WO2017106584A1 - Traitement du système nerveux central et de troubles mentaux avec des agonistes des récepteurs bêta-3 adrénergiques - Google Patents

Traitement du système nerveux central et de troubles mentaux avec des agonistes des récepteurs bêta-3 adrénergiques Download PDF

Info

Publication number
WO2017106584A1
WO2017106584A1 PCT/US2016/067066 US2016067066W WO2017106584A1 WO 2017106584 A1 WO2017106584 A1 WO 2017106584A1 US 2016067066 W US2016067066 W US 2016067066W WO 2017106584 A1 WO2017106584 A1 WO 2017106584A1
Authority
WO
WIPO (PCT)
Prior art keywords
adrb3
agonist
subject
nervous system
mirabegron
Prior art date
Application number
PCT/US2016/067066
Other languages
English (en)
Inventor
Nay L. SAW
Mehrdad Shamloo
Bitna YI
Original Assignee
The Board Of Trustees Of The Leland Stanford Junior University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Board Of Trustees Of The Leland Stanford Junior University filed Critical The Board Of Trustees Of The Leland Stanford Junior University
Publication of WO2017106584A1 publication Critical patent/WO2017106584A1/fr

Links

Classifications

    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86

Definitions

  • the present invention pertains generally to treatment of central nervous system (CNS) and mental disorders.
  • the invention relates to methods of treating CNS disorders and mental disorder with selective agonists of ⁇ 3 -adrenoceptor (ADRB3), such as Mirabegron and Amibegron.
  • ADRB3 selective agonists of ⁇ 3 -adrenoceptor
  • Neurodegenerative diseases are characterized by the dysfunction and death of neurons, leading to the loss of functions mediated by the brain, spinal cord and the peripheral nervous system. These disorders have a major impact on society. For example, approximately 4 to 5 million Americans are afflicted with the chronic neurodegenerative disease known as Alzheimer's disease. Other examples of chronic neurodegenerative diseases include diabetic peripheral neuropathy, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, Huntington's disease and Parkinson's disease. Normal brain aging is also associated with loss of normal neuronal function and may entail the depletion of certain neurons.
  • Stroke is the third ranking cause of death in the United States, and accounts for half of neurology inpatients. Depending on the area of the brain that is damaged, a stroke can cause coma, paralysis, speech problems and dementia. The major causes of cerebral infarction are vascular thrombosis, cerebral embolism, hypotension, hypertensive hemorrhage, and anoxia/hypoxia. However, the adult brain retains capacity for plasticity and functional reorganization throughout the life span, even after stroke or brain ischemia. Neuronal connections are continuously remodeled. The potential capability of the brain to compensate for the damaged part of the brain has relevance for stroke rehabilitation. Neuroimaging in stroke patients suggests some functional reorganization.
  • one aspect of brain plasticity is that in stroke patients, the neuronal connections can be modified by sensory input, experience and learning, and the brain can respond by functional and structural reorganization, upregulation or downregulation of a neural response to an event, and the establishment of new functional and structural connections by collateral sprouting and compensatory synaptogenesis, as well as neurogenesis.
  • the invention is based on the discovery that ADRB3 agonists are effective in treating CNS disorders and mental disorders.
  • the invention includes a method of treating a subject for a CNS disorder or mental disorder, the method comprising administering to the subject a therapeutically effective amount of an ADRB3 agonist.
  • the ADRB3 agonist is selected from the group consisting of Mirabegron and Amibegron.
  • the CNS disorder is Alzheimer's disease or stroke (e.g., ischemic or hemorrhagic).
  • the mental disorder is an anxiety disorder or schizophrenia.
  • an ADRB3 agonist e.g., Mirabegron or Amibegron
  • an ADRB3 agonist an amount that, when administered as described herein, brings about a positive therapeutic response with respect to treatment of an individual for a CNS disorder or mental disorder such as an amount that enhances cognitive function or immune function in the nervous system.
  • a therapeutically effective dose or amount of an ADRB3 agonist may improve learning or memory, modulate peripheral or central inflammation in the nervous system, or reduce pathological neurological deterioration.
  • an ADRB3 agonist may have antidepressant or anxiolytic effects.
  • An ADRB3 agonist may be administered by any suitable mode of
  • the ADRB3 agonist is administered according to a daily dosing regimen or intermittently.
  • the method further comprises administering an antagonist of ADRB3.
  • ADRB3 antagonists include L-748,328, L- 748,337, and SR59230A.
  • the ADRB3 agonist is active in the central nervous system and the ADRB3 antagonist is active in the peripheral nervous system, wherein the ADRB3 antagonist does not cross the blood-brain barrier.
  • the method further comprises administering one or more other drugs for treating a CNS disorder or mental disorder.
  • the method may further comprise administering an acetylcholinesterase inhibitor (e.g., Donepezil (Aricept), Rivastigmine (Exelon), and Galantamine (Razadyne)) or an N- methyl D-aspartate (NMD A) receptor antagonist (e.g., Memantine (Namenda)).
  • an acetylcholinesterase inhibitor e.g., Donepezil (Aricept), Rivastigmine (Exelon), and Galantamine (Razadyne)
  • NMD A N- methyl D-aspartate
  • the invention includes a method of improving learning or memory in a subject who has Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of an ADRB3 agonist.
  • the ADRB3 agonist is selected from the group consisting of Mirabegron and Amibegron.
  • the invention includes a method of increasing the monocyte or white blood cell count in a subject who has Alzheimer's disease, the method comprising administering to the subject a therapeutically effective amount of an ADRB3 agonist.
  • the ADRB3 agonist is selected from the group consisting of Mirabegron and Amibegron.
  • the invention includes a composition comprising a ⁇ 3 - adrenoceptor (ADRB3) agonist for use in the treatment of a central nervous system (CNS) disorder.
  • the composition comprises Mirabegron or Amibegron.
  • the composition further comprises one or more other drugs for treating a CNS disorder or mental disorder.
  • the composition may further comprise an acetylcholinesterase inhibitor (e.g., Donepezil (Aricept), Rivastigmine (Exelon), and Galantamine (Razadyne)) or an N-methyl D- aspartate (NMD A) receptor antagonist (e.g., Memantine (Namenda)).
