US20190240194A1 - Macrophages/microglia in neuro-inflammation associated with neurodegenerative diseases - Google Patents

Macrophages/microglia in neuro-inflammation associated with neurodegenerative diseases Download PDF

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US20190240194A1
US20190240194A1 US16/328,956 US201716328956A US2019240194A1 US 20190240194 A1 US20190240194 A1 US 20190240194A1 US 201716328956 A US201716328956 A US 201716328956A US 2019240194 A1 US2019240194 A1 US 2019240194A1
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cromolyn
compound
cells
microglial
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David R. Elmaleh
Rudolph E. Tanzi
Timothy M. Shoup
Ana Gricluc
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General Hospital Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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

Definitions

  • NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice,” Nature, 2013, 493(7434):674-8; Theeriault, et al., “The dynamics of monocytes and microglia in Alzheimer's disease,” Alzheimers Res Ther., 2015, 7:41; Nau et al., “Strategies to increase the activity of microglia as efficient protectors of the brain against infections,” Front Cell Neurosci., 2014, 8:138.)
  • AD Alzheimer's Disease
  • ALS Amyotrophic Lateral Sclerosis
  • a ⁇ amyloid- ⁇
  • microglial cells surrounding A ⁇ plaques are not as efficacious in degrading A ⁇ as newly infiltrated macrophages or monocytes (See, Thériault, et al., 2015; Varnum, et al., “The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain,” Arch. Immunol. Ther. Exp. (Warsz), 2012, 60(4):251-66)
  • microglia are indeed capable of internalizing fibrillar and soluble A ⁇ , but are unable to process these peptides.
  • See Chung, et al. “Uptake, degradation, and release of fibrillar and soluble forms of Alzheimer's amyloid beta-peptide by microglial cells,” J Biol. Chem., 1999, 274:32301-8).
  • microglia undergo a switch from an M2- to an M1-skewed activation phenotype during aging.
  • Mphi1 and Mphi2 can be re-polarized by Th2 or Th1 cytokines, respectively, and respond to exogenous danger signals
  • microglia are activated by extracellularly deposited A ⁇ peptide (Lotz, et al., “Amyloid beta peptide 1-40 enhances the action of Toll-like receptor-2 and -4 agonists but antagonizes Toll-like receptor-9-induced inflammation in primary mouse microglial cell cultures,” J. Neurochem., 2005, 94:289-298; Reed-Geaghan, et al., “CD14 and toll-like receptors 2 and 4 are required for fibrillar A ⁇ -stimulated microglial activation,” J. Neurosci., 2009, 29:11982-11992).
  • M1 activated microglia can produce reactive oxygen species and result in increased production of pro-inflammatory cytokines such as TNF ⁇ and interleukin (IL)-1 ⁇ .
  • the M1-type response of microglial cells has been shown to lower amyloid load but exacerbate neurofibrillary tangle pathology.
  • Shaftel et al. (Shaftel, et al., “Sustained hippocampal IL-1 ⁇ overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology,” J. Clin. Invest., 2007, 117(6):1595-604) have shown that IL-1 ⁇ expression may underlie a beneficial neuroinflammatory response in AD, and that IL-1 ⁇ overexpression in the hippocampus of APP/PS1 transgenic mice results in decreased amyloid burden.
  • the authors suggest that IL-1 ⁇ -mediated activation of microglia is the mechanism for the reductions in amyloid deposition. Further, Montgomery et al.
  • Macrophage M2 activation is associated with mediators that are known to contribute to the anti-inflammatory actions and reorganization of extracellular matrix (Zhu, et al., “Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation”, Science, 2004, 304(5677):1678-82; Walker, et al., 2015; Wilcock, et al., 2012).
  • Microglia with M2a phenotypes have increased phagocytosis and produce growth factors such as insulin-like growth factor-1 and anti-inflammatory cytokines such as IL-10.
  • M2a Stimulation of macrophages by IL-4 and/or IL-13 results in an M2a state, sometimes called a wound-healing macrophage (Edwards, et al., “Biochemical and functional characterization of three activated macrophage populations,” J. Leukoc Biol., 2006, 80(6):1298-307) and it is generally characterized by low production of pro-inflammatory cytokines (IL-1, TNF and IL-6).
  • IL-1, TNF and IL-6 pro-inflammatory cytokines
  • the M2a responses are primarily observed in allergic responses, extracellular matrix deposition, and remodeling.
  • M2b macrophages are unique in that they express high levels of pro-inflammatory cytokines, characteristic of M1 activation, but also express high levels of the anti-inflammatory cytokine IL-10. (See, Moser D M., “The many faces of macrophage activation,” J. Leukoc Biol., 2003, 73(2):209-12).
  • M2c macrophage state is stimulated by IL-10 and is sometimes referred to as a regulatory macrophage.
  • M2c macrophages have anti-inflammatory activity that plays a role in the phagocytosis of cellular debris without the classical pro-inflammatory response (See, Moser D M., 2003). These cells express TGF ⁇ and high IL-10 as well as matrix proteins. (See, Mantovani, et al., “The chemokine system in diverse forms of macrophage activation and polarization,” Trends Immunol., 2004, 25:677-686; Wilcock, et al., 2012). Plunkett et al.
  • microglia activated by extracellularly deposited A ⁇ protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing A ⁇ via phagocytosis. This is a potential avenue for new therapeutic targets.
  • Yamamoto, et al. “Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice,” Am. J. Pathol., 2007, 170:680-692; Yamamoto, et al., “Cytokine-mediated inhibition of fibrillar amyloid-beta peptide degradation by human mononuclear phagocytes,” J. Immunol., 2008, 181:3877-3886).
  • Mantovani et al. (Mantovani, et al., 2004) studied the effect of IL-4 as an important modulator of M2a microglial activation. It has been shown that gene delivery of IL-4 into APP+PS1 mice partially suppressed glial accumulation in the hippocampus, directly enhanced neurogenesis, restored impaired spatial learning, and also reduced A ⁇ deposition (Kiyota, et al., 2010).
  • Yamamoto et al. (Yamamoto, et al., 2007, 2008) examined macrophage-mediated A ⁇ degradation using pro- and anti-inflammatory cytokines in primary cultured human monocyte-derived macrophages (MDM) and microglia. These studies showed that anti-inflammatory and regulatory cytokines lead to an increase in M2a or M2c activation and enhanced A ⁇ clearance. Kiyota et al. (Kiyota et al., 2011) have shown sustained expression of IL-4 reduced astro/microgliosis, amyloid- ⁇ peptide (A ⁇ ) oligomerization and deposition, and enhanced neurogenesis.
  • MDM monocyte-derived macrophages
  • the invention encompasses methods of treating a neuron inflammation condition comprising administering a therapeutically effective amount to a patient in need thereof of at least one compound having the following formula:
  • the method uses the following compounds:
  • the neuron inflammation condition is at least one of ALS, AD, ischemic stroke, or prion disease.
  • the compounds may be administered intraperitoneally (IP) and/or intravenously (IV).
