes with treatment by omega-3 formulations to assess its modulation, by known methods in the art that include but are not limited to serum or plasma BDNF measurements, mRNA expression of BDNF in the brain (i.e., the hippocampus) or in peripheral tissue (i.e., in cells or cell structures), or in cerebrospinal fluid.
  • the modulation of these neurotrophic factors may improve neurotrophic support in important brain structures, including the hippocampus and prefrontal cortex, and may promote angiogenesis, cellular proliferation, neurogenesis, or synaptic plasticity in certain brain structures.
  • the omega-3 formulations may be administered alone or in combination with another active agent, such as an antidepressant or mood stabilizing drug, to treat depression, for instance.
  • high purity Omega-3 fatty acid formulations including formulations which are disclosed in US Patent Nos. 8,071,646 and 7,652,068, can provide higher doses of EPA and DHA, in a safer manner, than is capable through the ingestion of fish or low purity omega-3 fish oils.
  • the present disclosure also provides methods for using highly purified omega-3 fatty acid formulations comprising EPA and DHA in a weight to weight ratio from about 3.5 to about 6.99: 1, and, more particularly, in a weight ratio from about 3.5: 1 to about 5: 1, from about 3.7: 1 to about 5: 1, and, from about 4: 1 to about 5: 1, and most specifically about 4: 1 or about 4.8: 1, the practice of which is disclosed in US Patent Nos. 8,071,646 and 7,652,068.
  • the pharmaceutical compositions comprise omega-3 fatty acids present in a concentration of at least 40% by weight as compared to the total fatty acid content of the composition.
  • the omega-3 fatty acids comprise at least 60% by weight of EPA and DHA as compared to the total weight content of the composition, and the EPA and DHA are in a weight ratio of EPA:DHA of from 99: 1 to 1 :99.
  • the omega-3 fatty acid composition mainly being EPA and DHA, may be present in any form or mixture of forms, including ethyl esters, triglycerides, and free fatty acid forms, as would be known to one of skill in the art in manufacturing omega-3 fatty acid formulations.
  • the duration of treatment with omega-3 fatty acid formulations for effecting the modulation of BDNF may vary and can be evaluated on a regular basis over an extended period of time, e.g. 1 to 12 weeks, and accompany monitoring of the core symptoms of the underlying disorder being treated, for instance, major depressive disorder or bipolar depression, with appropriate medical supervision, though monitoring BDNF over longer periods of time (i.e., 18 weeks, 26 weeks, 52 weeks) may be warranted to determine optimal efficacy in modulating BDNF and treating the disorder or disorders involving BDNF.
  • These compounds can be, for example, racemates or optically active forms.
  • these compounds can additionally be mixtures of diastereomers.
  • all optical isomers in pure form and mixtures thereof are encompassed.
  • compounds with carbon- carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds.
  • the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates.
  • Racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. All forms are contemplated herein regardless of the methods used to obtain them.
  • depression includes major depressive disorder, dysthymic disorder, depressive disorder not otherwise specified (for instance, premenstrual dysphoric disorder), and depressive episodes that may be present in another disorder (e.g. as in other mood disorders such as bipolar disorder or a mood disorder due to a general medical condition).
  • Remission in clinical studies of depression often refers to achieving at, or below, a particular numerical rating score on a depression symptoms rating scale (for instance, less than or equal to 7 on the HRSDn; or less than or equal to 5 on the QIDS-SR16; or less than or equal to 10 on the MADRS).
  • DHA is docosahexaenoic acid and "EPA” is eicosapentaenoic acid.
  • the terms EPA and DHA are used to indicate triglyceride, esterified and free fatty acid forms of these omega-3 fatty acids unless the triglyceride, esterified, or free fatty acid form is clearly indicated by the context.
  • DHA and EPA also include pharmaceutically acceptable fatty acid salts.
  • EPA and DHA may also represent the active ingredients of conjugated molecules wherein the omega-3 fatty acid provides an active ingredient in vivo but is conjugated with another drug, as the vehicle for its delivery.
  • Examples include fatty acid conjugates with salicylates, thioacetic acid salicylates, lipoic acid acylated salicylates, fibrates, fumarate, mycophenolate, raloxifene, niacin, acifran, or acipimox.