  • FIG. 1 shows expression of beta3 -adrenergic receptors, adipsin, and uncoupling protein (UCP) in rat brain regions.
  • RT/PCR utilized the unlabeled primers: ⁇ 3 ⁇ 1 (beta3 -adrenergic receptor ex on 1), P3sp (beta3 -adrenergic receptor intron-spanning), Adp (adipsin) and UCP (uncoupling protein).
  • PCR products were identified by hybridization to independent probes. Product sizes were determined by comparison with a 100 bp DNA latter.
  • FIGS. 2A-2D show the selective beta3 -adrenergic receptor antagonist L- 748,337 impairs cognitive function.
  • FIG. 2A shows the structure of L-748,337.
  • FIGS. 2B-2D show that L-748,337 treated mice have impaired spontaneous alternation behavior in a Y-maze, reflected in the % alternation (FIG. 2A), number of entries (FIG. 2B), and the number of pellets (FIG. 2C) in the Y-maze, indicating that acute inhibition of beta3 -adrenergic receptor with the selective antagonist L-748,337 impairs spatial memory.
  • FIGS. 1 shows the structure of L-748,337.
  • FIGS. 2B-2D show that L-748,337 treated mice have impaired spontaneous alternation behavior in a Y-maze, reflected in the % alternation (FIG. 2A), number of entries (FIG. 2B), and the number of pellets (FIG. 2C) in the
  • FIG. 3A and 3B show structures of beta3 -adrenergic receptor agonists.
  • FIG. 3A shows Amibegron (SR-58,611 A), the first orally active beta3 -adrenergic receptor agonist. It is CNS permeable, and has antidepressant and anxiolytic effects. Fourteen human clinical trials have been completed for its indication in depressive disorder.
  • FIG. 3B shows Mirabegron, a first-in-class agonist of beta3 -adrenergic receptors. It has a chiral center, but it was developed as an R-enantiomer.
  • An Oral Controlled Absorption System (OCAS) tablet was approved in the United States since 2014. However, it was not developed for the CNS indication.
  • OFS Oral Controlled Absorption System
  • FIGS. 4A-4C show that Mirabegron (an example of Peta3 -adrenoceptor agonist) enhances learning and memory in the Morris water maze (MWM).
  • FIG. 4A shows the MWM, a large water tank (178 cm in diameter) filled with water, which was used for experiments. A circular platform was placed about 1 cm below the water surface approximately 17 cm away from the wall in one quadrant of the tank.
  • Nontoxic tempera paints were used to make the water opaque. During the three consecutive days of hidden platform training, mice were released from drop locations and given 60 seconds to find the platform. Upon completion of the hidden platform training, the platform was removed, and a 60-second probe trial was conducted.
  • FIG. 4B shows results with an APP transgenic mouse, a transgenic model of Alzheimer's disease, which expresses human APP751 cDNA containing the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the murine Thyl gene.
  • FIG. 4C shows that during the probe trial, APP transgenic mice performed poorly and did not distinguish target quadrant from non-target quadrants, indicating that they had cognitive deficits. APP transgenic mice dosed with Mirabegron spent more time in the target quadrant relative to non-target quadrants, indicating that Mirabegron restored the cognitive deficits associated with Alzheimer's disease.
  • FIGS. 5A-5D show that Mirabegron (an example of Peta3 -adrenoceptor agonist) enhances learning and memory in a fear conditioning test.
  • FIG. 5 A shows for the assessment of conditional learning and memory, a trace fear conditioning protocol was used for the training day followed by tone-cued and contextual memory retrieval tests.
  • mice were placed in the chamber for a 3-minute baseline recording followed by three tone-shock pairings with ITIs (intertone intervals) of 100 second.
  • the shocks (0.5 mA, 2 seconds) were delivered 18 seconds following the tone (80 dB, 2 kHz, 20 seconds).
  • a novel context was used for the training day followed by tone-cued and contextual memory retrieval tests.
  • FIGS. 5B-5D show in the fear conditioning test, APP transgenic mice showed deficits in trace memory (FIGS. 5B and 5C) and contextual memory retrieval (FIG. 5D) compared to the wild-type (WT) mice. Mirabegron administration restored the deficits seen in the APP mice to the WT mice level.
  • FIGS. 6 A and 6B show the beta3 -adrenergic receptor modulates an inflammatory response.
  • FIGS. 6 A and 6B show that activation of the beta3 -adrenergic receptor modulates the immune response.
  • APP transgenic mice showed lower white- blood cells (WBCs) and monocytes compared to the wild-type (WT) mice.
  • WBCs white- blood cells
  • WT wild-type mice.
  • Beta3- adrenergic receptor activation with the selective agonist Mirabegron increased the WBC (FIG. 6A) and monocytes (FIG. 6B) of APP transgenic mice to the WT levels.
  • FIG. 7 shows that Mirabegron (an example of a Peta3 -adrenoceptor agonist) produces anxiolytic effects. Effect of mirabegron on anxiety-related behavior was determined in activity chamber test where mice were placed in the corner of the square arena (43.2x43.2 cm 2 ) located inside of a sound-attenuated chamber
  • Alzheimer's Disease Advances in Genetics, Molecular and Cellular Biology (S.S. Sisodia and R.E. Tanzi eds., Springer; 1 st edition, 2007); Alzheimer's Disease: Targets or New Clinical Diagnostic and Therapeutic Strategies (Frontiers in Neuroscience, R.D. Wegrzyn and A.S. Rudolph eds., CRC Press; 1 st edition, 2012); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (3 rd Edition, 2001); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.).
  • agonist means a molecule such as a compound, a drug, an enzyme activator or a hormone that enhances the activity of another molecule or the activity of ADRB3.
  • “Pharmaceutically acceptable excipient or carrier” refers to an excipient that may optionally be included in the compositions of the invention and that causes no significant adverse toxicological effects to the patient.
  • “Pharmaceutically acceptable salt” includes, but is not limited to, amino acid salts, salts prepared with inorganic acids, such as chloride, sulfate, phosphate, diphosphate, bromide, and nitrate salts, or salts prepared from the corresponding inorganic acid form of any of the preceding, e.g., hydrochloride, etc., or salts prepared with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, ethyl succinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para- toluenesulfonate, palmoate, salicylate and stearate, as well as estolate, gluceptate and lactobionate salts.
  • salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (including substituted ammonium).
