Method and drug for preventing or treating neurodegenerative disease

Abstract

Disclosed in the present application are a method and drug for preventing or treating a neurodegenerative disease, whereby a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof or a combination of gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof is used or comprised. The method and drug of the present invention can significantly alleviate symptoms such as hyposmia, cognitive dysfunction, and psychiatric symptoms in patients with neurodegenerative diseases that cannot be treated with existing drugs, and can be particularly used for controlling the progression of neurodegenerative diseases.

Description

A method and drug for the prevention or treatment of neurodegenerative diseases Technical Field

[0001] This invention relates to novel uses of pharmaceuticals, specifically to methods and pharmaceuticals for the prevention or treatment of neurodegenerative diseases, particularly those related to protein aggregation, such as Parkinson's disease, multiple system atrophy, and Lewy body dementia. Background Technology

[0002] Neurodegenerative diseases (NDDs), also known as neurodegenerative disorders, are a group of diseases characterized by the gradual atrophy and loss of specific neurons in the nervous system, leading to chronic, progressive structural lesions and functional impairments. It is known in this field that the aggregation of brain proteins such as α-synuclein (α-Syn), Tau protein, Aβ amyloid, and TAR DNA-binding protein (TDP-43) plays an important role in the pathogenesis of neurodegenerative diseases. These neurodegenerative diseases associated with protein aggregation include Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia (DLB). Because the etiology of neurodegenerative diseases is not fully understood, there is currently no treatment that can prevent the occurrence and progression of these diseases. Symptomatic treatment is the only treatment option for these diseases; dopamine replacement therapy (DRT) is a typical example in the treatment of Parkinson's disease. While symptomatic treatment may temporarily improve symptoms, it cannot reverse the gradual degeneration and functional decline of nerves. This uncontrolled progression of the disease places a tremendous psychological and physical burden on patients and their families. Therefore, there is an urgent need for therapeutic drugs that can effectively control the progression of neurodegenerative diseases.

[0003] According to literature reports, the mRNA expression level of SUR1 (sulfonylurea receptor 1) in the substantia nigra of the brain of deceased Parkinson's disease patients was significantly increased compared with that of normal individuals (Schiemann J, Schlaudraff F, Klose V, Bingmer M, Seino S, Magill PJ, Zaghhloul KA, Schneider G, Liss B, Roeper JK-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration. Nat Neurosci. 2012 Sep; 15(9):1272-80. PMID:22902720). Similarly, reports have also found increased SUR1 expression levels in the substantia nigra of the brains of Parkinson's disease model mice, and knocking down SUR1 in Parkinson's models can improve abnormal neuronal discharges (Liu M, Liu C, Xiao X, Han SS, Bi MX, Jiao Q, Chen X, Yan CL, Du XX, Jiang H. Role of upregulation of the KATP channel subunit SUR1 in dopaminergic neuron degeneration in Parkinson's disease. Aging Cell. 2022 May; 21(5):e13618. PMID:35441806.). However, this paper also reported that administering SUR1 blockers did not improve abnormal neuronal discharges in Parkinson's disease models, providing only negative experimental evidence regarding the potential of using SUR1 blockers to treat Parkinson's disease.

[0004] Gliclazide is a sulfonylurea drug approved in several countries for the treatment of type 2 diabetes. To date, no reports have been found linking gliclazide to neurodegenerative diseases. Acetaminophen (paracetamol) is a widely used antipyretic, analgesic, and anti-inflammatory drug in clinical practice. Regarding its association with Parkinson's disease, there are reports that prophylactic continuous administration of acetaminophen to Parkinson's disease model mice can prevent motor dysfunction and dopamine neuron death (Labib AY, Ammar RM, El-Naga RN, El-Bahy AAZ, Tadros MG, Michel HE. Mechanistic insights into the protective effect of paracetamol against rotenone-induced Parkinson's disease in rats: Possible role of endocannabinoid system modulation. Int Immunopharmacol. 2021 May; 94:107431. PMID:33578261). However, to date, there have been no reports of acetaminophen being used in combination with gliclazide for the prevention or treatment of neurodegenerative diseases.

[0005] Therefore, there remains an unmet medical need for methods and drugs that can safely and effectively prevent or treat neurodegenerative diseases, especially those related to protein aggregation.

[0006] Invention Overview

[0007] To provide a method and medicine that can safely and effectively prevent or treat neurodegenerative diseases (especially those related to protein aggregation), the inventors of this application have conducted extensive and repeated research. The research results showed that gliclazide, used alone or in combination with acetaminophen, can improve symptoms of neurodegenerative diseases that cannot be improved by existing drugs (such as decreased sense of smell and cognitive impairment), and can control disease progression. Based on the above findings, the inventors completed this invention.

[0008] The present invention can be described from different aspects. The invention described in any aspect of the present invention and any embodiment thereof is independent of each other but related to each other and together constitutes the content of the present invention.

[0009] One aspect of the present invention provides a method for preventing or treating a patient’s neurodegenerative disease (particularly a neurodegenerative disease related to protein aggregation), the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof.

[0010] Another aspect of the present invention provides a method for preventing or treating a patient’s neurodegenerative disease (particularly a neurodegenerative disease related to protein aggregation), the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof.

[0011] Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases in patients (especially neurodegenerative diseases related to protein aggregation), the pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0012] Another aspect of the invention provides a pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof, acetaminophen or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0013] Another aspect of the invention provides a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases in patients, particularly neurodegenerative diseases related to protein aggregation, the pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof, acetaminophen or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0014] Another aspect of the present invention provides a combination pharmaceutical product comprising (1) a first pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a second pharmaceutical composition comprising acetaminophen or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) an insert or label indicating the use of the first pharmaceutical composition and the second pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, particularly neurodegenerative diseases related to protein aggregation.

[0015] The first and second pharmaceutical compositions contained in the combination drug products of the present invention can be administered to patients in need in chronological order at the same or different time intervals.

[0016] Another aspect of the invention provides the use of gliclazide or a pharmaceutically acceptable salt thereof in the preparation of pharmaceutical products for the prevention or treatment of neurodegenerative diseases in patients, particularly those related to protein aggregation. The pharmaceutical products referred to herein may be pharmaceutical compositions according to the invention or combination pharmaceutical products according to the invention.

[0017] Another aspect of the invention provides the use of gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical product for the prevention or treatment of neurodegenerative diseases in patients, particularly neurodegenerative diseases related to protein aggregation. The pharmaceutical product referred to herein can be a pharmaceutical composition according to the invention or a combination pharmaceutical product according to the invention. Therefore, gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof can be formulated together in a single formulation for simultaneous administration to patients in need, or they can be formulated separately in individual formulations for sequential administration to patients in need.

[0018] Another aspect of the invention provides a pharmaceutical combination for the prevention or treatment of neurodegenerative diseases in patients (particularly neurodegenerative diseases related to protein aggregation), comprising gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof, wherein gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof may be formulated together in a single formulation for simultaneous administration to patients in need, or each may be formulated in a separate formulation for sequential administration to patients in need.

[0019] The methods, pharmaceutical compositions, combination pharmaceutical products, or combinations of drugs of the present invention can be used to prevent or treat neurodegenerative diseases, particularly those related to protein aggregation. For example, they can improve symptoms such as decreased sense of smell, cognitive impairment, and psychotic symptoms in patients with neurodegenerative diseases that are untreatable by existing drugs, and can prevent or delay the onset of psychotic symptoms or improve existing psychotic symptoms. In particular, the methods, pharmaceutical compositions, combination pharmaceutical products, or combinations of drugs of the present invention can be used to control the progression of neurodegenerative diseases, especially those related to protein aggregation. Attached Figure Description

[0020] The accompanying drawings provided in this application are intended to illustrate the invention. The drawings should not be construed as limiting the invention in any way.

[0021] Figure 1 shows the efficacy evaluation of this invention in treating olfactory hypoolemia in an MPTP mouse model. Two-way ANOVA was used to express *P<0.05, ***P<0.001, ****P<0.0001, followed by... Multiple comparison tests.

[0022] Figure 2 shows the efficacy evaluation of this invention in treating decreased grip strength in an MPTP mouse model. Two-way ANOVA was used to express *P<0.05, **P<0.01, followed by... Multiple comparison tests.

[0023] Figure 3 shows the efficacy evaluation of the present invention in treating dopamine neuron degeneration in an MPTP mouse model. The comparison mediator group was validated using Kruskal-Wallis, with *P<0.05 and **P<0.01, followed by Conover's multiple comparison test.

[0024] Figure 4 shows the efficacy results of gliclazide compared with drugs such as glibenclamide in an MPTP-induced mouse model. Figures a and b show that gliclazide significantly improved motor dysfunction in Parkinson's disease compared with glibenclamide, exenatide, and levodopa; and Figure 4c shows that the area of ​​tyrosine hydroxylase-positive neurons was significantly reduced in the MPTP model mediator group compared with the sham model mediator group.

[0025] Figure 5 shows the efficacy evaluation results of the present invention in the AAV-hSyn-SNCA+PFF mouse model.

[0026] Invention Details

[0027] Based on the above overview of the present invention, the following describes the implementation schemes and methods of the present invention in more detail.

[0028] To facilitate understanding of this invention, certain terms used herein are specifically defined. For terms used in this invention that are not specifically defined herein, their meanings are as understood by those skilled in the art in conjunction with the disclosure herein in a manner conducive to achieving the objectives of this invention; that is, they have the meanings commonly understood by those skilled in the art and beneficial to achieving the objectives of this invention. If the meaning of a term specifically defined in this specification differs from the meaning commonly understood by those skilled in the art, the meaning specifically defined in this specification shall prevail.

