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EP4561566A1 - Compositions et méthodes pour la prévention du déclin cognitif provoqué par des maladies dégénératives - Google Patents

Compositions et méthodes pour la prévention du déclin cognitif provoqué par des maladies dégénératives

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Publication number
EP4561566A1
EP4561566A1 EP23847607.1A EP23847607A EP4561566A1 EP 4561566 A1 EP4561566 A1 EP 4561566A1 EP 23847607 A EP23847607 A EP 23847607A EP 4561566 A1 EP4561566 A1 EP 4561566A1
Authority
EP
European Patent Office
Prior art keywords
sigma
disease
receptor
effective amount
receptor agonist
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP23847607.1A
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German (de)
English (en)
Inventor
Christopher U. Missling
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Anavex Life Sciences Corp
Anavex Life Sciences Corp
Original Assignee
Anavex Life Sciences Corp
Anavex Life Sciences Corp
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Filing date
Publication date
Application filed by Anavex Life Sciences Corp, Anavex Life Sciences Corp filed Critical Anavex Life Sciences Corp
Publication of EP4561566A1 publication Critical patent/EP4561566A1/fr
Pending legal-status Critical Current

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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

Definitions

  • the present invention relates generally to disease prevention and treatment, such as degenerative diseases involving abnormal amyloid formation and/or deposit.
  • Neurodegenerative diseases have impeded greatly on patients’ daily life, due to memory loss and/or cognition decline. It is critical to develop preventive and prophylactic therapy to block the onset and/or deter the progress of neurodegenerative diseases, with the goal to restore memory and to deter cognition decline.
  • compositions and kits for therapeutically or prophylactically treating or preventing a degenerative disease related to amyloid.
  • the compositions and kits comprise a therapeutic agent of sigma- 1 receptor agonist, an allosteric sigma agonist, and/or a dual agonist of sigma 1 and M1.
  • the compositions and kits elicit effects of delaying the onset, deterring the progress, and/or diminish the likelihood of the degenerative disease, such as deterring the cognition decline in Alzheimer’s disease.
  • the therapeutic or the prophylactic agent comprises ANAVEX2-73 (A2-73), ANAVEX 19-144, ANAVEX1- 41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L- 687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof.
  • ANAVEX2-73 (A2-73) has a chemical name of tetrahydro-N,N-dimethyl-2,2-diphenyl- 3-furanmethanamine hydrochloride.
  • ANAVEX 19-144 (A19-144) has a chemical name of 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride.
  • ANAVEX 1-41 (A1-41) has a chemical name of tetrahydro-N,N-dimethyl-5,5- diphenyl-3-furanmethanamine hydrochloride.
  • AV1066 has a chemical name of 1-(3- 4(((1 R,3S,5S)-adamantan-1-yl)(pheny)methyl)propyl)-4-methylpiperazine.
  • ANAVEX3-71 (A3-71 , AF-710B) has a chemical name of 1-(2,8-dimethyl-1-thia-3,8- diazaspiro[4.5]decan-3-yl)-3-(1 H-indol-3-yl)propan-1 -one.
  • the therapeutic or prophylactic agent comprises A3-71 amorphous form, a A3-71 crystal form, a A3-71 enantiomer, a A3-71 prodrug, or a combination thereof.
  • the degenerative disease may comprise Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, amyloidosis, non-alcoholic fatty liver disease, a disorder related to abnormal amyloid formation, or a disorder related to amyloid deposit.
  • the effective amount used is to diminish or reduce the likelihood or seriousness of the degenerative disease.
  • the prophylactively effective amount is the amount to prevent the onset or deter the progress of the degenerative disease. The onset or progress may be manifested by memory loss and/or cognitive decline.
  • the therapeutically or prophylactically effective amount ranges from about 0.10 mg to about 500 mg, such as between 5 mg and 30 mg.
  • the subject is a human subject or a non-human mammal.
  • One aspect of the present disclosure encompasses a composition for the aforementioned medical use.
  • Another aspect of the present disclosure encompasses a kit comprising the composition and an instruction for the aforementioned medical use.
  • the present disclosure provides use of a therapeutically or prophylactically effective amount of a sigma-1 receptor agonist in the manufacture of a medicament for use in any of the methods as disclosed herein.