  • IP intraperitoneally
  • IV intravenously
  • the compounds may be administered at a dose between about 1 mg and about 1000 mg per day.
  • the method of administration may be transdermally or by inhalation.
  • the method is a method of treating ALS further comprising co-administering CD4+; siRNA; miRNA that ameliorate ALS; glial morphology modifier; SOD1 control; Riluzole; or another M1; M2 conversion active drug that controls neuroinflammation.
  • the invention relates to any of the methods described herein, provided the compound is not cromolyn disodium. In certain embodiments, the invention relates to any of the methods described herein, provided the compound is not cromolyn disodium, F-cromolyn disodium, ET-cromolyn, or F-ET-cromolyn when the neuron inflammation condition is AD.
  • the invention relates to any one of the following compounds:
  • FIG. 1B illustrates representative images of localization of amyloid deposits (6E10) and microglia (Iba1) in mice treated with Cromolyn Sodium (3.15 mg/kg) or PBS daily for seven days.
  • FIG. 1C illustrates the effect of Cromolyn Sodium on microglial A ⁇ uptake in vitro, where after the incubation, the concentrations of A ⁇ x-40 ( FIG. 1C left) A ⁇ x-42 ( FIG. 1C , right) in media were measured using A ⁇ ELISA.
  • FIG. 2 illustrates the plaques and the microglial cells surrounding those deposits in Tg-2576 mice of the study of Example 2.
  • the figure shows representative pictures of amyloid deposits and Iba-1 positive microglia.
  • FIG. 3 illustrates the results of BV2 microglial cells treated with cromolyn, and with cromolyn and ibuprofen exhibit increased A ⁇ 42 uptake levels relative to BV2 microglia treated with the vehicle.
  • FIG. 4 illustrates the results of an A ⁇ aggregation inhibition assay using various compounds described herein.
  • FIG. 5 graphically illustrates that Cromolyn significantly affects the levels of brain TBS soluble A ⁇ and the ratios of A ⁇ (42:40).
  • FIG. 6A shows na ⁇ ve BV2 microglial cells treated with DMSO (control) for 16 h. Afterwards, cells were incubated with fluorescently-labeled A ⁇ 42 and DMSO or cromolyn sodium for 2 hours. After incubation, cells were labeled with a plasma membrane dye (PM) and imaged.
  • PM plasma membrane dye
  • FIG. 6B shows na ⁇ ve BV2 microglial cells treated with DMSO (control) for 16 h. Afterwards, cells were incubated with fluorescently-labeled A ⁇ 42 and DMSO or cromolyn sodium for 2 hours.
  • FIG. 6C showns na ⁇ ve BV2 microglial cells treated with cromolyn sodium (500 ⁇ M) for 16 hours. Afterwards, cells were incubated with fluorescently-labeled A ⁇ 42 and DMSO or cromolyn sodium for 2 hours. After incubation, cells were labeled with a plasma membrane dye (PM) and imaged.
  • PM plasma membrane dye
  • FIG. 6D showns na ⁇ ve BV2 microglial cells treated with cromolyn sodium (500 ⁇ M) for 16 hours. Afterwards, cells were incubated with fluorescently-labeled A ⁇ 42 and DMSO or cromolyn sodium for 2 hours.
  • FIG. 7A graphically illustrates that cromolyn sodium promotes microglial A ⁇ 42 uptake.
  • BV2 microglial cells were treated with DMSO or different concentrations of cromolyn sodium for 16 hours. Then, cells were incubated with soluble untagged A ⁇ 42 and DMSO or cromolyn sodium for 2 hours, and collected for ELISA analysis. Both na ⁇ ve BV2 and BV2-CD33 WT microglial cells treated with cromolyn sodium exhibited increased A ⁇ 42 uptake levels in comparison to cells treated with the vehicle (DMSO).
  • FIG. 7B graphically illustrates that cromolyn sodium promotes microglial A ⁇ 42 uptake.
  • BV2 cells stably expressing CD33 (BV2-CD33 WT ) were treated with DMSO or different concentrations of cromolyn sodium for 16 hours. Then, cells were incubated with soluble untagged A ⁇ 42 and DMSO or cromolyn sodium for 2 hours, and collected for ELISA analysis. Both na ⁇ ve BV2 and BV2-CD33 WT microglial cells treated with cromolyn sodium exhibited increased A ⁇ 42 uptake levels in comparison to cells treated with the vehicle (DMSO).
  • DMSO vehicle
  • FIG. 8 graphically illustrates that compound C8 displays toxicity when tested at 100 ⁇ M or higher concentration in LDH assay.
  • Na ⁇ ve BV2 microglial cells were treated with DMSO or cromolyn derivatives for 3 hours at different concentrations.
  • C1, C2, C5, C6, C7 and C8 were tested at 10, 50, 100 and 150 ⁇ M, while C3 and C4 were assessed at 5, 25, 50 and 75 ⁇ M due to solubility limit in DMSO.
  • cells were incubated with soluble untagged A ⁇ 42 peptide and DMSO or cromolyn derivatives for 2 hours.
  • LDH lactate dehydrogenase
  • BV2 microglial cells treated with the cromolyn derivative C8 exhibited increased toxicity at 100 and 150 ⁇ M in comparison to cells treated with the vehicle (DMSO).
  • FIG. 9 graphically illustrates that compound C4 promotes A ⁇ 42 uptake in na ⁇ ve BV2 microglial cells.
  • BV2 cells were treated with DMSO (vehicle) or cromolyn derivatives at different concentrations ranging from 5 to 150 ⁇ M for 3 hours. Then, cells were incubated with soluble untagged A ⁇ 42 and DMSO or cromolyn derivatives for additional 2 hours and collected for ELISA analysis.
  • BV2 microglial cells treated with the cromolyn derivative C4 at 75 ⁇ M exhibited significantly increased A ⁇ 42 uptake levels in comparison to cells treated with the vehicle.
  • FIG. 10 graphically illustrates that compound C4 promotes A ⁇ 42 uptake in microglial BV2-CD33 WT cells.
  • Microglial cells stably expressing CD33 WT were treated with DMSO as control or cromolyn derivatives (C1, C3-8) at different concentrations for 3 hours. Afterwards, cells were incubated with DMSO or cromolyn derivatives in the presence of the A ⁇ 42 peptide for additional 2 hours. Cell lysates were analyzed for intracellular levels of A ⁇ 42 using an A ⁇ 42-specific ELISA kit. Treatment with the cromolyn derivative C4 at 75 ⁇ M led to increased uptake of A ⁇ 42 in BV2-CD33 WT cells in comparison to DMSO treatment and displayed a dose-dependent effect at 50 ⁇ M.
  • FIG. 11 graphically illustrates that compound C4 promotes A ⁇ 42 uptake in BV2-CD33 WT cells.
  • BV2-CD33 WT cells were treated with DMSO (vehicle) or cromolyn derivatives (C1, C2, and C4-7) at different concentrations for 3 hours. Afterwards, cells were treated with DMSO or cromolyn derivatives and soluble A ⁇ 42 peptide for 2 hours. Cell lysates were analyzed using A ⁇ 42-specific ELISA kit and intracellular A ⁇ 42 levels were quantified. The cromolyn derivative C4 effectively induced A ⁇ 42 uptake at 50 and 75 ⁇ M in BV2-CD33 WT cells in comparison to cells treated with DMSO.
