Compositions and methods for preventing cognitive decline caused by degenerative disease

Abstract

The present disclosure provides methods, compositions, and kits for the prophylactic treatment or prevention of amyloid-associated degenerative diseases. The compositions and kits comprise a sigma-1 receptor agonist, an allosteric sigma agonist, and / or a dual agonist of sigma-1 and M1. The compositions and kits induce an effect of delaying the onset of the degenerative disease, preventing the progression of the degenerative disease, and / or reducing the likelihood of the degenerative disease, such as preventing memory loss and / or cognitive decline in Alzheimer's disease (Alzheimer's disease).

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 393,555, filed on July 29, 2022, entitled “COMPOSITIONS AND METHODS FOR PREVENTION OF COGNITIVE DECLINECAUSED BY DEGENERATIVE DISEASES,” the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] The present invention relates generally to the prevention and treatment of diseases, such as degenerative diseases involving abnormal amyloid formation and / or deposition. Background Art

[0004] Neurodegenerative diseases greatly hinder patients' daily lives due to memory loss and / or cognitive decline. It is crucial to develop preventive and prophylactic therapies to halt the onset of neurodegenerative diseases and / or to stop the progression of neurodegenerative diseases, with the goal of restoring memory and halting cognitive decline. Summary of the invention

[0005] The present disclosure provides methods, compositions and kits for therapeutic or prophylactic treatment or prevention of degenerative diseases associated with amyloid. The compositions and kits contain therapeutic agents of sigma-1 receptor agonists, allosteric sigma agonists and / or dual agonists of sigma1 and M1. The compositions and kits induce the effects of delaying the onset of the degenerative disease, preventing the progression of the degenerative disease and / or reducing the likelihood of the degenerative disease, such as preventing cognitive decline in Alzheimer's disease.

[0006] In one aspect of the present disclosure, the therapeutic agent or the preventive agent comprises ANAVEX2-73 (A2-73), ANAVEX19-144, ANAVEX1-41, AV1066, ANAVEX3-71, PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, dimethyltryptamine, (+)-pentazocine, or any one of their crystal forms, enantiomers, and pharmaceutically acceptable salts thereof. The chemical name of ANAVEX2-73 (A2-73) is tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride. The chemical name of ANAVEX19-144 (A19-144) is 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethylamine hydrochloride. The chemical name of ANAVEX1-41 (A1-41) is tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine hydrochloride. The chemical name of AV1066 is 1-(3-4(((1R,3S,5S)-adamantan-1-yl)(phenyl)methyl)propyl)-4-methylpiperazine. The chemical name of ANAVEX3-71 (A3-71, AF-710B) is 1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one.

[0007] In another aspect of the present disclosure, the therapeutic agent or the prophylactic agent comprises A3-71 amorphous form, A3-71 crystalline form, A3-71 enantiomer, A3-71 prodrug, or a combination thereof.

[0008] In another aspect of the present disclosure, 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 associated with abnormal amyloid formation, or a disorder associated with amyloid deposition.

[0009] In another aspect of the present disclosure, the effective amount used is to reduce or lower the likelihood or severity of the degenerative disease. In yet another aspect of the present invention, the preventive effective amount is an amount that prevents the onset of the degenerative disease or stops the progression of the degenerative disease. The onset or progression may manifest as memory loss and / or cognitive decline.

[0010] In yet another aspect of the present disclosure, the therapeutically effective amount or the prophylactically effective amount ranges from about 0.10 mg to about 500 mg, such as 5 mg to 30 mg. In another aspect, the subject is a human subject or a non-human mammal.

[0011] 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 for the aforementioned medical use and instructions.

[0012] In another aspect, the present disclosure provides the use of a therapeutically effective amount or a prophylactically effective amount of a sigma-1 receptor agonist for the preparation of a medicament for use in any of the methods as disclosed herein.

[0013] References to color figures

[0014] The application file contains at least one color photograph. Copies of this patent application publication with color photographs will be provided by the Office upon request and payment of the necessary fee. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 yes 3-71 Illustrative workflow for rat studies of 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.

[0016] Figure 2A-2B Depicted are the novel object recognition (NOR) test and results. Figure 2A Exposure of rats to the objects is demonstrated. Figure 2B The percentage of rats in each group that were able to find the novel object is plotted: *P≤0.05; **P≤0.01.

[0017] Figure 3A-3B Depicted is the social preference (SP) test. Figure 3A Rats were exposed to either social or nonsocial factors. Figure 3B The percentage of rats in each group that preferred to join the social group is plotted: ***P≤0.001; ****P≤0.0001.

[0018] Figures 4A-4C Depicted are the acquisition training phases for the Morris Water Maze (MWM). Figure 4A Rats exposed to MWM are shown. Figure 4B Escape latency relative to training days is plotted for each group. Figure 4CThe mean escape latency from day 3 to day 5 is plotted. Tg-sal required more time to find the hidden platform than wt-sal (P ≤ 0.01). In contrast, Tg-ANAVEX performed significantly better than Tg-sal (P ≤ 0.05).

[0019] Figures 5A-5C The effects of A3-71 administration on extracellular Aβ deposition in the cortex and hippocampus are depicted. Figure 5A Patchy staining in the cortex and CA1 is shown. Figure 5B The integrated density of plaque CA1 cortex in the treated group Tg-ANAVEX and the non-treated group Tg-sal is plotted, **P ≤ 0.01. Figure 5C The integrated cortical density of plaques in the treated group Tg-ANAVEX and the non-treated group Tg-sal is plotted, *P≤0.05.