[0029] As used in this invention, the term "neurodegenerative disease" refers to any disease in which certain neurons in the nervous system gradually atrophy and are lost, leading to chronic progressive lesions and functional impairments in the corresponding structures, particularly neurodegenerative diseases related to protein aggregation. In some embodiments, "protein aggregation" refers to the aggregation or deposition in the brain of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43). In a preferred embodiment, the neurodegenerative disease related to protein aggregation is selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia. In a more preferred embodiment, the neurodegenerative disease related to protein aggregation is Parkinson's disease.

[0030] The term "prevention or treatment of neurodegenerative diseases" as used in this invention refers to preventing or delaying the occurrence of one or more of the symptoms of said neurodegenerative diseases, such as motor symptoms, depressive symptoms, hyposmia, and cognitive impairment; or improving the symptoms of said neurodegenerative diseases, such as motor symptoms, depressive symptoms, hyposmia, and cognitive impairment, wherein the improvement may be a reduction in the severity of said symptoms or a shortening of their duration.

[0031] Unless the context otherwise requires, the term “patient” as used herein refers to a human being suffering from the aforementioned neurodegenerative disease, including children, adults, and the elderly as commonly understood.

[0032] Unless the context otherwise requires, the phrase "therapeuticly effective amount" as used herein refers to the amount of gliclazide or a pharmaceutically acceptable salt thereof, or a combination of gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof, that achieves the "preventive or therapeutic" effect. This effect may be the prevention or delay of the onset of one or more symptoms of the neurodegenerative disease, such as motor symptoms, depressive symptoms, hyposmia, and cognitive impairment; or it may be an improvement in one or more symptoms of the neurodegenerative disease, such as motor symptoms, depressive symptoms, hyposmia, and cognitive impairment, which may be a reduction in the severity of the symptoms or a shortening of their duration.

[0033] The pharmaceutically active ingredient "gliclazide" used in this invention refers to a compound having the following chemical structural formula:

[0034] Its chemical name is 1-(3-azabicyclo[3.3.0]octyl)-3-p-toluenesulfonylurea. Methods for synthesizing or preparing gliclazide are known to those skilled in the art.

[0035] Pharmaceutically acceptable salts of gliclazide that can be used in this invention include any salt thereof that can be used to prepare a human medicine and will not produce unacceptable toxicity or adverse reactions when administered to a patient in need. Metabolites and prodrugs of gliclazide having the same pharmacological activity can also be used in this invention. Gliclazide as referred to in this invention includes solvates, such as hydrates, of gliclazide or its pharmaceutically acceptable salts. Where necessary, those skilled in the art can synthesize solvates and hydrates of gliclazide using methods and materials known in the art.

[0036] Furthermore, the gliclazide mentioned in this invention also includes isotopically labeled gliclazide. Isotopically labeled gliclazide means that, except that one or more atoms are replaced by atoms having atomic weights or mass numbers different from those normally found in nature, the isotopically labeled gliclazide has the same chemical structure as the gliclazide shown above. Examples of applicable isotopes include isotopes of hydrogen, carbon, oxygen, and nitrogen, including but not limited to... 2 H, 13 C 17 O、 18 O and 15 N. When necessary, those skilled in the art can prepare isotopically labeled gliclazide by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents using methods known in the art.

[0037] The phrase "pharmaceutically acceptable" as used in this invention means that the substance or composition in question is chemically, physiologically and / or toxicologically compatible with other components contained in the formulation and / or the mammal being treated.

[0038] The pharmaceutically acceptable salts of gliclazide or acetaminophen described in this invention include their various pharmaceutically acceptable salts, including acid salts suitable for forming with acids and base salts suitable for forming with bases. Examples of alkaline salts include alkali metal salts such as lithium, sodium, and potassium salts; alkaline earth metal salts such as calcium and barium salts; transition metal salts such as zinc and iron salts; magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, meglumine, and procaine; aralkyl amine salts such as N,N-dibenzylethylenediamine; heterocyclic aromatic amine salts such as pyridine, methylpyridine, quinoline, and isoquinoline; quaternary ammonium salts such as tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltributylammonium, methyltrioctylammonium, and tetrabutylammonium; and basic amino acid salts such as arginine salts and lysine salts. Examples of acid salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, bicarbonate, hydrobromide, hydroiodide, and perchlorate; organic acid salts such as formate, acetate, propionate, trifluoroacetate, citrate, lactate, tartrate, oxalate, fumarate, maleate, succinate, amygdalinate, glutarate, malate, benzoate, phthalate, and ascorbate; sulfonates such as methanesulfonate, ethanesulfonate, hydroxyethanesulfonate, benzenesulfonate, and p-toluenesulfonate; and acidic amino acid salts such as aspartate and glutamate. When necessary, those skilled in the art can synthesize pharmaceutically acceptable salts of gliclazide or acetaminophen using methods and materials known in the art.

[0039] According to one aspect of the invention, a method for preventing or treating a patient’s neurodegenerative disease (especially a neurodegenerative disease related to protein aggregation) is provided, the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof.

[0040] In some implementations of the method, the treatment includes improving one or more symptoms of the neurodegenerative disease, including motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0041] In other embodiments of the method, the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease.

[0042] In some other embodiments of the method, the treatment includes controlling or preventing the progression of the neurodegenerative disease.

[0043] In some embodiments of the method, the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0044] In some other embodiments of the method, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein aggregation.

[0045] In some other embodiments of the method, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Tau protein aggregation.

[0046] In some other embodiments of the method, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Aβ amyloid aggregation.

[0047] In some other embodiments of the method, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with the aggregation of TAR DNA-binding protein (TDP-43).

[0048] In some further embodiments of the method, the neurodegenerative disease is selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0049] In some further embodiments of the method, the neurodegenerative disease is Parkinson's disease.

[0050] In some further embodiments of the method, the neurodegenerative disease is multiple system atrophy.

[0051] In some further embodiments of the method, the neurodegenerative disease is Lewy body dementia.

[0052] In further embodiments of the method, a method for treating a patient with a neurodegenerative disease related to protein aggregation is provided, the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or more of the following symptoms of the neurodegenerative disease related to protein aggregation: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0053] In some further embodiments of the method, a method for treating a patient with a neurodegenerative disease related to protein aggregation is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or both of olfactory impairment and cognitive dysfunction in the patient with the neurodegenerative disease related to protein aggregation.

[0054] In some further embodiments of the method, a method for treating a patient with a neurodegenerative disease associated with protein aggregation is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof, said treatment comprising controlling or preventing the progression of the neurodegenerative disease associated with protein aggregation.

[0055] In further embodiments of the method, a method for treating a patient with an α-synuclein-related neurodegenerative disease is provided, the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or more of the following symptoms of the α-synuclein-related neurodegenerative disease: motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0056] In further embodiments of the method, a method for treating a patient with an α-synuclein-related neurodegenerative disease is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or both of olfactory impairment and cognitive dysfunction in the patient with the α-synuclein-related neurodegenerative disease.

[0057] In further embodiments of the method, a method for treating a patient with an α-synuclein-related neurodegenerative disease is provided, the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof, said treatment comprising controlling or halting the progression of the α-synuclein-related neurodegenerative disease.

[0058] In some further embodiments of the method, a method for treating a patient with Parkinson's disease is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or more of the following symptoms of Parkinson's disease: motor symptoms, depressive symptoms, decreased sense of smell, and cognitive impairment.

[0059] In some further embodiments of the method, a method for treating a patient with Parkinson's disease is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or both of olfactory impairment and cognitive dysfunction in a patient with Parkinson's disease.

[0060] In some further embodiments of the method, a method for treating a patient with Parkinson's disease is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof, said treatment comprising controlling or halting the progression of Parkinson's disease.

[0061] In some further embodiments of the method, the progression of the condition includes further complications of the patient’s symptoms, such as the appearance of new symptoms or complications (including sleep disorders and psychotic symptoms), decreased response to medication, and other symptoms that affect the patient’s quality of life.

[0062] According to another aspect of the invention, a method for preventing or treating a patient’s neurodegenerative disease (especially a neurodegenerative disease related to protein aggregation) is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof.

[0063] In some implementations of the method, the treatment includes improving one or more symptoms of the neurodegenerative disease, including motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0064] In other embodiments of the method, the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease.

[0065] In some other embodiments of the method, the treatment includes controlling or preventing the progression of the neurodegenerative disease.

[0066] In some embodiments of the method, the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0067] In some other embodiments of the method, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein aggregation.

[0068] In some other embodiments of the method, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Tau protein aggregation.

[0069] In some other embodiments of the method, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Aβ amyloid aggregation.

[0070] In some other embodiments of the method, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with the aggregation of TAR DNA-binding protein (TDP-43).

[0071] In some further embodiments of the method, the neurodegenerative disease is selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0072] In some further embodiments of the method, the neurodegenerative disease is Parkinson's disease.

[0073] In some further embodiments of the method, the neurodegenerative disease is multiple system atrophy.

[0074] In some further embodiments of the method, the neurodegenerative disease is Lewy body dementia.

[0075] In further embodiments of the method, a method for treating a patient with a neurodegenerative disease associated with protein aggregation is provided, the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or more of the following symptoms of the neurodegenerative disease associated with protein aggregation: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0076] In further embodiments of the method, a method for treating a patient with a neurodegenerative disease related to protein aggregation is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or both of the patient’s olfactory impairment and cognitive dysfunction related to the neurodegenerative disease related to protein aggregation.