  • DMSO vehicle
  • cromolyn derivatives C1, C2, and C4-7
  • the invention encompasses anti-inflammatory compounds to reduce the toxic effect of pro-inflammatory cytokines by converting microglia from a pro-inflammatory M1 state to an M2 state in which the toxic effects are reduced and their phagocytic activity toward amyloidosis, tauopathies and other cytotoxic events is enhanced.
  • the invention also encompasses the use of the compounds to affect therapy early in the disease process.
  • the compounds described herein are the only effective, non-cytokine (e.g. IL-10) compounds exhibiting M1-to-M2 activity.
  • the invention encompasses the compounds and the methods of treating neuron inflammation conditions by administration of a therapeutic effective amount of at least one of the compounds.
  • compounds of the invention include those having the following formula and their analogs and isomers:
  • X may include, but is not limited to, halides, and OCO(C 1 -C 8 alkyls).
  • Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and pentyl.
  • Halides include fluoro, chloro, bromo, and iodo.
  • Y may include, but is not limited to, —CH 2 OH, —CH 2 OAc, or —CH 2 OMe.
  • the compounds of the invention include those compounds attached at the 5 position.
  • compounds also include 5-[3-(2-carboxy-4-oxochromen-5-yl)oxy-2-hydroxypropoxy]-4-oxochromene-2-carboxylic acid derivatives and isomeric forms.
  • the invention encompasses methods of treating a variety of neuron inflammation conditions.
  • Neuron inflammation conditions include, but are not limited to, diseases such as ALS, autism spectrum disorder (ASD), ischemic stroke, and prion disease.
  • the compounds may be used to treat ALS including, but not limited to, slowing down or halting the progression of the disease.
  • the compounds may be administered in combination with other anti-inflammatory agents to control the spread of the progressive and fatal effect of ALS.
  • the invention encompasses a combination treatment for ALS of M1, M2 conversion active drugs that control neuroinflammation, such as the drugs in the above formulas, with other immune targeting therapies such as CD4+, siRNA, miRNA that ameliorates ALS, glial morphology modifiers, SOD1 controls, or Riluzole, the only approved drug for ALS.
  • M1, M2 conversion active drugs that control neuroinflammation such as the drugs in the above formulas
  • other immune targeting therapies such as CD4+, siRNA, miRNA that ameliorates ALS, glial morphology modifiers, SOD1 controls, or Riluzole, the only approved drug for ALS.
  • the compounds will slow down or halt neuron damage for neurons located in the brain stem and/or the spinal cord, neurons, or motor neurons that affect voluntary body muscles.
  • the compounds may be administered using known methods for the administration of drugs, for example, IP, IV, transdermally, by inhalation.
  • the invention relates to methods of treating or slowing down the aggressive progression of a neurological disease, such as AD, Ischemic Stroke, ALS, or Prion, and the compound is administered by infusion or intraperitoneal administration.
  • the invention also provides pharmaceutical compositions comprising one or more compounds described herein in association with a pharmaceutically acceptable carrier.
  • these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the compounds may be incorporated into transdermal patches designed to deliver the appropriate amount of the drug in a continuous fashion.
  • the principal active ingredient is mixed with a pharmaceutically acceptable carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture.
  • a pharmaceutically acceptable carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water
  • a pharmaceutically acceptable carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical dilu
  • a dry powder composition is micronized for inhalation to the lungs. See for example, U.S. Patent Application publication 2016/0263257, expressly incorporated herein by reference in its entirety, and in particular regarding the dry powder cromolyn formulations described therein.
  • the dry powder composition further comprises at least one excipient.
  • the at least one excipient comprises Lactose monohydrate and/or Magnesium stearate.
  • the compounds may be administered in doses that treat the particular indication.
  • the dose is specifically tailored to lead to blood, brain, and CSF concentrations that allow the drugs to act as M1-to-M2 modifiers.
  • Such doses may include from about 1 mg to about 1000 mg per day.
  • the dosage of the active agents will generally be dependent upon a number of factors, including the pharmacodynamic characteristics of the compound, mode and route of administration of the compound, the health of the patient being treated, the extent of treatment desired, the nature and kind of concurrent therapy, if any, and the frequency of treatment and the nature of the effect desired.
  • dosage ranges of the compound often range from about 0.001 to about 250 mg/kg body weight per day.
  • a dosage may range from about 0.1 to about 25 mg/kg body weight.
  • some variability in this general dosage range may be required depending on the age and weight of the subject being treated, the intended route of administration, the particular agent being administered, and the like.
  • the determination of dosage ranges and optimal dosages for a particular mammal is also well within the ability of one of ordinary skill in the art having the benefit of the instant disclosure.
  • Dosages for compounds may be as low as 5 ng/d.
  • Dosage ranges for active agents may be from 5 ng/d to 100mg/day. In certain embodiments, dosage ranges for active agents may be from about 5 ng/day to about 10 ng/day, about 15 ng/day, about 20 ng/day, about 25 ng/day, about 30 ng/day, about 35 ng/day, about 40 ng/day, about 45 ng/day, about 50 ng/day, about 60 ng/day, about 70 ng/day, about 80 ng/day, about 90 ng/day, about 100 ng/day, about 200 ng/day, about 300 ng/day, about 400 ng/day, about 500 ng/day, about 600 ng/day, about 700 ng/day, about 800 ng/day, or about 900 ng/day.
  • dosage ranges for compounds may be from about 1 ⁇ g/day to about 2 ⁇ g/day, about 3m/day, about 4 ⁇ g/day, about 5 ⁇ g/day, about 10 ⁇ g/day, about 15 ⁇ g/day, about 20 ⁇ g/day, about 30 ⁇ g/day, about 40 ⁇ g/day, about 50 ⁇ g/day, about 60 ⁇ g/day, about 70 ⁇ g/day, about 80 ⁇ g/day, about 90 ⁇ g/day, about 100 ⁇ g/day, about 200 ⁇ g/day, about 300 ⁇ g/day, about 400 ⁇ g/day about 500 ⁇ g/day, about 600 ⁇ g/day, about 700 ⁇ g/day, about 800 ⁇ g/day, or about 900 ⁇ g/day.
  • dosage ranges for active agents may be from about 1mg/day to about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about 10 mg/day, about 15 mg/day, about 20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day, or about 900 mg/day.
  • the compounds are administered in pM or nM concentrations. In certain embodiments, the compounds are administered in about 1 pM, about 2 pM, about 3 pM, about 4 pM, about 5 pM, about 6 pM, about 7 pM, about 8 pM, about 9 pM, about 10 pM, about 20 pM, about 30 pM, about 40 pM, about 50 pM, about 60 pM, about 70 pM, about 80 pM, about 90 pM, about 100 pM, about 200 pM, about 300 pM, about 400 pM, about 500 pM, about 600 pM, about 700 pM, about 800 pM, about 900 pM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 20 pM,
  • the dosage form is a solid dosage form, and the size of the compound in the dosage form is important.