[0020] Figures 6A-6C The effects of A3-71 administration on neurons in the hippocampus are depicted. Fig. 6A Immunostaining of the different test groups is shown. Figure 6B The number of Iba1-IR cells near NeuN is plotted, *P ≤ 0.05. Figure 6C The number of GFAP-IR cells in the vicinity of NeuN is plotted, *P ≤ 0.05. DETAILED DESCRIPTION

[0021] The present disclosure provides methods, compositions and kits for the prophylactic treatment or prevention of degenerative diseases associated with amyloid. Amyloid is an aggregate of proteins characterized by a fibrous morphology of typically 7–13 nm in diameter, a β-sheet secondary structure (called cross-β) and the ability to be stained by specific dyes such as Congo red. Pathogenic amyloid forms when previously healthy proteins lose their normal structure and physiological function (misfolding) and form fibrous deposits in and around cells. These protein misfolding and deposition processes destroy the healthy function of tissues and organs, known as amyloidosis. Amyloid plaques are aggregates of misfolded proteins formed in the spaces between nerve cells. When amyloid plaques form and / or plaques accumulate in areas of the brain associated with memory and other cognitive functions, degenerative diseases such as Alzheimer's disease may be caused. Degenerative diseases are characterized by worsening of symptoms due to functional and structural deterioration of affected body parts, causing disability, death and morbidity. One type of degenerative disease is called neurodegenerative disease (degenerative nervous system disease), which affects the neurons of the central nervous system, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion diseases or multiple sclerosis.

[0022] The compositions and kits contain sigma-1 receptor agonists, allosteric sigma agonists and / or dual agonists of sigma-1 and muscarinic acetylcholine receptor M1. The compositions and kits induce effects that prevent or delay the onset of the degenerative disease, prevent the progression of the degenerative disease and / or reduce the likelihood of the degenerative disease, such as preventing memory loss and / or cognitive decline in Alzheimer's disease. Sigma-1 receptors have been shown to be involved in higher-order brain functions including memory and cognition. Therefore, sigma-1 receptor agonist therapy is often prescribed to patients with decreased memory or cognitive function, such as patients with neurodegenerative disorders. It was found that after a subject was treated with a sigma-1 receptor agonist, his or her gene expression profile was changed: a set of selected genes were expressed differently, and their related gene clusters were over-represented. The altered gene profile can be used as a benchmark for evaluating the therapeutic effect of another therapeutic agent. It can also be used to select a sigma-1 receptor agonist for a subject. In addition, it can also be used to determine whether a subject responds to sigma-1 receptor agonist therapy. Finally, sigma-1 receptor agonists can be used as probes to see if a subject has, is suspected of having, or is at increased risk of having a disease associated with an altered gene expression profile.

[0023] Degenerative diseases manifested as abnormal formation and / or deposition of amyloid may include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and prion diseases. Neurodegenerative diseases are a subset of degenerative diseases and refer to hereditary and sporadic conditions characterized by progressive nervous system dysfunction. These conditions are usually associated with atrophy of central or peripheral nervous system structures and may have symptoms in the form of cognitive 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 impaired memory, judgment, attention span and problem-solving abilities. In the final stage, severe apraxia and a comprehensive loss of cognitive abilities may occur. The disease is marked by a triple pathological sign of severe cortical atrophy and senile plaques, neurofibrillary tangles and neuropil threads. Parkinson's disease is a progressive degenerative neurological disease characterized by maximum tremor at rest, backwardness (i.e., tendency to fall backward), rigidity, stooped posture, slow voluntary movements, and mask-like facial expressions. Pathological features include the 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 the locus coeruleus, but may also be found in related conditions characterized by dementia combined with varying degrees of parkinsonism. Secondary parkinsonism refers to a condition whose clinical manifestations caused by known or suspected conditions are similar to those of primary parkinsonism, such as parkinsonism caused by vascular damage, drugs, trauma, toxin exposure, tumors, infections, and degenerative or hereditary conditions. Clinical features may include bradykinesia, rigidity, parkinsonian gait, and mask-like facial features. Typically, the tremor in secondary parkinsonism is not as obvious as the tremor in the primary form. Huntington's disease is a familial disorder inherited as an autosomal dominant trait and is 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. Terminal symptoms include intellectual disability, loss of fine motor control, athetosis and diffuse chorea involving the development of axial and limb musculature, leading to a vegetative state within 10-15 years after the onset of the disease. Its adolescent variant has a more explosive course, including epileptic seizures, ataxia, dementia and chorea. Amyotrophic lateral sclerosis is a degenerative disorder that affects upper motor neurons in the brain and lower motor neurons in the brainstem and spinal cord. The disease usually breaks out after the age of 50, and the process is usually fatal within 3 to 6 years. Clinical manifestations include progressive weakness, atrophy, fasciculations, hyperreflexia, dysarthria, dysphagia, and ultimately paralysis of respiratory function. Pathological features include replacement of motor neurons by fibrous astrocytes and atrophy of the anterior spinal nerve roots and corticospinal tracts.Prion diseases are a group of inherited, infectious or sporadic degenerative human and animal neurological disorders associated with abnormal prions. These diseases are characterized by the conversion of normal prion proteins into abnormal configurations through post-translational processes. In humans, these conditions are usually characterized by dementia, ataxia and fatal consequences. Pathological features include spongiform encephalopathy without signs of inflammation. Some older literature occasionally refers to these as unconventional slow virus diseases.

[0024] One aspect of the present disclosure encompasses methods of selecting therapeutic and prophylactic agents for a subject suffering from a disease or disorder such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion disease, diabetic cardiomyopathy, or nonalcoholic fatty liver disease.

[0025] In one aspect of the disclosure, if a neurodegenerative therapy is identified as ineffective for the subject, subsequent actions can be taken, such as switching to another neurodegenerative therapy, supplementing with another neurodegenerative therapy, adjusting the dosage if the neurodegenerative therapy is a drug therapy, or switching to a combination neurodegenerative therapy.

[0026] In another aspect of the present disclosure, neurodegenerative therapy can be sigma-1 receptor agonist therapy or NMDA therapy or physical therapy that enhances cognition. For example, neurodegenerative therapy can be a drug therapy comprising a sigma-1 receptor agonist (such as ANAVEX2-73 (A2-73), ANAVEX19-144, ANAVEX1-41, AV1066, ANAVEX3-71, PRE-084, donepezil, fluvoxamine, amitriptyline, L-687,384, SA-4503, dextromethorphan, dimethyltryptamine, (+)-pantazolone or any one of their crystalline forms, enantiomers, and pharmaceutically acceptable salts thereof). The chemical name of ANAVEX2-73 (A2-73) is tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethylamine hydrochloride. The chemical name of ANAVEX19-144 (A19-144) is 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethylamine hydrochloride. The chemical name of ANAVEX1-41 (A1-41) is tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethylamine hydrochloride. The chemical name of AV1066 is 1-(3-4(((1R,3S,5S)-adamantan-1-yl)(phenyl)methyl)propyl)-4-methylpiperazine. The chemical name of ANAVEX3-71 (A3-71, AF-710B) is 1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one. For example, the neurodegenerative therapy is an A2-73 drug therapy comprising A2-73 free base, A2-73 amorphous form, A2-73 crystalline Form I, A2-73 crystalline Form II, A2-73 crystalline Form III, a (-) A2-73 enantiomer, or a (+) A2-73 enantiomer.

