WO2018039526A1 - Traitement de troubles neurodégénératifs et de la douleur - Google Patents

Traitement de troubles neurodégénératifs et de la douleur Download PDF

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Publication number
WO2018039526A1
WO2018039526A1 PCT/US2017/048555 US2017048555W WO2018039526A1 WO 2018039526 A1 WO2018039526 A1 WO 2018039526A1 US 2017048555 W US2017048555 W US 2017048555W WO 2018039526 A1 WO2018039526 A1 WO 2018039526A1
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Prior art keywords
fluoxetine
pharmaceutically acceptable
acceptable salt
effective amount
therapeutically effective
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PCT/US2017/048555
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English (en)
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Adrian M. Corbett
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Wright State University
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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
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present disclosure relates generally to treatment of neurodegenerative disorders and pain, and to pharmaceutical compositions for the treatment of neurodegenerative disorders and pain.
  • Neurodegenerative disorders such as, e.g. , Alzheimer' s disease, Parkinson' s disease, and Huntington's disease, generally involve a decrease in neurogenesis. Neurogenesis is decreased by stress and increased by certain growth factors, such as, e.g. , brain-derived neurotrophic factor (hereinafter, "BDNF") and certain sex hormones, such as, e.g., estrogen, prolactin, and testosterone. Further, BDNF increases stem cell proliferation and neurogenesis. Despite ongoing research into neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, and Huntington' s disease remain incurable.
  • BDNF brain-derived neurotrophic factor
  • a subject in need thereof a therapeutically effective amount of simvastatin or a pharmaceutically acceptable salt thereof
  • C a therapeutically effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof.
  • compositions for the treatment of neurodegenerative disorders include: (A) a therapeutically effective amount of simvastatin or a pharmaceutically acceptable salt thereof, (B) a therapeutically effective amount of at least one of fluoxetine racemate or a pharmaceutically acceptable salt thereof, enantiopure (S) -fluoxetine or a pharmaceutically acceptable salt thereof, or enantioenriched fluoxetine having an enantiomeric excess of (S)-fluoxetine or a pharmaceutically acceptable salt thereof, and (C) a therapeutically effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof.
  • methods for the treatment or management of pain include administering to a subject in need thereof: (A) a therapeutically effective amount of simvastatin or a pharmaceutically acceptable salt thereof, (B) therapeutically effective amount of at least one of fluoxetine racemate or a pharmaceutically acceptable salt thereof, enantiopure (S) -fluoxetine or a pharmaceutically acceptable salt thereof, or enantioenriched fluoxetine having an enantiomeric excess of (S)-fluoxetine or a pharmaceutically acceptable salt thereof, and (C) a therapeutically effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof.
  • compositions for the treatment or management of pain include: (A) a therapeutically effective amount of simvastatin or a pharmaceutically acceptable salt thereof, (B) therapeutically effective amount of at least one of fluoxetine racemate or a pharmaceutically acceptable salt thereof, enantiopure (S) -fluoxetine or a pharmaceutically acceptable salt thereof, or enantioenriched fluoxetine having an enantiomeric excess of (S)-fluoxetine or a pharmaceutically acceptable salt thereof, and (C) a therapeutically effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof.
  • FIG. 1 is representative images of Ki67 staining in anterior ventricles of 11 month-old female Sprague Dawley rats, wherein Panel (A) shows Ki67 staining in control rats administered vehicle for 30 days, wherein the scale bar shows 100 micrometers; Panel (B) shows Ki67 staining in rats administered simvastatin (1 mg/kg per day), ascorbic acid (20 mg/kg per day), and fluoxetine (5 mg/kg per day) for 30 days; Panel (C) shows the respective mask used to measure the area of Ki67 staining in ImageJ from Panel (A); and Panel (D) shows the respective mask used to measure the area of Ki67 staining in Panel (D);
  • FIG. 2 is a graph of Female Sprague Dawley rats administered vehicle (i.e. , Control), simvastatin (i.e., Simvastatin, 1 mg/kg per day), fluoxetine (i.e., Fluoxetine, 5 mg/kg per day), fluoxetine + simvastatin (i.e., Fluoxetine, Statin), or fluoxetine + simvastatin + ascorbic acid (20 mg/kg per day) (i.e., collectively SAAF) for 30 days with respect to Ki67 area (mm ).
  • simvastatin i.e., Simvastatin, 1 mg/kg per day
  • fluoxetine i.e., Fluoxetine, 5 mg/kg per day
  • fluoxetine + simvastatin i.e., Fluoxetine, Statin
  • fluoxetine + simvastatin + ascorbic acid 20 mg/kg per day
  • Each symbol represents the mean area of Ki67 staining of the subventricular zone of 25 coronal brain sections taken from a single rat.
  • the mean for each group is indicated by the wide horizontal bar.
  • the error bar represents the standard deviation for each group.
  • FIG. 3 is graph of Male Sprague Dawley rats administered vehicle (i.e., Control), simvastatin (i.e., Statin, 1 mg/kg per day), fluoxetine (i.e., Fluoxetine, 5 mg/kg per day), fluoxetine + simvastatin (i.e., Fluoxetine, Statin), or fluoxetine + simvastatin + ascorbic acid (20 mg/kg per day) (i.e., SAAF) for 30 days with respect to Ki67 area (mm ).
  • simvastatin i.e., Statin, 1 mg/kg per day
  • fluoxetine i.e., Fluoxetine, 5 mg/kg per day
  • fluoxetine + simvastatin i.e., Fluoxetine, Statin
  • fluoxetine + simvastatin + ascorbic acid 20 mg/kg per day
  • Each symbol i.e., circle, square, triangle, shaded circle, and diamond
  • the mean for each group is indicated by the wide horizontal bar.