  • the compound is less than about 3 ⁇ m, less than about 2 ⁇ m, or less than about 1 ⁇ m in diameter.
  • the active agent is about 0.1 ⁇ m to about 3.0 ⁇ m in diameter. In certain embodiments, the active agent is from about 0.5 ⁇ m to about 1.5 ⁇ m in diameter.
  • the active agent is about 0.2 ⁇ m, about 0.3 ⁇ m, about 0.4 ⁇ m, about 0.5 ⁇ m, about 0.6 ⁇ m, about 0.7 ⁇ m, about 0.8 ⁇ m, about 0.9 ⁇ m, about 1.0 ⁇ m, about 1.1 ⁇ m, about 1.2 ⁇ m, about 1.3 ⁇ m, about 1.4 ⁇ m, or about 1.5 ⁇ m in diameter.
  • a formulation intended for oral administration to humans may contain from about 0.1 mg to about 5 g of the active agent (or compound) compounded with an appropriate and convenient carrier material varying from about 5% to about 95% of the total composition.
  • Unit dosages will generally contain between about 0.5 mg to about 1500 mg of the active agent.
  • the dosage may be about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg, 65, mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 100 mg, etc., up to about 1500 mg of the compound.
  • the invention relates to combination of two active agents.
  • the ratio of the first active agent to the second active agent is about: 200:1, 190:1, 180:1, 170:1, 160:1, 150:1, 140:1, 130:1, 120:1, 110:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1. It further may be preferable to have a more equal distribution of pharmaceutical agents.
  • the ratio of the first active agent to the second active agent is about: 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, or 1:4. It may also be advantageous for the pharmaceutical combination to have a relatively large amount of the second component compared to the first component. In certain instances, the ratio of the second active agent to the first active agent is about 200:1, 190:1, 180:1, 170:1, 160:1, 150:1, 140:1, 130:1, 120:1, 110:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 10:1, 9:1, 8:1, 7:1, 6:1, or 5:1.
  • a composition comprising any of the above identified combinations of the first therapeutic agent and second therapeutic agent may be administered in divided doses about 1, 2, 3, 4, 5, 6, or more times per day or in a form that will provide a rate of release effective to attain the desired results.
  • the dosage form may contain both the first and second active agents.
  • the dosage form may be administered one time per day if it contains both the first and second active agents.
  • a formulation intended for oral administration to humans may contain from about 0.1 mg to about 5 g of the first therapeutic agent and about 0.1 to about 5 g of the second therapeutic agent, both of which are compounded with an appropriate and convenient about of carrier material varying from about 5% to about 95% of the total composition.
  • Unit dosages will generally contain between about 0.5 mg to about 1500 mg of the first therapeutic agent and 0.5 mg to 1500 mg of the second therapeutic agent.
  • the dosage may be about: 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 100 mg, etc., up to about 1500 mg of the first therapeutic agent.
  • the dosage may be about: 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 100 mg, etc., up to about 1500 mg of the second therapeutic agent.
  • the inventions relates to a method of treating a Alzheimer's disease comprising administering by inhalation a micronized, dry powder comprising about 1 mg to 100 mg of Cromolyn Disodium per day to a patient in need thereof.
  • FIG. 1B illustrates representative images of localization of amyloid deposits (6E10) and microglia (Iba1) in mice treated with Cromolyn Sodium (3.15mg/kg) or PBS daily for seven days.
  • FIG. 1C illustrates the effect of Cromolyn Sodium on microglial A ⁇ uptake in vitro. Microglial cells were cultured and incubated with 50 nM of synthetic A ⁇ 40 or A ⁇ 42 and 0, 10 nM, 10 ⁇ M or 1 mM of Cromolyn Sodium for 16 hours. After the incubation, the concentrations of A ⁇ x-40 ( FIG.
  • FIG. 2 illustrates representative plaques of all the plaques and the microglial cells surrounding those deposits in Tg-2576 mice of the study.
  • An image analysis looking at the percentage of Iba-1 positive processes colocalizing with the amyloid staining versus the total amount of Iba-1 signal surrounding the plaque demonstrated that there was more Iba-1/Amyloid colocalization when the mice were treated with Cromolyn Sodium as opposed to any other groups. This result correlates with our results in Example 1 and our in vitro data.
  • BV2 microglial cell cultures were treated with cromolyn and/or ibuprofen (10 ⁇ M, 100 ⁇ M, 1 mM) for 16 hours. Afterwards, cells were incubated with soluble A ⁇ 42 and the compounds for 3 hours. After incubation, cells were collected for ELISA analysis.
  • FIG. 3 graphically illustrates the results of BV2 microglial cells treated with cromolyn, and with cromolyn and ibuprofen exhibit increased A ⁇ 42 uptake levels relative to BV2 microglia treated with the vehicle.
  • Acetic anhydride (0.5 g, 4.6 mmol) was slowly added to a mixture of 5,5′-[(2-hydroxy-1,3-propanediyl)bis(oxy)]bis[4-oxo-4H-1-benzopyran-2-ethanol (0.5 g, 1.14 mmol) in pyridine (20 mL) cooled to 0-5° C. The mixture was stirred for 3 hr at 0-5° C. and then allowed to warm to room temperature. TLC indicted the reaction was complete. Methylene chloride was added and the mixture was washed with 10% HCl until the aqueous phase was acidic. The methylene chloride layer was dried over anhydrous sodium sulfate and solvent was evaporated.
  • Synthetic Aa ⁇ 42 in final 5 uM was incubated with 10, 100, 1,000 nM of test compounds for 1 hour.
  • the aggregation was initiated with heparin at 0.5 mg/ml in final concentration.
  • the assay buffer consisted of 125 mM NaCl, 2.5 mM KCl, 1 mM MgCl 2 , 1.25 mM Na 2 H 2 PO 4 , 2 mM CaCl 2 , 25 mM Glucose, and NaHCO 3 to adjust pH to 7.4.
  • the assay buffer was used as a control.
  • the aggregation was measured by intensity of Thioflavin T binding, which was detected by fluorescent excitation/emission at 450 nm/480 nm (Spectra Max M3 plate reader, Molecular Devices) in a kinetic mode. Aggregation was recorded as the kinetics was calculated as Vmax by the plate reader's software. The assay was performed in triplicate and expressed as standard mean ⁇ SD. Blue dotted line indicate the assay buffer control.
  • FIG. 4 illustrates the results of the assay.
  • FIG. 5 graphically illustrates the results of a one-way of the differences in the A ⁇ levels and the ratios of A ⁇ (42:40).
  • BV2-CD33 WT The effect of compounds in BV2 cells stably expressing full-length human CD33 was assessed to explore whether they reverse CD33-mediated inhibition of A ⁇ uptake (Griciuc et al., 2013 Neuron 78, 631-643).
  • the compound numbers, molecular weight and concentration of the stock solutions are summarized in Table 1.
