Compositions and methods for preventing cognitive decline caused by degenerative diseases

Abstract

The present disclosure provides methods, compositions, and kits for prophylactically treating or preventing amyloid-associated degenerative diseases. The compositions and kits include a sigma-1 receptor agonist, an allosteric sigma agonist, and / or a dual sigma-1 and M1 agonist. The compositions and kits induce effects that delay the onset, inhibit the progression, and / or reduce the likelihood of degenerative diseases, such as inhibiting memory loss and / or cognitive decline in Alzheimer's disease.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 393,555, filed July 29, 2022, entitled "COMPOSITIONS AND METHODS FOR PREVENTION OF COGNITIVE DECLINE CAUSED BY DEGENERATIVE DISEASES," the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates generally to the prevention and treatment of diseases, such as degenerative diseases, that involve abnormal amyloid formation and / or deposition. [Background technology]

[0003] Neurodegenerative diseases significantly disrupt patients' daily lives due to memory loss and / or cognitive decline. It is important to develop preventive and prophylactic therapies to block the onset and / or arrest the progression of neurodegenerative diseases, with the goal of restoring memory and halting cognitive decline. Summary of the Invention

[0004] The present disclosure provides methods, compositions, and kits for therapeutically or prophylactically treating or preventing amyloid-associated degenerative diseases. The compositions and kits include therapeutic sigma-1 receptor agonists, allosteric sigma agonists, and / or dual sigma-1 and M1 agonists. The compositions and kits induce effects that delay the onset, inhibit the progression, and / or reduce the likelihood of degenerative diseases, such as inhibiting cognitive decline in Alzheimer's disease.

[0005] In one embodiment of the present disclosure, the therapeutic or prophylactic agent comprises ANAVEX 2-73 (A2-73), ANAVEX 19-144, ANAVEX 1-41, AV1066, ANAVEX 3-71, PRE-084, donepezil, fluvoxamine, amitriptyline, L-687,384, SA-4503, dextromethorphan, dimethyltryptamine, (+)-pentazocine, or any of their crystalline forms, enantiomers, and pharmaceutically acceptable salts. ANAVEX 2-73 (A2-73) has the chemical name tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride. ANAVEX 19-144 (A19-144) has the chemical name 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride. ANAVEX1-41 (A1-41) has the chemical name tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride. AV1066 has the chemical name 1-(3-4(((1R,3S,5S)-adamantan-1-yl)(phenyl)methyl)propyl)-4-methylpiperazine. ANAVEX3-71 (A3-71, AF-710B) has the chemical name 1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl)-3-(1H-indol-3-yl)propan-1-one.

[0006] In another aspect of the disclosure, the therapeutic or prophylactic agent comprises an A3-71 amorphous form, an A3-71 crystalline form, an A3-71 enantiomer, an A3-71 prodrug, or a combination thereof.

[0007] In another aspect of the disclosure, the degenerative disease can include 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.

[0008] In another aspect of the present disclosure, the effective amount used is for reducing or diminishing the likelihood or severity of a degenerative disease. In yet another aspect of the present invention, the prophylactically effective amount is an amount that prevents the onset or arrests the progression of a degenerative disease. The onset or progression may be manifested by memory loss and / or cognitive decline.

[0009] In yet another embodiment of the present disclosure, the therapeutically or prophylactically effective amount ranges from about 0.10 mg to about 500 mg, for example, from 5 mg to 30 mg. In another embodiment, the subject is a human subject or a non-human mammal.

[0010] One aspect of the present disclosure includes a composition for the aforementioned medical use. Another aspect of the present disclosure includes a kit comprising the composition for the aforementioned medical use and instructions.

[0011] In another aspect, the disclosure provides the 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 disclosed herein.