[0027] In another aspect of the disclosure, the therapeutic agent comprises A3-71 amorphous form, A3-71 crystalline form, A3-71 enantiomer, A3-71 prodrug, or a combination thereof.

[0028] In another aspect of the present disclosure, the effective amount used is to reduce or lower the likelihood or severity of the degenerative disease. In yet another aspect of the present invention, a prophylactic effective amount is an amount that prevents the onset of the degenerative disease or stops the progression of the degenerative disease. The onset or progression may manifest as memory loss and / or cognitive decline.

[0029] In yet another aspect of the present disclosure, the therapeutically effective amount or the prophylactically effective amount ranges from about 0.10 mg to about 500 mg, such as 5 mg to 30 mg of A2-73. In another aspect, the subject is a human subject or a non-human mammal.

[0030] 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 for the aforementioned medical use and instructions.

[0031] I. Treatment

[0032] As used herein, the term "treatment" refers to an action taken on a subject (which may be a human or animal subject) with the intent to improve, prevent, slow down, stop, reduce, alleviate, or cure the symptoms and / or effects associated with a recited disease state or condition. "Therapeutic treatment" refers to treatment that at least partially prevents, slows down, stops, reduces, alleviates, or cures the symptoms and / or effects associated with a recited disease state or condition.

[0033] As used herein, the term "prophylactic" in reference to treatment refers to actions taken on a subject before symptoms or symptomatic conditions are detected to maintain health by delaying, alleviating or avoiding the onset, or reducing the likelihood or severity of symptoms, onset, disease states or conditions. "Prophylactic effect" in the context of this specification should not be understood to encompass complete or complete prevention of symptoms or symptomatic conditions.

[0034] As used herein, the term "prophylactically effective amount" relates to an amount of a compound or composition as disclosed herein, which is effective to produce the desired prophylactic effect when administered as disclosed herein.

[0035] As used herein, the term "therapeutically effective amount" refers to an amount of a compound or composition as disclosed herein, which is effective to produce the desired therapeutic effect when administered as disclosed herein. A therapeutic effect encompasses a prophylactic effect.

[0036] II. Pharmaceutical composition

[0037] One aspect of the present disclosure encompasses a pharmaceutical composition comprising a neurodegenerative agent and / or a sigma-1 receptor agonist. The pharmaceutical composition comprises a therapeutically effective amount or a prophylactically effective amount of an active pharmaceutical ingredient and any pharmaceutically acceptable salt thereof.

[0038] Pharmaceutically acceptable salts include, but are not limited to, acetate, aspartate, benzoate, bitartrate, citrate, formate, gluconate, glucuronate, glutamate, fumarate, hydrochloride, hydrobromide, hydroiodide, hypophosphite, isobutyrate, isocitrate, lactate, malate, maleate, meconate, methyl bromide, methanesulfonate, monohydrate, acetalate, nitrate, oxalate, phenylpropionate, phosphate, phthalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tannate, tartrate, terephthalate, valerate, and the like.

[0039] When the active pharmaceutical ingredient is A2-73, the composition can contain about 1 mg to about 50 g, about 0.1 g to about 5 g, about 0.5 g to about 3 g, about 1 mg to about 55 mg, about 5 mg to about 30 mg, about 40 mg to about 60 mg, about 80 mg to about 120 mg, about 180 mg to about 220 mg, about 0.1 g to about 5 g, or about 0.5 g to about 3 g of A2-73. Formulations comprising A2-73 can be found, for example, in U.S. Pat. No. 9,750,746, U.S. Pat. Publication No. 20170360798, U.S. Pat. Publication No. 20190022052, U.S. Pat. Publication No. 20180360796, U.S. Pat. Publication No. 20180169059, U.S. Pat. Publication No. 20180177756, U.S. Pat. Publication No. 20180169060, and U.S. Pat. Publication No. 20190117615, the disclosures of which are incorporated herein by reference in their entirety. When the active pharmaceutical ingredient is A3-71, the composition can include about 1 mg to about 50 g, about 0.1 g to about 5 g, about 0.5 g to about 3 g, about 1 mg to about 55 mg, about 5 mg to about 30 mg, about 40 mg to about 60 mg, about 80 mg to about 120 mg, about 180 mg to about 220 mg, about 0.1 g to about 5 g or about 0.5 g to about 3 g of A3-71. The active pharmaceutical ingredient can be used every day, twice a day or three times a day. The duration of use can be about 3-6 weeks, 6-11 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or long-term. For example, A2-73 or A3-71 can be used once a day in an amount of about 40 mg to about 60 mg, for about 6-11 weeks, or used every day in an amount of about 50 mg for up to 11 weeks. A3-71 or A2-73 may also be administered once daily in ascending doses starting at about 10 mg and ending at about 50 mg.

[0040] 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 a dosage unit formulation containing conventional nontoxic pharmaceutically acceptable adjuvants, carriers, excipients and vehicles, as desired. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrathecal or intrasternal injection or infusion techniques. The formulation of pharmaceutical compositions is discussed, for example, in 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, NY (1980).

[0041] The pharmaceutical composition also comprises one or more pharmaceutically acceptable excipients. Non-limiting examples of excipients include chemical enhancers, wetting agents, pressure-sensitive adhesives, antioxidants, solubilizers, thickeners, plasticizers, adjuvants, carriers, excipients, vehicles, coatings, and any combination thereof. One or more excipients may be selected for oral, transdermal, parenteral, intraperitoneal, intravascular, subcutaneous, by inhalation spray, rectal or intrapulmonary administration.