[0077] In further embodiments of the method, a method for treating a patient with a neurodegenerative disease associated with protein aggregation is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof, said treatment comprising controlling or preventing the progression of the neurodegenerative disease associated with protein aggregation.

[0078] In further embodiments of the method, a method for treating a patient with an α-synuclein-related neurodegenerative disease is provided, the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or more of the following symptoms of the α-synuclein-related neurodegenerative disease: motor symptoms, depressive symptoms, olfactory impairment, and cognitive impairment.

[0079] In further embodiments of the method, a method for treating a patient with an α-synuclein-related neurodegenerative disease is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or both of olfactory impairment and cognitive dysfunction in the patient with the α-synuclein-related neurodegenerative disease.

[0080] In further embodiments of the method, a method for treating a patient with an α-synuclein-related neurodegenerative disease is provided, the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof, said treatment comprising controlling or halting the progression of the α-synuclein-related neurodegenerative disease.

[0081] In some further embodiments of the method, a method for treating a patient with Parkinson's disease is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or more of the following symptoms of Parkinson's disease: motor symptoms, depressive symptoms, decreased sense of smell, and cognitive impairment.

[0082] In some further embodiments of the method, a method for treating a patient with Parkinson's disease is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof, said treatment comprising improving one or both of olfactory impairment and cognitive dysfunction in a patient with Parkinson's disease.

[0083] In some further embodiments of the method, a method for treating a patient with Parkinson's disease is provided, the method comprising the step of administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof, said treatment comprising controlling or preventing the progression of Parkinson's disease.

[0084] In some further embodiments of the method, the progression of the condition includes further complications of the patient’s symptoms, such as the appearance of new symptoms or complications (including sleep disorders and psychotic symptoms), decreased response to medication, and other symptoms that affect the patient’s quality of life.

[0085] In some further embodiments of the method, the treatment includes preventing or delaying the onset of psychotic symptoms in the patient or improving psychotic symptoms that the patient already has, optionally selected from depression, anxiety, hallucinations, illusions, and delusions.

[0086] According to another aspect of the invention, a pharmaceutical composition is provided for the prevention or treatment of neurodegenerative diseases in patients (especially neurodegenerative diseases related to protein aggregation), the pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0087] In some embodiments of the pharmaceutical composition, the treatment includes improving one or more of the following symptoms of the neurodegenerative disease: motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0088] In some other embodiments of the pharmaceutical composition, the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease.

[0089] In some other embodiments of the pharmaceutical composition, the treatment includes controlling or preventing the progression of the neurodegenerative disease.

[0090] In some embodiments of the pharmaceutical composition, the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0091] In some other embodiments of the pharmaceutical composition, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein aggregation.

[0092] In some other embodiments of the pharmaceutical composition, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Tau protein aggregation.

[0093] In some other embodiments of the pharmaceutical composition, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Aβ amyloid aggregation.

[0094] In some other embodiments of the pharmaceutical composition, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with the aggregation of TAR DNA-binding protein (TDP-43).

[0095] In some further embodiments of the pharmaceutical composition, the neurodegenerative disease is selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0096] In some further embodiments of the pharmaceutical composition, the neurodegenerative disease is Parkinson's disease.

[0097] In some further embodiments of the pharmaceutical composition, the neurodegenerative disease is multiple system atrophy.

[0098] In some further embodiments of the pharmaceutical composition, the neurodegenerative disease is Lewy body dementia.

[0099] In further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with protein aggregation, the treatment including improving one or more of the following symptoms of the neurodegenerative diseases associated with protein aggregation: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0100] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with protein aggregation, the treatment including improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative diseases associated with protein aggregation.

[0101] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with protein aggregation, the treatment including controlling or preventing the progression of the neurodegenerative disease associated with protein aggregation.

[0102] In further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with α-synuclein, the treatment including improving one or more of the following symptoms of the neurodegenerative diseases associated with α-synuclein: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0103] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with α-synuclein, said treatment comprising improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative diseases associated with α-synuclein.

[0104] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with α-synuclein, the treatment including controlling or preventing the progression of the neurodegenerative disease associated with α-synuclein.

[0105] In further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat Parkinson's disease, the treatment including improving one or more of the following symptoms of Parkinson's disease: motor symptoms, depressive symptoms, decreased sense of smell, and cognitive impairment.

[0106] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat Parkinson's disease, the treatment including improving one or both of olfactory impairment and cognitive dysfunction in patients with Parkinson's disease.

[0107] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat Parkinson's disease, the treatment including controlling or preventing the progression of Parkinson's disease.

[0108] In some further embodiments of the pharmaceutical composition, the progression of the condition includes further complications of the patient’s symptoms, such as the appearance of new symptoms or complications (including sleep disorders and psychotic symptoms), decreased response to the medication, and other symptoms that affect the patient’s quality of life.

[0109] Another aspect of the invention provides a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases in patients, particularly neurodegenerative diseases related to protein aggregation, the pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof, acetaminophen or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0110] In some embodiments of the pharmaceutical composition, the treatment includes improving one or more of the following symptoms of the neurodegenerative disease: motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0111] In some other embodiments of the pharmaceutical composition, the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease.

[0112] In some other embodiments of the pharmaceutical composition, the treatment includes controlling or preventing the progression of the neurodegenerative disease.

[0113] In some embodiments of the pharmaceutical composition, the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0114] In some other embodiments of the pharmaceutical composition, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein aggregation.

[0115] In some other embodiments of the pharmaceutical composition, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Tau protein aggregation.

[0116] In some other embodiments of the pharmaceutical composition, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Aβ amyloid aggregation.

[0117] In some other embodiments of the pharmaceutical composition, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with the aggregation of TAR DNA-binding protein (TDP-43).

[0118] In some further embodiments of the pharmaceutical composition, the neurodegenerative disease is selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0119] In some further embodiments of the pharmaceutical composition, the neurodegenerative disease is Parkinson's disease.

[0120] In some further embodiments of the pharmaceutical composition, the neurodegenerative disease is multiple system atrophy.

[0121] In some further embodiments of the pharmaceutical composition, the neurodegenerative disease is Lewy body dementia.

[0122] In further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with protein aggregation, the treatment including improving one or more of the following symptoms of the neurodegenerative diseases associated with protein aggregation: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0123] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with protein aggregation, the treatment including improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative diseases associated with protein aggregation.

[0124] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with protein aggregation, the treatment including controlling or preventing the progression of the neurodegenerative disease associated with protein aggregation.

[0125] In further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with α-synuclein, the treatment including improving one or more of the following symptoms of the neurodegenerative diseases associated with α-synuclein: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0126] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with α-synuclein, said treatment comprising improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative diseases associated with α-synuclein.

[0127] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat neurodegenerative diseases associated with α-synuclein, the treatment including controlling or preventing the progression of the neurodegenerative disease associated with α-synuclein.

[0128] In further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat Parkinson's disease, the treatment including improving one or more of the following symptoms of Parkinson's disease: motor symptoms, depressive symptoms, decreased sense of smell, and cognitive impairment.

[0129] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat Parkinson's disease, the treatment including improving one or both of olfactory impairment and cognitive dysfunction in patients with Parkinson's disease.

[0130] In some further embodiments of the pharmaceutical composition, the pharmaceutical composition is used to treat Parkinson's disease, the treatment including controlling or preventing the progression of Parkinson's disease.

[0131] In some further embodiments of the pharmaceutical composition, the progression of the condition includes further complications of the patient’s symptoms, such as the appearance of new symptoms or complications (including sleep disorders and psychotic symptoms), decreased response to the medication, and other symptoms that affect the patient’s quality of life.

[0132] In some further embodiments of the pharmaceutical composition, the treatment includes preventing or delaying the onset of psychotic symptoms in a patient or improving psychotic symptoms that the patient already has, optionally selected from depression, anxiety, hallucinations, illusions, and delusions.

[0133] According to another aspect of the invention, a combination pharmaceutical product is provided comprising (1) a first pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a second pharmaceutical composition comprising acetaminophen or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) an insert or label indicating the use of the first pharmaceutical composition and the second pharmaceutical composition for the prevention or treatment of neurodegenerative diseases, particularly neurodegenerative diseases related to protein aggregation.

[0134] In some embodiments of this combination drug product, the first and second drug compositions may be administered to patients in need in chronological order at the same or different time intervals.

[0135] In some embodiments of this combination drug product, the treatment includes improving one or more of the following symptoms of the neurodegenerative disease: motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0136] In other embodiments of the combination drug product, the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease.

[0137] In some other embodiments of the combination drug product, the treatment includes controlling or preventing the progression of the neurodegenerative disease.

[0138] In some embodiments of this combination drug product, the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0139] In other embodiments of this combination drug product, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein aggregation.

[0140] In other embodiments of this combination drug product, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Tau protein aggregation.

[0141] In other embodiments of this combination drug product, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Aβ amyloid aggregation.

[0142] In other embodiments of the combination drug product, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with the aggregation of TAR DNA-binding protein (TDP-43).

[0143] In some further embodiments of this combination drug product, the neurodegenerative disease is selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0144] In some further embodiments of this combination drug product, the neurodegenerative disease is Parkinson's disease.

[0145] In some further embodiments of this combination drug product, the neurodegenerative disease is multiple system atrophy.

[0146] In some further embodiments of this combination drug product, the neurodegenerative disease is Lewy body dementia.

[0147] In further embodiments of the combination drug product, the combination drug product is used to treat neurodegenerative diseases associated with protein aggregation, the treatment including improving one or more of the following symptoms of the protein aggregation-related neurodegenerative disease: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0148] In some further embodiments of the combination drug product, the combination drug product is used to treat neurodegenerative diseases associated with protein aggregation, the treatment including improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative diseases associated with protein aggregation.