  • FIG. 1 is an illustrative workflow on the rat study of ANAVEX® 3-71 against the onset, development, and/or progression of Alzheimer’s Disease. Data are presented as mean ⁇ SEM. *P ⁇ 0.05; **P ⁇ 0.01 ; ***P ⁇ 0.001 ; ****P ⁇ 0.0001 .
  • FIG.2A-2B depicts Novel Object Recognition (NOR) tests and the results.
  • FIG. 2A illustrates rats were exposed to objects.
  • FIG. 2B plots the percentage of rats in each group that were able to find the novel objects: *P ⁇ 0.05; **P ⁇ 0.01.
  • FIG.3A-3B depicts the Social Preference (SP) test.
  • FIG. 3A illustrates rats were exposed to either social or non-social factor.
  • FIG. 3B plots the percentage of rats in each group that preferred to join the social group: ***P ⁇ 0.001 ; ****P ⁇ 0.0001.
  • FIG.4A-4C depicts the acquisition phase of the Morris Water Maze (MWM).
  • FIG. 4A illustrates rats were exposed to MWM.
  • FIG. 4B plots the escape latency of each group against the training days.
  • FIG. 4C plots the average escape latencies from day 3 to 5.
  • the Tg-sal required more time to find the hidden platform than wt-sal (P ⁇ 0.01 ).
  • Tg-ANAVEX performed significantly better than the Tg-sal (P ⁇ 0.05).
  • FIG.5A-5C depicts the impact of A3-71 administration on the cortical and hippocampal extracellular A0 deposition.
  • FIG. 5A shows the plaques staining in cortex and CA1.
  • FIG. 5A shows the plaques staining in cortex and CA1.
  • FIG. 5B plots the plaques CA1 integrated density cortex in the treated group Tg-ANAVEX and non-treated group Tg-sal, **P ⁇ 0.01 .
  • FIG. 5C plots the plaques cortex integrated density in the treated group Tg-ANAVEX and nontreated group Tg-sal ,*P ⁇ 0.05.
  • FIG.6A-6C depicts the impact of A3-71 administration on neurons in hippocampus.
  • FIG. 6A shows the immune staining of different testing groups.
  • FIG. 6B plots the number of Iba1-IR cells in NeuN proximity, *P ⁇ 0.05.
  • FIG. 6C plots the number of GFAP-IR cells NeuN proximity, *P ⁇ 0.05.
  • the present disclosure provides methods, compositions and kits for prophylactic treating or preventing a degenerative disease related to amyloid.
  • Amyloids are aggregates of proteins characterized by a fibrillar morphology of typically 7-13 nm in diameter, a 0-sheet secondary structure (known as cross-0) and ability to be stained by particular dyes, such as Congo red.
  • Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions (misfolding) and form fibrous deposits within and around cells. These protein misfolding and deposition processes disrupt the healthy function of tissues and organs, known as amyloidosis.
  • Amyloid plaques are aggregates of misfolded proteins that form in the spaces between nerve cells.
  • amyloid plaques develop and/or plaques build up in the areas of the brain concerned with memory and other cognitive functions, it may cause a degenerative disease, such as Alzheimer's disease.
  • a degenerative disease is characterized by the worsening condition due to the deterioration of the function and structure of the affected body part, thus causing disability, mortality, and morbidity.
  • One type of degenerative diseases is called neurodegenerative disease (degenerative nervous system diseases), which affects the neurons of the central nervous system, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, Prion disease, or Multiple sclerosis.
  • compositions and kits comprise Sigma-1 receptor agonist, an allosteric sigma agonist, and/or a dual agonist of sigma 1 and muscarinic acetylcholine receptor M1 .
  • the compositions and kits elicit effects of preventing or delaying the onset, deterring the progress, and/or diminish the likelihood of the degenerative disease, such as deterring the memory loss and/or cognition decline in Alzheimer’s disease.
  • Sigma-1 receptors are shown to be involved in higher-ordered brain functions including memory and cognition.
  • a Sigma-1 receptor agonist therapy is often prescribed to patients having declined memory or cognition functions, such as those with neurodegenerative disorders.
  • a subject is being treated with a Sigma-1 receptor agonist, his or her gene expression profiles are altered: a set of selected genes are differentially expressed, and their relevant gene clusters are overrepresented.