  • a “dosage form” means a unit of administration of an active agent.
  • dosage forms include tablets, capsules, particularly gel and liquid capsules, suspensions, liquids, candy and chewable formulations, emulsions, creams, ointments, suppositories, and the like.
  • an effective amount or "therapeutically effective amount” means an amount effective, when administered to a patient, to provide any therapeutic benefit.
  • a therapeutic benefit may be an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of a central nervous system disorder, an autoimmune disorder, chronic pain, an inflammatory disorder, or cardiovascular disease. In certain circumstances a patient may not present symptoms of a condition for which the patient is being treated.
  • a therapeutically effective amount of an active agent may also be an amount sufficient to provide a significant positive effect on any indicium of a disease, disorder, or condition, e.g. an amount sufficient to significantly reduce the frequency and severity of symptoms.
  • an “effective amount” or “therapeutically effective amount” of the omega-3 formulations provided herein may also be an amount of about of the formulation or of any dosage amount approved by a governmental authority such as the U.S. FDA, for use in treatment.
  • Effectiveness means the ability of an active agent administered to a patient to produce a therapeutic effect in the patient.
  • Gel capsule means any soft gelatin, liquid-filled capsule that contains a liquid, liquid suspension, solution, gel, or emulsion.
  • Liquid capsule is a capsule with a hard or soft capsule shell filled with a non-solid formulation.
  • the formulation may be for example a liquid, solution, suspension, emulsion or gel.
  • a "patient” means a human or non-human animal in need of medical treatment.
  • Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment.
  • the patient is a human patient.
  • Patients also includes veterinary patients, dogs, cats and horses are particularly included.
  • Providing means giving, administering, selling, distributing, transferring
  • Salts as used herein describes "pharmaceutically acceptable salts" of omega-3 fatty acids and other active agents discussed herein and also includes solvates and hydrates of such active agents.
  • the active agent may be modified by making non-toxic acid or base addition salt thereof.
  • pharmaceutically acceptable salts include mineral or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues; and the like, and combinations comprising one or more of the foregoing salts.
  • the pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the active agent.
  • non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like
  • alkaline earth metal salts such as calcium salt, magnesium salt, and the like, and combinations comprising one or more of the foregoing salts.
  • organic salts include salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC— (CH.sub.2).sub.n- COOH where n is 04, and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, ⁇ , ⁇ '- dibenzylethylenediamine salt, and the like; and amino acid salts such as argin,
  • omega-3 fatty acid formulations provided in this invention to modulate BDNF comprise omega-3 fatty acid compositions or formulations wherein EPA and DHA are present in a concentration of at least 40% by weight as compared to the total fatty acid content of the composition or formulation of omega-3 fatty acids.
  • the omega-3 fatty acids comprise at least 60% by weight of EPA and DHA as compared to the total fatty acid content of the composition or formulation, and the EPA and DHA are in a weight ratio of EPArDHA of from 99: 1 to 1 :99.
  • omega-3 fatty acid composition mainly being EPA and DHA in preferred compositions or formulations, may be present in any form or mixture of forms of EPA and DHA, including ethyl esters, triglycerides, and free fatty acids, as would be known to one of skill in the art in manufacturing omega-3 fatty acid compositions or
  • the quality of products and the Omega-3 concentration is highly variable across the range of available products, from the prescription drug Lovaza (greater than 90% Omega-3 concentration and greater than 80% EPA plus DHA); to Epanova (a high purity mixture of free fatty acid forms of EPA and DHA), to supplements, such as, OMAX3 (greater than 90% Omega-3 concentration; EPA + DHA concentration >84%, ethyl ester form); to less optimal products that are less than 30% Omega-3 purity (and having low EPA + DHA concentrations) and may carry large amounts of saturated fats or other unhealthy ingredients.
  • the products may vary in ratios of EPA to DHA, from pure EPA to pure DHA.