[0149] In some further embodiments of the combination drug product, the combination drug product is used to treat neurodegenerative diseases associated with protein aggregation, the treatment including controlling or preventing the progression of the neurodegenerative disease associated with protein aggregation.

[0150] In further embodiments of the combination drug product, the combination drug product is used to treat neurodegenerative diseases associated with α-synuclein, the treatment including improving one or more of the following symptoms of the α-synuclein-related neurodegenerative diseases: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0151] In some further embodiments of the combination drug product, the combination drug product is used to treat neurodegenerative diseases associated with α-synuclein, said treatment including improving one or both of olfactory impairment and cognitive dysfunction in patients with the α-synuclein-related neurodegenerative diseases.

[0152] In some further embodiments of the combination drug product, the combination drug product is used to treat neurodegenerative diseases associated with α-synuclein, the treatment including controlling or preventing the progression of the neurodegenerative disease associated with α-synuclein.

[0153] In some further embodiments of the combination drug product, the combination drug product is used to treat Parkinson's disease, the treatment including improving one or more of the following symptoms of Parkinson's disease: motor symptoms, depressive symptoms, decreased sense of smell, and cognitive impairment.

[0154] In some further embodiments of the combination drug product, the combination drug product is used to treat Parkinson's disease, the treatment including improving one or both of olfactory impairment and cognitive dysfunction in patients with Parkinson's disease.

[0155] In some further embodiments of the combination drug product, the combination drug product is used to treat Parkinson's disease, the treatment including controlling or preventing the progression of Parkinson's disease.

[0156] In some further embodiments of this combination drug product, the progression of the condition includes further complications of the patient’s symptoms, such as the appearance of new symptoms or complications (including sleep disorders and psychotic symptoms), decreased response to the drug, and other symptoms that affect the patient’s quality of life.

[0157] In some further embodiments of the combination drug product, the treatment includes preventing or delaying the onset of psychotic symptoms in the patient or improving psychotic symptoms that the patient already has, optionally selected from depression, anxiety, hallucinations, illusions, and delusions.

[0158] According to another aspect of the invention, the use of gliclazide or a pharmaceutically acceptable salt thereof in the preparation of pharmaceutical products for the prevention or treatment of neurodegenerative diseases in patients, particularly neurodegenerative diseases related to protein aggregation is provided.

[0159] In some embodiments of this use, the pharmaceutical product may be a pharmaceutical composition according to the invention, or a combination pharmaceutical product according to the invention.

[0160] In other embodiments of this use, the treatment includes improving one or more of the following symptoms of the neurodegenerative disease: motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0161] In some other embodiments of this use, the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease.

[0162] In some other embodiments of this use, the treatment includes controlling or preventing the progression of the neurodegenerative disease.

[0163] In some embodiments of this use, the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0164] In other embodiments of this use, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein aggregation.

[0165] In some other embodiments of this use, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Tau protein aggregation.

[0166] In some other embodiments of this use, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Aβ amyloid aggregation.

[0167] In some other embodiments of this use, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with the aggregation of TAR DNA-binding protein (TDP-43).

[0168] In some further embodiments of this use, the neurodegenerative disease is selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0169] In some further embodiments of this use, the neurodegenerative disease is Parkinson's disease.

[0170] In some further embodiments of this use, the neurodegenerative disease is multiple system atrophy.

[0171] In some further embodiments of this use, the neurodegenerative disease is Lewy body dementia.

[0172] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to protein aggregation, and the treatment includes improving one or more of the following symptoms of the protein aggregation-related neurodegenerative disease: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0173] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to protein aggregation, and the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease related to protein aggregation.

[0174] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to protein aggregation, and the treatment includes controlling or preventing the progression of the neurodegenerative disease related to protein aggregation.

[0175] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to α-synuclein, and the treatment includes improving one or more of the following symptoms of the α-synuclein-related neurodegenerative disease: motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0176] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to α-synuclein, and the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease related to α-synuclein.

[0177] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to α-synuclein, and the treatment includes controlling or preventing the progression of the neurodegenerative disease related to α-synuclein.

[0178] In some further embodiments of this use, the neurodegenerative disease is Parkinson's disease, and the treatment includes improving one or more of the following symptoms of Parkinson's disease: motor symptoms, depressive symptoms, decreased sense of smell, and cognitive impairment.

[0179] In some further embodiments of this use, the neurodegenerative disease is Parkinson's disease, and the treatment includes improving one or both of the decreased sense of smell and cognitive impairment in patients with Parkinson's disease.

[0180] In some further embodiments of this use, the neurodegenerative disease is Parkinson's disease, and the treatment includes controlling or halting the progression of Parkinson's disease.

[0181] In some further embodiments of this use, the progression of the condition includes further complications of the patient’s symptoms, such as the appearance of new symptoms or complications (including sleep disorders and psychotic symptoms), decreased response to medication, and other symptoms that affect the patient’s quality of life.

[0182] According to another aspect of the invention, the use of gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical product for the prevention or treatment of neurodegenerative diseases in patients, particularly neurodegenerative diseases related to protein aggregation is provided.

[0183] In some embodiments of this use, the pharmaceutical product may be a pharmaceutical composition according to the invention, or a combination pharmaceutical product according to the invention.

[0184] In other embodiments of this use, gliclazide or a pharmaceutically acceptable salt thereof may be formulated together with acetaminophen or a pharmaceutically acceptable salt thereof in a single formulation for simultaneous administration to patients in need, or may be formulated separately in individual formulations for sequential administration to patients in need.

[0185] In some embodiments of this use, the treatment includes improving one or more of the following symptoms of the neurodegenerative disease: motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0186] In other embodiments of this use, the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease.

[0187] In some other embodiments of this use, the treatment includes controlling or preventing the progression of the neurodegenerative disease.

[0188] In some embodiments of this use, the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0189] In other embodiments of this use, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein aggregation.

[0190] In some other embodiments of this use, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Tau protein aggregation.

[0191] In some other embodiments of this use, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Aβ amyloid aggregation.

[0192] In some other embodiments of this use, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with the aggregation of TAR DNA-binding protein (TDP-43).

[0193] In some further embodiments of this use, the neurodegenerative disease is selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0194] In some further embodiments of this use, the neurodegenerative disease is Parkinson's disease.

[0195] In some further embodiments of this use, the neurodegenerative disease is multiple system atrophy.

[0196] In some further embodiments of this use, the neurodegenerative disease is Lewy body dementia.

[0197] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to protein aggregation, and the treatment includes improving one or more of the following symptoms of the protein aggregation-related neurodegenerative disease: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0198] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to protein aggregation, and the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease related to protein aggregation.

[0199] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to protein aggregation, and the treatment includes controlling or preventing the progression of the neurodegenerative disease related to protein aggregation.

[0200] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to α-synuclein, and the treatment includes improving one or more of the following symptoms of the α-synuclein-related neurodegenerative disease: motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0201] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to α-synuclein, and the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease related to α-synuclein.

[0202] In some further embodiments of this use, the neurodegenerative disease is a neurodegenerative disease related to α-synuclein, and the treatment includes controlling or preventing the progression of the neurodegenerative disease related to α-synuclein.

[0203] In some further embodiments of this use, the neurodegenerative disease is Parkinson's disease, and the treatment includes improving one or more of the following symptoms of Parkinson's disease: motor symptoms, depressive symptoms, decreased sense of smell, and cognitive impairment.

[0204] In some further embodiments of this use, the neurodegenerative disease is Parkinson's disease, and the treatment includes improving one or both of the decreased sense of smell and cognitive impairment in patients with Parkinson's disease.

[0205] In some further embodiments of this use, the neurodegenerative disease is Parkinson's disease, and the treatment includes controlling or halting the progression of Parkinson's disease.

[0206] In some further embodiments of this use, the progression of the condition includes further complications of the patient’s symptoms, such as the appearance of new symptoms or complications (including sleep disorders and psychotic symptoms), decreased response to medication, and other symptoms that affect the patient’s quality of life.

[0207] In some further embodiments of this use, the treatment includes preventing or delaying the onset of psychotic symptoms in a patient or improving psychotic symptoms that the patient already has, optionally selected from depression, anxiety, hallucinations, illusions, and delusions.

[0208] According to another aspect of the invention, a pharmaceutical combination is provided for the prevention or treatment of neurodegenerative diseases (especially neurodegenerative diseases related to protein aggregation) in a patient, comprising gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof.

[0209] In other embodiments of this drug combination, gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof may be formulated together in a single formulation for simultaneous administration to patients in need, or they may be formulated separately for sequential administration to patients in need.

[0210] In some embodiments of this drug combination, the treatment includes improving one or more of the following symptoms of the neurodegenerative disease: motor symptoms, depressive symptoms, olfactory impairment, and cognitive dysfunction.

[0211] In some other embodiments of the drug combination, the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease.

[0212] In some other embodiments of the drug combination, the treatment includes controlling or preventing the progression of the neurodegenerative disease.

[0213] In some embodiments of the drug combination, the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0214] In some other embodiments of the drug combination, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein aggregation.

[0215] In some other embodiments of the drug combination, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Tau protein aggregation.

[0216] In some other embodiments of the drug combination, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with Aβ amyloid aggregation.

[0217] In some other embodiments of the drug combination, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with the aggregation of TAR DNA-binding protein (TDP-43).