  • CNS disorders include, but are not limited to, stroke, ischemic stroke, neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, diabetic peripheral neuropathy, and multiple sclerosis, inherited ataxias, motor neuron diseases, epilepsy, traumatic brain injury, and spinal cord injury.
  • neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, diabetic peripheral neuropathy, and multiple sclerosis, inherited ataxias, motor neuron diseases, epilepsy, traumatic brain injury, and spinal cord injury.
  • stroke broadly refers to the development of neurological deficits associated with impaired blood flow to the brain regardless of cause.
  • Potential causes include, but are not limited to, thrombosis, hemorrhage and embolism. Thrombus, embolus, and systemic hypotension are among the most common causes of cerebral ischemic episodes.
  • Other injuries may be caused by hypertension, hypertensive cerebral vascular disease, rupture of an aneurysm, an angioma, blood dyscrasias, cardiac failure, cardiac arrest, cardiogenic shock, septic shock, head trauma, spinal cord trauma, seizure, bleeding from a tumor, or other blood loss.
  • an "effective amount" of an ADRB3 agonist is an amount sufficient to effect beneficial or desired results, such as an amount that activates ADRB3 or modulates the inflammatory response in the nervous system.
  • An effective amount can be administered in one or more administrations, applications, or dosages.
  • a therapeutically effective dose or amount of a ADRB3 agonist is intended an amount that, when administered as described herein, brings about a positive therapeutic response with respect to treatment of an individual for a CNS disorder or mental disorder, such as an amount that enhances cognitive function or immune function in the nervous system.
  • a therapeutically effective dose or amount of an ADRB3 agonist may improve learning or memory, modulate peripheral and central inflammation in the nervous system, and reduce pathological neurological deterioration.
  • an ADRB3 agonist may have antidepressant or anxiolytic effects.
  • the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, mode of administration, and the like. An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation, based upon the information provided herein.
  • substantially purified generally refers to isolation of a substance (e.g., compound, molecule, agent) such that the substance comprises the majority percent of the sample in which it resides.
  • a substantially purified component comprises 50%, preferably 80%-85%, more preferably 90-95% of the sample.
  • subject refers to any vertebrate subject, including, without limitation, humans and other primates, including non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses;
  • domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; birds, including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like.
  • domestic mammals such as dogs and cats
  • laboratory animals including rodents such as mice, rats and guinea pigs
  • birds including domestic, wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like.
  • wild and game birds such as chickens, turkeys and other gallinaceous birds, ducks, geese, and the like.
  • the term does not denote a particular age. Thus, both adult and newborn individuals are intended to be covered.
  • the present invention is based on the discovery that ADRB3 agonists are useful in treating CNS disorders and mental disorders.
  • the ADRB3 agonist Mirabegron was shown to improve learning and memory, restore immune function, and prevent neurological deterioration (see Examples 1-5).
  • ADRB3 agonists and their use in treating CNS disorders and mental disorders.
  • the methods of the present invention include
  • ADRB3 agonists that can be used in the practice of the invention include, but are not limited to, Mirabegron, Amibegron (SR-58611 A), CL-316,243, L- 742,791, L-796,568, LY-368,842, Ro40-2148, and Solabegron (GW-427,353).
  • Such agonists may improve learning and memory, restore immune function by modulating peripheral and central inflammation in the nervous system, and prevent pathological neurological deterioration.
  • ADRB3 is a G protein-coupled receptor that regulates adenylate cyclase.
  • the receptor is activated physiologically by epinephrine and norepinephrine.
  • One or more agonists, acting alone or in concert may be used to activate ADRB3for treatment of a CNS disorder or mental disorder.
  • ADRB3 agonists e.g., Mirabegron and Amibegron
  • compositions optionally comprising one or more pharmaceutically acceptable excipients.
  • excipients include, without limitation,
  • compositions include water, alcohols, polyols, glycerine, vegetable oils,
  • a carbohydrate such as a sugar, a derivatized sugar such as an alditol, aldonic acid, an esterified sugar, and/or a sugar polymer may be present as an excipient.
  • Specific carbohydrate excipients include, for example:
  • the excipient can also include an inorganic salt or buffer such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.
  • a composition of the invention can also include an antimicrobial agent for preventing or deterring microbial growth.
  • antimicrobial agents suitable for the present invention include benzalkonium chloride,
  • benzethonium chloride benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimersol, and combinations thereof.
  • An antioxidant can be present in the composition as well. Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the ADRB3 agonist, or other components of the preparation. Suitable antioxidants for use in the present invention include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabi sulfite, and combinations thereof.
  • a surfactant can be present as an excipient.
  • exemplary surfactants include: polysorbates, such as “Tween 20” and “Tween 80,” and pluronics such as F68 and F88 (BASF, Mount Olive, New Jersey); sorbitan esters; lipids, such as phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines (although preferably not in liposomal form), fatty acids and fatty esters; steroids, such as cholesterol; chelating agents, such as EDTA; and zinc and other such suitable cations.
  • Acids or bases can be present as an excipient in the composition.
  • acids that can be used include those acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.
  • Suitable bases include, without limitation, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumerate, and combinations thereof.
  • the amount of the ADRB3 agonist (e.g., when contained in a drug delivery system) in the composition will vary depending on a number of factors, but will optimally be a therapeutically effective dose when the composition is in a unit dosage form or container (e.g., a vial).