[0012] Color Shape Reference The application file will contain at least one photograph executed in color. A copy of this patent application publication with a color photograph will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0013] [Figure 1] 1 is an exemplary workflow for a rat study of ANAVEX® 3-71 on the onset, development, and / or progression of Alzheimer's disease. Data are expressed as mean ± SEM. *P≦0.05, **P≦0.01, ***P≦0.001, ****P≦0.0001. [Figure 2A] Novel object recognition (NOR) test and results are shown. Figure 2A shows rats exposed to the object. Figure 2B plots the percentage of rats in each group that were able to find the novel object: *P≦0.05, **P≦0.01. [Figure 2B] Novel object recognition (NOR) test and results are shown. Figure 2A shows rats exposed to the object. Figure 2B plots the percentage of rats in each group that were able to find the novel object: *P≦0.05, **P≦0.01. [Figure 3A] Figure 3 shows the social preference (SP) test. Figure 3A shows rats exposed to either a social or a non-social cue. Figure 3B plots the percentage of rats in each group that preferred to join the social group: ***P≦0.001, ****P≦0.0001. [Figure 3B] Figure 3 shows the social preference (SP) test. Figure 3A shows rats exposed to either a social or a non-social cue. Figure 3B plots the percentage of rats in each group that preferred to join the social group: ***P≦0.001, ****P≦0.0001. [Figure 4A] Figure 4 shows the acquisition phase of the Morris Water Maze (MWM). Figure 4A shows rats exposed to the MWM. Figure 4B plots the escape latency of each group against the number of training days. Figure 4C plots the mean escape latency from days 3 to 5. Tg-sal rats took longer to find the hidden platform than wt-sal rats (P ≤ 0.01). Conversely, Tg-ANAVEX rats were significantly better than Tg-sal rats (P ≤ 0.05). [Figure 4B] Figure 4 shows the acquisition phase of the Morris Water Maze (MWM). Figure 4A shows rats exposed to the MWM. Figure 4B plots the escape latency of each group against the number of training days. Figure 4C plots the mean escape latency from days 3 to 5. Tg-sal rats took longer to find the hidden platform than wt-sal rats (P ≤ 0.01). Conversely, Tg-ANAVEX rats were significantly better than Tg-sal rats (P ≤ 0.05). [Figure 4C]Figure 4 shows the acquisition phase of the Morris Water Maze (MWM). Figure 4A shows rats exposed to the MWM. Figure 4B plots the escape latency of each group against the number of training days. Figure 4C plots the mean escape latency from days 3 to 5. Tg-sal rats took longer to find the hidden platform than wt-sal rats (P ≤ 0.01). Conversely, Tg-ANAVEX rats were significantly better than Tg-sal rats (P ≤ 0.05). [Figure 5A] Figure 5 shows the effect of A3-71 administration on cortical and hippocampal extracellular Aβ deposition. Figure 5A shows plaque staining in the cortex and CA1. Figure 5B plots the plaque CA1 integrated density cortex in the treated group Tg-ANAVEX and the untreated group Tg-sal, **P≦0.01. Figure 5C plots the plaque cortical integrated density in the treated group Tg-ANAVEX and the untreated group Tg-sal, *P≦0.05. [Figure 5B] Figure 5 shows the effect of A3-71 administration on cortical and hippocampal extracellular Aβ deposition. Figure 5A shows plaque staining in the cortex and CA1. Figure 5B plots the plaque CA1 integrated density cortex in the treated group Tg-ANAVEX and the untreated group Tg-sal, **P≦0.01. Figure 5C plots the plaque cortical integrated density in the treated group Tg-ANAVEX and the untreated group Tg-sal, *P≦0.05. [Figure 5C] Figure 5 shows the effect of A3-71 administration on cortical and hippocampal extracellular Aβ deposition. Figure 5A shows plaque staining in the cortex and CA1. Figure 5B plots the plaque CA1 integrated density cortex in the treated group Tg-ANAVEX and the untreated group Tg-sal, **P≦0.01. Figure 5C plots the plaque cortical integrated density in the treated group Tg-ANAVEX and the untreated group Tg-sal, *P≦0.05. [Figure 6A] Figure 6 shows the effect of A3-71 administration on neurons in the hippocampus. Figure 6A shows immunostaining of different test groups. Figure 6B plots the number of Iba1-IR cells in proximity to NeuN, *P≦0.05. Figure 6C plots the number of GFAP-IR cells in proximity to NeuN, *P≦0.05. [Figure 6B]Figure 6 shows the effect of A3-71 administration on neurons in the hippocampus. Figure 6A shows immunostaining of different test groups. Figure 6B plots the number of Iba1-IR cells in proximity to NeuN, *P≦0.05. Figure 6C plots the number of GFAP-IR cells in proximity to NeuN, *P≦0.05. [Figure 6C] Figure 6 shows the effect of A3-71 administration on neurons in the hippocampus. Figure 6A shows immunostaining of different test groups. Figure 6B plots the number of Iba1-IR cells in proximity to NeuN, *P≦0.05. Figure 6C plots the number of GFAP-IR cells in proximity to NeuN, *P≦0.05. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present disclosure provides methods, compositions, and kits for prophylactically treating or preventing amyloid-associated degenerative diseases. Amyloids are protein aggregates characterized by a fibrillar morphology, typically 7-13 nm in diameter, a beta-sheet secondary structure (known as cross-beta), and the ability to stain with certain dyes such as Congo Red. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological function (misfold) and form fibrillar deposits within and around cells. This process of protein misfolding and deposition disrupts the healthy function of tissues and organs, a condition known as amyloidosis. Amyloid plaques are aggregates of misfolded proteins that form in the spaces between nerve cells. Amyloid plaque development and / or plaque accumulation in brain regions associated with memory and other cognitive functions can lead to degenerative diseases such as Alzheimer's disease. Degenerative diseases are characterized by a worsening condition due to deterioration of the function and structure of the affected body parts, thus causing disability, mortality, and morbidity. One type of degenerative disease is called neurodegenerative disease (degenerative nervous system disease) and affects 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.

[0015] The compositions and kits include 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, retard progression, and / or reduce the likelihood of degenerative diseases, such as preventing memory loss and / or cognitive decline in Alzheimer's disease. Sigma-1 receptors have been shown to be involved in higher brain functions, including memory and cognition. Therefore, sigma-1 receptor agonist therapy is often prescribed for patients with impaired memory or cognitive function, such as those with neurodegenerative disorders. It has been discovered that after a subject is treated with a sigma-1 receptor agonist, the subject's gene expression profile is altered, with a select set of genes differentially expressed and their associated gene clusters overrepresented. The altered gene profile can be used as a benchmark for evaluating the therapeutic efficacy of other therapeutic agents. It can also be used to select a sigma-1 receptor agonist for the subject. Furthermore, it can be used to determine whether a subject will be responsive to sigma-1 receptor agonist therapy. Finally, sigma-1 receptor agonists can be used to determine whether a subject has, is suspected of having, or is at increased risk of having a disease associated with an altered gene expression profile.