  • the altered genetic profile can be used as a benchmark to evaluate the therapeutic effect of another therapeutic agent. It can also be used to select a Sigma-1 receptor agonist for a subject. Further, it can also be used to determine if a subject is responsive to a Sigma-1 receptor agonist therapy. Finally, the Sigma-1 receptor agonist can be used a probe to see if a subject is having, or suspect of having, or at an increased risk of having, a disease linked to the altered gene expression profiles.
  • the degenerative disease manifested by abnormal amyloid formation and/or deposit may include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, and Prion disease.
  • Neurodegenerative diseases are a subset of the degenerative diseases, which refer to hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the central or peripheral nervous system structures and may have symptoms in the form of cognition impairment, memory loss, and movement disorders.
  • Alzheimer’s disease is a degenerative disease of the brain characterized by the insidious onset of dementia. Early symptoms include impairment of memory, judgment, attention span, and problem-solving skills. In late stage, severe apraxias and a global loss of cognitive abilities may occur.
  • Parkinson’s disease is a progressive, degenerative neurologic disease characterized by a tremor that is maximal at rest, retropulsion (i.e. a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression.
  • Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem.
  • Lewy bodies are present in the substantia nigra and locus coeruleus but may also be found in a related condition characterized by dementia in combination with varying degrees of parkinsonism.
  • Secondary Parkinson’s disease refer to conditions which feature clinical manifestations resembling primary Parkinson’s disease that are caused by a known or suspected condition, such as parkinsonism caused by vascular injury, drugs, trauma, toxin exposure, neoplasms, infections and degenerative or hereditary conditions. Clinical features may include bradykinesia, rigidity, parkinsonian gait, and masked facies. In general, tremor is less prominent in secondary parkinsonism than in the primary form.
  • Huntington’s disease is a familial disorder inherited as an autosomal dominant trait and characterized by the onset of progressive chorea and dementia in the fourth or fifth decade of life. Common initial manifestations include paranoia, poor impulse control, depression, hallucinations, and delusions. Late symptoms include intellectual impairment, loss of fine motor control, athetosis, and diffuse chorea involving axial and limb musculature develops, leading to a vegetative state within 10-15 years of disease onset. Its juvenile variant has a more fulminant course including seizures, ataxia, dementia, and chorea.
  • Amyotrophic Lateral Sclerosis is a degenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord.
  • Prion disease is a group of genetic, infectious, or sporadic degenerative human and animal nervous system disorders associated with abnormal prions. These diseases are characterized by conversion of the normal prion protein to an abnormal configuration via a post-translational process. In humans, these conditions generally feature dementia, ataxia, and a fatal outcome.
  • One aspect of the present disclosure encompasses a method of selecting a therapeutic and prophylactic agent for a subject suffering from a disease or a disorder, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, Prion disease, diabetic cardiomyopathy, or non-alcoholic fatty liver disease,
  • a follow-up action can be taken, such as switching to another neurodegenerative therapy, supplementing with another neurodegenerative therapy, adjusting dose if the neurodegenerative therapy being a drug therapy, or switching to a combined neurodegenerative therapy.
  • the neurodegenerative therapy can be a Sigma-1 receptor agonist therapy, or a NMDA therapy, or a cognition enhancing physical therapy.
  • neurodegenerative therapy can be a drug therapy comprising a Sigma-1 receptor agonist, such as ANAVEX2-73 (A2-73), ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, Dimethyltryptamine, (+)-pentazocine, or any of their crystal forms, enantiomers and pharmaceutically acceptable salts thereof.
  • a Sigma-1 receptor agonist such as ANAVEX2-73 (A2-73), ANAVEX 19-144, ANAVEX1-41 , AV1066, ANAVEX3-71 , PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-450
  • ANAVEX2-73 has a chemical name of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride.
  • ANAVEX 19-144 has a chemical name of 1-(2,2-diphenyltetrahydrofuran- 3-yl)-N-methylmethanamine hydrochloride.
  • ANAVEX 1-41 (A1-41) has a chemical name of tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride.
  • AV1066 has a chemical name of 1-(3-4(((1 R,3S,5S)-adamantan-1- yl)(pheny)methyl)propyl)-4-methylpiperazine.