  • the error bar represents the standard deviation for each group. Fluoxetine significantly decreased stem cell proliferation compared to both Control and SAAF (one way ANOVA);
  • FIG. 4A is a bar graph of 11-month old Male Sprague Dawley rats and 11-month old Female Sprague Dawley rats administered vehicle (i.e., Control) with respect to Ki67 area (mm ).
  • Each bar represents the mean Ki67 staining area and standard error of the mean (i.e., SEM) for Male versus Female Sprague Dawley rats, wherein the subventricular zone is separated into anterior region (i.e., light gray, speckled bars - left), middle region (i.e., gray bars - middle), and posterior region (i.e., black bars - right).
  • Significant differences were shown by a line over the significantly different group with the P value on top of the line (2-way ANOVA);
  • FIG. 4B is a bar graph of Male Sprague Dawley rats and Female Sprague Dawley rats administered 1 mg/kg simvastatin for 30 days with respect to Ki67 area (mm ).
  • Each bar represents the mean Ki67 staining area and SEM for Male versus Female Sprague Dawley rats, wherein the subventricular zone is separated into anterior region (i.e., light gray speckled bars - left), middle region (i.e., gray bars - middle in Male rats, right in Female rats), and posterior region (i.e., black bars - right in Male rats, not present in Female rats).
  • anterior region i.e., light gray speckled bars - left
  • middle region i.e., gray bars - middle in Male rats, right in Female rats
  • posterior region i.e., black bars - right in Male rats, not present in Female rats.
  • Significant differences were shown by a line over the significantly different group with the P value on top of the line (2- way ANOVA);
  • FIG. 4C is a bar graph of Male Sprague Dawley rats and Female Sprague Dawley rats administered 5 mg/kg fluoxetine for 30 days with respect to Ki67 area (mm ).
  • Each bar represents the mean Ki67 staining area and SEM for Male versus Female Sprague Dawley rats, wherein the subventricular zone is separated into anterior region (i.e., light gray speckled bars - left), middle region (i.e., gray bars - middle), and posterior region (i.e., black bars - right).
  • anterior region i.e., light gray speckled bars - left
  • middle region i.e., gray bars - middle
  • posterior region i.e., black bars - right
  • FIG. 4D is a bar graph of Male Sprague Dawley rats and Female Sprague Dawley rats administered 5 mg/kg fluoxetine and 1 mg/kg simvastatin for 30 days with respect to Ki67 area (mm ).
  • Each bar represents the mean Ki67 staining area and SEM for Male versus Female Sprague Dawley rats, wherein the subventricular zone is separated into anterior region (i.e., light gray speckled bars - left), middle region (i.e., gray bars - middle), and posterior region (i.e., black bars - right).
  • anterior region i.e., light gray speckled bars - left
  • middle region i.e., gray bars - middle
  • posterior region i.e., black bars - right
  • FIG. 4E is a bar graph of Male Sprague Dawley rats and Female Sprague Dawley rats administered 5 mg/kg fluoxetine, 1 mg/kg simvastatin, and 20 mg/kg ascorbic acid for 30 days with respect to Ki67 area (mm ).
  • Each bar represents the mean Ki67 staining area and SEM for Male versus Female Sprague Dawley rats, wherein the subventricular zone is separated into anterior region (i.e. , light gray speckled bars - left), middle region (i.e. , gray bars - middle), and posterior region (i.e., black bars - right).
  • Significant differences were shown by a line over the significantly different group with the P value on top of the line (2-way ANOVA);
  • FIG. 5 is a graph of female rats administered (S)-Fluoxetine (5 mg/kg), Simvastatin (1 mg/kg) and Ascorbic Acid (20 mg/kg) (i.e., FS-fluoxetine), female rats administered (R)- Fluoxetine (5 mg/kg), Simvastatin (1 mg/kg) and Ascorbic Acid (20 mg/kg) (i.e.
  • FR-fluoxetine male rats administered (S)-Fluoxetine (5 mg/kg), Simvastatin (1 mg/kg) and Ascorbic Acid (20 mg/kg) (i.e., MS-fluoxetine), and male rats administered (K)-Fluoxetine (5 mg/kg), Simvastatin (1 mg/kg) and Ascorbic Acid (20 mg/kg) (i.e., MR-fluoxetine) for a period of six days following stroke with respect to Evans Blue dye (i.e., ⁇ g/gm) measured in brain tissue surrounding the infarcted region of the brain;
  • Evans Blue dye i.e., ⁇ g/gm
  • FIG. 6 is a histological image of the coronal brain sections of male rats administered Fluoxetine (5 mg/kg), Simvastatin (1 mg/kg), and Ascorbic Acid (20 mg/kg) 6-12 hours post- stroke induction (Panel (B)), 20-26 hours post-stroke induction (Panel (C)), or 48-56 hours post- stroke induction (Panel (D)) stained with Hematoxylin and eosin stain.
  • Control rats (Panel (A)) were not administered any drugs.
  • Enclosed dashed lines represent the infarcted area in the right hemisphere of the rats. The stained region within the enclosed dashed lines indicates migration of microglia, macrophages, and/or neutrophils into the cortex surrounding the infarction.
  • the scale bar in Panel (C) is 500 micrometers; and
  • FIG. 7 is a graph of male rats administered Fluoxetine (5 mg/kg), Simvastatin (1 mg/kg), and Ascorbic Acid (20 mg/kg) 6- 12 hours post-stroke induction (i.e. , 6- 12 hours), 20-26 hours post-stroke induction (i.e., 20-26 hours), or 48-54 hours post-stroke induction (i.e., 48-54 hours), or administered no drug treatment (i.e. , Control) with respect to volume of infarction (i.e., Volume of Infarcts (mm )). The volume of infarction was measured in coronal brain sections of rats.