[0016] Degenerative diseases manifested by abnormal amyloid formation and / or deposition include Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. Neurodegenerative diseases are a subset of degenerative diseases, referring to hereditary and sporadic conditions characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of central or peripheral nervous system structures and may manifest as cognitive impairment, memory loss, and motor disorders. Alzheimer's disease is a degenerative brain disease characterized by the insidious onset of dementia. Early symptoms include declines in memory, judgment, attention span, and problem-solving ability. In later stages, severe apraxia and general loss of cognitive abilities may occur. The disease is pathologically characterized by severe cortical atrophy and a triad of senile plaques, neurofibrillary tangles, and interstitial threads. Parkinson's disease is a progressive degenerative neurological disease characterized by tremor maximal at rest, posturing (i.e., tendency to fall backward), rigidity, stooped posture, slowness of spontaneous movements, and a mask-like facial expression. Pathological features include loss of melanin-containing neurons in the substantia nigra and other pigmented brainstem nuclei. Lewy bodies are present in the substantia nigra and locus coeruleus, but can also be found in related conditions characterized by dementia combined with varying degrees of parkinsonism. Secondary Parkinson's disease refers to conditions characterized by clinical symptoms similar to primary Parkinson's disease caused by known or suspected conditions, such as vascular injury, drugs, trauma, toxin exposure, neoplasms, infections, and Parkinson's disease caused by degenerative or genetic conditions. Clinical features may include bradykinesia, rigidity, parkinsonian gait, and mask-like facies. Tremor is generally less pronounced in secondary parkinsonism than in primary parkinsonism. 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 third or fourth decade of life. Common early symptoms include paranoia, impulse control disorders, depression, hallucinations, and delusions. Late symptoms include intellectual disability, loss of fine motor control, athetosis, and diffuse chorea involving axial and limb muscle development, leading to a vegetative state within 10 to 15 years of disease onset.Its juvenile subtype has a more fulminant course, including seizures, ataxia, dementia, and chorea. Amyotrophic lateral sclerosis is a degenerative disorder affecting the upper motor neurons of the brain and the lower motor neurons of the brainstem and spinal cord. Disease onset usually occurs after the age of 50, and the process is usually fatal within 3 to 6 years. Clinical symptoms include progressive weakness, atrophy, fasciculations, hyperreflexia, dysarthria, dysphagia, and eventual paralysis of respiratory function. Pathological features include replacement of motor neurons with fibrous astrocytes and atrophy of the spinal nerve anterior roots and corticospinal tracts. Prion diseases are a group of genetic, infectious, or sporadic degenerative human and animal nervous system disorders associated with abnormal prions. These diseases are characterized by the conversion of normal prion protein to an abnormal configuration via post-translational processes. In humans, these conditions are generally characterized by dementia, ataxia, and fatal outcomes. Pathological features include bovine spongiform encephalopathy without evidence of inflammation. In some older literature, these may sometimes be referred to as uncommon slow-onset viral diseases.

[0017] One aspect of the present disclosure includes methods for 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 non-alcoholic fatty liver disease.

[0018] In one aspect of the present disclosure, if a neurodegenerative therapy is identified as ineffective for a subject, follow-up actions can be taken, such as switching to an alternative neurodegenerative therapy, supplementing with an alternative neurodegenerative therapy, adjusting the dose if the neurodegenerative therapy is a drug therapy, or switching to a concomitant neurodegenerative therapy.

[0019] In yet another embodiment of the present disclosure, the neurodegenerative therapy can be a sigma-1 receptor agonist therapy, or an NMDA therapy, or a cognitive enhancement physical therapy. For example, the neurodegenerative therapy can be a drug therapy including 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, (+)-pentazocine, or any of their crystalline forms, enantiomers, and pharmaceutically acceptable salts. ANAVEX2-73 (A2-73) has the chemical name tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride. ANAVEX 19-144 (A19-144) has the chemical name 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride. ANAVEX 1-41 (A1-41) has the chemical name tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride. AV1066 has the chemical name 1-(3-4(((1R,3S,5S)-adamantan-1-yl)(phenyl)methyl)propyl)-4-methylpiperazine. ANAVEX 3-71 (A3-71, AF-710B) has the chemical name 1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl)-3-(1H-indol-3-yl)propan-1-one. For example, the neurodegenerative therapy is an A2-73 medication that includes A2-73 free base, A2-73 amorphous form, A2-73 crystalline form I, A2-73 crystalline form II, A2-73 crystalline form III, the (-) A2-73 enantiomer, or the (+) A2-73 enantiomer.

[0020] In another aspect of the disclosure, the therapeutic agent comprises an A3-71 amorphous form, an A3-71 crystalline form, an A3-71 enantiomer, an A3-71 prodrug, or a combination thereof.