  • ANAVEX3-71 (A3-71 , AF-710B) has a chemical name of 1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl)-3-(1 H-indol- 3-yl)propan-1-one.
  • the neurodegenerative therapy is a A2-73 drug therapy comprising A2-73 free base, A2-73 amorphous form, A2-73 Crystal Form I, A2-73 Crystal Form II, A2-73 Crystal Form III, (-) A2-73 enantiomer, or (+) A2-73 enantiomer.
  • the therapeutic agent comprises A3-71 amorphous form, a A3-71 crystal form, a A3-71 enantiomer, a A3- 71 prodrug, or a combination thereof.
  • the effective amount used is to diminish or reduce the likelihood or seriousness of the degenerative disease.
  • the prophylactically effective amount is the amount to prevent the onset or deter the progress of the degenerative disease. The onset or progress may be manifested by memory loss and/or cognitive decline.
  • the therapeutically or prophylactically effective amount ranges from about 0.10 mg to about 500 mg, such as between 5 mg and 30 mg of A2-73.
  • the subject is a human subject or a non-human mammal.
  • One aspect of the present disclosure encompasses a composition for the aforementioned medical use.
  • Another aspect of the present disclosure encompasses a kit comprising the composition and an instruction for the aforementioned medical uses.
  • treatment refers an action taken with respect to a subject, which may be a human or an animal subject, intended to ameliorate, prevent, slow, deter, diminish, relieve or cure symptoms and/or effects associated with a recited disease state or condition.
  • a “therapeutic treatment” is a treatment which at least partly prevents, slows, deters, diminishes, relieves or cures symptoms and/or effects associated with a recited disease state or condition.
  • prophylactic refers to action taken with respect to the subject before detection of a symptom or symptomatic condition, to maintain health by delaying, mitigating or avoiding the onset, or diminishing the likelihood or seriousness of a symptom, episode, disease state or condition.
  • a “prophylactic effect” in the context of the present specification should not be understood to encompass total or complete prevention of symptoms or symptomatic conditions.
  • prophylactically effective amount pertains to an amount of a compound or composition as disclosed herein, which is effective for producing a desired prophylactic effect when administered as disclosed herein.
  • therapeutically effective amount refers to an amount of a compound or composition as disclosed herein, which is effective for producing a desired therapeutic effect when administered as disclosed herein.
  • a therapeutic effect encompasses a prophylactic effect.
  • One aspect of the disclosure encompasses a pharmaceutical composition comprising a neurodegenerative agent and/or a Sigma-1 receptor agonist.
  • a pharmaceutical composition comprises a therapeutically or prophylactically effective amount of an active pharmaceutical ingredient, and any pharmaceutically acceptable salt thereof.
  • Pharmaceutically acceptable salts include, without limitation, acetate, aspartate, benzoate, bitartrate, citrate, formate, gluconate, glucuronate, glutamate, fumarate, hydrochloride, hydrobromide, hydroiodide, hypophosphite, isobutyrate, isocitrate, lactate, malate, maleate, meconate, methylbromide, methanesulfonate, monohydrate, mucate, nitrate, oxalate, phenylpropionate, phosphate, phthalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tannate, tartrate, terephthalate, valerate, and the like.
  • a composition may comprise from about 1 mg to about 50 g, from about 0.1 to about 5 g, from about 0.5 g to about 3 g, from about 1 mg to about 55 mg, from about 5 mg to about 30 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, from about 180 mg to about 220 mg, from about 0.1 g to about 5 g, or from about 0.5 g to about 3 g of A2-73.
  • Formulations comprising A2-73 can be found in, e.g., U.S. Patent No. 9750746, U.S. Patent Publication No. 20170360798, U.S. Patent Publication No. 20190022052, U.S. Patent Publication No.
  • a composition may comprise from about 1 mg to about 50 g, from about 0.1 to about 5 g, from about 0.5 g to about 3 g, from about 1 mg to about 55 mg, from about 5 mg to about 30 mg, from about 40 mg to about 60 mg, from about 80 mg to about 120 mg, from about 180 mg to about 220 mg, from about 0.1 g to about 5 g, or from about 0.5 g to about 3 g of A3-71 .