  • a therapeutically effective dose can be determined experimentally by repeated administration of increasing amounts of the composition in order to determine which amount produces a clinically desired endpoint.
  • the amount of any individual excipient in the composition will vary depending on the nature and function of the excipient and particular needs of the composition. Typically, the optimal amount of any individual excipient is determined through routine experimentation, i.e., by preparing compositions containing varying amounts of the excipient (ranging from low to high), examining the stability and other parameters, and then determining the range at which optimal performance is attained with no significant adverse effects. Generally, however, the excipient(s) will be present in the composition in an amount of about 1% to about 99% by weight, preferably from about 5% to about 98% by weight, more preferably from about 15 to about 95% by weight of the excipient, with concentrations less than 30% by weight most preferred.
  • compositions encompass all types of formulations and in particular those that are suited for injection, e.g., powders or lyophilates that can be reconstituted with a solvent prior to use, as well as ready for injection solutions or suspensions, dry insoluble compositions for combination with a vehicle prior to use, and emulsions and liquid concentrates for dilution prior to administration.
  • suitable diluents for reconstituting solid compositions prior to injection include bacteriostatic water for injection, dextrose 5% in water, phosphate buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.
  • solutions and suspensions are envisioned.
  • Additional preferred compositions include those for oral, ocular, or localized delivery.
  • compositions comprising one or more ADRB3 agonists e.g., Mirabegron and Amibegron
  • the compositions comprising one or more ADRB3 agonists are in unit dosage form, meaning an amount of a conjugate or composition of the invention appropriate for a single dose, in a premeasured or pre-packaged form.
  • compositions herein may optionally include one or more additional agents, such as other drugs for treating a CNS disorder or mental disorder, or other medications used to treat a subject for a condition or disease.
  • additional agents such as other drugs for treating a CNS disorder or mental disorder, or other medications used to treat a subject for a condition or disease.
  • Particularly preferred are compounded preparations including at least one ADRB3 agonist (e.g., Mirabegron and Amibegron) and one or more other drugs for treating a CNS disorder or mental disorder, such as analgesics, including nonsteroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen and naproxen), acetaminophen, and narcotics; sedatives (e.g., lorazepam, alprazolam, clorazepate, diazepam, and buspirone); anticonvulsants (e.g., carbamazepine, phenytoin, and gaba
  • such agents can be contained in a separate composition from the composition comprising an ADRB3 agonist (e.g., Mirabegron or Amibegron) and co-administered concurrently, before, or after the composition comprising an ADRB3 agonist.
  • an ADRB3 agonist e.g., Mirabegron or Amibegron
  • At least one therapeutically effective cycle of treatment with an ADRB3 agonist will be administered to a subject for treatment of a CNS disorder or mental disorder.
  • CNS disorders include, but are not limited to stroke, ischemic stroke, neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, diabetic peripheral neuropathy, and multiple sclerosis, inherited ataxias, motor neuron diseases, epilepsy, traumatic brain injury, and spinal cord injury.
  • Mental disorders include, but are not limited to anxiety disorders and schizophrenia.
  • a therapeutically effective cycle of treatment is intended a cycle of treatment that when administered, brings about a positive therapeutic response with respect to treatment of an individual for a CNS disorder or mental disorder.
  • a cycle of treatment with an ADRB3 agonist e.g., Mirabegron or Amibegron
  • an ADRB3 agonist e.g., Mirabegron or Amibegron
  • a therapeutically effective dose or amount of an ADRB3 agonist may improve learning or memory, modulate peripheral or central
  • an ADRB3 agonist may have antidepressant or anxiolytic effects.
  • compositions comprising one or more ADRB3 agonists (e.g., Mirabegron and
  • compositions of the present invention are typically, although not necessarily, administered orally, via injection (subcutaneously, intravenously, or intramuscularly), by infusion, or locally. Additional modes of administration are also contemplated, such as topical, intralesion, intracerebral, intracerebroventricular,
  • intraparenchymatous pulmonary, rectal, transdermal, transmucosal, intrathecal, pericardial, intra-arterial, intraocular, intraperitoneal, and so forth.
  • compositions according to the invention are also suitable for local treatment.
  • a composition of the invention is used for localized delivery of an ADRB3 agonist for the treatment of a CNS disorder or mental disorder.
  • compositions may be administered locally into cerebrospinal fluid or the brain of a subject.
  • the particular preparation and appropriate method of administration are chosen to target the ADRB3 agonist to the site where activation of ADRB3 is desired.
  • the pharmaceutical preparation can be in the form of a liquid solution or suspension immediately prior to administration, but may also take another form such as a syrup, cream, ointment, tablet, capsule, powder, gel, matrix, suppository, or the like.
  • the pharmaceutical compositions comprising one or more ADRB3 agonists and other agents may be administered using the same or different routes of administration in accordance with any medically acceptable method known in the art.
  • compositions comprising one or more ADRB3 agonists and/or other agents are administered prophylactically, e.g., to prevent neurological deterioration and cognitive decline associated with progression of a CNS disorder or mental disorder.
  • prophylactic uses will be of particular value for subjects with a genetic predisposition for developing a CNS disorder or mental disorder.
  • the pharmaceutical compositions comprising one or more ADRB3 agonists and/or other agents are in a sustained- release formulation, or a formulation that is administered using a sustained-release device.