[0021] In another aspect of the present disclosure, the effective amount used is for reducing or diminishing the likelihood or severity of a degenerative disease. In yet another aspect of the present invention, the prophylactically effective amount is an amount that prevents the onset or arrests the progression of a degenerative disease. The onset or progression may be manifested by memory loss and / or cognitive decline.

[0022] In yet another embodiment of the present disclosure, the therapeutically or prophylactically effective amount ranges from about 0.10 mg to about 500 mg, for example, 5 mg to 30 mg, of A2-73. In another embodiment, the subject is a human subject or a non-human mammal.

[0023] One aspect of the present disclosure includes a composition for the aforementioned medical use. Another aspect of the present disclosure includes a kit comprising the composition for the aforementioned medical use and instructions.

[0024] I. Treatment Method As used herein, the term "treatment" refers to an action taken on a subject, which may be a human or animal subject, intended to ameliorate, prevent, delay, inhibit, reduce, alleviate, or cure the symptoms and / or effects associated with the recited disease state or condition. A "therapeutic treatment" is a treatment that at least partially prevents, delays, inhibits, reduces, alleviates, or cures the symptoms and / or effects associated with the recited disease state or condition.

[0025] The term "prophylactic," as used herein to refer to treatment, refers to an action taken on a subject to delay, alleviate, or avoid the onset of, or maintain health by reducing the likelihood or severity of, a symptom, episode, disease state, or condition prior to detection of the symptom or symptomatic condition. A "prophylactic effect" in the context of this specification should not be understood to encompass total or complete prevention of the symptom or symptomatic condition.

[0026] As used herein, the term "prophylactically effective amount" relates to an amount of a compound or composition disclosed herein that, when administered, is effective to produce the desired prophylactic effect.

[0027] As used herein, the term "therapeutically effective amount" refers to an amount of a compound or composition disclosed herein that, when administered, is effective to produce the desired therapeutic effect. A therapeutic effect includes a prophylactic effect. II. Pharmaceutical Compositions

[0028] One aspect of the present disclosure encompasses pharmaceutical compositions comprising a neurodegenerative agent and / or a sigma-1 receptor agonist, the pharmaceutical composition comprising a therapeutically or prophylactically effective amount of an active pharmaceutical ingredient, and any pharmaceutically acceptable salts thereof.

[0029] 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, methyl bromide, methanesulfonate, monohydrate, mucate, nitrate, oxalate, phenylpropionate, phosphate, phthalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tannate, tartrate, terephthalate, valerate, and the like.

[0030] When the active pharmaceutical ingredient is A2-73, the composition may contain about 1 mg to about 50 g, about 0.1 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. Patent No. 9,750,746, U.S. Patent Publication No. 2017 / 0360798, U.S. Patent Publication No. 2019 / 0022052, U.S. Patent Publication No. 2018 / 0360796, U.S. Patent Publication No. 2018 / 0169059, U.S. Patent Publication No. 2018 / 0177756, U.S. Patent Publication No. 2018 / 0169060, and U.S. Patent Publication No. 2019 / 0117615, the disclosures of which are incorporated herein in their entireties. When the active pharmaceutical ingredient is A3-71, the composition may contain about 1 mg to about 50 g, about 0.1 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 may be administered daily, twice daily, or three times daily. The duration of administration may be about 3 to 6 weeks, 6 to 11 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, or chronically. For example, A2-73 or A3-71 may be administered in an amount of about 40 mg to about 60 mg once daily for about 6 to 11 weeks, or about 50 mg daily for up to 11 weeks. A3-71 or A2-73 may also be administered daily in escalating doses starting from about 10 mg once daily and ending at about 50 mg.

[0031] 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 non-toxic 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).

[0032] 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. The one or more excipients can be selected for oral, transdermal, parenteral, intraperitoneal, intravascular, subcutaneous, inhalation spray, rectal, or pulmonary administration.

[0033] Active pharmaceutical ingredients can generally be formulated to improve patient compliance and prevent the subject from removing the drug delivery device. For example, sigma-1 receptor agonists can be formulated to improve patient compliance and prevent the subject from removing the drug delivery device by providing a formulation for extended delivery. The extended delivery can be for a period ranging from more than one day to several months. This can be particularly relevant for patients with impaired cognitive and / or motor control abilities. The extended delivery period can range from about one day to about one year, from about one day to about one week, from about three days to about one month, from about two weeks to about six months, or from about two months to about four months.

[0034] Extended-release formulations can be used for substantially continuous delivery of a drug at a preselected rate. For example, for A2-73 or A3-71, the drug 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 to about 60 gm / day, or about 10 to about 30 gm / day. The appropriate amount of crystalline A2-73 can be readily determined by one of skill in the art based on, for example, the intended duration of drug delivery by the extended-release formulation, the delivery mechanism, the particular formulation, and the relative potency of the drug, among other factors.

[0035] Binder Non-limiting examples of binders suitable for various formulation embodiments include starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamide, polyvinyloxoazolidone, polyvinyl alcohol, C12-C18 fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof. Polypeptides can be any sequence of amino acids ranging from about 100 to about 300,000 daltons.

[0036] The binder may be introduced into the mixture to be granulated in a solid form, including but not limited to, crystals, particles, powder, or any other finely divided solid form known in the art. Alternatively, the binder may be dissolved or suspended in a solvent and sprayed onto the mixture in the granulation device as a binder fluid during granulation.