  • Cromolyn derivatives, C3 and C4 displayed lower solubility in DMSO in comparison to C1, C2, C5, C6, C7 and C8. Therefore, a 25 mM stock solutions for all the compounds except for C3 and C4 were prepared.
  • the stock solutions for C3 and C4 were prepared at 5 mM and 7.5 mM, respectively.
  • C1 is the parent compound—cromolyn disodium.
  • na ⁇ ve BV2 cells were treated with DMSO (control) or cromolyn at 500 ⁇ M for 16 hours. Afterwards, cells were washed with PBS and treated with DMSO or cromolyn in the presence of the fluorescently-tagged A ⁇ 42 peptide (400 nM, red) for 2 hours. At the end of the treatment, the cells were washed and labeled them with a plasma membrane dye (green). Using confocal microscopy and the fluorescence signal in the red channel, the levels of intracellular A ⁇ 42 peptide were quantified. All the quantifications were performed by a blind observer with the ImageJ software. Remarkably, cromolyn sodium led to increased uptake of A ⁇ 42 in na ⁇ ve BV2 microglial cells ( FIG. 6A - FIG. 6D ).
  • cromolyn sodium modulates A ⁇ 42 uptake in na ⁇ ve BV2 microglial cells was determined by using the ELISA assay. Additionally, whether cromolyn sodium leads to increased A ⁇ 42 uptake levels in BV2 cells stably expressing full-length human CD33 (BV2-CD33 WT ) was determined. To this purpose, both na ⁇ ve BV2 and BV2-CD33 WT cell lines were treated with DMSO (control) or cromolyn at different concentrations for 16 hours. Then, the cells were washed with PBS and treated with DMSO or cromolyn and soluble untagged A ⁇ 42 peptide (400 nM) for 2 hours. The collected cell lysates were analyzed for A ⁇ 42 uptake levels using the A ⁇ 42-specific ELISA kit from Wako. The ELISA results were normalized to the protein concentration levels that were previously quantified using the BCA assay.
  • na ⁇ ve BV2 or BV2-CD33 WT cells were plated in proliferating media.
  • cells were treated with DMSO (control) or the compounds at different concentrations in proliferating media for 3 hours.
  • C1, C2, C5, C6, C7 and C8 were tested at 10, 50, 100 and 150 ⁇ M, while C3 and C4 were assessed at 5, 25, 50 and 75 ⁇ M due to solubility limit in DMSO.
  • cells were washed with PBS and treated with DMSO or compounds in the presence of the untagged A ⁇ 42 peptide (400 nM) in DMEM media for 2 hours.
  • na ⁇ ve BV2 microglial cells were incubated with DMSO (vehicle) or cromolyn derivatives at different concentrations for 3 hours. The cells were then washed and incubated with DMSO or compounds and soluble untagged A ⁇ 42 for additional 2 hours. Afterwards, the cell media was collected and measured LDH released by the damaged cells to identify the compounds that induce cytolysis. The LDH assay showed that the cromolyn derivative C8 is the only compound showing toxicity when tested at 100 and 150 ⁇ M ( FIG. 8 ). Therefore, 100 and 150 ⁇ M concentrations for C8 were excluded from the A ⁇ 42 uptake assays.
  • na ⁇ ve BV2 microglial cells were treated with DMSO (control) or cromolyn derivative compounds at different concentrations for 3 hours. Afterwards, the cells were washed and treated with DMSO or compounds in the presence of untagged A ⁇ 42 peptide for 2 hours. At the end of the treatment, the cell lysates were collected. The analysis for intracellular A ⁇ 42 levels is performed using an A ⁇ 42-specific ELISA kit. The parent compound C1 (cromolyn sodium) led to a modest increase of A ⁇ 42 uptake at 100 and 150 ⁇ M in BV2 cells.
  • BV2-CD33 WT cells were treated with DMSO (control) or cromolyn derivatives at different concentrations ranging between 5 and 150 ⁇ M.
  • the cromolyn derivatives C1 and C3-8 were tested.
  • the compound C2 was tested with other cromolyn derivatives in the second set of experiments.
  • Treatment with the compound C4 at 75 ⁇ M resulted in a two-fold increase in A ⁇ 42 uptake in comparison to DMSO treatment and displayed a dose-dependent effect at 50 ⁇ M ( FIG. 10 ).
  • the IC 50 for C4 was 54.7 ⁇ M in BV2-CD33 WT cells.
  • the compound C6 exhibits a dose-dependent effect in mediating inhibition of A ⁇ 42 uptake in BV2-CD33 WT cells when compared to DMSO treatment.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022178278A1 (en) * 2021-02-19 2022-08-25 The Trustees Of Columbia University In The City Of New York Compositions and methods for modeling human microglia

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9925282B2 (en) 2009-01-29 2018-03-27 The General Hospital Corporation Cromolyn derivatives and related methods of imaging and treatment
EP2911664B1 (en) 2012-10-25 2019-05-08 The General Hospital Corporation Combination therapies for the treatment of alzheimer's disease and related disorders
US10525005B2 (en) 2013-05-23 2020-01-07 The General Hospital Corporation Cromolyn compositions and methods thereof
US10188757B2 (en) 2013-10-22 2019-01-29 The General Hospital Corporation Cromolyn derivatives and related methods of imaging and treatment
EP3380095B1 (en) * 2015-11-23 2022-01-05 The General Hospital Corporation Compositions and methods for treating ischemic stroke
US20190240194A1 (en) 2016-08-31 2019-08-08 The General Hospital Corporation Macrophages/microglia in neuro-inflammation associated with neurodegenerative diseases
CN111163770A (zh) * 2017-07-08 2020-05-15 综合医院公司 鉴定用于治疗阿尔茨海默氏病的治疗性药物或试剂的筛选平台
MX2020000577A (es) 2017-07-20 2020-09-10 Aztherapies Inc Formulaciones en polvo de cromolina sodica e ibuprofeno.