  • treat refers to delaying acquisition, inhibiting development or progression of, stabilizing, and/or causing regression of a disease, disorder, and/or symptom thereof.
  • the term "subject in need thereof as used herein, refers to a subject at risk for developing a neurodegenerative disorder, a subject exhibiting symptoms associated with a neurodegenerative disorder, a subject having a neurodegenerative disorder, a subject at risk for developing pain, a subject exhibiting symptoms associated with pain, and/or a subject having pain.
  • therapeutically effective amount refers to an amount necessary or sufficient to realize a desired biologic effect.
  • the therapeutically effective amount may vary depending on a variety of factors known to those of ordinary skill in the art, including but not limited to, the particular composition being administered, the activity of the composition being administered, the size of the subject, the sex of the subject, the age of the subject, the general health of the subject, the timing and route of administration, the rate of excretion, the administration of additional medications, and/or the severity of the disease or disorder being treated.
  • the term therapeutically effective amount refers to the amount of the simvastatin, fluoxetine, or ascorbic acid necessary or sufficient to treat a neurodegenerative disorder and/or pain.
  • the term therapeutically effective amount refers to the amount of the simvastatin, fluoxetine, or ascorbic acid necessary or sufficient to increase stem/progenitor cell proliferation and/or neurogenesis in a subject relative to a baseline level. In other specific embodiments, the term therapeutically effective amount refers to the amount of the simvastatin, fluoxetine, or ascorbic acid necessary or sufficient to transform at least one Ml inflammatory type microglial cell to at least one M2 neuroprotective microglial cell. In still other specific embodiments, the term therapeutically effective amount refers to the amount of the simvastatin, fluoxetine, or ascorbic acid necessary or sufficient to restore impermeability of the blood brain barrier.
  • the term therapeutically effective amount refers to the amount of simvastatin, fluoxetine, or ascorbic acid necessary or sufficient to reduce infarction size and/or to reduce migration of macrophages, neutrophils, and/or proliferation of activated microglia within an infarcted region following an ischemic event.
  • pharmaceutically acceptable refers to a pharmaceutically active agent and/or other agents/ingredients for use in a pharmaceutical composition which are not deleterious to a subject receiving the pharmaceutical composition and/or which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like commensurate with a reasonable benefit/risk ratio.
  • salts derived from inorganic bases include: aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium chloride, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include: salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include: acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, /?-toluenesulfonic acid, and the like.
  • representative pharmaceutically acceptable salts include but are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexyl-resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine
  • carrier refers to a solid or liquid filler, diluent or encapsulating substance. These materials are well known to those skilled in the pharmaceutical arts.
  • substances that can serve as pharmaceutical carriers include sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols, such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline
  • enantiomeric excess is used herein according to its commonly understood definition. That is, for two enantiomers A and B that may be present in a mixture in molar amounts MA and MB, respectively, the enantiomeric excess E of the enantiomer present in a higher molar amount in the mixture may be expressed by the relation where E>0%.
  • the same mixture may be regarded in the alternative as a mixture consisting of 80% racemic mixture of A and B in combination with 20% enantiopure A, inasmuch as each molecule of B (40% of the mixture) may be paired with a molecule of A in the mixture (40% of the mixture) to leave unpaired an excess of molecules of A (20% of the mixture).
  • enantiopure with regard to a molecule having two enantiomers, A and B, refers to a compound or composition containing substantially only one of the enantiomers A or B, but not both A and B .
  • an “enantiopure” complex 97% ⁇ E ⁇ 100%.
  • an “enantioenriched” refers, in its broadest sense, to a compound or composition containing a molecule having two enantiomers, A and B, such that the compound or composition has an enantiomeric excess of one of the enantiomers, either A or B .
  • an "enantioenriched mixture of A and B” may refer to a mixture with an enantiomeric excess of A or to a mixture with an enantiomeric excess of B, wherein 0% ⁇ E ⁇ 100% for either A or B .
  • the enantiomeric excess of either A or B may be greater than 0.01%, greater than 1%, greater than 10%, greater than 25%, greater than 40%, greater than 50%, greater than 75%, greater than 90%, greater than 98%, greater than 99%, greater than 99.9%, or even equal to 100%.
  • Embodiments of the present disclosure relate to methods for treating neurodegenerative disorders or pain, to methods for managing pain, to pharmaceutical compositions for treating neurodegenerative disorders or pain, and to pharmaceutical compositions for managing pain. Embodiments of methods for treating neurodegenerative disorders or pain will now be described in detail. Thereafter, embodiments of the pharmaceutical compositions for managing pain and/or treating neurodegenerative disorders or pain will be described in detail.
  • the methods include administering to a subject in need thereof: (A) a therapeutically effective amount of simvastatin or a pharmaceutically acceptable salt thereof, (B) at least one of a therapeutically effective amount of fluoxetine racemate or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of enantiopure (S)- fluoxetine or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of enantioenriched fluoxetine having an enantiomeric excess of (S)-fluoxetine or a pharmaceutically acceptable salt thereof, and (C) a therapeutically effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof.
  • a combination of (A) simvastatin, (B) at least one of fluoxetine racemate, enantiopure (S)-fluoxetine, or enantioenriched fluoxetine having an enantiomeric excess of (S)-fluoxetine, and (C) ascorbic acid is administered to treat neurodegenerative disorders.
  • simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase (i.e. , HMG CoA reductase) inhibitor or a statin.