[0037] Diluent Non-limiting examples of diluents (also referred to as "fillers" or "thinners") 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, polyhydric alcohols, starches, pre-fabricated direct compression diluents, and mixtures of any of the foregoing.

[0038] Disintegrant Disintegrants can be effervescent or non-effervescent.Non-limiting examples of non-effervescent disintegrants include starches 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, carob, karaya, pesitin, 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.

[0039] preservatives 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), butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), caffeic acid, canthaxanthin, alpha-carotene, beta-carotene, beta-carotene, beta-apocarotenoic acid, carnosol, Carvacrol, catechin, 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-phenylenediamine (DPPD), dilauryl thiodipropionate, distearyl thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate, edetic acid, ellagic acid, erythorbic acid, sodium erythorbate, 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., catechin, epicatechin, epicatechin gallate, epigallocatechin (EGC), epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate), flavones (e.g., apigenin, chrysin, luteolin), flavonols (e.g., dacisin, myricetin, denferro), flavanones, fraxetin, fumaric acid, gallic acid, gentian extract, gluconic acid, glycine, gum yu bok choy (gum guaiacum), hesperetin, alpha-hydroxybenzylphosphinic acid, hydroxycinnamic acid, hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid, hydroxytrilosol, hydroxyurea, rice bran extract, lactic acid and its salts, lecithin, lecithin citrate, R-alpha-lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxytryptamine, methyl gallate, monoglyceride citrate, monoisopropyl citrate, morin, beta-naphthoflavone, nordihydroguaretic acid (NDGA), octyl gallate, oxalic acid, palmityl citrate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphate salts, phytic acid, phytyl bichromenol, pimento extract, gall Propyl acetate, polyphosphate, quercetin, trans-resveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid, succinic acid, stearyl citrate, syringic acid, tartaric acid, thymol, tocopherols (i.e., alpha-, beta-, gamma-, and delta-tocopherol), tocotrienols (i.e., alpha-, beta-, gamma-, and delta-tocotrienol), tyrosol, vanillic acid, 2,6-di-tert-butyl-4-hydroxymethylphenol (i.e., Ionox 100), 2,4-(tris-3',5'-bi-tert-butyl-4'-hydroxybenzyl)-mesitylene (i.e., Ionox 330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tertiary butylhydroquinone (TBHQ), thiodipropionic acid, trihydroxybutyrophenone, tryptamine, tyramine, uric acid, vitamin K and derivatives, vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof.

[0040] Flavor modifiers Suitable flavor modifiers include flavors, flavorings, sweeteners, etc. Flavorings include, but are not limited to, synthetic flavor oils, flavoring aromatics, and / or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof. Other non-limiting examples of flavors include cinnamon oil, oil of wintergreen, peppermint oil, clover oil, hay oil, anise oil, eucalyptus, vanilla, lemon oil, orange oil, citrus oils such as grape and grapefruit oil, fruit essential oils including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0041] Flavoring agents include, but are not limited to, cellulose hydroxypropyl ethers (HPC), low-substituted hydroxypropyl ethers (L-HPC), such as Klucel®, Nisswo HPC, and PrimaFlo HP22; 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®; ethylcellulose (EC), such as E461, Ethocel®, Aqualon®-EC, and Surelease, and mixtures thereof; polyvinyl alcohol (PVA), such as Opadry AMB; hydroxyethylcellulose, such as Natrosol®; carboxymethylcellulose and salts of carboxymethylcellulose (CMC), such as Aualon®-CMC; Polyvinyl alcohol and polyethyl glycol copolymers such as IR®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® RD100, and Eudragit® E100, Sepifilm such as a mixture of cellulose acetate phthalate, HPMC, and stearic acid, cyclodextrin, and mixtures of these materials. In other embodiments, additional flavor masking agents contemplated are those described in U.S. Patent Nos. 4,851,226, 5,075,114, and 5,876,759, each of which is incorporated herein by reference in its entirety.

[0042] 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 sodium ene, dipeptide sweeteners such as aspartame, dihydrochalcone compounds, glycyrrhizin, Stevia rebaudiana (stevioside), chloro 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), as well as the sodium and calcium salts thereof.

[0043] Lubricants and Glidants Lubricant compositions can be utilized to lubricate the components forming the pharmaceutical composition. As glidants, lubricants facilitate the 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 oil, Sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. Pharmaceutical compositions will generally contain from about 0.01% to about 10% by weight of a lubricant. In some embodiments, pharmaceutical compositions will contain from about 0.1% to about 5% by weight of a lubricant. In further embodiments, pharmaceutical compositions will contain from about 0.5% to about 2% by weight of a lubricant.

[0044] Dispersants Dispersing agents may include, but are not limited to, starch, alginic acid, polyvinylpyrrolidone, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isomorphous silicates, and microcrystalline cellulose as a high hydrophilic lipophilic balance (HLB) emulsifier surfactant.

[0045] coloring agent Depending on the embodiment of the present disclosure, it may be desirable to include a coloring agent. 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 embodiments of the present disclosure.

[0046] 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.

[0047] chelating agents Chelating agents may be included as excipients to immobilize oxidative groups, including but not limited to metal ions, to inhibit oxidative degradation of the morphinan by these oxidative groups. Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamate, aspartate, and disodium ethylenediaminetetraacetic acid (NaEDTA).