[0042] Active pharmaceutical ingredients can be formulated to improve patient compliance and prevent subjects from removing drug delivery devices. For example, sigma-1 receptor agonists can be formulated to improve patient compliance and prevent removal of drug delivery devices by providing a formulation that extends delivery. The scope of extended delivery can be a period ranging from more than one day to several months. This may be particularly relevant to patients with impaired cognitive and / or motor control abilities. The scope of the extended delivery period can be 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.

[0043] Extended release formulations can be used to deliver medicine continuously at a preselected rate. For example, for A2-73 or A3-71, medicine can be delivered at a rate of about 1 mg to about 100 mg / day, about 5 mg to about 30 mg / day, about 40 gm to about 60 gm / day, or about 10 gm to about 30 gm / day. One of ordinary skill in the art can easily determine an appropriate amount of crystallized A2-73 based on factors such as the expected duration of use of the medicine of the extended release formulation, delivery mechanism, specific formulation, and the relative effectiveness of the medicine.

[0044] Adhesives

[0045] The non-limiting examples of the binder suitable for the preparation of various aspects include starch, pregelatinized starch, gelatin, polyvinyl pyrrolidone, cellulose, methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, polyacrylamide, polyvinyl oxazolidinone, polyvinyl alcohol, C12-C18 fatty acid alcohol, polyethylene glycol, polyol, sugar, oligosaccharide, polypeptide, oligopeptide and their combination.Polypeptide can be any arrangement of the amino acid ranging from about 100 dalton to about 300,000 dalton.

[0046] The binder can be introduced into the mixture to be granulated in solid form, including but not limited to crystals, granules, powders or any other finely divided solid form known in the art. Alternatively, the binder can be dissolved or suspended in a solvent and sprayed onto the mixture in the granulation device as a binder fluid during granulation.

[0047] Thinner

[0048] Non-limiting examples of diluents (also referred to as "fillers" or "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, sugars such as sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol and sorbitol, polyols; starch; preformed direct compression diluents; and mixtures of any of the foregoing.

[0049] Disintegrants

[0050] Disintegrants can be effervescent or non-effervescent. Non-limiting examples of non-effervescent disintegrants include starch (such as corn starch, potato starch, pregelatinized and modified starches thereof) sweeteners, clays (such as bentonite), microcrystalline cellulose, alginates, sodium starch glycolate, gums (such as agar, guar gum, locust bean gum, karaya gum, pectin and tragacanth). Suitable effervescent disintegrants include, but are not limited to, combinations of sodium bicarbonate and citric acid and combinations of sodium bicarbonate and tartaric acid.

[0051] preservative

[0052] 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, anthranilic acid, p-aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxanthin, alpha-carotene, beta-carotene, beta-carotene, beta-apo-carotenoic acid, and beta-carotene. acid), carnosol, carvacrol, catechins, hexadecyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p-coumaric acid, 3,4-dihydroxybenzoic acid, N,N'-diphenyl-p-phenylenediamine (DPPD), dilauryl thiodipropionate, distearyl thiodipropionate, 2,6-di-tert-butylphenol, lauryl gallate, edetic acid, ellagic acid, isoascorbic acid, sodium isoascorbate, esculetin, esculin, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline, ethyl gallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA), eucalyptus extract, eugenol, ferulic acid, flavonoids (e.g., catechins, epicatechin, epicatechin Gallic acid esters, epigallocatechin (EGC), epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate), flavonoids (e.g., apigenin, chrysin, luteolin), flavonols (e.g., quercetin, myricetin, daemfero), flavanones, ash lactones, fumaric acid, gallic acid, gentian extract, gluconic acid, glycine, guaiac, hesperidin, α-hydroxybenzylphosphinic acid, hydroxycinnamic acid, hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid, hydroxytyrosol, hydroxyurea, rice bran extract, lactic acid and its salts, lecithin, lecithin citrate; R-α-lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxytryptamine, methyl gallate, monocitrate; monoisopropyl citrate;Morin, β-naphthoflavone, nordihydroguaiaretic acid (NDGA), octyl gallate, oxalic acid, palmityl citrate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphate, phytic acid, phytylubichromenol, pimento extract, propyl gallate, polyphosphate, quercetin, resveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid, succinic acid, stearyl citrate esters, syringic acid, tartaric acid, thymol, tocopherols (i.e., α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol), tocotrienols (i.e., α-tocotrienol, β-tocotrienol, γ-tocotrienol and δ-tocotrienol), tyrosol, vanillic acid, 2,6-di-tert-butyl-4-hydroxymethylphenol (i.e., Ionox 100), 2,4-(tri-3',5'-di-tert-butyl-4'-hydroxybenzyl)-mesitylene (i.e., Ionox 330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tert-butylhydroquinone (TBHQ), sulfodipropionic acid, trihydroxybutyrophenone, tryptamine, tyramine, uric acid, vitamin K and its derivatives, vitamin Q10, wheat germ oil, zeaxanthin or a combination thereof. ;

[0053] Flavor modifier

[0054] Suitable flavor modifiers include flavoring agents, masking agents, sweeteners, etc. Flavoring agents include, but are not limited to, synthetic flavoring 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 oil, wintergreen oil, peppermint oil, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oils (such as lemon oil, orange oil), grape and grapefruit oils, fruit essences, including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0055] Taste masking agents include, but are not limited to, hydroxypropyl cellulose (HPC), such as Nisswo HPC and PrimaFloHP22; low-substituted hydroxypropyl ether (L-HPC); hydroxypropyl methylcellulose ether (HPMC), such as Seppifilm-LC, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824 and Benecel MP843; methylcellulose polymers such as and Ethyl cellulose (EC) and its mixtures, such as E461, -EC, Surelease; polyvinyl alcohol (PVA), such as Opadry AMB; hydroxyethyl cellulose, such as Carboxymethyl cellulose and salts of carboxymethyl cellulose (CMC), such as -CMC; copolymers of polyvinyl alcohol and polyethylene glycol, such as Kollicoat Monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic acid polymers, and mixtures of acrylic acid polymers and cellulose ethers, such as EPO, RD100 and E100; cellulose acetate phthalate; sepifilm, such as a mixture of HPMC and stearic acid, cyclodextrin, and mixtures of these materials. In other aspects, additional taste masking agents contemplated are those described in U.S. Pat. Nos. 4,851,226; 5,075,114; and 5,876,759, each of which is hereby incorporated by reference in its entirety.