  • the present disclosure also provides methods for using highly purified omega-3 fatty acid formulations comprising EPA and DHA in a weight to weight ratio from about 3.5 to about 6.99: 1, and, more particularly, in a weight ratio from about 3.5: 1 to about 5: 1 , from about 3.7: 1 to about 5: 1 , and, from about 4: 1 to about 5: 1, and most specifically about 4: 1 or about 4.8: 1, the practice of which is disclosed in US Patent Nos. 8,071,646 and 7,652,068.
  • the invention provides omega-3 fatty acid formulations in which the amount of cholesterol in the formulation is less than 5% by weight, less than 2.5% by weight, or less than 1% by weight.
  • the invention also includes omega-3 fatty acid formulations in which the formulation comprises less than 20 milliequivalents per kg peroxides, less than 10 milliequivalents per kg peroxides, or less than 5 milliequivalents per kg peroxides.
  • the disclosure also provides dosage forms of such formulations comprising at least 50 mg DHA and at least 300 mg EPA in a unit dosage form.
  • the duration of treatment with omega-3 fatty acid formulations for the modulation of BDNF may vary and should be evaluated on a regular basis over an extended period of time, e.g. 1 to 12 weeks, and accompany monitoring of the core symptoms of the underlying disorder being treated, for instance, major depressive disorder or bipolar depression, with appropriate medical supervision, though monitoring BDNF for longer periods of time (i.e., 18 weeks, 26 weeks, 52 weeks) may be warranted to determine optimal efficacy on modulating BDNF.
  • an effective amount of an omega-3 fatty acid formulation as described herein, BDNF can be measured in conjunction with obtaining the patient's HAM-D scores or another depression symptom rating scale.
  • the HAM-D (Hamilton Depression) rating scale is a numerical scoring of depression symptoms that provides an indication of depression and over time provides a guide to treatment progress.
  • a HAM-D score of 10-13 indicates mild depression, 14-17 indicates mild to moderate depression and a score of greater than 17 indicates severe depression.
  • the present invention includes method sof using Omega-3 fatty acid formulations to modulate expression of BDNF, as measured by mRNA BDNF or BDNF protein, in the central nervous system, in particular within the hippocampus, or in the serum or blood or plasma, cerebrospinal fluid, or in cells or peripheral tissues.
  • BDNF modulates other neurotrophic factors or the tyrosine kinase family of receptors (trkA, trkB, or trkC) that derive signals from BDNF.
  • the Omega-3 fatty acids expressed neurotrophic factors that bound to the family of tyrosine receptor kinases and also have activity on tryrosine receptor kinases independent of neurotrophic signaling.
  • Omega-3 formulations and most particularly preferred embodiments of omega-3 formulations comprising EPA and DHA in a weight to weight ratio from about 3.5 to about 6.99: 1 , and, more particularly, in a weight ratio from about 3.5: 1 to about 5: 1 , from about 3.7: 1 to about 5:1, and, from about 4: 1 to about 5: 1 , and most specifically at about 4: 1 or about 4:8: 1.
  • Formulations having other EPA to DHA weight to weight ratios, and EPA and DHA concentrations, are also provided herein.
  • the disclosure also provides highly purified omega- 3 fatty acid formulations in which the content of EPA and DHA, taken together, is greater than 84% of the formulation by weight, and the omega-3 fatty acids comprise greater than 90% of the formulation by weight. Dosage, frequency and methods of administration of omega-3 fatty acid formulations are also described herein.
  • Omega-3 fatty acids play an important role in the human body and have a therapeutic role in a variety of central nervous system, autoimmune and inflammatory diseases, and cardiovascular disorders.
  • the Omega-3 fatty acids EPA and DHA play an important role in the oxidative metabolism of arachidonic acid, a pro-inflammatory mediator, and have been shown to exert multiple effects across a range of inflammatory, immunologic, and intracellular pathways. Most prominently, EPA and DHA decrease production of prostaglandin E 2 (PGE 2 ), thromboxane A 2 , and leukotriene B 4 .
  • PGE 2 prostaglandin E 2
  • thromboxane A 2 thromboxane A 2
  • leukotriene B 4 leukotriene
  • Such inflammatory mediators induce various inflammatory cascades and contribute to vascoconstriction, platelet aggregation, and oxidative damage.