[0048] antibacterial agents 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.

[0049] Controlled Release Polymers The release-controlling polymer may be included in various embodiments of solid dosage pharmaceutical compositions incorporating compounds according to the present disclosure. In one embodiment, the release-controlling polymer may be used as a tablet coating. In other embodiments, including but not limited to bilayer tablets, the release-controlling polymer may be mixed with granules and other excipients before forming tablets by known processes, including but not limited to, compression in a tablet die. Suitable release-controlling polymers include, but are not limited to, hydrophilic polymers and hydrophobic polymers.

[0050] Suitable hydrophilic controlled-release polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ether, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose, nitrocellulose, cross-linked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonium alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, sodium carmellose alginate, calcium carmellose, carrageenan, fucoidan, furcellaran, gum arabic, carrageen gum, gum ghatti, guar gum, karaya gum, and locust bean gum. , okra gum, tragacanth gum, scleroglucan gum, xanthan gum, hypnea, laminaran, acrylic polymers, acrylate polymers, carboxyvinyl polymers, copolymers of maleic anhydride and styrene, copolymers of maleic anhydride and ethylene, copolymers of propylene maleic anhydride or copolymers of isobutylene maleic anhydride), crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, diesters of polyglucans, polyacrylamide, polyacrylic acid, polyamides, polyethylene glycol, polyethylene oxide, poly(hydroxyalkyl methacrylates), polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polystyrene, polyvinylpyrrolidone, anionic and cationic hydrogels, and combinations thereof.

[0051] coating A solid dosage containing a compound according to the present disclosure may include a coating, which may control the release of the compound, function as a moisture barrier or buffer, or modify the pH. As used herein, a "control-releasing coating" or "controlled-release coating" is defined to mean a functional coating that may include, for example, at least one pH-independent polymer, pH-dependent polymer (e.g., an enteric or reverse enteric polymer), soluble polymer, insoluble polymer, lipid, lipid material, or a combination thereof. When applied to a dosage form, the coating may be slow (e.g., when applied to a normal-release matrix dosage form), even slower (e.g., when applied to a controlled-release matrix dosage form), or, when applied to an uncoated dosage form, modify the release rate of a compound according to the present disclosure. For example, a controlled-release coating may be designed such that, when applied to a dosage form, the dosage form in combination with the controlled-release coating may exhibit a release of a compound according to the present disclosure that is "modified release," "controlled release," "sustained release," "extended release," "delayed release," "extended release," or a combination thereof. A "controlled release coating" may optionally include additional materials that may alter the function of the controlled release coating.

[0052] As used herein, the term "moisture barrier" refers to a barrier that inhibits or delays the absorption of moisture. Compounds according to the present disclosure may be hygroscopic and therefore susceptible to degradation over time under high humidity conditions. The proportions of the moisture barrier components and the amount of moisture barrier optionally applied on the controlled-release coating or on the core are typically such that the moisture barrier does not fall within the USP definition and requirements of an enteric coating. Preferably, the moisture barrier comprises an enteric and / or acrylic polymer, preferably an acrylic polymer, optionally a plasticizer, and a permeation enhancer. The permeation enhancer is a hydrophilic substance that allows water to enter without physically disrupting the coating. The moisture barrier may additionally comprise other conventional inert excipients, which may improve the processing of the extended-release formulation.

[0053] Coating and matrix materials that can be used in accordance with the present invention are those known in the art for use in controlled release formulations, such as synthetic polymers of the polyvinyl type, for example, polyvinyl chloride, polyvinyl acetate and its copolymers, polyvinyl alcohol, and polyvinylpyrrolidone; synthetic polymers of the polyethylene type, for example, polyethylene and polystyrene; acrylic acid polymers; biopolymers or modified biopolymers, for example, cellulose polymers, shellac, and gelatin; fats, oils, higher fatty acids, and higher alcohols (i.e., acids and alcohols containing alkyl chains of at least 10 carbon atoms), for example, aluminum monostearate, cetyl alcohol, hydrogenated beef tallow, hydrogenated castor oil, 12-hydroxystearyl alcohol, glyceryl mono- or dipalmitate; glyceryl mono-, di-, or tristearate; myristyl alcohol, stearic acid, stearyl alcohol, and polyethylene glycol; waxes; sugars and sugar alcohols.

[0054] The pH buffering properties of the coating may be enhanced by incorporating into the coating a material selected from the 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 phosphorus, carbon, citric acid, or other suitable weak, inorganic, or organic acids; or suitable organic bases, including basic amino acids; and salts or combinations thereof.

[0055] A pH-dependent coating functions to release a drug in a desired region of the gastrointestinal (GI) tract, e.g., the stomach or small intestine. If a pH-independent coating is desired, the coating is designed to achieve optimal release regardless of pH changes in the environmental 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 often referred to as an "enteric coating." The pH-dependent coating may include, but is not limited to, acrylic acid polymers and copolymers, such as polymers formed from acrylic acid, methacrylic acid, methyl acrylate, methyl acrylate, ammoniomethyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate (e.g., Eudragit®), cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, and hydroxypropyl methyl cellulose succinate and sodium carboxymethylcellulose, vinyl polymers and copolymers such as shellac (purified lac), polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate (PVAP), vinyl acetate chlorphosphate copolymer, and ethylene vinyl acetate copolymer, zein, and salts and combinations thereof. Oral tablets and capsules typically have a coating.