[0056] 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 (stevioside); chlorinated derivatives of sucrose, such as sucralose; sugar alcohols, such as sorbitol, mannitol, xylitol, 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 its sodium and calcium salts.

[0057] Lubricants and glidants

[0058] Lubricant compositions can be used to lubricate the ingredients that form pharmaceutical compositions. As glidants, lubricants help remove solid dosage forms during the preparation process. Non-limiting examples of lubricants and glidants can include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, hydrogenated castor oil, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate and light mineral oil. Pharmaceutical compositions will typically include lubricants of about 0.01 % by weight to about 10 % by weight. In some aspects, pharmaceutical compositions will include lubricants of about 0.1 % by weight to about 5 % by weight. In other aspects, pharmaceutical compositions will include lubricants of about 0.5 % by weight to about 2 % by weight.

[0059] Dispersants

[0060] Dispersants may include, but are not limited to, starch, alginic acid, polyvinyl pyrrolidone, guar gum, kaolin, bentonite, purified lignocellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high hydrophilic-lipophilic balance (HLB) emulsifier surfactants.

[0061] Colorants

[0062] According to aspects of the present disclosure, it may be desirable to include a colorant. 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 and their corresponding lakes, as well as certain natural and derived colorants may be suitable for use in various aspects of the present disclosure.

[0063] pH Adjusters

[0064] Non-limiting examples of pH adjusters include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate, and sodium bicarbonate.

[0065] Chelating agents

[0066] Chelating agents can be included as excipients to immobilize oxidative groups (including but not limited to metal ions) to inhibit oxidative degradation of morphinan by these oxidative groups. Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamate, aspartate, and disodium ethylenediaminetetraacetate (Na2EDTA).

[0067] Antimicrobial Agents

[0068] Antimicrobial agents may be included as excipients to minimize degradation of compounds according to the present disclosure by microbial agents, including but not limited to bacteria and fungi. Non-limiting examples of antimicrobial agents include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites, including but not limited to sulfur dioxide, sodium bisulfite, and potassium bisulfite.

[0069] Release Control Polymers

[0070] Release controlling polymers can be included in various aspects of solid dosage pharmaceutical compositions incorporating compounds according to the present disclosure. In one aspect, release controlling polymers can be used as tablet coatings. In other aspects, including but not limited to bilayer tablets, release controlling polymers can be mixed with particles and other excipients before forming tablets by known processes, including but not limited to compression in tablet molds. Suitable release controlling polymers include but are not limited to hydrophilic polymers and hydrophobic polymers.

[0071] Suitable hydrophilic release controlling polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, nitrocellulose, cross-linked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, sodium carboxymethyl cellulose alginate, calcium carboxymethyl cellulose, carrageenan, fucoidan, furcellaran, gum arabic, carrageens gum, dawa gum, guar gum, karaya gum, locust bean gum, okra gum gum, tragacanth gum, scleroglucan gum, xanthan gum, hypnea, laminarin, acrylic acid polymers, acrylate polymers, carboxyvinyl polymers, copolymers of maleic anhydride and styrene, copolymers of maleic anhydride and ethylene, copolymers of maleic anhydride propylene or maleic anhydride isobutylene, cross-linked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, diesters of polydextran, polyacrylamide, polyacrylic acid, polyamide, polyethylene glycol, polyethylene oxide, poly(hydroxyalkyl methacrylate), polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, anionic and cationic hydrogels, and combinations thereof.

[0072] Coating

[0073] Solid dosage forms comprising compounds according to the present disclosure may include coatings, wherein such coatings can control the release of compounds, act as moisture barriers, or buffer or change pH. As used herein, "controlled release coatings" or "controlled release coatings" are defined as meaning functional coatings, which may, for example, include at least one pH-independent polymer, pH-dependent polymer (e.g., enteric or reverse enteric polymer), soluble polymer, insoluble polymer, lipid, lipid material, or a combination thereof. When applied to dosage forms, coatings may slow down (e.g., when applied to normal release matrix dosage forms), further slow down (e.g., when applied to controlled release matrix dosage forms) or change the release rate of compounds according to the present disclosure when applied to uncoated dosage forms. For example, controlled release coatings may be designed so that when controlled release coatings are applied to dosage forms, dosage forms may be combined with controlled release coatings to display the release of compounds according to the present disclosure, such as "modified release," "controlled release," "slow release," "extended release," "delayed release," "lasting release," or a combination thereof. A "controlled release coat" may optionally contain additional materials that may alter the function of the controlled release coat.

[0074] As used herein, the term "moisture barrier" refers to a barrier that hinders or delays the absorption of moisture. Compounds according to the present disclosure may be hygroscopic and therefore may be prone to decomposition over time under highly humid conditions. The proportions of the components of the moisture barrier and the amount of the moisture barrier optionally applied to the controlled release coating or on the core generally make the moisture barrier not within the USP definition and requirements of enteric coatings. Suitably, the moisture barrier may comprise enteric and / or acrylic polymers, suitably comprising acrylic polymers, optionally comprising plasticizers and permeation enhancers. A permeation enhancer is a hydrophilic substance that allows water to enter without causing physical damage to the coating. The moisture barrier may additionally comprise other conventional inert excipients, which may improve the processing of extended release formulations.