CA3096545A1 (en) * 2018-04-09 2019-10-17 The General Hospital Corporation Combination therapies for the treatment of amyotropic lateral sclerosis and related disorders
WO2020010049A1 (en) 2018-07-02 2020-01-09 The General Hospital Corporation POWDERED FORMULATIONS OF CROMOLYN SODIUM AND α-LACTOSE
JP2021535181A (ja) * 2018-09-05 2021-12-16 ザ ジェネラル ホスピタル コーポレイション サイトカイン放出症候群を処置する方法
CN113727736A (zh) * 2018-12-10 2021-11-30 通用医疗公司 色甘酸酯及其用途
JP2023520580A (ja) 2020-04-06 2023-05-17 ザ ジェネラル ホスピタル コーポレイション コロナウイルス誘発炎症状態の処置方法
CN112375058A (zh) * 2020-11-11 2021-02-19 杭州卢普生物科技有限公司 色甘酸二乙酯和色甘酸钠的制备方法
WO2022146914A1 (en) * 2020-12-28 2022-07-07 The General Hospital Corporation Cromolyn derivatives and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060142241A1 (en) * 2004-11-01 2006-06-29 Yoo Seo H Methods and compositions for reducing neurodegeneration in amyotrophic lateral sclerosis
US10092564B2 (en) * 2016-03-25 2018-10-09 Ab Science Use of masitinib for treatment of an amyotrophic lateral sclerosis patient subpopulation

Family Cites Families (127)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3686412A (en) 1965-03-25 1972-08-22 Colin Fitzmaurice Compositions containing bis-chromonyl compounds for inhibiting antigen-antibody reactions
GB1144905A (en) 1965-03-25 1969-03-12 Fisons Pharmaceuticals Ltd Substituted bis-(2-carboxy-chromonyl-oxy) derivatives and preparation and pharmaceutical compositions thereof
US3957965A (en) 1967-08-08 1976-05-18 Fisons Limited Sodium chromoglycate inhalation medicament
GB1242211A (en) 1967-08-08 1971-08-11 Fisons Pharmaceuticals Ltd Pharmaceutical composition
GB1257162A (enExample) 1968-02-16 1971-12-15
US4405598A (en) 1976-01-30 1983-09-20 Fisons, Limited Composition for treating asthma
DE3104294A1 (de) 1981-02-07 1982-08-19 Hoechst Ag, 6000 Frankfurt Substituierte diazaspirodecane, ihre herstellung, ihre verwendung als stabilisatoren fuer organische polymere, sowie die so stabilisierten polymeren
US4429545A (en) 1981-08-03 1984-02-07 Ocean & Atmospheric Science, Inc. Solar heating system
BE897058A (fr) 1982-06-25 1983-12-16 Sandoz Sa Utilisation d'un derive du spiro-succinimide dans le traitement de la demence du type alzheimer
US4996296A (en) 1983-07-27 1991-02-26 Yeda Research & Development Co., Ltd. Cromolyn binding protein in highly purifed form, and methods for the isolation thereof
US5231170A (en) 1986-08-27 1993-07-27 Paul Averback Antibodies to dense microspheres
US4919915A (en) 1987-03-03 1990-04-24 Paul Averback Method for detecting the ability to prevent red-to-green congophilic birefringence
WO1990013327A1 (en) 1989-04-28 1990-11-15 Riker Laboratories, Inc. Dry powder inhalation device
US5376386A (en) 1990-01-24 1994-12-27 British Technology Group Limited Aerosol carriers
DE4405387A1 (de) 1994-02-19 1995-08-24 Hoechst Ag Verfahren zur Herstellung von Polyalkyl-1-oxa-diazaspirodecan-Verbindungen
US6168776B1 (en) 1994-07-19 2001-01-02 University Of Pittsburgh Alkyl, alkenyl and alkynyl Chrysamine G derivatives for the antemortem diagnosis of Alzheimer's disease and in vivo imaging and prevention of amyloid deposition
CA2174583A1 (en) 1995-05-05 1996-11-06 Alexander Chucholowski Sulfuric acid esters of sugar alcohols
US6026809A (en) 1996-01-25 2000-02-22 Microdose Technologies, Inc. Inhalation device
US6126919A (en) 1997-02-07 2000-10-03 3M Innovative Properties Company Biocompatible compounds for pharmaceutical drug delivery systems
US6565885B1 (en) 1997-09-29 2003-05-20 Inhale Therapeutic Systems, Inc. Methods of spray drying pharmaceutical compositions
WO1999016421A1 (en) 1997-09-29 1999-04-08 Inhale Therapeutic Systems, Inc. Stabilized bioactive preparations and methods of use
US6309623B1 (en) 1997-09-29 2001-10-30 Inhale Therapeutic Systems, Inc. Stabilized preparations for use in metered dose inhalers
US5904937A (en) 1997-10-03 1999-05-18 Fmc Corporation Taste masked pharmaceutical compositions
TWI239847B (en) 1997-12-02 2005-09-21 Elan Pharm Inc N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease
DK1083952T3 (da) 1998-06-12 2006-04-24 Microdose Technologies Inc Apparat til uddeling af medicinalvarer og medikamenter
US6197963B1 (en) 1998-08-13 2001-03-06 The Trustees Of The University Of Pennsylvania Non-peptide peptidomimetics
HU226164B1 (en) 1998-11-13 2008-05-28 Jagotec Ag Use of magnesium stearate in dry powder compositions suitable for inhalation and compositions suitable for inhalation
ATE252386T1 (de) 1998-12-24 2003-11-15 Janssen Pharmaceutica Nv Galantamin-zusammensetzung mit gesteuerter freisetzung
JP2001151673A (ja) 1999-09-06 2001-06-05 Nikken Chem Co Ltd 吸入用粉末製剤の製造方法
US20020107173A1 (en) 1999-11-04 2002-08-08 Lawrence Friedhoff Method of treating amyloid beta precursor disorders
US20020009491A1 (en) 2000-02-14 2002-01-24 Rothbard Jonathan B. Compositions and methods for enhancing drug delivery across biological membranes and tissues
ES2248283T3 (es) 2000-02-21 2006-03-16 Pharmexa A/S Nuevo procedimiento para reducir los niveles de amiloide.
CA2406383A1 (en) 2000-04-13 2001-10-25 Mayo Foundation For Medical Education And Research A.beta.42 lowering agents
US20080021085A1 (en) 2000-04-13 2008-01-24 Mayo Foundation For Medical Education And Research Method of reducing abeta42 and treating diseases
PE20011227A1 (es) 2000-04-17 2002-01-07 Chiesi Farma Spa Formulaciones farmaceuticas para inhaladores de polvo seco en la forma de aglomerados duros
AR035642A1 (es) 2000-05-26 2004-06-23 Pharmacia Corp Uso de una composicion de celecoxib para el alivio rapido del dolor
US20020016359A1 (en) 2000-06-29 2002-02-07 Hellberg Mark R. Compositions and methods of treating neurodegenerative diseases
US8519005B2 (en) 2000-07-27 2013-08-27 Thomas N. Thomas Compositions and methods to prevent toxicity of antiinflammatory agents and enhance their efficacy
FR2815030A1 (fr) 2000-10-05 2002-04-12 Lipha Derives nitroso de la diphenylamine, compositions pharmaceutiques les contenant et leur utilisation pour la preparation de medicaments
US6511960B2 (en) 2001-01-05 2003-01-28 Alphamed Pharmaceuticals Corp Cromolyn for eye and ear infections
ATE349446T1 (de) 2001-04-23 2007-01-15 Univ Pennsylvania Amyloid plaque aggregationshemmer und diagnostische bilderzeugungsmittel
US20040259952A1 (en) 2001-11-29 2004-12-23 Richat Abbas Formulations for oral administration of cromolyn sodium
ES2337350T3 (es) 2002-05-10 2010-04-23 Oriel Therapeutics, Inc. Inhalador de polvo seco para uso con medios de dispensacion activados por polimeros piezoelectricos y envases de blisteres asociado que comprende un material polimerico piezoelectrico.