  • Simvastatin is commercially available, such as, e.g., in tablet form, such as Zocor.
  • ascorbic acid ascorbic acid (i.e. , Vitamin C) is an antioxidant. Ascorbic acid is commercially available.
  • fluoxetine is a selective serotonin reuptake inhibitor (hereinafter, "SSRI").
  • SSRI selective serotonin reuptake inhibitor
  • the general term "fluoxetine” may refer to at least one of fluoxetine racemate, enantioenriched fluoxetine having an enantiomeric excess of (K)-fluoxetine, enantiopure (S)-fluoxetine, or enantioenriched fluoxetine having an enantiomeric excess of (S)-fluoxetine.
  • Fluoxetine racemate refers to a racemic mixture of (S) -fluoxetine and (R) -fluoxetine.
  • the structures of (S)-fluoxetine and (K)-fluoxetine are as provided below:
  • Fluoxetine is commercially available as fluoxetine hydrochloride. Fluoxetine is available in multiple dosage forms, including, e.g. , capsule form, such as Prozac, and tablet form, such as Sarafem.
  • Commercially available forms of fluoxetine are believed to include either fluoxetine racemate (such as, e.g. , Prozac) or enantioenriched fluoxetine having an enantiomeric excess of (K)-fluoxetine (such as, e.g. , a generic form of fluoxetine).
  • enantioenriched fluoxetine having an enantiomeric excess of (K)-fluoxetine it is believed that such commercially available form includes about 60% (R)- fluoxetine and about 40% (S)-fluoxetine.
  • (S)-fluoxetine is also commercially available, such as, e.g. , from Sigma Aldrich (St. Louis, MO). In embodiments, (S) -fluoxetine is (S)-(+)-fluoxetine hydrochloride.
  • administering the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid is effective to treat the neurodegenerative disorder by increasing stem cell proliferation in the subject relative to a baseline level.
  • administering the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid is effective to treat the neurodegenerative disorder by increasing neural stem cell proliferation in a subventricular zone (hereinafter, "SVZ") of the subject relative to a baseline level.
  • SVZ subventricular zone
  • administering the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid is effective to treat the neurodegenerative disorder by increasing neural stem cell proliferation in an anterior region, a middle region, and/or a posterior region of a SVZ relative to a baseline level.
  • the SVZ is a paired brain structure situated throughout the lateral walls of the lateral ventricles.
  • the SVZ is a source of neural stem cells.
  • the baseline level refers to a level of stem and/or progenitor cell proliferation, such as, e.g., neural stem cell proliferation, in an untreated control.
  • the untreated control is an untreated control population of subjects having a neurodegenerative disorder and/or an untreated control population of cells known to those of skill in the art for studying neurodegenerative disorders.
  • a combination of (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid is administered to treat pain and/or to manage pain.
  • administering the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid is effective to treat pain and/or to manage pain by transforming at least one Ml inflammatory type microglial cell to at least one M2 neuroprotective microglial cell.
  • the methods for managing pain and/or treating a neurodegenerative disorder or pain include administering (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid, or pharmaceutically-acceptable salts thereof, to a subject in need thereof, wherein the subject is a mammal.
  • the subject is a mammal chosen from humans, non-human primates, canines, felines, murines, bovines, equines, porcines, and lagomorphs.
  • the subject is a rat or a human.
  • the subject is female or male.
  • the subject is female.
  • the subject is a post-menopausal female.
  • the subject is male.
  • the subject is a male who is suffering from and/or who has suffered from chronic stress.
  • the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid, or pharmaceutically acceptable salts thereof are administered systemically.
  • Systemic administration of the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid, or pharmaceutically acceptable salts thereof may be chosen from sublingual, subcutaneous, intravenous, intramuscular, intranasal, intrathecal, intraperitoneal, percutaneous, intranasal, enteral, oral, or a combination thereof.
  • the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid, or pharmaceutically acceptable salts thereof are administered orally.
  • the methods for managing pain and/or treating a neurodegenerative disorder or pain include administering (A) simvastatin, or a pharmaceutically acceptable salt thereof, in a dose of from about 0.5 mg/kg to about 1.0 mg/kg in rats.
  • the methods for managing pain and/or treating a neurodegenerative disorder or pain include administering (B) fluoxetine, or a pharmaceutically acceptable salt thereof, in a dose of from about 5 mg/kg to about 10 mg/kg, or from about 6 mg/kg to about 9 mg/kg, or from about 7 mg/kg to about 8 mg/kg in rats.
  • the methods for managing pain and/or treating a neurodegenerative disorder or pain include administering (C) ascorbic acid, or a pharmaceutically acceptable salt thereof, in a dose of from about 20 mg/kg to about 100 mg/kg, or from about 40 mg/kg to about 80 mg/kg, or from about 50 mg/kg to about 60 mg/kg in rats.
  • such dosages correlate to human dosages of from about 5 mg to about 10 mg of (A) simvastatin, of from about 20 mg to about 40 mg of (B) fluoxetine, and from about 200 mg to about 1000 mg of (C) ascorbic acid.
  • A simvastatin
  • B fluoxetine
  • C ascorbic acid
  • the methods for managing pain and/or treating a neurodegenerative disorder or pain include administering (A) simvastatin or a pharmaceutically acceptable salt thereof in a dose of about 5 mg, (B) fluoxetine or a pharmaceutically acceptable salt thereof in a dose of about 40 mg, and (C) ascorbic acid or a pharmaceutically acceptable salt thereof in a dose of about 200 mg to a human subject. It is contemplated that such doses serve as non-limiting examples of suitable doses of the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid, or pharmaceutically acceptable salts thereof, for a subject in need thereof.