  • the active pharmaceutical ingredient may be administered daily, twice daily, or three times daily.
  • the duration of administration may be about 3-6 weeks, 6-11 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or chronically.
  • A2-73 or A3-71 may be administered in an amount of about 40 mg to about 60 mg once daily for about 6-11 weeks, or is administered in about 50 mg daily for up to 11 weeks.
  • A3-71 or A2-73 may also be administered daily in an escalating dose starting from about 10 mg to ending at about 50 mg once daily.
  • the active pharmaceutical ingredient can be formulated and administered to a subject by any route such as oral, parenteral, intraperitoneal, intravascular, transdermal, subcutaneous, or intrapulmonary in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable adjuvants, carriers, excipients, and vehicles as desired.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrathecal, or intrasternal injection, or infusion techniques. Formulation of pharmaceutical compositions is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975), and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980).
  • a pharmaceutical composition also comprises one or more pharmaceutically acceptable excipients.
  • excipients include chemical enhancers, humectants, pressure sensitive adhesives, antioxidants, solubilizers, thickening agents, plasticizers, adjuvants, carriers, excipients, vehicles, coatings, and any combinations thereof.
  • One or more excipients can be selected for oral, transdermal, parenteral, intraperitoneal, intravascular, subcutaneous, by inhalation spray, rectal, or intrapulmonary administration.
  • the active pharmaceutical ingredient can in general be formulated for improving patient compliance, preventing a subject from removing the drug-delivery device.
  • Sigma-1 receptor agonists can be formulated for improved patient compliance and preventing removal of a drug-delivery device by providing formulations for extended delivery.
  • Extended delivery can range for periods ranging from more than one day, to months. This may be especially relevant for patients with compromised cognitive and/or motor-control abilities. Extended delivery for periods can range from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, or from about 2 months to about 4 months.
  • Extended release formulations could be used for substantially continuous delivery of drug at a preselected rate.
  • the drug can be delivered at a rate of from about 1 mg to about 100 mg/day, from about 5 mg to about 30 mg/day, from about 40 to about 60 gm/day, or from about 10 to about 30 gm/day.
  • Appropriate amounts of crystalline A2-73 can be readily determined by the ordinarily skilled artisan based upon, for example, the intended duration of administration of the drug by the extended release formulation, the delivery mechanism, the particular formulation, and the relative potency of the drug among other factors.
  • Non-limiting examples of binders suitable for the formulations of various aspects include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
  • the polypeptide may be any arrangement of amino acids ranging from about 100 to about 300,000 Daltons.
  • the binder can be introduced into the mixture to be granulated in a solid form, including but not limited to a crystal, a particle, a powder, or any other finely divided solid form known in the art.
  • the binder can be dissolved or suspended in a solvent and sprayed onto the mixture in a granulation device as a binder fluid during granulation.
  • Non-limiting examples of diluents include carbohydrates, inorganic compounds, and biocompatible polymers, such as polyvinylpyrrolidone (PVP).
  • Other non-limiting examples of diluents include dibasic calcium sulfate, tribasic calcium sulfate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, saccharides such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol, polyhydric alcohols; starches; pre-manufactured direct compression diluents; and mixtures of any of the foregoing.
  • Disintegrents can be effervescent or non-effervescent.
  • non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth.
  • Suitable effervescent disintegrants include but are not limited to sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.
  • Non-limiting examples of preservatives include, but are not limited to, ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate, anoxomer, N- acetylcysteine, benzyl isothiocyanate, m-aminobenzoic acid, o-aminobenzoic acid, p- aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, alpha-carotene, beta-carotene, beta-caraotene, beta-apo-carotenoic acid, carnosol, carvacrol, catechins, cetyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p-coumaric acid, 3,4-dihydroxybenzoic acid, N,N'-diphenyl-p-phenylened
  • Suitable flavor-modifying agents include flavorants, taste-masking agents, sweeteners, and the like.
  • Flavorants include, but are not limited to, synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof.
  • Other non-limiting examples of flavors include cinnamon oils, oil of Wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.