  • sustained-release devices include, for example, transdermal patches, and miniature implantable pumps that can provide for drug delivery over time in a continuous, steady-state fashion at a variety of doses to achieve a sustained- release effect with a non-sustained-release pharmaceutical composition.
  • the invention also provides a method for administering a conjugate comprising an ADRB3 agonist as provided herein to a patient suffering from a condition that is responsive to treatment with an ADRB3 agonist contained in the conjugate or composition.
  • the method comprises administering, via any of the herein described modes, a therapeutically effective amount of the conjugate or drug delivery system, preferably provided as part of a pharmaceutical composition.
  • the method of administering may be used to treat any condition that is responsive to treatment with an ADRB3 agonist.
  • the compositions herein are effective in treating a CNS disorder (e.g., Alzheimer's disease or stroke) or mental disorder (e.g., anxiety disorder or schizophrenia).
  • ADRB3 agonist can effectively treat.
  • the actual dose to be administered will vary depending upon the age, weight, and general condition of the subject as well as the severity of the condition being treated, the judgment of the health care professional, and conjugate being administered.
  • Therapeutically effective amounts can be determined by those skilled in the art, and will be adjusted to the particular requirements of each particular case.
  • a therapeutically effective amount will range from about 0.50 mg to 5 grams of an ADRB3 agonist daily, more preferably from about 5 mg to 2 grams daily, even more preferably from about 7 mg to 1.5 grams daily.
  • such doses are in the range of 10-600 mg four times a day (QID), 200-500 mg QID, 25- 600 mg three times a day (TID), 25-50 mg TID, 50-100 mg TID, 50-200 mg TID, 300-600 mg TID, 200-400 mg TID, 200-600 mg TID, 100 to 700 mg twice daily (BID), 100-600 mg BID, 200-500 mg BID, or 200-300 mg BID.
  • the amount of compound administered will depend on the potency of the specific ADRB3 agonist and the magnitude or effect desired and the route of administration.
  • a purified ADRB3 agonist (again, preferably provided as part of a
  • analgesics including nonsteroidal antiinflammatory drugs (e.g., aspirin, ibuprofen and naproxen), acetaminophen, and narcotics; sedatives (e.g., lorazepam, alprazolam, clorazepate, diazepam, and buspirone); anticonvulsants (e.g., carbamazepine, phenytoin, and gabapentin);
  • nonsteroidal antiinflammatory drugs e.g., aspirin, ibuprofen and naproxen
  • acetaminophen e.g., acetaminophen
  • narcotics e.g., acetaminophen, and narcotics
  • sedatives e.g., lorazepam, alprazolam, clorazepate, diazepam, and buspirone
  • anticonvulsants e.g., carbamaze
  • antidepressants e.g., tricyclic antidepressants (e.g., amitriptyline), selective serotonin reuptake inhibitors (e.g., fluoxetine, paroxetine, and sertraline), tetracyclic
  • antidepressants e.g., maprotiline
  • monoamine oxidase (MAO) inhibitors e.g., phenelzine
  • anti-inflammatory drugs e.g., nonsteroidal anti-inflammatory drugs, such as aspirin, fenoprofen, ibuprofen, indomethacin, naproxen, and tolmetin
  • nonsteroidal anti-inflammatory drugs such as aspirin, fenoprofen, ibuprofen, indomethacin, naproxen, and tolmetin
  • medications for Alzheimer's disease such as cholinesterase inhibitors, (e.g., galantamine, rivastigmine, donepezil) and N-methyl D-aspartate (NMD A) antagonists (e.g., memantine); medications for stroke such as anticoagulants (e.g., warfarin), antiplatelet medicines (e.g., aspirin, dipyridamole, clopidogrel), and cholesterol- lowering and blood-pressure-lowering medicines (e.g., statins, angiotensin II receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, calcium channel blockers, and diuretics); or other medications used to treat a particular condition or disease according to a variety of dosing schedules depending on the judgment of the clinician, needs of the patient, and so forth.
  • cholinesterase inhibitors e.g., galantamine, rivastigmine, donepezil
  • dosing schedules include, without limitation, administration five times a day, four times a day, three times a day, twice daily, once daily, three times weekly, twice weekly, once weekly, twice monthly, once monthly, and any combination thereof.
  • Preferred compositions are those requiring dosing no more than once a day.
  • an antagonist of ADRB3 may be administered in combination with an ADRB3 agonist, wherein the ADRB3 agonist is active in the central nervous system and the ADRB3 antagonist is active in the peripheral nervous system and does not cross the blood-brain barrier.
  • ADRB3 antagonists include L-748,328, L-748,337, and SR59230A.
  • ADRB3 antagonists see, e.g., Candelore et al. (1999) J. Pharmacol. Exp. Ther. 290(2):649-655, Nisoli et al. (1996) Mol. Pharmacol. 49(1):7-14; herein incorporated by reference.
  • An ADRB3 agonist can be administered prior to, concurrent with, or subsequent to other agents. If provided at the same time as other agents, one or more ADRB3 agonists can be provided in the same or in a different composition. Thus, one or more ADRB3 agonists and other agents can be presented to the individual by way of concurrent therapy.
  • concurrent therapy is intended administration to a subject such that the therapeutic effect of the combination of the substances is caused in the subject undergoing therapy.
  • concurrent therapy may be achieved by administering a dose of a pharmaceutical composition comprising an ADRB3 agonist and a dose of a pharmaceutical composition comprising at least one other agent, such as another ADRB3 agonist or drug for treating a CNS disorder or mental disorder, or ADRB3 antagonist, which in combination comprise a therapeutically effective dose, according to a particular dosing regimen.
  • a pharmaceutical composition comprising an ADRB3 agonist and a dose of a pharmaceutical composition comprising at least one other agent, such as another ADRB3 agonist or drug for treating a CNS disorder or mental disorder, or ADRB3 antagonist, which in combination comprise a therapeutically effective dose, according to a particular dosing regimen.
  • one or more ADRB3 agonists and one or more other therapeutic agents can be administered in at least one therapeutic dose.
  • compositions can be performed simultaneously or at different times (i.e., sequentially, in either order, on the same day, or on different days), as long as the therapeutic effect of the combination of these substances is caused in the subject undergoing therapy.
  • kits comprising one or more containers holding compositions comprising at least one ADRB3 agonist and optionally one or more other agents for treating a CNS disorder or mental disorder, or an ADRB3 antagonist.