  • the dose of the (A) simvastatin, (B) fluoxetine, and/or (C) ascorbic acid, or pharmaceutically acceptable salts thereof is administered daily.
  • the (A) simvastatin, (B) fluoxetine, and/or (C) ascorbic acid, or pharmaceutically acceptable salts thereof is administered at least once a day.
  • the (A) simvastatin, (B) fluoxetine, and/or (C) ascorbic acid, or pharmaceutically acceptable salts thereof is administered at least two times a day, at least three times a day, at least four times a day, at least five times a day, and/or at least six times a day.
  • the (A) simvastatin, (B) fluoxetine, and/or (C) ascorbic acid, or pharmaceutically acceptable salts thereof is administered from one time a day.
  • the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid are as depicted in Table 1.
  • the methods for managing pain and/or treating a neurodegenerative disorder or pain further include monitoring disease development and/or progression and repeating administration of the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid, or pharmaceutically acceptable salts thereof, one or more times, thereby treating the neurodegenerative disorder. Development and/or progression of the neurodegenerative disorder or pain may be monitored in a variety of ways known to the skilled clinician.
  • the methods for managing pain and/or treating a neurodegenerative disorder or pain further include monitoring disease development and/or progression and repeating administration of the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid, or pharmaceutically acceptable salts thereof, one or more times, thereby managing the pain and/or treating the neurodegenerative disorder or the pain.
  • Successive rounds of administering the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid, or pharmaceutically acceptable salts thereof, coupled with monitoring development and/or progression of the pain or the neurodegenerative disorder may be necessary in order to achieve the desired management and/or treatment of the pain or the neurodegenerative disorder.
  • the (A) simvastatin, (B) fluoxetine, and/or (C) ascorbic acid, or pharmaceutically acceptable salts thereof is administered in a pharmaceutical composition including at least one of an excipient, adjuvant, or pharmaceutically acceptable carrier.
  • excipients include water, saline, Ringer's solution, dextrose solution, and solutions of ethanol, glucose, sucrose, dextran, mannose, mannitol, sorbitol, polyethylene glycol (PEG), phosphate, acetate, gelatin, collagen, Carbopol®, and vegetable oils.
  • suitable adjuvants include inorganic compounds (e.g.
  • ⁇ aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide, and beryllium
  • mineral oil e.g. , paraffin oil
  • bacterial products e.g. , killed bacteria Bordetelle pertussis, Mycobacterium bovis, and toxoids
  • nonbacterial organics e.g. , squalene and thimerosal
  • delivery systems e.g. , detergents (Quil A)
  • cytokines e.g. , IL- 1, IL-2, and IL- 12
  • combinations e.g., Freund' s complete adjuvant, Freund' s incomplete adjuvant.
  • pharmaceutically acceptable carriers include a wide range of known diluents (i.e.
  • a preparation resulting from the inclusion of a pharmaceutically acceptable carrier may incorporate, if necessary, one or more solubilizing agents, buffers, preservatives, colorants, perfumes, flavorings and the like, as widely used in the field of pharmaceutical preparation.
  • suitable preservatives, stabilizers, antioxidants, antimicrobials, and buffering agents include BHA, BHT, citric acid, ascorbic acid, tetracycline, and the like.
  • Cream or ointment bases useful in formulation include lanolin, Silvadene® (Marion), Aquaphor® (Duke Laboratories).
  • a pharmaceutical composition for the management of pain and/or treatment of a neurodegenerative disorder or pain may be prepared according to methods known in the pharmaceutical field using a pharmaceutically acceptable carrier.
  • oral forms such as tablets, capsules, granules, pills and the like are prepared according to known methods using excipients such as saccharose, lactose, glucose, starch, mannitol and the like; binders such as syrup, gum arabic, sorbitol, tragacanth, methylcellulose, polyvinylpyrrolidone and the like; disintegrates such as starch, carboxymethylcellulose or the calcium salt thereof, microcrystalline cellulose, polyethylene glycol and the like; lubricants such as talc, magnesium stearate, calcium stearate, silica and the like; and wetting agents such as sodium laurate, glycerol and the like.
  • Injections, solutions, emulsions, suspensions, syrups and the like may be prepared according to known methods suitably using solvents for dissolving the simvastatin, fluoxetine, and/or ascorbic acid, or pharmaceutically acceptable salts thereof, such as ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, sesame oil and the like; surfactants such as sorbitan fatty acid ester, polyoxyethylenesorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene of hydrogenated castor oil, lecithin and the like; suspending agents such as cellulose derivatives including carboxymethylcellulose sodium, methylcellulose and the like, natural gums including tragacanth, gum arabic and the like; and preservatives such as parahydroxybenzoic acid esters, benzalkonium chloride, sorbic acid salts and the like.
  • compositions for the management of pain and/or treatment of a neurodegenerative disorder or pain as described herein may be administered to a subject in need thereof in accordance with the methods for managing pain and/or treating a neurodegenerative disorder or pain, as described in an earlier section.
  • the methods disclosed herein are useful in the treatment of neurodegenerative disorders including Alzheimer' s disease, Huntington' s disease, Parkinson's disease, amyotrophic lateral sclerosis (hereinafter, "ALS"), and/or damage from brain injury, such as, e.g. , an ischemic event.
  • the neurodegenerative disorder is Alzheimer's disease.
  • the methods disclosed herein are useful in the management or treatment of pain including any pain known in the art, such as, e.g. , pain caused by a disease, disorder, condition, and/or circumstance.
  • the pain is chosen from nociceptive pain, neuropathic pain, and/or inflammatory pain.
  • the pain is chosen from chronic pain and/or acute pain.