  • Taste-masking agents include but are not limited to cellulose hydroxypropyl ethers (HPC) such as Klucel®, Nisswo HPC and PrimaFlo HP22; low- substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel® and Metolose®; Ethylcelluloses (EC) and mixtures thereof such as E461 , Ethocel®, Aqualon®-EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol®; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aualon®-CMC; polyvinyl alcohol and polyethylene glycol
  • Non-limiting examples of sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, sylitol, hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-1 ,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.
  • dipeptide sweeteners such as aspartame
  • dihydrochalcone compounds glycyrrhizin
  • Stevia rebaudiana Stevia rebaudian
  • the lubricant compositions may be utilized to lubricate ingredients that form a pharmaceutical composition.
  • the lubricant facilitates removal of solid dosage forms during the manufacturing process.
  • Non-limiting examples of lubricants and glidants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.
  • the pharmaceutical composition will generally comprise from about 0.01 % to about 10% by weight of a lubricant. In some aspects, the pharmaceutical composition will comprise from about 0.1 % to about 5% by weight of a lubricant. In a further aspect, the pharmaceutical composition will comprise from about 0.5% to about 2% by weight of a lubricant.
  • Dispersants may include but are not limited to starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high hydrophilic-lipophilic balance (HLB) emulsifier surfactants.
  • HLB hydrophilic-lipophilic balance
  • Suitable color additives include but are not limited to food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors or dyes, along with their corresponding lakes, and certain natural and derived colorants, may be suitable for use in various aspects of the disclosure. pH modifiers
  • Non-limiting examples of pH modifiers include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate and sodium bicarbonate.
  • An antimicrobial agent may be included as an excipient to minimize the degradation of the compound according to this disclosure by microbial agents, including but not limited to bacteria and fungi.
  • microbial agents including but not limited to bacteria and fungi.
  • Non-limiting examples of antimicrobials include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites including but not limited to sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite. Release-controlling polymers
  • Release-controlling polymers may be included in the various aspects of the solid dosage pharmaceutical compositions incorporating compounds according to this disclosure.
  • the release-controlling polymers may be used as a tablet coating.
  • a releasecontrolling polymer may be mixed with the granules and other excipients prior to the formation of a tablet by a known process including but not limited to compression in a tablet mold.
  • Suitable release-controlling polymers include but are not limited to hydrophilic polymers and hydrophobic polymers.
  • Suitable hydrophilic release-controlling polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, crosslinked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, alginate sodium carmellose, calcium carmellose, carrageenan, fucoidan, furcellaran, arabic gum, carrageens gum, ghafti gum, guar gum, karaya gum, locust bean gum, okra gum, tragacanth gum,
  • a solid dosage comprising a compound according to this disclosure may comprise a coating, wherein such a coating may control release of the compound, act as a moisture barrier, or buffer or modify pH.
  • a “control releasing coat” or “controlled release coat” as used herein is defined to mean a functional coat which can for example comprise at least one pH independent polymer, pH dependent polymer (for example enteric or reverse enteric type polymers), soluble polymer, insoluble polymer, lipids, lipidic materials, or combinations thereof.
  • the coating when applied onto a dosage form, may slow (for example when applied to a normal release matrix dosage form), further slow (for example when applied to a controlled release matrix dosage form) or modify the rate of release of a compound according to this disclosure when applied to an uncoated dosage form.
  • the control releasing coat can be designed such that when the control releasing coat is applied to a dosage form, the dosage form in conjunction with the control releasing coat can exhibit the release of the compound according to this disclosure, such as a “modified-release”, “controlled-release”, “sustained-release”, “extended-release”, “delayed-release”, “prolonged-release,” or combinations thereof.
  • the “control releasing coat” may optionally comprise additional materials that may alter the functionality of the control releasing coat.
  • moisture barrier is one which impedes or retards the absorption of moisture.
  • Compounds according to this disclosure may be hygroscopic and, as such, may be susceptible to decomposition over time under highly humid conditions.
  • the proportion of the components of the moisture barrier and the amount of the moisture barrier optionally applied onto the control-releasing coating or onto the core are typically such that the moisture barrier does not fall within the USP definition and requirement for an enteric coat.
  • the moisture barrier may comprise an enteric and/or acrylic polymer, suitably an acrylic polymer, optionally a plasticizer, and a permeation enhancer.
  • the permeation enhancer is a hydrophilic substance, which allows water to enter without physical disruption of the coating.