[0075] The coating and matrix materials that can be used according to the present invention are coating and matrix materials known in the art for controlled release preparations, such as synthetic polymers of the polyvinyl type, for example, polyvinyl chloride, polyvinyl acetate and copolymers thereof, polyvinyl alcohol and polyvinyl pyrrolidone; synthetic polymers of the polyvinyl type, for example, polyethylene and polystyrene; acrylic polymers; biopolymers or modified biopolymers, such as cellulose polymers, shellac and gelatin; fats, oils, higher fatty acids and higher alcohols (i.e. acids and alcohols containing an alkyl chain of at least 10 carbon atoms), such as aluminum monostearate, cetyl alcohol, hydrogenated tallow, hydrogenated castor oil, 12-hydroxystearyl alcohol, glyceryl monopalmitate or glyceryl dipalmitate; glyceryl monostearate, glyceryl distearate or glyceryl tristearate; myristyl alcohol, stearic acid, stearyl alcohol and polyethylene glycol; waxes; sugars and sugar alcohols.

[0076] The pH buffering properties of the coating can be enhanced by introducing into the coating a substance selected from a group of compounds commonly used in antacid preparations, such as magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate; complex aluminum / magnesium compounds, such as Al2O3·6MgO·CO2·12H2O, (Mg6Al2(OH)16CO3·4H2O), MgO·Al2O3·2SiO2.nH2O, aluminum bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH buffering compounds, such as sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, carbonic acid, citric acid or other suitable weak acids, inorganic acids or organic acids; or suitable organic bases, including basic amino acids; and salts or combinations thereof.

[0077] pH-dependent coatings are used to release the drug in a desired area of ​​the gastrointestinal (GI) tract, e.g., the stomach or small intestine. When a pH-independent coating is desired, the coating is designed to achieve optimal release regardless of pH changes in the ambient fluid (e.g., the GI tract). When a coating is formulated to release a compound according to the present disclosure in the intestine (particularly the upper small intestine), the coating is generally referred to as an "enteric coating." pH-dependent coatings may include, but are not limited to, acrylic polymers and copolymers, such as polymers formed from acrylic acid, methacrylic acid, methyl acrylate, ammonium methacrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate (e.g., Eudragit TM ); cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, and sodium carboxymethylcellulose; shellac (purified shellac); vinyl polymers and copolymers such as polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate (PVAP), vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; zein; and salts and combinations thereof. Oral tablets and capsules are typically coated.

[0078] definition

[0079] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those commonly understood by those of ordinary skill in the art to which the invention belongs. The following references provide general definitions of many of the terms used in the present invention for technicians: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale and Marham, The Harper Collins Dictionary of Biology (1991). As used herein, unless otherwise stated, the following terms have the meanings assigned to them.

[0080] When introducing elements of the present disclosure or preferred aspects thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0081] As various changes could be made in the above described cells and methods without departing from the scope of the invention, it is intended that all matter contained in the above description and examples given below shall be interpreted as illustrative and not in a limiting sense.

[0082] The term "comprising" means "including but not necessarily limited to"; it specifically indicates an open inclusion or membership in the combination, group, series, etc. described thereby. As used herein, the terms "comprising" and "including" are inclusive and / or open ended, and do not exclude additional, unrecited agents or method procedures. The term "consisting essentially of is more restrictive than "comprising," but less restrictive than "consisting of." Specifically, the term "consisting essentially of limits membership to the specified materials or steps, as well as materials or steps that do not substantially affect the basic characteristics of the claimed invention.

[0083] As used herein, the term "gene" means a DNA segment containing all information about the biosynthesis of the regulation of RNA products, including promoters, exons, introns, and other untranslated regions that control expression. As used herein, "expression" includes but is not limited to one or more of the following: the gene is transcribed into a pre-mRNA; the pre-mRNA is spliced ​​and other processed to produce a mature mRNA; mRNA stability; the mature mRNA is translated into protein (including codon usage and tRNA availability); and the translation product is glycosylated and / or otherwise modified (if correctly expressed and functionally required). As used herein, the term "differentially expressed genes" means that the expression level of a gene under two experimental conditions or in two samples has a statistically significant difference or change. As used herein, the term "overrepresented" gene or gene cluster means that the genes from a predefined set are more present than expected.

[0084] As used herein, the term "transcriptome analysis" means characterizing transcriptional activity (coding and non-coding), focusing on a subset of related target genes and transcripts, or outlining thousands of genes at a time to create a gene profile. As used herein, the term "mutant" means any heritable changes in the wild type caused by mutation, for example, single nucleotide polymorphisms ("SNPs") and insertions / deletions. Throughout the specification, the term "mutant" is used interchangeably with the term "marker," "biomarker," and "target."

[0085] As used herein, the term "polynucleotide" means any RNA or DNA, which may be unmodified or modified RNA or DNA. Polynucleotides include, but are not limited to, single-stranded and double-stranded DNA, DNA as a mixture of single-stranded and double-stranded regions, single-stranded and double-stranded RNA, RNA as a mixture of single-stranded 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-stranded and double-stranded regions. In addition, polynucleotides refer to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The term polynucleotide also includes DNA or RNA containing one or more modified bases, and DNA or RNA with a main chain modified for stability or other reasons.

[0086] As used herein, the term "polypeptide" means any polypeptide comprising two or more amino acids linked to each other by peptide bonds or modified peptide bonds (i.e., peptide isosteres). Polypeptides refer to both short chains, commonly referred to as peptides, glycopeptides, or oligomers, and longer chains, commonly referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. Polypeptides include amino acid sequences modified by natural processes such as post-translational processing or by chemical modification techniques well known in the art. Such modifications are described in detail in basic texts and in more detailed monographs as well as in a large research literature.

[0087] As used herein, the terms "disease," "disorder," or "dysfunction" are used interchangeably in this disclosure. They refer to any condition, disorder, or disease manifested by one or more physiological, physical, and / or psychological symptoms or dysfunctions for which treatment is desired, and include previously and newly identified diseases, disorders, or dysfunctions of any organ, tissue, or biological activity. As used herein, the term "medical use" is any use or means related to restoring, remedying, or protecting the health or well-being of a subject.

[0088] As used herein, the term "subject" means that preferably the subject is a mammal, such as a human, but can also be an animal, for example, domestic animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., cynomolgus monkeys, rats, mice, guinea pigs, etc.).

[0089] As used herein, administration of a medicament or drug to a subject or patient includes self-administration and administration by another person. It is also understood that the various treatment or prevention modes of medical conditions as described are intended to represent "substantial," which include complete treatment or prevention but also include less complete treatment or prevention, and in which some biologically or medically relevant result is achieved.