  • the fluoxetine racemate or a pharmaceutically acceptable salt thereof a therapeutically effective amount of enantiopure (S)-fluoxetine or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of enantioenriched fluoxetine having an enantiomeric excess of (S) -fluoxetine or a pharmaceutically acceptable salt thereof
  • S enantiopure
  • Embodiments of the methods for managing pain and/or treating a neurodegenerative disorder or pain have been described in detail.
  • Embodiments of pharmaceutical compositions for managing pain and/or treating a neurodegenerative disorder or pain will now be described in detail.
  • compositions for the management of pain and/or treatment of a neurodegenerative disorder or pain are disclosed.
  • pharmaceutical compositions including: (A) a therapeutically effective amount of simvastatin or a pharmaceutically acceptable salt thereof, (B) at least one of a therapeutically effective amount of fluoxetine racemate or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of enantiopure (S)-fluoxetine or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of enantioenriched fluoxetine having an enantiomeric excess of (S) -fluoxetine or a pharmaceutically acceptable salt thereof, and (C) a therapeutically effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof are disclosed.
  • the (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid, or pharmaceutically acceptable salts thereof, are as previously described.
  • the neurodegenerative disorder and pain are also as previously described.
  • the pharmaceutical compositions for the management of pain and/or treatment of a neurodegenerative disorder or pain include a combination of (A) simvastatin, (B) fluoxetine, and (C) ascorbic acid, or pharmaceutically acceptable salts thereof, and also include an excipient, an adjuvant, and/or a pharmaceutically acceptable carrier.
  • the excipient, adjuvant, and pharmaceutically acceptable carrier of the pharmaceutical composition are as previously described.
  • the pharmaceutical compositions can be prepared as previously described, such as, e.g. , using a pharmaceutically acceptable carrier.
  • a method for treating a neurodegenerative disorder includes administering to a subject in need thereof: (A) a therapeutically effective amount of simvastatin or a pharmaceutically acceptable salt thereof, (B) at least one of a therapeutically effective amount of fluoxetine racemate or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of enantiopure (S)-fluoxetine or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of enantioenriched fluoxetine having an enantiomeric excess of (S)-fluoxetine or a pharmaceutically acceptable salt thereof, and (C) a therapeutically effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof.
  • a method according to the first aspect wherein administration of (A), (B), and (C) is effective to treat the neurodegenerative disorder by increasing at least one of stem cell proliferation or progenitor cell proliferation in the subject relative to a baseline level.
  • the method according to any of the first or the second aspects is disclosed, wherein administration of (A), (B), and (C) is effective to treat the neurodegenerative disorder by increasing at least one of neural stem cell proliferation or progenitor cell proliferation in a subventricular zone of the subject relative to a baseline level.
  • the method according to any of the first to the third aspects is disclosed, wherein administration of (A), (B), and (C) is effective to treat the neurodegenerative disorder by increasing at least one of neural stem cell proliferation or progenitor cell proliferation in an anterior region, a middle region, and a posterior region of a subventricular zone of the subject relative to a baseline level.
  • the method according to any of the first to the fourth aspects is disclosed, wherein the subject is a mammal.
  • the method according to any of the first to the fifth aspects is disclosed, wherein the subject is a rat or a human.
  • a seventh aspect the method according to any of the first to the sixth aspects is disclosed, wherein the subject is a female.
  • the method according to any of the first to the tenth aspects is disclosed, wherein (C) is administered in a daily dose of from about 200 mg to about 1000 mg.
  • the method according to any of the first to the eleventh aspects is disclosed, wherein at least one of (A), (B), or (C) is administered in a pharmaceutical composition including at least one of an adjuvant, an excipient, or a pharmaceutically acceptable carrier.
  • the method according to any of the first to the twelfth aspects is disclosed, wherein the neurodegenerative disorder includes at least one of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), or damage from brain injury.
  • the neurodegenerative disorder includes at least one of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), or damage from brain injury.
  • a pharmaceutical composition for the treatment of a neurodegenerative disorder includes (A) a therapeutically effective amount of simvastatin or a pharmaceutically acceptable salt thereof, (B) at least one of a therapeutically effective amount of fluoxetine racemate or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of enantiopure (S)-fluoxetine or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of enantioenriched fluoxetine having an enantiomeric excess of (S)-fluoxetine or a pharmaceutically acceptable salt thereof, and (C) a therapeutically effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition according to the fourteenth aspect is disclosed, wherein the neurodegenerative disorder includes at least one of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), or damage from brain injury.
  • the neurodegenerative disorder includes at least one of Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), or damage from brain injury.
  • ALS amyotrophic lateral sclerosis
  • a method for treating or managing pain includes administering to a subject in need thereof: (A) a therapeutically effective amount of simvastatin or a pharmaceutically acceptable salt thereof, (B) at least one of a therapeutically effective amount of fluoxetine racemate or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of enantiopure (S) -fluoxetine or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of enantioenriched fluoxetine having an enantiomeric excess of (S) -fluoxetine or a pharmaceutically acceptable salt thereof, and (C) a therapeutically effective amount of ascorbic acid or a pharmaceutically acceptable salt thereof.
  • the method according to the sixteenth aspect is disclosed, wherein at least one of (A), (B), or (C) is administered in a pharmaceutical composition including at least one of an adjuvant, an excipient, or a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for the treatment or management of pain includes: (A) a
  • Example 1 Characterization of the Effect of Simvastatin, Fluoxetine, and/or Ascorbic Acid to Increase Stem Cell Proliferation in Rats
  • This method of voluntary drug delivery alleviated daily stress associated with other drug delivery methods such as, e.g., oral gavage and intraperitoneal (hereinafter, "IP" injections.