  • Omega-3 fatty acids have been shown to affect of a host of cytokines and interleukins, all mediators of
  • BDNF and BDNF protein in the hippocampus represent an important, novel approach to modifying and increasing neurotrophic support in the central nervous system.
  • the increased expression of BDNF protein in the human brain, especially the hippocampus may play an important role in hippocampal neurogenesis, improved synaptic plasticity, and enhanced neuronal
  • trkB a tryosine protein kinase
  • trkB a tryosine protein kinase
  • Measurement of BDNF may be performed by analysis and quantification of BDNF protein or mRNA BDNF expression in the brain, in particular the hippocampus, or in the serum or blood or plasma, or cerebrospinal fluid, or in peripheral tissue or cells, of a mammal, and therefore can be utilized as a biomarker target for modification or modulation through the use of omega-3 fatty acid formulations.
  • BDNF levels are measured in a patient's serum following a blood sampling of the patient prior to treatment with the omega-3 fatty acid formulation. After a specified period of time with treatment by a therapeutically effective amount of an omega-3 fatty acid formulation as disclosed herein, serum BDNF is obtained from the patient following a blood sampling and demonstrates an increase in serum BDNF, therefore reflecting the therapeutic modulation of BNDF with the omega-3 fatty acid formulation.
  • serum BNDF is determined to be below a specific level for optimizing the efficacy for treatment with omega-3 fatty acid formulations, for instance, serum BDNF is determined to be less than 10 ⁇ g/mL, less than 15 ⁇ g/mL, less than 20 ⁇ g/mL, or less than 25 and treatment with omega-3 fatty acid formulations results in an increase in serum BDNF over the pre-treatment level.
  • the measurement of serum BDNF in a patient is accompanied with a pretreatment diagnosis of any one or more of the following: Alzheimer's dementia, anomic disorders (including drug induced anomia), anxiety disorders (generalized anxiety disorder, social anxiety disorder, phobias, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, acute stresss disorder), asperger's disorder, attention deficit disorder, attention-deficit hyperactivity disorder, autism, bipolar disorders, borderline personality disorder, chronic fatigue syndrome, cocaine and alcohol addition, cognitive disorders, communication disorders, dementia (including Alzheimer's, vascular, HIV, head trauma, Parkinson's,, Huntington's, Pick's Creutzfield Jacob, substance induced dementias, among others), depressive disorders (including major depressive disorder, dysthymia, childhood and adolescent depression, atypical depression, bipolar disorder, bipolar depression, bipolar mania, mania and hypomania), eating disorders (such as anorexia nervosa or bulimia nervo
  • dyslexia non-verbal learning disability, stuttering, reading, spelling, mathematics, receptive, expressive language, cooridination and motor skills disorders
  • Lyme's disease associated cognitive problems mild cognitive impairment, migraine, mood disorders, multiple sclerosis, neurocogntive decline (including related to surgery or cardiotomy or coronary artery bypass graft surgery), oppositional-defiant disorder,
  • Parkinson's disease pervasive developmental disorders, premenstrual dysphoric disorder (also known as premenstrual syndrome), psychotic disorders (including prodromal risk syndrome for first psychosis, brief psychotic disorder, schizopreniform disorder,
  • serum BNDF is determined to be below a specific level for optimizing the efficacy for treatment with omega-3 fatty acid formulations, for instance, serum BDNF is determined to be less than 10 ⁇ g/mL, less than 15 ⁇ g/mL, less than 20 g/mL, or less than 25 g mL ⁇ , and treatment with omega-3 fatty acid formulations results in an increase in serum BDNF over the pre-treatment level.
  • Serum BDNF measurements after treatment is initiated can also be used in conjunction with accepted scales and assessments for monitoring symptoms of any one or more of these diagnoses in a patient or for patients in a clinical study.
  • Methods of using serum BDNF as a biomarker target for the identification or selection of patients for treatment with omega-3 fatty acids formulations, and for modulation of BDNF (as measured by serum BDNF for instance) alone or in combination with monitoring symptoms of the disorder which is diagnosed pre-treatment, is another embodiment of this invention.