[0218] In some further embodiments of this drug combination, the neurodegenerative disease is selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0219] In some further embodiments of this drug combination, the neurodegenerative disease is Parkinson's disease.

[0220] In some further embodiments of this drug combination, the neurodegenerative disease is multiple system atrophy.

[0221] In some further embodiments of this drug combination, the neurodegenerative disease is Lewy body dementia.

[0222] In some further embodiments of the drug combination, the neurodegenerative disease is a neurodegenerative disease related to protein aggregation, and the treatment includes improving one or more of the following symptoms of the protein aggregation-related neurodegenerative disease: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0223] In some further embodiments of the drug combination, the neurodegenerative disease is a neurodegenerative disease related to protein aggregation, and the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease related to protein aggregation.

[0224] In some further embodiments of the drug combination, the neurodegenerative disease is a neurodegenerative disease related to protein aggregation, and the treatment includes controlling or preventing the progression of the neurodegenerative disease related to protein aggregation.

[0225] In some further embodiments of the drug combination, the neurodegenerative disease is a neurodegenerative disease related to α-synuclein, and the treatment includes improving one or more of the following symptoms of the α-synuclein-related neurodegenerative disease: motor symptoms, depressive symptoms, hyposmia, and cognitive impairment.

[0226] In some further embodiments of the drug combination, the neurodegenerative disease is a neurodegenerative disease related to α-synuclein, and the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with the neurodegenerative disease related to α-synuclein.

[0227] In some further embodiments of the drug combination, the neurodegenerative disease is an α-synuclein-related neurodegenerative disease, and the treatment includes controlling or preventing the progression of the α-synuclein-related neurodegenerative disease.

[0228] In some further embodiments of the drug combination, the neurodegenerative disease is Parkinson's disease, and the treatment includes improving one or more of the following symptoms of Parkinson's disease: motor symptoms, depressive symptoms, decreased sense of smell, and cognitive impairment.

[0229] In some further embodiments of the drug combination, the neurodegenerative disease is Parkinson's disease, and the treatment includes improving one or both of olfactory impairment and cognitive dysfunction in patients with Parkinson's disease.

[0230] In some further embodiments of this drug combination, the neurodegenerative disease is Parkinson's disease, and the treatment includes controlling or halting the progression of Parkinson's disease.

[0231] In some further embodiments of this drug combination, the progression of the condition includes further complications of the patient’s symptoms, such as the appearance of new symptoms or complications (including sleep disorders and psychotic symptoms), decreased response to the drug, and other symptoms that affect the patient’s quality of life.

[0232] In some further embodiments of the drug combination, the treatment includes preventing or delaying the onset of psychotic symptoms in the patient or improving psychotic symptoms that the patient already has, optionally selected from depression, anxiety, hallucinations, illusions, and delusions.

[0233] Those skilled in the art can use methods known in the art to prepare pharmaceutical compositions of the present invention into formulations convenient for patient use using suitable pharmaceutically acceptable excipients. Methods for preparing pharmaceutical formulations suitable for specific dosing regimens are entirely within the knowledge of those skilled in the art. The selection of specific excipients will depend on the route of administration or the type and state of disease for treating a particular patient. For example, pharmaceutically acceptable excipients include binders, disintegrants, lubricants, sweeteners, flavoring agents, preservatives, chelating agents, antioxidants, cooling agents, coating agents, stabilizers, flow aids, thickeners, solubilizers, viscous agents, buffers, fragrances, colorants, adsorbents, humectants, moisture-proofing agents, antistatic agents, plasticizers, defoamers, surfactants, emulsifiers, etc., which are conventional in the pharmaceutical field. For instance, pharmaceutically acceptable excipients may include binders (e.g., corn starch), fillers (e.g., lactose, microcrystalline cellulose), disintegrants (e.g., sodium starch glycolate), and lubricants (e.g., magnesium stearate).

[0234] Those skilled in the art can use methods known in the art to formulate the pharmaceutical compositions of the present invention into suitable dosage forms. Suitable dosage forms may be liquid dosage forms, solid dosage forms, and other dosage forms. Liquid dosage forms may be solutions, colloids, emulsions, or suspensions, etc. Solid dosage forms may be, for example, tablets (e.g., intraorally disintegrating tablets, chewable tablets, effervescent tablets), powders, suppositories, granules, or capsules, etc. Other dosage forms include aerosols, implants, patches, or liniments, etc.

[0235] Those skilled in the art can use methods known in the art to prepare the pharmaceutical compositions of the present invention into unit dose forms for patient use. The term "unit dose form" here means a physically discrete unit suitable for convenient patient administration containing a certain amount of gliclazide or a pharmaceutically acceptable salt thereof, or a combination of gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof, each unit containing an amount of gliclazide or a pharmaceutically acceptable salt thereof, or a combination of gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof, sufficient to achieve the desired therapeutic purpose.

[0236] The pharmaceutical compositions of the present invention can be administered in any manner and form commonly used in the art. For example, the pharmaceutical compositions of the present invention can be administered via a selection of methods including oral administration, inhalation via spray, rectal administration, nasal administration, vaginal administration, topical administration, and parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intrasternal, intrasternal, or intracranial injection, with oral, intramuscular, intraperitoneal, or intravenous administration being preferred. Oral administration is preferred for patients in need.

[0237] For oral administration, any suitable pharmaceutical excipient commonly used in the preparation of solid dosage forms can be used, and formulation techniques known in the art can be employed to formulate the pharmaceutical compositions of the present invention into solid dosage forms, such as tablets, capsules, and powders. Alternatively, any suitable pharmaceutical excipient commonly used in the preparation of liquid dosage forms can be used, and formulation techniques known in the art can be employed to formulate the pharmaceutical compositions of the present invention into liquid dosage forms, such as solutions, syrups, suspensions, and emulsions. Sustained-release formulations may be used if necessary.

[0238] For parenteral administration, any suitable excipient commonly used in the preparation of parenteral formulations can be used. The pharmaceutical compositions of the present invention can be formulated into formulations suitable for parenteral administration using formulation techniques known in the art, such as sterile injections, lyophilized powders, transdermal patches, aerosols, oral / nasal inhalation formulations, and suppositories. Parenteral administration routes include intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and local routes. Sustained-release formulations may be used if necessary.

[0239] In the methods, uses, pharmaceutical combinations, pharmaceutical compositions, or combination pharmaceutical products of the present invention, the dosage and frequency of administration of gliclazide or its pharmaceutically acceptable salts and acetaminophen or its pharmaceutically acceptable salts are not particularly limited, and can be determined based on their administration method or route, the physical condition of the patient being treated, the disease being treated, and the severity of the disease being treated. In practicing the present invention, those skilled in the art can readily determine their respective dosages to produce the desired therapeutic effect based on the disclosure herein. The dosage is not particularly limited; preferably, the daily dosage of gliclazide is 1–320 mg, administered once daily or in multiple divided doses, and the daily dosage of acetaminophen is 10–4000 mg, administered once daily or in multiple divided doses.

[0240] In carrying out this invention, when gliclazide or a pharmaceutically acceptable salt thereof is used in combination with acetaminophen or a pharmaceutically acceptable salt thereof, those skilled in the art can readily determine the respective dosages or content ratios of gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof, based on the disclosure in this specification.

[0241] The present invention includes the following typical embodiments.

[0242] Implementation Plan 1. Use of gliclazide or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical product for the prevention or treatment of patients with neurodegenerative diseases selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0243] Implementation Scheme 2. The use according to Implementation Scheme 1, wherein the neurodegenerative disease is Parkinson's disease.

[0244] Implementation Scheme 3. The use according to Implementation Scheme 2, wherein the pharmaceutical product is used to treat a patient with Parkinson's disease.

[0245] Implementation Scheme 4. The use according to Implementation Scheme 3, wherein the treatment is to control or prevent the progression of Parkinson's disease.

[0246] Implementation Scheme 5. The use according to Implementation Scheme 3, wherein the treatment is to improve one or more of the following symptoms of Parkinson's disease: motor symptoms, decreased sense of smell, and cognitive impairment.

[0247] Implementation Plan 6. Use of gliclazide or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical product for the prevention or treatment of neurodegenerative diseases associated with protein aggregation in patients.

[0248] Implementation Scheme 7. The use according to Implementation Scheme 6, wherein the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more or all of α-synuclein, Tau protein, Aβ amyloid protein and TAR DNA-binding protein (TDP-43).

[0249] Implementation Scheme 8. The use according to Implementation Scheme 6, wherein the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein.

[0250] Implementation Scheme 9. A pharmaceutical composition for the prevention or treatment of neurodegenerative diseases selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia in patients, the pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof.

[0251] Implementation Scheme 10. A pharmaceutical composition for use according to Implementation Scheme 9, wherein the neurodegenerative disease is Parkinson's disease.

[0252] Implementation Scheme 11. A pharmaceutical composition for use according to Implementation Scheme 10, wherein the pharmaceutical product is used to treat a patient with Parkinson's disease.

[0253] Implementation Scheme 12. A pharmaceutical composition for use according to Implementation Scheme 11, wherein the treatment is to control or prevent the progression of Parkinson's disease.

[0254] Implementation Scheme 13. A pharmaceutical composition for use according to Implementation Scheme 11, wherein the treatment is to improve one or more of the motor symptoms, decreased sense of smell, and cognitive impairment of Parkinson's disease.

[0255] Implementation Scheme 14. A pharmaceutical composition for the prevention or treatment of neurodegenerative diseases associated with protein aggregation in patients, the pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof.

[0256] Implementation Scheme 15. A pharmaceutical composition for use according to Implementation Scheme 14, wherein the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0257] Implementation Scheme 16. A pharmaceutical composition for use according to Implementation Scheme 14, wherein the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein.