  • Compositions can be in liquid form or can be lyophilized. Suitable containers for the compositions include, for example, bottles, vials, syringes, and test tubes. Containers can be formed from a variety of materials, including glass or plastic.
  • a container may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the kit can further comprise a second container comprising a pharmaceutically-acceptable buffer, such as phosphate-buffered saline, Ringer's solution, or dextrose solution. It can also contain other materials useful to the end- user, including other pharmaceutically acceptable formulating solutions such as buffers, diluents, filters, needles, and syringes or other delivery devices.
  • a pharmaceutically-acceptable buffer such as phosphate-buffered saline, Ringer's solution, or dextrose solution.
  • the delivery device may be pre-filled with the compositions.
  • the kit can also comprise a package insert containing written instructions for methods of using the compositions comprising ADRB3 agonists for treating a subject for a CNS disorder or mental disorder.
  • the package insert can be an unapproved draft package insert or can be a package insert approved by the Food and Drug
  • ADRB3 selective agonists of ADRB3
  • Mirabegron an example of a p 3 -adrenoceptor agonist, enhanced learning and memory and modulated the inflammatory response in a Thyl-APPLond/Swe+ mouse model of Alzheimer disease. Mirabegron as well as other ADRB3 agonists can also be used for enhancement of cognitive function and modulation of the inflammatory response for treatment of neurocognitive disorders.
  • mice treated with L-748,337 showed impaired spontaneous alternation behavior in a Y-maze, indicating that acute inhibition of the beta3 -adrenergic receptor with the selective antagonist L-748,337 impaired spatial memory.
  • the pharmacological properties of L-748,337 are shown in Table 1. As shown in Table 1, the L-748,337 antagonist inhibits ADRB3 with a Ki of 4 nM and shows selectivity for ADRB3 over other adrenergic receptors.
  • the ADRB3 agonist, Mirabegron, enhanced learning and memory in an APP transgenic mouse model of Alzheimer' s disease The amyloid precursor protein (APP) transgenic mouse expresses human APP751 cDNA containing the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the murine Thyl gene (Faizi et al. (2012) Brain Behav. 2(2): 142-154, herein incorporated by reference in its entirety).
  • APP transgenic mice display hyperactivity, deficits in spontaneous alternation behavior, memory retrieval impairment, and apparent decreased social memory and discrimination (Faizi et al., supra).
  • the cognitive and psychiatric deficits of these APP transgenic mice mimic those exhibited by human patients who have Alzheimer's disease.
  • APP transgenic mice were placed in a Morris water maze (MWM) containing a large water tank (178 cm in diameter) filled with water. A circular platform was placed about 1 cm below the water surface approximately 17 cm away from the wall in one quadrant of the tank. Nontoxic tempera paints were used to make the water opaque.
  • MWM Morris water maze
  • mice were released from drop locations and given 60 seconds to find the platform.
  • the platform was removed and a 60- second probe trial was conducted.
  • Successful learning of the MWM by the mice was determined by observing a gradual decrease in escape latency during the hidden platform training and discriminative quadrant exploration during the probe trial (FIG. 4A).
  • the APP transgenic mice were dosed with Mirabegron (5 mg/kg) to determine what effects an ADRB3 agonist would have on learning.
  • the APP transgenic mice treated with Mirabegron exhibited improved learning compared to those treated with vehicle as indicated by decreased escape latency during the hidden platform training (FIG. 4B).
  • APP transgenic mice performed poorly and did not distinguish target quadrant from non-target quadrants, indicating that they had cognitive deficits.
  • APP transgenic mice dosed with Mirabegron spent more time in the target quadrant relative to non-target quadrants, indicating that Mirabegron restored the cognitive deficits associated with Alzheimer's disease (FIG. 4C).
  • a trace fear conditioning protocol was used for the training day followed by tone-cued and contextual memory retrieval tests.
  • APP transgenic mice were placed in the chamber for a 3 -minute baseline recording followed by three tone-shock pairings with ITIs (intertone intervals) of 100 seconds.
  • the shocks (0.5 mA, 2 seconds) were delivered for 18 seconds following the tone (80 dB, 2 kHz, 20 seconds).
  • a novel context new olfactory environment, different shape of chamber, new texture of the floor, and blue lighting was used for tone-cued testing.
  • three tones without shocks with ITIs of 100 seconds were presented to the mice.
  • mice were placed in the same context as the first day for 5 minutes with no shocks or tones to test contextual memory retrieval (FIG. 5A).
  • APP transgenic mice showed deficits in trace memory and contextual memory retrieval compared to the wild-type (WT) mice. Mirabegron administration restored the APP mice to the level of functioning of WT mice (FIG. 5B).
  • APP transgenic mice showed lower white-blood cells (WBCs) and monocytes compared to wild-type (WT) mice.
  • WBCs white-blood cells
  • WT wild-type mice
  • Beta3 -adrenergic receptor activation with the selective agonist Mirabegron increased the white-blood cells and monocytes of APP transgenic mice to wild-type levels (FIGS. 6A and 6B).
  • Mirabegron restores the inflammatory response in a mouse model of Alzheimer disease.
  • Mirabegron may have pro-cognitive effects and prevent the pathology associated with neurocognitive disorders.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des méthodes d'utilisation d'agonistes des récepteurs β3-adrénergiques pour le traitement du système nerveux central et de troubles mentaux. L'invention concerne en particulier des méthodes de traitement du système nerveux central et de troubles mentaux avec des agonistes sélectifs des récepteurs β3-adrénergiques comme le mirabégron ou l'amibégron pour améliorer la fonction cognitive, moduler l'inflammation systémique et centrale et prévenir la détérioration pathologique.
PCT/US2016/067066 2015-12-16 2016-12-16 Traitement du système nerveux central et de troubles mentaux avec des agonistes des récepteurs bêta-3 adrénergiques WO2017106584A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562268329P 2015-12-16 2015-12-16
US62/268,329 2015-12-16