  • Methods of treatment with the omega-3 fatty acid formulations described herein include prophylaxis with Omega-3 formulations to prevent post-cardiotomy (including but not limited to coronary artery bypass graft surgery and valve surgery) complications (including but not limited to depression, neuro-cognitive decline, congestive heart failure and infarction, clotting events, and arrhythmias) and post-thoracotomy complications as well as for the treatment for such complications.
  • post-cardiotomy including but not limited to coronary artery bypass graft surgery and valve surgery
  • complications including but not limited to depression, neuro-cognitive decline, congestive heart failure and infarction, clotting events, and arrhythmias
  • post-thoracotomy complications including but not limited to depression, neuro-cognitive decline, congestive heart failure and infarction, clotting events, and arrhythmias
  • Increased neurotrophic support in the central nervous system as signaled by elevated BDNF may play an important role in a number of clinical conditions, in particular depression, bipolar disorder, schizophrenia, Alzheimer's disease, mild cognitive impairment, multiple sclerosis, autism, ADHD, ADD, learning disorders, dyslexia, response to stress, on account of its neurotrophic activity.
  • serum BDNF levels may represent a basis for the selection of patients at-risk for central nervous system disorders that may be amenable for Omega-3 fatty acid treatments as a primary or secondary prevention strategy; or may represent a biomarker which can be monitored and modulated as disease modifying target reflective of neurotrophic events occurring in various brain structures or structure in the periphery.
  • Omega-3 fatty acid formulations may also play an important role in the cardiovascular system where BDNF exerts actions that may mediate the repair of damaged cells, influence cellular growth and neovascularization, and affect inflammatory mediators, among other important actions.
  • the modulation of these factors in other parts of the body, including the cardiovascular system may have special relevance in the treatment of cardiovascular diseases that rely on agiogenic remodeling, such as following injury caused by myocardial infarction.
  • serum BDNF could be used in such patients to select preferred patients for augmentation treatment, or adjunctive therapy, with omega-3 fatty acid formulations.
  • Serum BDNF may be determined pre-treatment and then during treatment as a biomarker target used to identify patients more likely to respond to treatment or for signifying positive therapeutic response, wherein monitoring is done through either measurement of serum BDNF alone or, preferably, in conjunction with monitoring of symptoms of the disorder.
  • Omega-3 fatty acid formulations and dosage forms provided herein may be used alone or in combination with one or more other active agents.
  • the omega-3 fatty acid formulations provided herein may be used with other psychotropic agents including, for example, lithium, pharmaceutical antidepressants, herbal antidepressants (e.g., St. John's Wort, S-adenosylmethionine), anti-convulsants, mood stabilizers, antipsychotic agents, benzodiazepines, psychostimulants, and alpha-2 agonists.
  • these other agents may either be given together with omega-3 fatty acid in a single dosage form, or they may be administered separately.
  • the omega-3 formulations described herein may also be provided in combination with other active agents used to treat cardiovascular or inflammatory disorders.
  • the omega-3 formulations may be used in combination with agents used to treat dyslipidemia, for example the formulations may be used in combination with statins, fibrates, and bile acid binding resins, including atorvastatin calcium (tradename, LIPITOR), fenofibrate (tradename, TRICOR), gemfibrozil (LOPID), simvastatin (tradename, ZOCOR), rosuvastatin calcium (tradename, CRESTOR), pravastatin (tradename, PRAVACHOL), lovastatin (MEVACOR), rovastatin, fluvastatin, ezetimibe (tradename, ZETIA), ezetimibe/simvastatin (tradename, VYTORIN), and clopidpgrel bisulfate (tradename, PLAVIX).
  • statins tradename, LIPITOR
  • fenofibrate tradename,
  • omega-3 formulations described herein may also be used in combination with other classes of agents used to treat cardiovascular disorders including niacin, niacin derivatives, aspirin, diuretics, calcium channel blockers, antianginal drugs, anticoagulants, antithrombotic agents, cardiac iontropic agents, such as, digoxin, antihypertensive, and antiarrhythmics, such as, Amiodarone, beta blockers, and ACE inhibitors.
  • the omega-3 formulations described herein may also be used in combination with other classes of agents used to treat inflammatory disorders including antirheumatic agents, immunomodulators, and non-steroidal anti-inflammatory agents.