[0258] Implementation Scheme 17. A method for the prevention or treatment of a patient with a neurodegenerative disease selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia, the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof.

[0259] Implementation Scheme 18. The method according to Implementation Scheme 17, wherein the neurodegenerative disease is Parkinson's disease.

[0260] Implementation Scheme 19. The method according to Implementation Scheme 18, wherein the method is used to treat a patient with Parkinson's disease.

[0261] Implementation Scheme 20. The method according to Implementation Scheme 19, wherein the treatment is to control or prevent the progression of Parkinson's disease.

[0262] Implementation Scheme 21. The method according to Implementation Scheme 19, wherein the treatment is to improve one or more of the following symptoms of Parkinson's disease: motor symptoms, decreased sense of smell, and cognitive impairment.

[0263] Implementation Scheme 22. A method for preventing or treating a patient with a neurodegenerative disease associated with protein aggregation, the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof.

[0264] Implementation Scheme 23. The method according to Implementation Scheme 22, wherein the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more or all of α-synuclein, Tau protein, Aβ amyloid protein and TAR DNA-binding protein (TDP-43).

[0265] Implementation Scheme 24. The method according to Implementation Scheme 22, wherein the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein.

[0266] Implementation Plan 25. Gliclazide or a pharmaceutically acceptable salt thereof, used for the prevention or treatment of patients with neurodegenerative diseases selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0267] Implementation Scheme 26. Gliclazide or a pharmaceutically acceptable salt thereof for use according to Implementation Scheme 25, wherein the neurodegenerative disease is Parkinson's disease.

[0268] Implementation Scheme 27. Gliclazide or a pharmaceutically acceptable salt thereof for use according to the purpose described in Implementation Scheme 26, for the treatment of patients with Parkinson's disease.

[0269] Implementation Scheme 28. Gliclazide or a pharmaceutically acceptable salt thereof for use according to Implementation Scheme 27, wherein the treatment is to control or prevent the progression of Parkinson's disease.

[0270] Implementation Scheme 29. Gliclazide or a pharmaceutically acceptable salt thereof for use according to Implementation Scheme 28, wherein the treatment is to improve one or more of the motor symptoms, decreased sense of smell and cognitive impairment of Parkinson's disease.

[0271] Implementation Plan 30. Gliclazide or a pharmaceutically acceptable salt thereof, used for the prevention or treatment of neurodegenerative diseases in patients associated with protein aggregation.

[0272] Implementation Scheme 31. Gliclazide or a pharmaceutically acceptable salt thereof for use according to Implementation Scheme 30, wherein the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more or all of α-synuclein, Tau protein, Aβ amyloid protein and TAR DNA-binding protein (TDP-43).

[0273] Implementation Scheme 32. Gliclazide or a pharmaceutically acceptable salt thereof for use according to Implementation Scheme 30, wherein the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein.

[0274] Implementation Scheme 33. Use of gliclazide or a pharmaceutically acceptable salt thereof with acetaminophen or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical product for the prevention or treatment of neurodegenerative diseases in patients.

[0275] Implementation Scheme 34. The use according to Implementation Scheme 33, wherein the neurodegenerative disease is a neurodegenerative disease related to protein aggregation.

[0276] Implementation Scheme 35. The use according to Implementation Scheme 34, wherein the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more or all of α-synuclein, Tau protein, Aβ amyloid protein and TAR DNA-binding protein (TDP-43).

[0277] Implementation Scheme 36. The use according to Implementation Scheme 34, wherein the neurodegenerative disease associated with protein aggregation is any one, multiple or all of Parkinson's disease, multiple system atrophy and Lewy body dementia.

[0278] Implementation Scheme 37. The use according to Implementation Scheme 34, wherein the neurodegenerative disease associated with protein aggregation is Parkinson's disease.

[0279] Implementation Scheme 38. The use according to Implementation Scheme 37, wherein the pharmaceutical product is used to treat a patient with Parkinson's disease.

[0280] Implementation Scheme 39. The use according to Implementation Scheme 38, wherein the treatment is to improve one or more of the motor symptoms, decreased sense of smell, and cognitive impairment of Parkinson's disease.

[0281] Implementation Scheme 40. The use according to Implementation Scheme 38, wherein the treatment is to control or prevent the progression of Parkinson's disease.

[0282] Implementation Scheme 41. The use according to Implementation Scheme 38, wherein the treatment is to prevent or delay the onset of psychotic symptoms in a Parkinson's disease patient.

[0283] Implementation Scheme 42. The use according to Implementation Scheme 38, wherein the treatment is for improving psychotic symptoms that have already appeared in the patient.

[0284] Implementation Scheme 43. The use according to Implementation Scheme 41 or Implementation Scheme 42, wherein the psychotic symptoms are selected from depression, anxiety, hallucinations, illusions and delusions.

[0285] Implementation Scheme 44. The use according to any one of Implementation Schemes 33-43, wherein gliclazide or a pharmaceutically acceptable salt thereof is formulated together with acetaminophen or a pharmaceutically acceptable salt thereof in a single formulation for simultaneous administration to a patient in need, or is formulated separately in individual formulations for sequential administration to a patient in need.

[0286] Implementation Scheme 45. A combination drug product comprising (1) a first pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, (2) a second pharmaceutical composition comprising acetaminophen or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and (3) an insert or label indicating the use of the first and second pharmaceutical compositions to prevent or treat neurodegenerative diseases or to improve one or more of the motor symptoms, olfactory impairment, and cognitive impairment of Parkinson's disease, or to control or prevent the progression of Parkinson's disease or to prevent or delay the onset of psychotic symptoms in patients with Parkinson's disease or to improve psychotic symptoms that have already appeared in patients.

[0287] Implementation Scheme 46. A pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof, acetaminophen or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0288] Implementation Scheme 47. A pharmaceutical composition for the prevention or treatment of neurodegenerative diseases in patients, the pharmaceutical composition comprising gliclazide or a pharmaceutically acceptable salt thereof and acetaminophen or a pharmaceutically acceptable salt thereof.

[0289] Implementation Scheme 48. A pharmaceutical composition for use according to Implementation Scheme 47, wherein the neurodegenerative disease is a neurodegenerative disease related to protein aggregation.

[0290] Implementation Scheme 49. A pharmaceutical composition for use according to Implementation Scheme 48, wherein the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0291] Implementation Scheme 50. A pharmaceutical composition for use according to Implementation Scheme 48, wherein the neurodegenerative disease associated with protein aggregation is any one, multiple, or all of Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0292] Implementation Scheme 51. A pharmaceutical composition for use according to Implementation Scheme 48, wherein the neurodegenerative disease associated with protein aggregation is Parkinson's disease.

[0293] Implementation Scheme 52. A pharmaceutical composition for use according to the purpose described in Implementation Scheme 51, wherein the pharmaceutical product is used to treat a patient with Parkinson's disease.

[0294] Implementation Scheme 53. A pharmaceutical composition for use according to Implementation Scheme 52, wherein the treatment is to improve one or more of the motor symptoms, decreased sense of smell, and cognitive impairment of Parkinson's disease.

[0295] Implementation Scheme 54. A pharmaceutical composition for use according to Implementation Scheme 52, wherein the treatment is to control or prevent the progression of Parkinson's disease.

[0296] Implementation Scheme 55. A pharmaceutical composition for use according to Implementation Scheme 52, wherein the treatment is to prevent or delay the onset of psychotic symptoms in a patient with Parkinson's disease.

[0297] Implementation Scheme 56. A pharmaceutical composition for use according to Implementation Scheme 52, wherein the treatment is to improve psychotic symptoms that have already appeared in a patient.

[0298] Implementation Scheme 57. A pharmaceutical composition for use according to Implementation Scheme 55 or Implementation Scheme 56, wherein the psychotic symptoms are selected from depression, anxiety, hallucinations, illusions, and delusions.

[0299] Implementation Scheme 58. A pharmaceutical composition for use according to any one of Implementation Schemes 47-57, wherein gliclazide or a pharmaceutically acceptable salt thereof is formulated together with acetaminophen or a pharmaceutically acceptable salt thereof in a single formulation for simultaneous administration to a patient in need, or is formulated separately in individual formulations for sequential administration to a patient in need.

[0300] Implementation Scheme 59. A method for preventing or treating a patient with a neurodegenerative disease, the method comprising administering to the patient a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof in combination with acetaminophen or a pharmaceutically acceptable salt thereof.

[0301] Implementation Scheme 60. The method according to Implementation Scheme 59, wherein the neurodegenerative disease is a neurodegenerative disease related to protein aggregation.

[0302] Implementation Scheme 61. The method according to Implementation Scheme 60, wherein the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more or all of α-synuclein, Tau protein, Aβ amyloid protein and TAR DNA-binding protein (TDP-43).

[0303] Implementation Scheme 62. The method according to Implementation Scheme 60, wherein the neurodegenerative disease associated with protein aggregation is any one, multiple or all of Parkinson's disease, multiple system atrophy and Lewy body dementia.

[0304] Implementation Scheme 63. The method according to Implementation Scheme 60, wherein the neurodegenerative disease associated with protein aggregation is Parkinson's disease.

[0305] Implementation Scheme 64. The method according to Implementation Scheme 63, wherein the method is used to treat a patient with Parkinson's disease.

[0306] Implementation Scheme 65. The method according to Implementation Scheme 64, wherein the treatment is to improve one or more of the following symptoms of Parkinson's disease: motor symptoms, decreased sense of smell, and cognitive impairment.