  • IP intraperitoneal
  • alleviation of daily stress is important to stimulate neurogenesis (See e.g., Corbett, A., McGowin, A., Sieber, S., Flannery, T., Sibbitt, B. 2012.
  • the rats were euthanized on day 31 after IP injection with 100 mg/kg pentobarbital (i.e., Euthasol) through cardioperfusion with phosphate buffered saline (hereinafter, "PBS") and PBS containing 4% paraformaldehyde.
  • PBS phosphate buffered saline
  • the brain was dissected and prepared for immunocytochemistry. All animal studies in this paper were reviewed and approved by the Institutional Animal Care and Use Committee (i.e., IACUC).
  • the brain was cut into 50 micron coronal sections, which were transferred into vials containing phosphate-buffered saline. Brain sections were incubated in blocking solution (i.e., PBS with 0.3% Tween-20 and 3% goat serum) at room temperature for one hour on an orbital shaker. Primary antibody (i.e., AbCam anti-Ki67 (AB 15580)) was added to the blocking solution at a 1: 1000 dilution and incubated overnight at 5 °C on an orbital shaker.
  • blocking solution i.e., PBS with 0.3% Tween-20 and 3% goat serum
  • Primary antibody i.e., AbCam anti-Ki67 (AB 15580)
  • the primary antibody solution was discarded and the brain sections were washed twice with PBS containing 0.3% Tween.
  • the brain sections were then placed in blocking solution containing a Vector biotinylated secondary antibody according to manufacturer instructions (i.e., from Vector ABC kit for Rabbit IgG with horseradish peroxidase) and incubated with shaking at room temperature for one hour.
  • This blocking solution was removed from the brain sections and the brain sections were washed twice with PBS containing 0.3% Tween.
  • the ABC reagent (from Vector) was mixed and allowed to sit for at least 30 minutes; then, it was placed onto the brain sections and the brain sections were incubated for one hour.
  • brain sections were washed twice with PBS containing 0.3% Tween. This solution was then removed from the brain sections.
  • Enzyme substrate i.e. , 3, 3-diaminobenzidine, hereinafter, "DAB" with nickel enhancement
  • DAB 3-diaminobenzidine
  • brain sections were resuspended in water. Brain sections were then mounted onto gel-subbed microscope slides, dried, and coverslipped using DPX Mounting Media as a permanent mountant.
  • anterior, middle or posterior was determined and the average Ki67 staining area per section for all of the replicate sections was indicated within that region for one particular rat.
  • an average of 7.5 sections analyzed for the anterior SVZ was employed, an average of 12 sections for the middle SVZ was employed, and an average of 5.8 sections for the posterior SVZ was employed.
  • an average of 8.8 sections for the anterior SVZ was employed, an average of 16 sections for the middle SVZ was employed, and an average of 5 sections for the posterior SVZ was employed.
  • mice Female Sprague Dawley rats were purchased at 10 months of age. The rats were administered various daily doses of drugs and/or drug combinations as set forth in Table 2 for a period of 30 days. All animals were euthanized at 11 months of age using cardio-perfusion to clear the blood and fix the brain with 4% paraformaldehyde. Coronal sections of the brain were incubated with Ki67 antibody overnight, washed, and then incubated with a secondary biotinylated antibody.
  • Ki67 marks a protein that only appears during mitosis, the number of stem/progenitor cells in the SVZ undergoing mitosis at the time of the animal's death was determined. This was a measure of stem/progenitor cell proliferation. ⁇ See e.g., Cowen, D.S., Takase, L.F., Fornal, C.A., Jacobs, B.L. 2008. Age-dependent decline in hippocampal neurogenesis is not altered by chronic treatment with fluoxetine. Brain research 1228, 14-9. doi: 10.1016/j.brainres.2008.06.059). Vector ABC kits (including horseradish peroxidase) were used to develop the stain using DAB as a substrate. Referencing FIG.
  • Panel (A) of FIG. 1 a control female rat with Ki67 staining in an anterior ventricle is shown.
  • Panel (C) of FIG. 1 a mask from ImageJ was used to measure the area of the particles.
  • Panel (B) of FIG. 1 Ki67 staining of an anterior ventricle from a female rat administered a combination of simvastatin, ascorbic acid, and fluoxetine (collectively, hereinafter, "SAAF") for thirty days with the ImageJ mask was used to measure the area of the particles in Panel (D) is shown.
  • SAAF simvastatin, ascorbic acid, and fluoxetine
  • FIG. 2 the area of Ki67 staining from approximately 25 coronal fifty micrometer thick brain sections throughout the SVZ of the lateral ventricles was analyzed, wherein the mean area of Ki67 staining for a section from the SVZ was determined for each animal.
  • the mean area of Ki67 staining for each animal in a group was shown by the individual points and the mean of the group was shown by a broad horizontal line, with error bars representing the standard deviation.
  • the mean endogenous female stem/progenitor cell proliferation in the rats administered Vehicle (i.e., Control) in the SVZ was quite low.
  • rats administered a combination of simvastatin and fluoxetine i.e., Fluoxetine, Statin
  • fluoxetine i.e., Fluoxetine, Statin
  • rats administered a daily combination of 1 mg/kg simvastatin, 20 mg/kg ascorbic acid, and 5 mg/kg fluoxetine i.e., SAAF
  • SAAF a daily combination of 1 mg/kg simvastatin, 20 mg/kg ascorbic acid, and 5 mg/kg fluoxetine
  • each point represented the mean area of Ki67 staining obtained from approximately 30 coronal slices throughout the SVZ of the lateral ventricles for a single male rat.
  • the overall group mean was given by the broad horizontal line in each group, with the error bars represented standard error of the mean.