  • patients taking anti-depressants will continue taking other active agents they have been taking prior to omega-3 fatty acid treatment during the time at which omega-3 fatty acid treatment is begun.
  • Optimal dosages for each of the drugs may then be determined sequentially. For example, administration of one agent may be initiated and then optimized followed by the initiation and optimization of omega-3 fatty acid treatment. The monitoring and modulation of serum BDNF in such cases would occur as already described in this invention.
  • the problem of adjusting the dosages of multiple therapeutic agents is one that is routinely encountered by physicians and can be solved using well-established procedures similar to those discussed herein.
  • Antidepressants include selective serotonin reuptake inhibitors, selective serotonin norepinephrine reuptake inhibitors, and dopamine norepinephrine reuptake inhibitors, as well the specific drugs mirtazapine, vilazodone and bupropion.
  • Selective serotonin reuptake inhibitors include, but are not limited to, citalopram, escitalopram, femoxetine, fluoxetine, fluvoxamine, paroxetine, sertraline, and zimeldine.
  • Mixed serotonergic agents include vilazodone.
  • Selective serotonin norepinephrine reuptake inhibitors include, but are not limited to, duloxetine, venlafaxine, desvenlafaxine, milnacipran, and clovoxamine.
  • Norepephrine reuptake inhibitors include, but are not limited to, atomoxetine and reboxetine.
  • a dopamine norepinephrine reuptake inhibitor includes buporpion.
  • Tricyclic antidepressants include, but are not limited to, doxepin, amitriptytine, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, and trimipramine.
  • Anti-manic agents and mood stabilizing agents include, but are not limited to, carbamazepine, valproic acid and lithium.
  • Each individual is instructed to obtain serum BDNF via blood draw and then take an omega-3 fatty acid formulation having an EPA plus DHA concentration >60% of the total weight content of the composition, dosed between 500 to 3500 mg per day orally based on clinical judgment and tolerability, for a 12 week period of acute treatment, with maintenance treatment following the initial 12 week acute treatment period.
  • the dose may be titrated during acute treatment to an optimal dose range between 825 to 2750 mg, or may be administered without titration at any given dose between 825 to 2750 mg per day, depending on the individual's clinical needs.
  • serum BDNF is monitored at intervals of 4 weeks, 8 weeks and 12 weeks, after initiation of treatment with the omega-3 fatty acid formulation, to assess modulation of serum BNDF with treatment by the omega-3 fatty acid formulation.
  • Serum BNDF measurements may be taken during maintenance treatment, for instance, at 26 and 52 weeks.
  • the individuals are monitored regularly for efficacy of treatment on depressive symptoms and adverse effects of treatment.
  • the omega- 3 formulation may be dosed once or twice daily, depending on tolerability and other clinical factors, and it is recommended that the depressive symptoms are scored on a standard depression symptoms rating scale and assessed in conjunction with measurement of serum BDNF in the patient.
  • the dose of the omega-3 fatty acid formulation is a therapeutically effective amount to increase serum BDNF over pre-treatment baseline.
  • Each individual is instructed to obtain serum BDNF via blood draw and then take an omega-3 fatty acid formulation having an EPA plus DHA concentration >60% of the total weight content of the composition, dosed between 500 to 3500 mg per day orally based on clinical judgment and tolerability, for a 12 week period of acute treatment, with maintenance treatment following the initial 12 week acute treatment period.
  • the dose may be titrated during acute treatment to an optimal dose range preferably between 825 to 2750 mg, or may be administered without titration at any given dose preferably between 825 to 2750 mg per day, depending on the individual's clinical needs.
  • serum BDNF is monitored at intervals of 4 weeks, 8 weeks and 12 weeks, after initiation of treatment with the omega-3 fatty acid formulation, to assess modulation of serum BNDF with treatment by the omega-3 fatty acid formulation.
  • Serum BNDF measurements may be taken during maintenance treatment, for instance, at 26 and 52.
  • the individuals are monitored regularly for efficacy of treatment on depressive symptoms, manic symptoms, mixed mood symptoms, and adverse effects of treatment.