[0307] Implementation Scheme 66. The method according to Implementation Scheme 64, wherein the treatment is to control or prevent the progression of Parkinson's disease.

[0308] Implementation Scheme 67. The method according to Implementation Scheme 64, wherein the treatment is to prevent or delay the onset of psychotic symptoms in a Parkinson's disease patient.

[0309] Implementation Scheme 68. The method according to Implementation Scheme 64, wherein the treatment is to improve psychotic symptoms that the patient has already experienced.

[0310] Implementation Scheme 69. The method according to Implementation Scheme 67 or Implementation Scheme 68, wherein the psychotic symptoms are selected from depression, anxiety, hallucinations, illusions and delusions.

[0311] Implementation Scheme 70. The method according to any one of Implementation Schemes 59-69, wherein gliclazide or a pharmaceutically acceptable salt thereof is formulated together with acetaminophen or a pharmaceutically acceptable salt thereof in a single formulation for simultaneous administration to patients in need, or each is formulated in a separate formulation for sequential administration to patients in need.

[0312] Implementation Scheme 71. A combination of medicines for the prevention or treatment of neurodegenerative diseases in patients, the combination of medicines comprising a therapeutically effective amount of gliclazide or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of acetaminophen or a pharmaceutically acceptable salt thereof.

[0313] Implementation Scheme 72. A pharmaceutical combination for the use described in Implementation Scheme 71, wherein the neurodegenerative disease is a neurodegenerative disease related to protein aggregation.

[0314] Implementation Scheme 73. A pharmaceutical combination for use according to Implementation Scheme 72, wherein the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43).

[0315] Implementation Scheme 74. A combination of drugs for the use described in Implementation Scheme 72, wherein the neurodegenerative disease associated with protein aggregation is any one, multiple, or all of Parkinson's disease, multiple system atrophy, and Lewy body dementia.

[0316] Implementation Scheme 75. A pharmaceutical combination for the use described in Implementation Scheme 72, wherein the neurodegenerative disease associated with protein aggregation is Parkinson's disease.

[0317] Implementation Scheme 76. A combination of drugs for the purpose of treating a patient with Parkinson's disease, according to the use described in Implementation Scheme 75.

[0318] Implementation Scheme 77. A combination of medicines for the purpose described in Implementation Scheme 76, wherein the treatment is to improve one or more of the motor symptoms, decreased sense of smell, and cognitive impairment of Parkinson's disease.

[0319] Implementation Scheme 78. A combination of drugs for the purpose described in Implementation Scheme 76, wherein the treatment is to control or prevent the progression of Parkinson's disease.

[0320] Implementation Scheme 79. A combination of drugs for the purpose described in Implementation Scheme 76, wherein the treatment is to prevent or delay the onset of psychotic symptoms in a patient with Parkinson's disease.

[0321] Implementation Scheme 80. A combination of drugs for the purpose described in Implementation Scheme 76, wherein the treatment is to improve psychotic symptoms that have already appeared in the patient.

[0322] Implementation Scheme 81. A combination of drugs for the purpose described in Implementation Scheme 79 or Implementation Scheme 80, wherein the psychotic symptoms are selected from depression, anxiety, hallucinations, illusions and delusions.

[0323] Implementation Scheme 82. A combination of drugs for any of the uses described in Implementation Schemes 71-81, wherein gliclazide or a pharmaceutically acceptable salt thereof is formulated together with acetaminophen or a pharmaceutically acceptable salt thereof in a single formulation for simultaneous administration to a patient in need, or is formulated separately in individual formulations for sequential administration to a patient in need. Example

[0324] The foregoing description of exemplary compositions, uses, and methods of the present invention is followed by embodiments of the invention, which are for illustrative purposes only and not intended to limit the invention. Unless otherwise specifically stated, all materials used in the present invention are commercially available.

[0325] Example 1: Pharmacodynamic evaluation in an MPTP-induced mouse Parkinson's disease model

[0326] A mouse model of Parkinson's disease was established by intraperitoneal injection of MPTP into mice. The efficacy of gliclazide monotherapy, acetaminophen monotherapy, combination therapy of gliclazide and acetaminophen, and levodopa were evaluated and compared by grip strength test and olfactory test.

[0327] Experimental animals: C57BL / 6J mice, 8 weeks old, male.

[0328] drug:

[0329] ·MPTP(1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

[0330] Methyl cellulose (MC)

[0331] • Saline

[0332] Gliclazide

[0333] Acetaminophen

[0334] ·L-DOPA

[0335] • Benserazide

[0336] Preparation:

[0337] • Preparation of medium (0.5% methylcellulose, w / w): Weigh methylcellulose, add physiological saline, stir vigorously, and store at 4°C.

[0338] Preparation of MTPT solution: Weigh MPTP, add it to physiological saline, mix well to a 3 mg / mL solution, and store frozen. The dosage is 10 mL / kg.

[0339] • Preparation of gliclazide suspension: Weigh gliclazide and mix it with 0.5% methylcellulose medium to prepare a suspension of 0.8 mg / mL. The dosage is 10 mg / kg.

[0340] • Preparation of acetaminophen solution: Weigh acetaminophen and mix it with 5% Tween 80 medium to prepare a solution of 1.5 mg / mL. The dosage is 10 mL / kg.

[0341] Preparation of levodopa solution: Weigh levodopa and mix it with physiological saline to prepare a solution of 2 mg / mL. The dosage is 5 mL / kg.

[0342] Preparation of benserazide solution: Weigh benserazide and mix it with physiological saline to prepare a solution of 3 mg / mL. The dosage is 15 mL / kg.

[0343] Table 1. Dosage Composition

[0344] MPTP-induced mouse Parkinson's model construction, administration, and evaluation:

[0345] A total of 48 mice were randomly divided into 6 groups of 8 mice each.

[0346] Before the experiment, the mice were allowed one week to adapt to the environment. Each mouse underwent a health check, including an assessment of its fur, limbs and mouthparts, and an examination of its posture and movements for any abnormal signs.

[0347] From day 1 to day 16, the model group was injected intraperitoneally with 30 mg / kg of MPTP daily.

[0348] From day 1 to day 16, mice in the sham model were injected intraperitoneally with a medium solution of 30 mg / kg daily.

[0349] On day 5, a grip strength test was conducted to confirm that motor dysfunction could be observed in all MPTP model mouse groups. From day 5 to day 16, the mice were administered drugs according to the dosage and route shown in Table 1 to evaluate the treatment effect.

[0350] On day 11, an olfactory test was conducted (to evaluate olfactory and cognitive functions, as shown in Figure 1); on day 17, a grip strength test was conducted (to evaluate motor symptoms, as shown in Figure 2); afterwards, all animals were euthanized, and their brains were removed for immunohistochemical analysis. Immunohistochemical staining was performed using anti-tyrosine hydroxylase antibodies to quantify the number of tyrosine hydroxylase (TH)-positive cells (the number of dopaminergic neurons) in the substantia nigra pars compacta (SNpc) region of the midbrain, as shown in Figure 3.

[0351] The olfactory testing experiment was conducted in two adjacent rooms where mice could move freely. One room contained bedding material familiar to each mouse from its cage, while the other room contained new, unused bedding material, thus quantifying the time mice spent in each room. Compared to the sham model group, which spent significantly more time in the familiar environment, the MPTP model group, characterized by olfactory degeneration and cognitive impairment, spent significantly more time in the new environment.

[0352] As shown in Figure 1, after administration of gliclazide monotherapy or gliclazide combined with acetaminophen, the olfactory impairment in the MPTP mouse model approached normal levels. These results indicate that these treatment methods can significantly improve olfactory and cognitive impairment associated with Parkinson's disease. Statistical analysis results are expressed as mean ± standard error of mean (SEM). A two-way repeated measures ANOVA was used for global testing; further analysis was conducted after a significant effect was found. Post-hoc tests were performed using multiple comparisons, and the significance level was indicated by asterisks (*P<0.05 was statistically significant; ***P<0.001 was highly statistically significant; ****P<0.0001 was extremely highly statistically significant).

[0353] As shown in Figure 2, administration of gliclazide monotherapy, acetaminophen monotherapy, gliclazide combined with acetaminophen, or levodopa significantly improved motor dysfunction in the MPTP mouse model. These results indicate that these treatment methods can significantly improve motor dysfunction associated with Parkinson's disease. Statistical analysis results are expressed as mean ± standard error of mean (SEM). A two-way repeated measures ANOVA was used for global testing; further analysis was conducted after a significant effect was found. Post-hoc tests were performed using multiple comparisons, and the significance level was indicated by asterisks (*P<0.05 was statistically significant; **P<0.01 was highly statistically significant).

[0354] As shown in Figure 3, administration of gliclazide monotherapy, acetaminophen monotherapy, or a combination of gliclazide and acetaminophen significantly improved the reduction of dopaminergic neurons in the SNpc of the MPTP mouse model. However, the existing therapeutic drug levodopa did not show any improvement. These results indicate that administration of gliclazide monotherapy, acetaminophen monotherapy, or a combination of gliclazide and acetaminophen can effectively control neuronal degeneration in Parkinson's disease. Statistical analysis results are expressed as mean ± standard error of mean (SEM). Non-parametric Kruskal-Wallis tests were used for overall comparisons among multiple groups. When significant differences were found, Conover post-hoc tests were used for pairwise comparisons, with asterisks indicating the significance level (*P < 0.05 was statistically significant; **P < 0.01 was highly statistically significant).

[0355] Example 2: Comparison of the efficacy of gliclazide and glibenclamide in an MPTP-induced mouse model.