EP1601380A1 (en) 2003-02-13 2005-12-07 Licentia OY Use of a mast cell activation or degranulation blocking agent in the manufacture of a medicament for the treatment of cerebral ischemia
US8163734B2 (en) * 2003-02-13 2012-04-24 Perttu J. Lindsberg Use of a mast cell activation or degranulation blocking agent in the manufacture of a medicament for the treatment of a patient subjected to thrombolyses
US20040223918A1 (en) 2003-05-07 2004-11-11 Chrysalis Technologies Incorporated Aerosolization of cromolyn sodium using a capillary aerosol generator
GB0321607D0 (en) 2003-09-15 2003-10-15 Vectura Ltd Manufacture of pharmaceutical compositions
EP1686960A4 (en) 2003-10-28 2007-03-07 Glaxo Group Ltd INHALABLE PHARMACEUTICAL PREPARATIONS EMPLOYING LACTOSE ANHYDRATE, AND METHODS OF ADMINISTERING SAID PREPARATIONS
GB0326632D0 (en) 2003-11-14 2003-12-17 Jagotec Ag Dry powder formulations
DE10355559A1 (de) 2003-11-21 2005-06-23 Orthogen Ag Transskin
US8088935B2 (en) 2003-12-23 2012-01-03 Ironwood Pharmaceuticals, Inc. Compounds and methods for the treatment of asthma
US20070093457A1 (en) 2004-02-11 2007-04-26 Nadir Arber Compositions for treatment of cancer and inflammation with curcumin and at least one nsaid
US20050182044A1 (en) 2004-02-17 2005-08-18 Bruinsma Gosse B. Combinatorial therapy with an acetylcholinesterase inhibitor and (3aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3,-b]indol-5-yl phenylcarbamate
WO2006001877A2 (en) 2004-04-13 2006-01-05 Myriad Genetics, Inc. Combination treatment for neurodegenerative disorders comprising r-flurbiprofen
BRPI0510119A (pt) 2004-04-23 2007-09-25 Cydex Inc formulação para dpi contendo sulfoaquil éter de ciclodextrina
ES2339790T3 (es) 2004-08-30 2010-05-25 Seo Hong Yoo Efecto neuroprotector de udca solubilizado en modelo isquemico focal.
GB0426146D0 (en) 2004-11-29 2004-12-29 Bioxell Spa Therapeutic peptides and method
RU2007143302A (ru) 2005-04-22 2009-05-27 Дженентек, Инк. (Us) Способ лечения деменции или болезни альцгеймера антителами к cd20
AU2006251832A1 (en) 2005-05-27 2006-11-30 Queen's University At Kingston Treatment of protein folding disorders
JP2009519972A (ja) 2005-12-15 2009-05-21 アキュスフィア， インコーポレイテッド 粒子ベースの経肺投与または経鼻投与用製薬の製造方法
US8263645B2 (en) 2006-02-03 2012-09-11 Pari Pharma Gmbh Disodium cromoglycate compositions and methods for administering same
AR059356A1 (es) 2006-02-14 2008-03-26 Astrazeneca Ab Nuevos radioligandos
EP1994011B1 (en) 2006-03-06 2010-10-13 RaQualia Pharma Inc Sulfonyl benzimidazole derivatives
EA200801967A1 (ru) 2006-03-09 2009-04-28 Ворэта Фармэсьютиклз Инк. Дозированная лекарственная форма на основе циклогексанового полиола (варианты), способ ее получения, способ лечения болезни альцгеймера с ее помощью и циклогексановый полиол в качестве средства при изготовлении лекарственного средства
WO2008118122A2 (en) 2006-05-08 2008-10-02 Molecular Neuroimaging, Llc Compounds and amyloid probes thereof for therapeutic and imaging uses
US8445437B2 (en) 2006-07-27 2013-05-21 The Brigham And Women's Hospital, Inc. Treatment and prevention of cardiovascular disease using mast cell stabilizers
US20100173960A1 (en) 2006-09-21 2010-07-08 Antonio Cruz The Combination of a Cyclohexanehexol and a NSAID for the Treatment of Neurodegenerative Diseases
WO2008061373A1 (en) 2006-11-24 2008-05-29 Waratah Pharmaceuticals Inc. Combination treatments for alzheimer's disease and similar diseases
DK2142513T3 (da) 2007-04-18 2014-06-10 Probiodrug Ag Nitrovinyl-diamin-derivater som glutaminyl-cyclase-inhibitorer
CN101970000A (zh) 2007-04-18 2011-02-09 杨森阿尔茨海默氏症免疫治疗公司 脑淀粉样血管病的预防和治疗
WO2008134618A2 (en) 2007-04-27 2008-11-06 The General Hospital Corporation Novel imaging tracers for early detection and treatment of amyloid plaques caused by alzheimer's disease and related disorders
EP2173380A4 (en) 2007-07-13 2011-08-31 Abbott Biotech Ltd METHOD AND COMPOSITIONS FOR PULMONARY ADMINISTRATION OF A TNFa HEMMER
GB0714134D0 (en) 2007-07-19 2007-08-29 Norton Healthcare Ltd Dry-powder medicament
DK2182983T3 (da) 2007-07-27 2014-07-14 Janssen Alzheimer Immunotherap Behandling af amyloidogene sygdomme med humaniserede anti-abeta antistoffer
JO3076B1 (ar) 2007-10-17 2017-03-15 Janssen Alzheimer Immunotherap نظم العلاج المناعي المعتمد على حالة apoe
CA2718035C (en) 2008-03-21 2017-10-24 The General Hospital Corporation Inositol derivatives for the detection and treatment of alzheimer' s disease and related disorders
ES2764480T3 (es) 2008-04-29 2020-06-03 Impact Coatings Ab Composiciones de combinación para tratar la enfermedad de Alzheimer y trastornos relacionados con zonisamida y acamprosato
KR20110117146A (ko) 2009-01-22 2011-10-26 라퀄리아 파마 인코포레이티드 Ｃｂ2 수용체 효능활성이 있는 ｎ-치환 포화 헤테로사이클릭 술폰 화합물
US8381454B1 (en) 2009-01-23 2013-02-26 Markus R. Robinson Segmented, elongated, expandable, 4-season, double-walled, low-cost, rigid extruded plastic panel structures
US9925282B2 (en) 2009-01-29 2018-03-27 The General Hospital Corporation Cromolyn derivatives and related methods of imaging and treatment
CN105061376A (zh) * 2009-01-29 2015-11-18 通用医疗公司 色甘酸衍生物以及成像和治疗的相关方法
EP2810652A3 (en) 2009-03-05 2015-03-11 AbbVie Inc. IL-17 binding proteins
CN102421775A (zh) 2009-03-11 2012-04-18 普莱希科公司 抑制Raf激酶的吡咯并[2，3-b]吡啶衍生物
AU2010225923B2 (en) 2009-03-16 2016-10-27 Ipintl, Llc Treating Alzheimer's disease and osteoporosis and reducing aging
EP2248517B1 (en) 2009-05-08 2014-03-26 PARI Pharma GmbH Concentrated mast cell stabilizing pharmaceutical formulations
JP2013501046A (ja) * 2009-08-06 2013-01-10 ニューラルタス ファーマシューティカルズ， インコーポレイテッド マクロファージ関連障害の処置