Publications (1)

Publication Number Publication Date
WO2017106584A1 true WO2017106584A1 (fr) 2017-06-22

Family

ID=59057881

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/067066 WO2017106584A1 (fr) 2015-12-16 2016-12-16 Traitement du système nerveux central et de troubles mentaux avec des agonistes des récepteurs bêta-3 adrénergiques

Country Status (1)

Country Link
WO (1) WO2017106584A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112336862A (zh) * 2020-11-04 2021-02-09 天津医科大学总医院 β3-肾上腺素能受体激动剂在制备治疗神经系统疾病的药物中的应用
CN117379424A (zh) * 2023-12-08 2024-01-12 细胞生态海河实验室 米拉贝隆在制备预防和/或治疗免疫系统功能障碍药物中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030212063A1 (en) * 2002-02-27 2003-11-13 Pfizer Inc. beta3 adrenergic receptor agonists
US20040229913A1 (en) * 2002-12-13 2004-11-18 Eisal Co., Ltd. Therapeutic agent for severe Alzheimer's dementia
US20060062851A1 (en) * 2002-12-23 2006-03-23 Vergez Juan A Delivery device containing venlafaxine and memantine and methods of use thereof
US8790889B2 (en) * 2009-12-21 2014-07-29 The University Of Queensland Neuronal stimulation
US8906955B2 (en) * 2012-01-30 2014-12-09 Shuguang LIN Use of adrenergic beta-3-receptor agonists in anti-aging