  • the omega-3 formulation may be dosed once or twice daily, depending on tolerability and other clinical factors, and it is recommended that the depressive symptoms are scored on a standard depression symptoms rating scale, or on the bipolar depression rating scale, and assessed in conjunction with measurement of serum BDNF in the patient.
  • the dose of the omega-3 fatty acid formulation is a therapeutically effective amount to increase serum BDNF over pre-treatment baseline.
  • Each individual is instructed to obtain serum BDNF via blood draw and then take an omega-3 fatty acid formulation having an EPA to DHA ratio of about 3.5 to about 5: 1, dosed between 500 to 3500 mg per day orally based on clinical judgment and tolerability, for a 12 week period of acute treatment, with maintenance treatment to following the initial 12 week acute treatment period.
  • the dose may be titrated during acute treatment to an optimal dose range preferably between 825 to 2750 mg, or may be administered without titration at any given dose range preferably between 825 to 2750 mg per day, depending on the individual's clinical needs.
  • serum BDNF is monitored at intervals of 4 weeks, 8 weeks and 12 weeks, after initiation of treatment with the omega-3 fatty acid formulation, to assess modulation of serum BNDF with treatment by the omega-3 fatty acid formulation.
  • Serum BNDF measurements may be taken during maintenance treatment at 26 and 52 weeks as well.
  • the individuals are monitored regularly for efficacy of treatment on depressive symptoms and adverse effects of treatment.
  • the omega-3 formulation may be dosed once or twice daily, depending on tolerability and other clinical factors, and it is recommended that the depressive symptoms are scored on a standard depression symptoms rating scale and assessed in conjunction with measurement of serum BDNF in the patient.
  • the dose of the omega-3 fatty acid formulation is a therapeutically effective amount to increase serum BDNF over pre-treatment baseline.
  • Each individual is instructed to obtain serum BDNF via blood draw and then take an omega-3 fatty acid formulation having an EPA to DHA ratio of about 3.5 to about 5: 1 , dosed between 500 to 3500 mg per day orally based on clinical judgment and tolerability, for a 12 week period of acute treatment, with maintenance treatment following the initial 12 week acute treatment period.
  • the dose may be titrated during acute treatment to an optimal dose preferably between 825 to 2750 mg, or may be administered without titration at any given dose range preferably between 825 to 2750 mg per day, depending on the individual's clinical needs.
  • serum BDNF is monitored at intervals of 4 weeks, 8 weeks and 12 weeks, after initiation of treatment with the omega-3 fatty acid formulation, to assess modulation of serum BNDF with treatment by the omega-3 fatty acid formulation.
  • Serum BNDF measurements may be taken during maintenance treatment at 26 and 52 weeks as well.
  • the individuals are monitored regularly for efficacy of treatment on depressive symptoms, manic symptoms, mixed mood symptoms, and adverse effects of treatment.
  • the omega-3 formulation may be dosed once or twice daily, depending on tolerability and other clinical factors, and it is recommended that the depressive symptoms are scored on a standard depression symptoms rating scale, or the bipolar depression rating scale, and assessed in conjunction with measurement of serum BDNF in the patient.
  • the dose of the omega-3 fatty acid formulation is a therapeutically effective amount to increase serum BDNF over pre- treatment baseline.
  • Sprague Dawley rats are administered omega-3 fatty acids with an EPA to DFIA ratio of about 3.5 to about 6.99, preferably in triglyceride form, dosed daily with same dose, from 50 to 150 mg/kg/day, for 30 days.
  • the brains are harvested following 30 days of treatment and post-mortem analysis of BDNF mRNA is determined by in situ hybridization analysis using standard procedures for subregions of the hippocampus (i.e., dentate gyrus, CAl, CA3) and the parietal cortex. Data is analyzed using analysis of variance (ANOVA) and Fisher's PLSD post hoc test, with a p ⁇ 0.05 as statistical significance.
  • ANOVA analysis of variance
  • Fisher's PLSD post hoc test with a p ⁇ 0.05 as statistical significance.
  • One-way ANOVA is used to establish a significant treatment effect for levels of BDNF mRNA in these brain regions, representing modulation, or increase, of BDNF by the therapeutically effective amount of
  • Sprague Dawley rats are administered omega-3 fatty acids with an EPA to DFIA ratio of about 4: 1, preferably in triglyceride form, dosed daily with same dose, from 50 to 150 mg/kg/day, for 30 days.