[0056] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which this invention belongs. The following references provide those skilled in the art with general definitions of many of the terms used in this invention: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them unless otherwise specified.

[0057] When introducing elements of the disclosure or preferred aspect(s) 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.

[0058] Since various changes can be made in the cells and methods described above without departing from the scope of the present invention, it is intended that all matter contained in the above description and in the examples given below should be interpreted in an illustrative and not a limiting sense.

[0059] The term "comprising" means "including, but not necessarily limited to," and specifically indicates open-ended inclusion or membership in such listed combinations, groups, series, etc. As used herein, the terms "comprising" and "including" are inclusive and / or open-ended and do not exclude additional, unrecited elements or method steps. 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 specified materials or steps, and to materials or steps that do not materially affect the essential characteristics of the claimed invention.

[0060] As used herein, the term "gene" refers to 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. As used herein, "expression" includes, but is not limited to, one or more of the following: transcription of a gene into precursor mRNA; splicing and other processing of the precursor mRNA to produce a 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 necessary for proper expression and function. As used herein, the term "differentially expressed gene" means that the expression levels of a gene in two experimental conditions or two samples have a statistically significant difference or change. As used herein, the term "overrepresented" gene or gene cluster means that a gene from a predefined set is more abundant than expected.

[0061] As used herein, the term "transcriptome analysis" refers to characterizing transcriptional activity (coding and non-coding), focusing on a subset of relevant target genes and transcripts, or profiling thousands of genes at once to create a genetic profile. As used herein, the term "mutant" refers to any inherited variation from wild-type that is the result of mutations, such as single nucleotide polymorphisms ("SNPs") and insertions / deletions. The term "mutant" is used interchangeably with the terms "marker," "biomarker," and "target" throughout this specification.

[0062] As used herein, the term "polynucleotide" refers to 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 a mixture of single- and double-stranded regions, and hybrid molecules containing DNA and RNA, which may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, polynucleotide refers to triple-stranded regions containing 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 backbones modified for stability or for other reasons.

[0063] As used herein, the term "polypeptide" refers to 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 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 that are 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 more detailed monographs, as well as in voluminous research literature.

[0064] As used herein, the terms "disease," "disorder," or "dysfunction" are used interchangeably in this disclosure. They refer to any condition, disorder, or illness that manifests as one or more physiological, physical, and / or psychological symptoms or malfunctions for which treatment is desirable, and include previously and newly identified diseases, disorders, or malfunctions in any organ, tissue, or biological activity. As used herein, the term "medical use" is any use or procedure related to restoring, treating, or maintaining the health or well-being of a subject.

[0065] As used herein, the term "subject" means that the subject is preferably a mammal such as a human, but can also be an animal, for example, a domestic animal (e.g., a dog, a cat, etc.), a farm animal (e.g., a cow, a sheep, a pig, a horse, etc.), and a laboratory animal (e.g., a cynomolgus monkey, a rat, a mouse, a guinea pig, etc.).

[0066] As used herein, administration of an agent or drug to a subject or patient includes self-administration and administration by another. It should also be understood that the various modes of treatment or prevention of medical conditions as described are intended to mean "substantial," which includes complete treatment or prevention, but also includes less than complete treatment or prevention, and in which some biologically or medically relevant result is achieved.

[0067] The publications discussed above are provided solely for their disclosure prior to the filing date of the present application, and nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. [Example]

[0068] The following examples are included to demonstrate the present disclosure. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques discovered by the inventors to work well in the practice of the present disclosure. However, those skilled in the art should, in light of the present disclosure, understand that many changes can be made in the present disclosure and still obtain the same or similar results without departing from the spirit and scope of the present disclosure, and therefore all matter set forth is to be construed as illustrative and not in a limiting sense.

[0069] Example 1. Background and Objectives 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 six drugs for treating Alzheimer's disease (AD), and their limited effectiveness is likely due to the progressive loss of cholinergic neurons. ANAVEX3-71 exploits the fact that acetylcholine postsynaptic M1 muscarinic brain receptor levels remain unchanged in AD. ANAVEX3-71 treatment attenuated AD characteristics in McGill-R-Thy1-APP transgenic rats when administered at an advanced stage of AD-like pathology. However, AD therapy in humans is more likely to be successful if applied early in the disease, before extensive brain damage occurs. It is desirable to test whether administering ANAVEX3-71 during the early amyloid pathology stage can prevent cognitive impairment, plaque deposition, plaque accumulation, and / or neuroinflammation.

[0070] Example 2. Study design for the preventive effect of ANAVEX3-71 on Alzheimer's disease A rat model study was designed to evaluate the preventive and therapeutic effects of ANAVEX3-71 on the onset, development, and / or progression of degenerative diseases, such as Alzheimer's disease. ANAVEX3-71 (10 μg / kg) or saline (sal) was orally administered daily for 7 months to four groups of pre-plaque McGill-R-Thy1-APP (Tg, n=22) and wild-type (Wt, n=22) rats. One month after drug discontinuation, behavioral tests were performed: novel object recognition (NOR), Morris water maze (MWM), and social preference (SP). Brains were extracted, fixed, and analyzed by histochemistry and immunohistochemistry (see Figure 1). Statistical analysis was performed on the four groups by 2 × 2 ANOVA followed by Tukey's multiple comparison test. For two-group analyses, a Mann-Whitney test (data normality violation) was used. Data are presented as mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ P ≤ 0.0001.