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030212063A1 (en) * 2002-02-27 2003-11-13 Pfizer Inc. beta3 adrenergic receptor agonists
US20040229913A1 (en) * 2002-12-13 2004-11-18 Eisal Co., Ltd. Therapeutic agent for severe Alzheimer's dementia
US20060062851A1 (en) * 2002-12-23 2006-03-23 Vergez Juan A Delivery device containing venlafaxine and memantine and methods of use thereof
US8790889B2 (en) * 2009-12-21 2014-07-29 The University Of Queensland Neuronal stimulation
US8906955B2 (en) * 2012-01-30 2014-12-09 Shuguang LIN Use of adrenergic beta-3-receptor agonists in anti-aging

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MANDREKAR ET AL.: "Microglia and Inflammation in Alzheimer's Disease", NIH PUBLIC ACCESS., 14 May 2013 (2013-05-14), pages 1 - 24 *
STEMMELIN ET AL.: "Stimulation of the beta3-Adrenoceptor as a Novel Treatment Strategy for Anxiety and Depressive Disorders", NEUROPSYCHOPHARMACOLOGY., vol. 33, 25 April 2007 (2007-04-25), pages 574 - 587, XP008163562 *
THERIAULT ET AL.: "The dynamics of monocytes and microglia in Alzheimer's disease", ALZHEIMER'S RESEARCH & THERAPY., vol. 7, 15 April 2015 (2015-04-15), pages 1 - 10, XP021215784 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112336862A (zh) * 2020-11-04 2021-02-09 天津医科大学总医院 β3-肾上腺素能受体激动剂在制备治疗神经系统疾病的药物中的应用
CN112336862B (zh) * 2020-11-04 2022-02-22 天津医科大学总医院 β3-肾上腺素能受体激动剂在制备治疗神经系统疾病的药物中的应用
CN117379424A (zh) * 2023-12-08 2024-01-12 细胞生态海河实验室 米拉贝隆在制备预防和/或治疗免疫系统功能障碍药物中的应用
CN117379424B (zh) * 2023-12-08 2024-03-01 细胞生态海河实验室 米拉贝隆在制备预防和/或治疗免疫系统功能障碍药物中的应用

Similar Documents

Publication Publication Date Title
JP5411504B2 (ja) 薬物嗜癖および行動嗜癖を治療するためのイブジラストの使用
JP4954085B2 (ja) 神経障害性疼痛及びその関連する症状を治療するためのイブジラスト
US20170239234A1 (en) Treatment of bdnf-related disorders using laquinimod
JP4846063B2 (ja) 選択的ｓ１ｐ１レセプターアゴニストの投与法
PT2187882E (pt) Tratamento de uma doença neurodegenerativa progressiva com ibudilast
KR20180054584A (ko) 펜플루라민을 사용하여 레녹스-가스토 증후군을 치료하는 방법
TWI428130B (zh) 治療急性躁狂症之藥學組成物及方法
CA2786155A1 (fr) Diazoxyde pour utilisation dans le traitement d'une maladie demyelinisante auto-immune du systeme nerveux central (snc)
EP3405211A1 (fr) Octréotide par voie orale pour le traitement de maladies
KR20150027800A (ko) 경도 인지 장해의 예방 및/또는 치료제
US11446283B2 (en) Methods and dosing regimens using ibudilast and a second agent for cancer therapy
US20090028816A1 (en) Treatment of depression, psychosis, and anxiety
WO2017106584A1 (fr) Traitement du système nerveux central et de troubles mentaux avec des agonistes des récepteurs bêta-3 adrénergiques
US20070281924A1 (en) MIF inhibitors for treating neuropathic pain and associated syndromes
US20080287402A1 (en) Use of a glial attenuator to prevent amplified pain responses caused by glial priming
EP2413970B1 (fr) Nouvelles approches thérapeutiques pour le traitement de maladies neuro-inflammatoires
Kieseier et al. Oral disease-modifying treatments for multiple sclerosis: the story so far
CN107789354B (zh) 预防和治疗抑郁症的化合物及其应用
CN111494366A (zh) 二甲基氨基含笑内酯在制备抗衰老药物上的应用
JP2020504721A (ja) イブジラストを使用した多形膠芽腫の治療方法
ES2959799T3 (es) Métodos para suprimir células supresoras de origen mieloide en pacientes
US20150335629A1 (en) Methods Of Treating Fragile X Syndrome And Related Disorders
Forst et al. Dose escalating safety study of CNS 5161 HCl, a new neuronal glutamate receptor antagonist (NMDA) for the treatment of neuropathic pain
US20230285367A1 (en) Methods of treating post-covid condition(s)
TW202010496A (zh) 双那布扶林己二酸酯和乙醯胺酚的藥物製劑及治療疼痛的方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16876736

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16876736

Country of ref document: EP

Kind code of ref document: A1