  • the moisture barrier may additionally comprise other conventional inert excipients, which may improve processing of an extended-release formulation.
  • Coating and matrix materials which may be used in accordance with the invention are those known in the art for use in controlled-release formulations, such as synthetic polymers of the polyvinyl type, e.g., polyvinylchloride, polyvinylacetate and copolymers thereof, polyvinylalcohol, and polyvinylpyrrolidone; synthetic polymers of the polyethylene type, e.g., polyethylene and polystyrene; acrylic acid polymers; biopolymers or modified biopolymers, such as cellulosic polymers, shellac and gelatin; fats, oils, higher fatty acids and higher alcohols (i . e.
  • synthetic polymers of the polyvinyl type e.g., polyvinylchloride, polyvinylacetate and copolymers thereof, polyvinylalcohol, and polyvinylpyrrolidone
  • synthetic polymers of the polyethylene type e.g., polyethylene and polystyrene
  • acrylic acid polymers
  • the pH-buffering properties of a coating may be strengthened by introducing into the coating substances chosen from a group of compounds usually used in antacid formulations, for example magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate; composite aluminum/magnesium compounds, for example AI2O3-6MgO CO2- 12H2O, (Mg6AI2(OH)16CO3-4H2O), MgO AI2O3-2SiO2.nH2O, aluminum bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH- buffering compounds, for example the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids; or suitable organic bases, including basic amino acids; and salts or combinations thereof.
  • a group of compounds usually used in antacid formulations for example magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate
  • composite aluminum/magnesium compounds for example AI2O3-6Mg
  • a pH-dependent coating serves to release the drug in desired areas of the gastrointestinal (Gl) tract, e.g., the stomach or small intestine.
  • Gl gastrointestinal
  • the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the Gl tract.
  • the coating is often called an “enteric coating”.
  • a pH-dependent coating may include, but is not limited to, acrylic acid polymers and copolymers, for example polymers formed from acrylic acid, methacrylic acid, methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate (e.g., EudragitTM); cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate and carboxymethylcellulose sodium; shellac (purified lac); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate (PVAP), vinylacetate crotonic acid cop
  • the term “comprising” means “including, but not necessarily limited to”; it specifically indicates open-ended inclusion or membership in a so-described combination, group, series and the like.
  • the terms “comprising” and “including” as used herein are inclusive and/or open-ended and do not exclude additional, unrecited elements or method processes.
  • the term “consisting essentially of” is more limiting than “comprising” but not as restrictive as “consisting of.” Specifically, the term “consisting essentially of” limits membership to the specified materials or steps and those that do not materially affect the essential characteristics of the claimed invention.
  • the term “gene” means a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression.
  • expression includes but is not limited to one or more of the following: transcription of the gene into precursor mRNA; splicing and other processing of the precursor mRNA to produce mature mRNA; mRNA stability; translation of the mature mRNA into protein (including codon usage and tRNA availability); and glycosylation and/or other modifications of the translation product, if required for proper expression and function.
  • the term “differentially expressed gene” means expression levels of a gene in two experimental conditions or in two samples possess statistically significant difference or change.
  • the terms “overrepresented” genes or gene clusters means genes from a predefined set are present more than expected.
  • transcriptome analysis means to characterize transcriptional activity (coding and non-coding), focus on a subset of relevant target genes and transcripts, or profile thousands of genes at once to create a genetic profile.
  • mutant means any heritable variation from the wild-type that is the result of a mutation, e.g., single nucleotide polymorphisms (“SNP”) and insertions/deletions.
  • SNP single nucleotide polymorphisms
  • mutant is used interchangeably with the terms “marker”, “biomarker”, and “target” throughout the specification.
  • polynucleotide means any RNA or DNA, which may be unmodified or modified RNA or DNA.
  • Polynucleotides include, without limitation, single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, RNA that is mixture of single- and double-stranded regions, and hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions.
  • polynucleotide refers to triplestranded regions comprising RNA or DNA or both RNA and DNA.
  • the term polynucleotide also includes DNAs or RNAs containing one or more modified bases and DNAs or RNAs with backbones modified for stability or for other reasons.
  • polypeptide means any polypeptide comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres.
  • Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins.