KR20180094126A (ko) 2009-09-24 2018-08-22 위스타 레보레이토리스 리미티드 결정질 메틸티오니늄 클로라이드（메틸렌 블루） 수화물
EP2322163A1 (en) 2009-11-03 2011-05-18 Pharnext New therapeutics approaches for treating alzheimer disease
US20110262442A1 (en) 2009-11-06 2011-10-27 Adenios, Inc. Compositions for treating cns disorders
JP5854476B2 (ja) 2009-11-30 2016-02-09 アデア ファーマスーティカルズ，インコーポレイテッド 圧縮性コーティングで被覆された医薬組成物及び錠剤並びに製造方法
EP2377860A1 (en) 2010-04-16 2011-10-19 AC Immune S.A. Novel compounds for the treatment of diseases associated with amyloid or amyloid-like proteins
WO2011136754A1 (en) 2010-04-26 2011-11-03 Mahmut Bilgic A medicament developed for the treatment of respiratory diseases
EA201300228A1 (ru) * 2010-08-12 2013-06-28 Ревалезио Корпорейшн Композиции и способы лечения таупатии
RU2580890C2 (ru) 2010-09-30 2016-04-10 КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. Применение стеарата магния в составах сухого порошка для ингаляции
US20120121656A1 (en) 2010-11-15 2012-05-17 Revalesio Corporation Methods and compositions for protecting against neurotoxicity of a neurotoxic agent, and improving motor coordination associated with a neurodegenerative condition or disease
SG192666A1 (en) 2011-02-11 2013-09-30 Wista Lab Ltd Phenothiazine diaminium salts and their use
SG11201406142XA (en) 2012-03-27 2014-10-30 Univ Duke Compositions and methods for the prevention and treatment of mast cell-induced vascular leakage
BR112014029442A2 (pt) 2012-05-25 2017-06-27 Xlear Inc composições antimucosas à base de xilitol e métodos e composições relacionados
US9655977B2 (en) * 2012-08-31 2017-05-23 The General Hospital Corporation Biotin complexes for treatment and diagnosis of alzheimer's disease
WO2014065275A1 (ja) 2012-10-23 2014-05-01 国立大学法人福井大学 腫瘍融解症候群の治療薬及び予防薬
US10058530B2 (en) 2012-10-25 2018-08-28 The General Hospital Corporation Combination therapies for the treatment of Alzheimer's disease and related disorders
EP2911664B1 (en) 2012-10-25 2019-05-08 The General Hospital Corporation Combination therapies for the treatment of alzheimer's disease and related disorders
US10525005B2 (en) 2013-05-23 2020-01-07 The General Hospital Corporation Cromolyn compositions and methods thereof
HK1218050A1 (zh) * 2013-05-23 2017-02-03 Aztherapies, Inc 用於递送色甘酸的方法
CN104288168B (zh) * 2013-07-17 2017-08-18 吉林敖东洮南药业股份有限公司 延龄草苷在制备用于治疗和/或预防小胶质细胞介导的疾病的药物中的用途
US10188757B2 (en) 2013-10-22 2019-01-29 The General Hospital Corporation Cromolyn derivatives and related methods of imaging and treatment
EP3653207A1 (en) 2014-02-10 2020-05-20 Respivant Sciences GmbH Mast cell stabilizers treatment for systemic disorders
PL3104854T3 (pl) * 2014-02-10 2020-11-30 Respivant Sciences Gmbh Stabilizatory komórek tucznych do leczenia choroby płuc
AU2015350142A1 (en) 2014-11-21 2017-06-15 Biohaven Pharmaceutical Holding Company Ltd. Sublingual administration of riluzole
WO2016196401A1 (en) 2015-05-29 2016-12-08 The Texas A&M University System Antimicrobial and anti-inflammatory compositions
EP3331522A1 (en) 2015-08-07 2018-06-13 Patara Pharma LLC Methods for the treatment of mast cell related disorders with mast cell stabilizers
US10265296B2 (en) 2015-08-07 2019-04-23 Respivant Sciences Gmbh Methods for the treatment of systemic disorders treatable with mast cell stabilizers, including mast cell related disorders
EP3368032A1 (en) * 2015-10-28 2018-09-05 AB Science Use of masitinib and other mast cell inhibitors for treatment of parkinson's disease
CN108472393A (zh) * 2015-11-19 2018-08-31 阿尔茨治疗方法公司 用于治疗阿尔茨海默病和有关病症的方法
EP3380095B1 (en) * 2015-11-23 2022-01-05 The General Hospital Corporation Compositions and methods for treating ischemic stroke
US20190240194A1 (en) 2016-08-31 2019-08-08 The General Hospital Corporation Macrophages/microglia in neuro-inflammation associated with neurodegenerative diseases
KR20190073365A (ko) 2016-09-08 2019-06-26 이메르고 테라퓨틱스, 인코포레이티드 사이토카인 과분비 및 바이러스성 감염의 치료를 위한 비만 세포 안정화제
MX2020000577A (es) 2017-07-20 2020-09-10 Aztherapies Inc Formulaciones en polvo de cromolina sodica e ibuprofeno.
CN108164409B (zh) 2018-01-24 2021-06-18 温州医科大学 一种2-亚苄基-1-茚酮类似物及应用
CA3096545A1 (en) 2018-04-09 2019-10-17 The General Hospital Corporation Combination therapies for the treatment of amyotropic lateral sclerosis and related disorders
CN108403708B (zh) 2018-05-22 2019-06-14 滨州医学院 秦皮苷在制备预防或治疗急性呼吸窘迫综合征药物中的应用
WO2020010049A1 (en) 2018-07-02 2020-01-09 The General Hospital Corporation POWDERED FORMULATIONS OF CROMOLYN SODIUM AND α-LACTOSE
JP2021535181A (ja) 2018-09-05 2021-12-16 ザ ジェネラル ホスピタル コーポレイション サイトカイン放出症候群を処置する方法
CN113727736A (zh) 2018-12-10 2021-11-30 通用医疗公司 色甘酸酯及其用途
JP2023520580A (ja) 2020-04-06 2023-05-17 ザ ジェネラル ホスピタル コーポレイション コロナウイルス誘発炎症状態の処置方法
IL298673A (en) 2020-06-04 2023-01-01 Massachusetts Gen Hospital Methods for treating the corona virus infection
WO2022146914A1 (en) 2020-12-28 2022-07-07 The General Hospital Corporation Cromolyn derivatives and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060142241A1 (en) * 2004-11-01 2006-06-29 Yoo Seo H Methods and compositions for reducing neurodegeneration in amyotrophic lateral sclerosis
US10092564B2 (en) * 2016-03-25 2018-10-09 Ab Science Use of masitinib for treatment of an amyotrophic lateral sclerosis patient subpopulation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022178278A1 (en) * 2021-02-19 2022-08-25 The Trustees Of Columbia University In The City Of New York Compositions and methods for modeling human microglia

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