  • the brains are harvested following 30 days of treatment and postmortem analysis of BDNF mRNA is determined by in situ hybridization analysis using standard procedures for subregions of the hippocampus (i.e., dentate gyrus, CA1, CA3) and the parietal cortex. Data is analyzed using analysis of variance (ANOVA) and Fisher's PLSD post hoc test, with a p ⁇ 0.05 as statistical significance.
  • ANOVA analysis of variance
  • Fisher's PLSD post hoc test with a p ⁇ 0.05 as statistical significance.
  • One-way ANOVA is used to establish a significant treatment effect for levels of BDNF mRNA in these brain regions, representing modulation, or increase, of BDNF by the therapeutically effective amount of the omega-3 fatty acid
  • Sprague Dawley rats are administered an omega-3 fatty acid formulation having an EPA plus DHA concentration > 60% of the total weight content of the composition, preferably in free fatty acid form, dosed daily with same dose, from 50 to 150 mg kg/day, for 30 days.
  • the brains are harvested following 30 days of treatment and post-mortem analysis of BDNF mRNA is determined by in situ hybridization analysis using standard procedures for subregions of the hippocampus (i.e., dentate gyrus, CA1, CA3) and the parietal cortex. Data is analyzed using analysis of variance (ANOVA) and Fisher's PLSD post hoc test, with a p ⁇ 0.05 as statistical significance.
  • ANOVA analysis of variance
  • Fisher's PLSD post hoc test with a p ⁇ 0.05 as statistical significance.
  • One-way ANOVA is used to establish a significant treatment effect for levels of BDNF mRNA in these brain regions, representing modulation of BDNF by the omega-3 fatty acid formulation.

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Abstract

Selon l'invention des formulations d'acides gras oméga-3 sont utilisées pour la modulation du facteur neutrophique dérivé du cerveau (BDNP) dans l'hippocampe, le sérum et le liquide céphalorachidien. Une telle modulation est utilisée dans des procédés pour le traitement de divers troubles neurologiques et psychiatriques à l'aide des formulations d'oméga-3, dans lesquels le BDNF est thérapeutiquement modulé, dont les troubles dépressifs, les troubles bipolaires, la schizophrénie et les troubles psychotiques apparentés, le trouble déficitaire de l'attention avec hyperactivité (TDAH), la maladie d'Alzheimer, les troubles de l'apprentissage, l'autisme, les troubles d'anxiété, un trouble cognitif léger, les syndromes amnésiques, l'accident vasculaire cérébral, la maladie de Huntington, divers troubles de l'apprentissage et la sclérose en plaques. De plus, une telle modulation peut être provoquée dans le cerveau, le sang et/ou dans des tissus périphériques pour cibler des troubles qui peuvent résulter de la dérégulation de ces facteurs de croissance. En outre, des patients peuvent également être identifiés et choisis parmi des patients pour le traitement à l'aide des formulations d'acides gras oméga-3 sur la base de taux sériques de BDNF.
PCT/US2011/065189 2010-12-15 2011-12-15 Modulation de facteurs neurotrophiques par des formulations d'acides gras oméga-3 Ceased WO2012083034A1 (fr)

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WO2015138224A1 (fr) * 2014-03-13 2015-09-17 Sears Barry D Compositions et procédés pour atténuer une inflammation chronique de faible intensité
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US10117844B2 (en) 2012-01-06 2018-11-06 Omthera Pharmaceuticals, Inc. DPA-enriched compositions of omega-3 polyunsaturated fatty acids in free acid form
CN103908450A (zh) * 2012-12-31 2014-07-09 北京科源创欣科技有限公司 一种治疗抑郁症的复方组合物
WO2015138224A1 (fr) * 2014-03-13 2015-09-17 Sears Barry D Compositions et procédés pour atténuer une inflammation chronique de faible intensité
EP3310349B1 (fr) 2015-06-22 2021-01-13 Société des Produits Nestlé S.A. Compositions et méthodes pour augmenter la neurogénèse chez l'animal

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