[0071] Example 3. Results As shown in Figure 2, in the novel object recognition test (NOR), Tg-sal (saline-treated) rats explored the novel object significantly less than wt-sal (P ≤ 0.01, wild-type). This deficit was rescued by the A3-71-treated group (Tg-ANAVEX, P ≤ 0.01). As shown in Figure 3, Tg-sal rats spent less time interacting with the "stranger rat" than wt-sal (P ≤ 0.001) rats in the social preference test (SP). This deficit was reversed by Tg-ANAVEX (P ≤ 0.0001). As shown in Figure 4, in the acquisition phase of the Morris water maze (MWM), rats showed significant differences in learning over the last 3 days. Mean escape latencies from days 3 to 5 indicated that Tg-sal rats took longer to find the hidden platform than wt-sal rats (P ≤ 0.01). Conversely, Tg-ANAVEX mice were significantly better than Tg-sal mice (P ≤ 0.05). Figure 5 shows that McSA1-immunoreactive (IR) plaque intensity in Tg-ANAVEX mice was significantly lower in the CA1 (P ≤ 0.01) and cortex (P ≤ 0.05) compared with Tg-sal mice. This result confirmed that A3-71 prevented McGill-APP rats from increasing extracellular Aβ deposition in the cortex and hippocampus. Figure 6 shows that Iba1-IR and GFAP-IR cells in Tg-ANAVEX mice were significantly less recruited in proximity to CA1 neurons than in Tg-sal mice (P ≤ 0.05 for both). This result indicated that A3-71 reduced the recruitment of microglia and astrocytes toward Aβ-laden neurons in the hippocampus.

[0072] Example 4. Conclusion In summary, the results demonstrated the long-term efficacy of ANAVEX 3-71 in preventing cognitive decline in McGill-R-Thy1-APP rats, even after a washout period. The results suggest preventative and prophylactic disease-modifying properties of ANAVEX 3-71 against AD-like amyloid pathology. The results also provide insight into the beneficial effects of M1 muscarinic and sigma-1 receptor agonists on neurodegenerative diseases, including amyloid pathology.

Claims

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

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

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

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

6. 6. The method of any one of claims 1 to 5, wherein the sigma-1 receptor agonist comprises any 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 combinations, crystalline forms, enantiomers, and pharmaceutically acceptable salts thereof.

7. The method of any one of claims 1 to 6, wherein the sigma-1 receptor agonist comprises an A3-71 amorphous form, an A3-71 crystalline form, an A3-71 enantiomer, an 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. 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. 10. The method of any one of claims 1 to 9, wherein the prophylactically effective amount is an amount that reduces or decreases the likelihood or severity of the degenerative disease.

11. 10. The method of any one of claims 1 to 9, wherein the prophylactically effective amount is an amount that substantially reduces the likelihood of the degenerative disease.

12. The method of any one of claims 1 to 9, wherein the prophylactically effective amount is an amount that prevents the onset of or inhibits the progression of the degenerative disease.

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

14. The method of 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 for the therapeutic or prophylactic treatment of a disease characterized by abnormal amyloid formation, amyloid plaques, plaque accumulation, or amyloid deposits in a subject, comprising administering to the subject a therapeutically or prophylactically effective amount of a sigma-1 receptor agonist.

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

18. The method according to claim 16 or 17, wherein the sigma-1 receptor agonist is a dual agonist for the sigma-1 receptor and the muscarinic receptor.

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

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

21. 21. The method of any one of claims 16 to 20, wherein the sigma-1 receptor agonist comprises any 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 crystalline form, enantiomer, or pharmaceutically acceptable salt thereof.

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

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

24. 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, 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 that reduces the likelihood or occurrence of the disease.

26. The method of any one of claims 16 to 24, wherein the prophylactically effective amount is an amount that reduces 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 that prevents the onset of or arrests the progression of the disease.

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

29. The method of any one of claims 16 to 28, wherein the therapeutically or prophylactically effective amount comprises from about 0.1 mg to about 500 mg, preferably from 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 in the manufacture 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, said effective amount being therapeutic or prophylactic against abnormal amyloid pathology.

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

34. 34. The pharmaceutical composition of claim 32 or claim 33, wherein the abnormal amyloid pathology is manifested as a degenerative disease.

35. 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. 36. The pharmaceutical composition of any one of claims 32 to 35, wherein the sigma-1 receptor agonist comprises any 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 crystalline form, enantiomer, or pharmaceutically acceptable salt thereof.

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

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

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

40. 38. The method of any one of claims 32 to 37, wherein the effective amount is a prophylactic amount that prevents the onset or arrests 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 that prevents memory loss and / or cognitive decline caused by the abnormal amyloid pathology.

42. 42. The pharmaceutical composition of 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. 43. The pharmaceutical composition of 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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