[0356] A mouse model of Parkinson's disease was established by intraperitoneal injection of MPTP into mice. The efficacy of gliclazide, glibenclamide, exenatide, and levodopa was compared by rotarod assay and quantitative analysis of the area of ​​tyrosine hydroxylase-positive neurons.

[0357] Experimental animals: Adult male C57BL / 6J mice

[0358] drug:

[0359] ·MPTP(1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

[0360] • Saline

[0361] Gliclazide

[0362] Glibenclamide

[0363] • Exenatide

[0364] ·L-DOPA

[0365] • Benserazide

[0366] Preparation:

[0367] • Preparation of MTPT solution: Weigh MPTP and add it to physiological saline to prepare a solution of 3 mg / mL. Mix well and store frozen. The dosage is 10 mL / kg.

[0368] • Preparation of MC medium (0.5% methylcellulose): Weigh methylcellulose, add physiological saline, stir vigorously, and store at 4°C.

[0369] • Preparation of DMSO medium (5% dimethyl sulfoxide): Weigh dimethyl sulfoxide, add physiological saline, stir vigorously, and store at 4°C.

[0370] • Preparation of gliclazide solution: Weigh gliclazide and mix it in MC medium to prepare a suspension of 0.8 mg / mL. The dosage is 10 mL / kg.

[0371] • Preparation of glibenclamide solution: Weigh glibenclamide and mix it in DMSO medium to prepare a solution of 0.1 mg / mL. The dosage is 10 mL / kg.

[0372] • Preparation of exenatide solution: Weigh exenatide and mix it in DMSO medium to prepare a solution of 1 mg / mL. The dosage is 10 mL / kg.

[0373] Preparation of levodopa solution: Weigh levodopa and mix it with physiological saline to prepare a solution of 2 mg / mL. The dosage is 5 mL / kg.

[0374] Preparation of benserazide solution: Weigh benserazide and mix it with physiological saline to prepare a solution of 3 mg / mL. The dosage is 15 mL / kg.

[0375] Table 2. Dosage Composition

[0376] Mouse model construction, administration, and evaluation:

[0377] A total of 48 mice were randomly divided into 6 groups of 8 mice each.

[0378] Before the experiment, the mice were allowed one week to adapt to the environment. Each mouse underwent a health check, including an assessment of its fur, limbs and mouthparts, and an examination of its posture and movements for any abnormal signs.

[0379] From day 1 to day 11, the model group was injected intraperitoneally with 30 mg / kg of MPTP daily.

[0380] From day 1 to day 11, mice in the sham model were injected intraperitoneally with saline solution daily.

[0381] All groups were administered the test compound from day 5 to day 11. On day 12, 19 hours after MPTP administration, a rotarod experiment was performed. After the rotarod experiment, brain tissue was collected after euthanasia for quantitative analysis of the area of ​​tyrosine hydroxylase-positive neurons.

[0382] In the rotundus experiment, the animal was placed on a rotating rod, and the rotation speed was linearly increased from 0 rpm to 50 rpm over 300 seconds. For each experiment, the time elapsed from when the mouse was placed on the rotundus until it fell off the rod (the drop latency) and the number of rotations were recorded.

[0383] The quantitative analysis of the area of ​​tyrosine hydroxylase-positive neurons was performed using immunohistochemistry. Mouse brain tissue sections were stained to specifically label and quantify the area of ​​tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta region.

[0384] Statistical analysis results are expressed as mean ± standard error of mean (SEM). Nonparametric Kruskal-Wallis tests were used for overall comparisons among multiple groups. When significant differences were found, Conover post-hoc tests were used for pairwise comparisons, with ###P<0.001 and *P<0.05 used as statistical significance criteria.

[0385] As shown in Figure 4ab, in the rotarod experiment, compared with the sham model group mice, the MPTP model group mice showed significantly reduced drop time and number of rotations. However, after administration of gliclazide, both drop time and number of rotations in the MPTP mouse model significantly increased. Furthermore, no significant changes were observed after administration of glibenclamide, exenatide, and levodopa. These results indicate that gliclazide can significantly improve motor dysfunction in Parkinson's disease.

[0386] As shown in Figure 4c, compared to the sham mediator group, the area of ​​tyrosine hydroxylase-positive neurons in the MPTP model mediator group was significantly reduced. However, after administration of gliclazide, the area of ​​tyrosine hydroxylase-positive neurons in the MPTP mouse model was significantly increased compared to the model mediator group. Furthermore, no significant changes were observed in mice administered glibenclamide, exenatide, or levodopa compared to the model mediator group. Moreover, compared to the glibenclamide, exenatide, and levodopa groups, the area of ​​tyrosine hydroxylase-positive neurons in the gliclazide group was significantly increased. These results indicate that only gliclazide can significantly inhibit the progression of Parkinson's disease.

[0387] Example 3: Efficacy evaluation in AAV-hSyn-SNCA+PFF mouse model

[0388] Human α-synuclein (hSyn) and α-synuclein precursor fibrils (PFF) were injected into the substantia nigra pars compacta (SNpc) of the midbrain of mice using an adeno-associated virus (AAV) vector, thus constructing a model that simulates the pathological features of abnormal α-synuclein aggregation in Parkinson's disease. The inhibitory effect of the drug on α-synuclein aggregation was then evaluated by using phosphorylated α-synuclein, a commonly used biomarker for quantifying α-synuclein aggregation.

[0389] Experimental animals: C57BL / 6J mice, 8 weeks old, male.

[0390] drug:

[0391] Hydroxypropyl methyl cellulose (HPMC)

[0392] • Saline

[0393] Gliclazide

[0394] ·L-DOPA

[0395] • Benserazide

[0396] Preparation:

[0397] • Preparation of HPMC medium (0.5% hydroxypropyl methylcellulose): Weigh hydroxypropyl methylcellulose and add it to physiological saline, stir vigorously, and store at 4°C.

[0398] • Preparation of gliclazide solution: Weigh gliclazide and mix it in HPMC medium to prepare a suspension of 0.8 mg / mL. The dosage is 10 mL / kg.

[0399] Preparation of levodopa solution: Weigh levodopa and mix it with physiological saline to prepare a solution of 2 mg / mL. The dosage is 5 mL / kg.

[0400] Preparation of benserazide solution: Weigh benserazide and mix it with physiological saline to prepare a solution of 3 mg / mL. The dosage is 15 mL / kg.

[0401] Table 3. Dosage Composition

[0402] Mouse model construction, administration, and evaluation:

[0403] A total of 32 mice were randomly divided into 4 groups of 8 mice each.

[0404] Before the experiment, the mice were allowed one week to adapt to the environment. Each mouse underwent a health check, including an assessment of its fur, limbs and mouthparts, and an examination of its posture and movements for any abnormal signs.

[0405] On the first day, the model group was injected into the substantia nigra pars compacta of the midbrain of mice with AAV virus carrying the human α-synuclein gene, α-synuclein precursor fibrils, and sterile water.

[0406] On the first day of the sham module, empty AAV virus and sterile water were injected into the substantia nigra pars compacta of the midbrain of mice.

[0407] The test compound was administered to all groups from week 7 to week 15, with a dosing period of 8 weeks. In week 15, brain tissue was collected after euthanasia for quantitative analysis of the positive area of ​​phosphorylated α-synuclein.

[0408] The quantitative analysis of the positive area of ​​phosphorylated α-synuclein was performed using immunohistochemistry. Mouse brain tissue sections were stained to specifically label and quantify the proportion of phosphorylated α-synuclein positive area in the substantia nigra pars compacta region.

[0409] Statistical analysis results are expressed as mean ± standard error of mean (SEM). The Mann-Whitney U test was used to compare the sham media group and the model media group; ####P < 0.0001 indicates a highly significant statistical difference between the two groups. The Kruskal-Wallis test was then used for overall comparisons among multiple groups. When significant differences were found, Dunn's post-hoc test was used for pairwise comparisons; *P < 0.05 was considered statistically significant.

[0410] As shown in Figure 5, compared to the sham model group mice, the proportion of phosphorylated α-synuclein-positive area was significantly increased in the model model group mice. However, after administration of gliclazide, the proportion of phosphorylated α-synuclein-positive area in the mouse model was significantly reduced compared to the model model group. Furthermore, no significant changes were observed in mice administered levodopa compared to the model model group mice. These results indicate that gliclazide alone can significantly inhibit α-synuclein aggregation, thereby suppressing the progression of Parkinson's disease.

Claims

Use of gliclazide or a pharmaceutically acceptable salt thereof in the preparation of pharmaceutical products for the prevention or treatment of patients with neurodegenerative diseases selected from Parkinson's disease, multiple system atrophy, and Lewy body dementia. According to the use of claim 1, the neurodegenerative disease is Parkinson's disease. According to claim 2, the pharmaceutical product is used to treat a patient with Parkinson's disease. According to claim 3, the treatment is for controlling or preventing the progression of Parkinson's disease. According to the use of claim 3, the treatment is to improve one or more of the following symptoms of Parkinson's disease: motor symptoms, decreased sense of smell, and cognitive impairment. Use of gliclazide or a pharmaceutically acceptable salt thereof in the preparation of pharmaceutical products for the prevention or treatment of patients with neurodegenerative diseases associated with protein aggregation. According to the use of claim 6, the neurodegenerative disease associated with protein aggregation is selected from neurodegenerative diseases associated with the aggregation of one, more, or all of α-synuclein, Tau protein, Aβ amyloid protein, and TAR DNA-binding protein (TDP-43). According to the use of claim 6, the neurodegenerative disease associated with protein aggregation is a neurodegenerative disease associated with α-synuclein.

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