  • endogenous stem/progenitor cell proliferation in rats administered Vehicle i.e. , Control
  • rats administered either simvastatin alone (i.e. , Statin) or fluoxetine alone i.e. , Fluoxetine
  • the Ki67 staining area was averaged over a different number of coronal sections.
  • an average of 7.5 coronal sections for the anterior SVZ was employed, an average of 12 sections for the middle SVZ was employed, and an average of 5.8 sections for the posterior SVZ was employed.
  • an average of 8.8 coronal sections for the anterior SVZ was employed, an average of 16 sections for the middle SVZ was employed, and an average of 5 sections for the posterior SVZ was employed.
  • simvastatin acts to stimulate endothelial nitric oxide synthase to produce BDNF (see e.g. , Wu, H., Lu, D., Jiang, H., Xiong, Y., Qu, C, Li, B., Mahmood, A., Zhou, D., Chopp, M. 2008.
  • Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. Journal of neurotrauma 25(2), 130-9. doi: 10.1089/neu.2007.0369), and/or to stimulate production of plasmin, which is capable of cleaving any released pro-BDNF to BDNF (see e.g., Tsai, S.J. 2007.
  • Statins may enhance the proteolytic cleavage of proBDNF: implications for the treatment of depression. Medical hypotheses 68(6), 1296-9. doi: 10.1016/j.mehy.2006.09.043 and Tsai, S.J. 2009. Statins may act through increasing tissue plasminogen activator/plasmin activity to lower risk of Alzheimer's disease. CNS spectrums 14(5), 234-5).
  • fluoxetine acts on microglial cells in an injury model (see e.g., Corbett, A.M., Sieber, S., Wyatt, N., Lizzi, J., Flannery, T., Sibbit, B., Sanghvi, S. 2015.
  • Increasing neurogenesis with fluoxetine, simvastatin and ascorbic Acid leads to functional recovery in ischemic stroke.
  • Recent patents on drug delivery & formulation 9(2), 158-66 to transform an Ml inflammatory type microglial cell to an M2 neuroprotective microglial cell (see e.g., Su, F., Yi, H., Xu, L., Zhang, Z. 2015.
  • Example 2 Characterization of the Effect of Simvastatin, (S)-Fluoxetine, (K)-Fluoxetine, and/or Ascorbic Acid to Increase Blood Brain Barrier Permeability Following Stroke
  • Example 3 Characterization of the Effect of Simvastatin, Fluoxetine, and/or Ascorbic Acid to Increase Migration of Macrophages and/or Neutrophils into Cortex and/or to Proliferate Activated Microglia in Cortex Following Stroke
  • Rats were administered daily doses of Fluoxetine (5 mg/kg) along with Simvastatin (1 mg/kg) and Ascorbic Acid (20 mg/kg) from 48-56 hours post-stroke induction until day 7 post-stroke. Control rats were not administered drugs. On post-stroke day 7, the rats were euthanized and brain tissue was stained with H&E stain. H&E stains incoming microglia, neutrophils, and macrophages blue. [0105] Results. As shown in panels (A), (B), and (D) of FIG. 6, microglia, macrophage, and neutrophil migration into the cortex surrounding infarction was observed (enclosed in dashed lines).

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Abstract

L'invention concerne également des méthodes de gestion de la douleur, de traitement de la douleur et de traitement des troubles neurodégénératifs. Les procédés comprennent l'administration à un sujet en ayant besoin : (A) d'une quantité thérapeutiquement efficace de simvastatine ou d'un sel pharmaceutiquement acceptable de celle-ci, (B) au moins l'une d'une quantité thérapeutiquement efficace de racémate de fluoxétine ou d'un sel pharmaceutiquement acceptable de celui-ci, d'une quantité thérapeutiquement efficace d'énantiomères (S)-fluoxétine ou un sel pharmaceutiquement acceptable de celle-ci, ou une quantité thérapeutiquement efficace de fluoxétine énantioenrichie ayant un excès énantiomérique de (S)-fluoxétine ou un sel pharmaceutiquement acceptable de celle-ci, et (C) une quantité thérapeutiquement efficace d'acide ascorbique ou d'un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également des compositions pharmaceutiques pour la gestion de la douleur, le traitement de la douleur et le traitement de troubles neurodégénératifs.
PCT/US2017/048555 2016-08-25 2017-08-25 Traitement de troubles neurodégénératifs et de la douleur WO2018039526A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030027817A1 (en) * 1998-05-29 2003-02-06 Tollefson Gary Dennis Combination therapy for treatment of bipolar disorders
US20120164245A1 (en) * 2009-09-04 2012-06-28 Munisekhar Medasani Method of treatment of neurodegenerative or neuro-muscular degenerative diseases and therapeutic agent to treat the same
US20120328583A1 (en) * 2011-06-01 2012-12-27 Anthrogenesis Corporation Treatment of pain using placental stem cells
US20160106727A1 (en) * 2011-09-12 2016-04-21 Wright State University Composition and method for the treatment of neurodegeneration

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030027817A1 (en) * 1998-05-29 2003-02-06 Tollefson Gary Dennis Combination therapy for treatment of bipolar disorders
US20120164245A1 (en) * 2009-09-04 2012-06-28 Munisekhar Medasani Method of treatment of neurodegenerative or neuro-muscular degenerative diseases and therapeutic agent to treat the same
US20120328583A1 (en) * 2011-06-01 2012-12-27 Anthrogenesis Corporation Treatment of pain using placental stem cells
US20160106727A1 (en) * 2011-09-12 2016-04-21 Wright State University Composition and method for the treatment of neurodegeneration

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