[0090] The publications discussed above are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

[0091] Example

[0092] The following examples are included to illustrate the present disclosure. It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques discovered by the inventors that work well in the practice of the present disclosure. However, in light of the present disclosure, it will be appreciated by those skilled in the art that many changes may be made in the present disclosure without departing from the spirit and scope of the present disclosure, and similar or similar results may still be obtained, and therefore all contents set forth shall be interpreted as illustrative, rather than limiting.

[0093] Example 1. Background and purpose

[0094] ANAVEX3-71 (also known as "AF710B" or "A3-71") is a selective allosteric M1 muscarinic and sigma-1 receptor agonist. Acetylcholinesterase inhibitors represent four of the six drugs used to treat Alzheimer's disease (AD), and their efficacy is time-limited, probably due to the gradual loss of cholinergic neurons. ANAVEX3-71 takes advantage of the fact that the levels of postsynaptic M1 muscarinic brain receptors for acetylcholine remain unchanged in AD. When administered in the late stages of AD-like pathology, ANAVEX3-71 treatment attenuated AD hallmarks in McGill-R-Thy1-APP transgenic rats. However, human AD therapy is more likely to be successful if applied early in the disease before extensive brain damage occurs. It is desirable to test whether administration of ANAVEX3-71 during the early amyloid pathology semester can prevent cognitive impairment, plaque deposition, plaque accumulation and / or neuroinflammation.

[0095] Example 2. Study Design of the Preventive Effect of ANAVEX3-71 on Alzheimer's Disease

[0096] A rat model study was designed to evaluate the preventive and therapeutic effects of ANAVEX3-71 against the onset, development and / or progression of degenerative diseases such as Alzheimer's disease. ANAVEX3-71 (10 μg / kg) or saline (sal) was administered po daily for seven months in preplaque McGill-R-Thy1-APP (Tg, n=22) and wild type (Wt, n=22) divided into four groups. After one month of drug interruption, behavioral tests were performed: novel object recognition (NOR), Morris water maze (MWM) and social preference (SP). The brain was extracted, fixed and analyzed by histochemistry and immunohistochemistry (see Figure 1 ). Statistical analysis was applied to four groups by 2 × 2 ANOVA, followed by Tukey's multiple comparisons test. For 2-group analysis, Mann Whitney test (data normality was violated) was used. Data are expressed as mean ± SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ P ≤ 0.0001.

[0097] Example 3. Results

[0098] As shown in FIG2 , in the NOR (novel object recognition test), Tg-sal (treated group administered with saline) explored the novel object significantly less than wt-sal (P ≤ 0.01, wild type administered with saline). The impairment was rescued after A3-71 was administered in the treated group (Tg-ANAVEX, P ≤ 0.01). As shown in FIG3 , in the social preference test (SP), Tg-sal rats spent less time interacting with the "strange rat" than wt-sal (P ≤ 0.001). Tg-ANAVEX restored this deficit (P ≤ 0.0001). As shown in FIG4 , in the acquisition training phase of the Morris water maze (MWM), rats showed significant differences in learning in the last three days. Averaging the escape latency from day 3 to day 5, Tg-sal required more time to find the hidden platform than wt-sal (P ≤ 0.01). In contrast, Tg-ANAVEX performed significantly better than Tg-sal (P ≤ 0.05). Figure 5 shows that compared with Tg-sal, Tg-ANAVEX has significantly reduced McSA1 immunoreactive (IR) plaque intensity in CA1 (P≤0.01) and cortex (P≤0.05). This result confirms that A3-71 prevents McGill-APP rats from increasing extracellular Aβ deposition in the cortex and hippocampus. Figure 6 shows that compared with Tg-sal, the recruitment of Iba1-IR and GFAP-IR cells in Tg-ANAVEX near CA1 neurons is significantly less (both P≤0.05). This result proves that A3-71 reduces the recruitment of microglia and astrocytes to Aβ-loaded neurons in the hippocampus.

[0099] Example 4. Conclusion

[0100] In conclusion, the results demonstrate that ANAVEX3-71 has a lasting effect in preventing cognitive decline in McGill-R-Thy1-APP rats, even after a washout period. The results suggest that ANAVEX3-71 has both preventative and prophylactic disease-modifying properties against AD-like amyloid pathology. The results also provide insights into the beneficial effects of M1 muscarinic and sigma-1 receptor agonists on neurodegenerative diseases involving amyloid pathology.

Claims

1. A method of prophylactically treating a degenerative disease manifested by amyloid pathology in a subject, the method comprising administering to the subject a prophylactically effective amount of a sigma-1 receptor agonist.

2. The method of claim 1, wherein the sigma-1 receptor agonist is an allosteric sigma-1 receptor agonist.

3. The method of claim 1 or 2, wherein the sigma-1 receptor agonist is a dual agonist of the sigma-1 receptor and the muscarinic receptor.

4. The method according to any one of claims 1 to 3, wherein the sigma-1 receptor agonist is an allosteric agonist of the sigma-1 receptor and the muscarinic receptor.

5. The method of any one of claims 1 to 4, wherein the sigma-1 receptor agonist is an allosteric agonist of the sigma-1 receptor and the muscarinic M1 receptor.

6. The method according to any one of claims 1 to 5, wherein the sigma-1 receptor agonist comprises any one of ANAVEX2-73 (A2-73), ANAVEX19-144, ANAVEX1-41, AV1066, ANAVEX3-71 (A3-71), PRE-084, Donepezil, Fluvoxamine, Amitriptyline, L-687,384, SA-4503, Dextromethorphan, dimethyltryptamine, (+)-pentazocine, or a combination thereof, a crystalline form, an enantiomer, and a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1 to 6, wherein the sigma-1 receptor agonist comprises A3-71 amorphous form, A3-71 crystalline form, A3-71 enantiomer, A3-71 prodrug, or a combination thereof.

8. The method of any one of claims 1 to 7, wherein the amyloid pathology comprises amyloid formation, amyloid deposition, or amyloid plaque accumulation.