  • Polypeptides may contain amino acids other than the 20 gene-encoded amino acids.
  • Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well-known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.
  • the terms “disease”, “disorder” or “dysfunction” are used interchangeably in the present disclosure. They refer to any condition, disorder or disease manifested as one or more physiological, physical and/or psychological symptoms or dysfunctions for which treatment is desirable, and includes previously and newly identified diseases, disorders or dysfunctions on any organs, tissues or biological activities.
  • the term “medical use” is any use or means related to restore, remedy, or preserve health or well being of a subject.
  • the term “subject” means that preferably the subject is a mammal, such as a human, but can also be an animal, e.g., domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., cynomolgus monkey, rats, mice, guinea pigs and the like).
  • domestic animals e.g., dogs, cats and the like
  • farm animals e.g., cows, sheep, pigs, horses and the like
  • laboratory animals e.g., cynomolgus monkey, rats, mice, guinea pigs and the like.
  • the administration of an agent or drug to a subject or patient includes self-administration and the administration by another. It is also to be appreciated that the various modes of treatment or prevention of medical conditions as described are intended to mean “substantial”, which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.
  • ANAVEX3-71 (aka “AF710B” or“A3-71”) is a selective allosteric M1 muscarinic and sigma-1 receptor agonist. Acetylcholinesterase inhibitors represent four out of six drugs for treating Alzheimer's disease (AD), with time-limited efficacy likely due to the progressive loss of cholinergic neurons. ANAVEX3-71 takes advantage of the fact that acetylcholine postsynaptic M1 muscarinic brain receptor levels remain unchanged in AD. ANAVEX3-71 treatment attenuated AD hallmarks in McGill-R-Thy1-APP transgenic rats when administered at advanced stages of the AD-like pathology.
  • AD therapy in humans has a greater likelihood of success if applied early in the disease prior to extensive brain damage arises. It is desirable to test if administration of ANAVEX3-71 during early amyloid pathology stages could prevent cognitive impairment, plaque deposition, plaque buildup and/or neuroinflammation.
  • a rat model study was designed to assess the prophylactic and therapeutic effect of ANAVEX3-71 against onset, development and/or progression of a degenerative disease, such as Alzheimer’s Disease.
  • Tg-sal treatment group with saline administration
  • Tg-ANAVEX treatment group with saline administration
  • SP Social Preference test
  • FIG.5 shows that McSA1 -immunoreactive (IR) plaques intensity of Tg-ANAVEX was significantly lower in CA1 (P ⁇ 0.01 ) and the cortex (P ⁇ 0.05) compared to the Tg-sal. This result confirmed that A3-71 prevented McGill-APP rats from increasing cortical and hippocampal extracellular Ap deposition.
  • FIG.6 shows that Iba1 -I R and GFAP-IR cells in Tg-ANAVEX were significantly less recruited in the proximity of the CA1 neurons compared to the Tg-sal (P ⁇ 0.05, for both). This result demonstrated that A3-71 reduced microglia and astrocytes recruitment towards A -burdened neurons in the hippocampus.
  • the results demonstrated the long-lasting effect of ANAVEX3-71 in preventing cognitive decline of McGill-R-Thy1-APP rats, even after a wash-out period.
  • the results suggest preventative and prophylactic diseasemodifying properties of ANAVEX3-71 over the AD-like amyloid pathology.
  • the results also provide insights on the beneficial effects of M1 muscarinic and sigma-1 receptor agonists for neurodegenerative diseases involving amyloid pathology.

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Abstract

La présente invention concerne des méthodes, des compositions et des kits pour le traitement prophylactique ou la prévention d'une maladie dégénérative liée à l'amyloïde. Les compositions et les kits comprennent un agoniste du récepteur sigma-1, un agoniste sigma allostérique et/ou un double agoniste sigma-1 et M1. Les compositions et les kits déclenchent des effets de retardement de l'apparition, de freinage de la progression, et/ou de diminution de la probabilité de la maladie dégénérative, telle que le freinage de la perte de mémoire et/ou du déclin cognitif dans la maladie d'Alzheimer.
EP23847607.1A 2022-07-29 2023-07-28 Compositions et méthodes pour la prévention du déclin cognitif provoqué par des maladies dégénératives Pending EP4561566A1 (fr)

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