9. The method of any one of claims 1 to 8, wherein the degenerative disease comprises Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion disease, or any combination thereof.

10. The method of any one of claims 1 to 9, wherein the prophylactically effective amount is an amount for reducing or decreasing the likelihood or severity of the degenerative disease.

11. The method of any one of claims 1 to 9, wherein the prophylactically effective amount is an amount for significantly reducing the likelihood of the degenerative disease.

12. The method according to any one of claims 1 to 9, wherein the prophylactically effective amount is an amount for preventing the onset of the degenerative disease or arresting the progression of the degenerative disease.

13. The method according to any one of claims 1 to 12, wherein the prophylactically effective amount is an amount for preventing memory loss and / or cognitive decline caused by the degenerative disease.

14. The method according to any one of claims 1 to 13, wherein the prophylactically effective amount comprises from about 0.1 mg to about 500 mg, preferably from about 5 mg to about 60 mg.

15. The method of any one of claims 1 to 14, wherein the subject is a human subject or a non-human mammal.

16. A method of therapeutically or prophylactically treating a disease characterized by abnormal amyloid formation, amyloid plaques, plaque accumulation or amyloid deposition in a subject, the method comprising administering to the subject a therapeutically effective amount or a prophylactically effective amount of a sigma-1 receptor agonist.

17. The method of claim 16, wherein the sigma-1 receptor agonist is an allosteric sigma-1 receptor agonist.

18. The method of claims 16 to 17, wherein the sigma-1 receptor agonist is a dual agonist of the sigma-1 receptor and the muscarinic receptor.

19. The method of any one of claims 16 to 18, wherein the sigma-1 receptor agonist is an allosteric agonist of a sigma-1 receptor and a muscarinic receptor.

20. The method of any one of claims 16 to 19, wherein the sigma-1 receptor agonist is an allosteric agonist of the sigma-1 receptor and the muscarinic M1 receptor.

21. The method according to any one of claims 16 to 20, wherein the sigma-1 receptor agonist comprises any one of ANAVEX2-73 (A2-73), ANAVEX19-144, ANAVEX1-41, AV1066, ANAVEX3-71 (A3-71), PRE-084, donepezil, fluvoxamine, amitriptyline, L-687,384, SA-4503, dextromethorphan, dimethyltryptamine, (+)-pantazocine, or their crystalline forms, enantiomers, and pharmaceutically acceptable salts thereof.

22. The method of any one of claims 16 to 21, wherein the sigma-1 receptor agonist comprises A3-71 amorphous form, A3-71 crystalline form, A3-71 enantiomer, A3-71 prodrug, or a combination thereof.

23. The method of any one of claims 16 to 22, wherein the disease manifests as amyloid plaques or plaque accumulation.

24. The method of any one of claims 16 to 23, wherein the disease comprises Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, a prion disease, or any combination thereof.

25. The method of any one of claims 16 to 24, wherein the therapeutically effective amount is an amount used to reduce the likelihood or onset of the disease.

26. The method of any one of claims 16 to 24, wherein the prophylactically effective amount is an amount for reducing the likelihood or severity of the disease.

27. The method of any one of claims 16 to 24, wherein the prophylactically effective amount is an amount for preventing the onset of the disease or arresting the progression of the disease.

28. The method of any one of claims 16 to 27, wherein the prophylactically effective amount is an amount for preventing memory loss and / or cognitive decline.

29. The method according to any one of claims 16 to 28, wherein the therapeutically effective amount or the prophylactically effective amount comprises about 0.1 mg to about 500 mg, preferably about 5 mg to about 60 mg.

30. The method of any one of claims 16 to 29, wherein the subject is a human subject or a non-human mammal.

31. Use of a sigma-1 receptor agonist for the preparation of a medicament for use in a method according to any one of claims 1 to 30.

32. A pharmaceutical composition comprising an effective amount of a sigma-1 receptor agonist, wherein the effective amount therapeutically or prophylactically targets abnormal amyloid pathology.

33. The pharmaceutical composition of claim 32, wherein the abnormal amyloid pathology comprises amyloid formation, amyloid plaques, amyloid plaque accumulation, or amyloid deposition.

34. The pharmaceutical composition of claims 32 to 33, wherein the abnormal amyloid pathology manifests as a degenerative disease.

35. The pharmaceutical composition of claim 34, wherein the degenerative disease comprises Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, prion disease, or any combination thereof.

36. The pharmaceutical composition of any one of claims 32 to 35, wherein the sigma-1 receptor agonist comprises any one of ANAVEX2-73 (A2-73), ANAVEX19-144, ANAVEX1-41, AV1066, ANAVEX3-71 (A3-71), PRE-084, donepezil, fluvoxamine, amitriptyline, L-687,384, SA-4503, dextromethorphan, dimethyltryptamine, (+)-pantazocine, or their crystalline forms, enantiomers, and pharmaceutically acceptable salts thereof.

37. The pharmaceutical composition of any one of claims 32 to 36, wherein the sigma-1 receptor agonist comprises A3-71 amorphous form, A3-71 crystalline form, A3-71 enantiomer, A3-71 prodrug, or a combination thereof.

38. The pharmaceutical composition of any one of claims 32 to 37, wherein the effective amount is a therapeutic amount for reducing the likelihood or onset of the abnormal amyloid pathology.

39. The method of any one of claims 32 to 37, wherein the effective amount is a prophylactic amount for reducing the likelihood or severity of the abnormal amyloid pathology.

40. The method of any one of claims 32 to 37, wherein the effective amount is a prophylactic amount for preventing the onset of the abnormal amyloid pathology or arresting the progression of the abnormal amyloid pathology.

41. The method of any one of claims 32 to 37, wherein the effective amount is a prophylactic amount for preventing memory loss and / or cognitive decline caused by the abnormal amyloid pathology.

42. The pharmaceutical composition according to any one of claims 32 to 41, wherein the effective amount comprises from about 0.1 mg to about 500 mg, preferably from about 5 mg to about 60 mg, of the sigma-1 receptor agonist.

43. A pharmaceutical composition according to any one of claims 32 to 42, wherein the composition comprises about 5 mg to about 30 mg of A3-71.

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