WO2022007578A1 - Combination for treating alzheimer's disease and use thereof - Google Patents
Combination for treating alzheimer's disease and use thereof Download PDFInfo
- Publication number
- WO2022007578A1 WO2022007578A1 PCT/CN2021/099204 CN2021099204W WO2022007578A1 WO 2022007578 A1 WO2022007578 A1 WO 2022007578A1 CN 2021099204 W CN2021099204 W CN 2021099204W WO 2022007578 A1 WO2022007578 A1 WO 2022007578A1
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- WO
- WIPO (PCT)
- Prior art keywords
- disease
- alzheimer
- modafinil
- pharmaceutical composition
- acetaminophen
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to the technical field of medicine, in particular to a combination for treating Alzheimer's disease and its application.
- AD Alzheimer's disease
- cognitive dysfunction is mainly manifested as memory impairment, aphasia, apraxia, agnosia and executive dysfunction, etc.
- mental disorders are mainly manifested as agitation, delusions, hallucinations, depression, and apathy.
- the pathological changes mainly include cerebral cortical atrophy, widening of sulci and gyri, enlargement of ventricle, massive reduction of neurons, accumulation of ⁇ -amyloid to form senile plaques, hyperphosphorylation of Tau protein to form neurofibrillary tangles, and significant content of choline acetylase and acetylcholine. reduce etc.
- Alzheimer's disease is mainly the elderly over 65 years old.
- the decline of patients' living functions and changes in personality and behavior have brought a very heavy burden to the society and the patient's family.
- the development of ⁇ -amyloid inhibitor drugs has been very popular.
- the cause of Alzheimer's disease is still unclear, and the failure of several amyloid beta inhibitors has cast a shadow over the development of subsequent drugs.
- the number of drugs currently approved for the treatment of Alzheimer's disease is small and the therapeutic effect is limited.
- the existing listed drugs mainly include cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, brain metabolism promoters, and intestinal flora regulators; the drugs under development mainly include ⁇ -amyloid inhibitor, Tau protein aggregation inhibitor, etc. Some of these drugs are symptomatic treatment, some can only improve a few pathological indicators, few can really improve the cognitive dysfunction caused by Alzheimer's disease, and there are many adverse reactions.
- Modafinil a drug introduced in the 1990s to treat narcolepsy, promotes wakefulness in people with narcolepsy. Since modafinil is considered to have psychostimulant effects and has a low potential for abuse, many studies have focused on the improvement of cognitive function with modafinil since its launch. But so far, there is no unified view in this field. For example, studies have shown that in healthy subjects, modafinil enhances performance on tests of digit span, visual pattern recognition memory, spatial planning, and stop-signal reaction time [1]. Multiple studies have shown that modafinil improves function in several cognitive domains, including working and episodic memory and other processes that depend on the prefrontal cortex and cognitive control [2].
- modafinil does not affect the cognitive function of healthy young volunteers, and produces more negative emotions such as psychological anxiety, aggression, etc. [3].
- the results of a double-blind trial showed that modafinil had no excitatory effect on human motor neurons and could not improve attention, agility and alertness [4].
- modafinil does not improve cognitive function, reduce fatigue, enhance mobility, or improve negative symptoms [5].
- modafinil failed to improve symptoms of apathy and activities of daily living in patients with Alzheimer's disease [6].
- Acetaminophen belongs to the nonsteroidal anti-inflammatory drugs (NSAIDs), which is mainly used for fever and mild to moderate pain caused by common cold or influenza in children. Acetaminophen has a certain central nervous system protective effect. It has been suggested that the neuroinflammation-modifying effects of acetaminophen may help treat neurological disorders. The role of neuroinflammation in the pathogenesis of AD has always attracted much attention. A large number of clinical and laboratory studies have confirmed that there is an inflammatory process in the occurrence and development of AD, but inflammation is a beneficial or harmful factor in the occurrence and development of AD, and is the cause of AD. The pathogenic factor or the pathological result is still unclear. The research literature on the relationship between NSAIDs and AD is inconsistent.
- NSAIDs can significantly reduce the risk of AD or delay the onset of AD (ie, prevention), but there are also research conclusions that the use of NSAIDs is not associated with the occurrence of dementia and cognitive decline. Unlike most epidemiological studies, clinical studies of NSAIDs in AD have not shown that they have a therapeutic effect on AD [8].
- the patent EP0946162 proposes that acetaminophen can treat Alzheimer's disease, and its in vitro tests show that acetaminophen can reduce the expression of various inflammatory factors in glioma cells T98G, but there is a lack of animal experiments or human experiments to further Prove validity.
- the present invention aims to solve at least one of the technical problems existing in the prior art.
- the present invention provides a combination, composition, kit, application, treatment method and the like for Alzheimer's disease. More specifically, a combination comprising modafinil and acetaminophen is provided.
- the inventors have surprisingly found in their research that the effect of modafinil can be significantly enhanced by acetaminophen when combined modafinil and acetaminophen are used to treat Alzheimer's disease. It shows that the combination of the two plays a synergistic effect; and acetaminophen also eliminates some of the adverse reactions of modafinil, such as anxiety, nervousness, etc.
- a first aspect of the present invention provides the use of a combination in the preparation of a drug or kit for treating Alzheimer's disease, the combination comprising active substances, the active substances comprising modafinil and acetaminophen , wherein the weight ratio of modafinil and paracetamol is 100:1 to 1:50.
- the treatment of Alzheimer's disease comprises amelioration of cognitive dysfunction, sleep disturbance, stress or anxiety, cholinergic dysfunction, cerebral metabolic disorder or beta caused by Alzheimer's disease One or more symptoms of amyloid disorders; preferably amelioration of cognitive dysfunction caused by Alzheimer's disease, and improvement of sleep disturbance, nervousness or anxiety, cholinergic dysfunction, brain dysfunction caused by Alzheimer's disease One or more symptoms of metabolic disorder or beta amyloid disorder.
- the weight ratio of modafinil to acetaminophen is 50:1 to 1:20, for example, the weight ratio is 50:1, 40:1, 30:1, 20 :1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3 , 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, or 1:20.
- the active substance consists of modafinil and acetaminophen.
- the active substances in the combination also include other active ingredients that are useful in the treatment of Alzheimer's disease.
- the active substance consists of modafinil, acetaminophen and other active substances useful in the treatment of Alzheimer's disease.
- the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from the group consisting of cholinesterase inhibitors, beta amyloid inhibitors, tau protein aggregation inhibitors, N-methyl - One or more of D-aspartate receptor antagonists, brain metabolism promoters, and intestinal flora regulators; more preferably, the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from One or more of tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromolyn, LMTX, memantine, NAMZARIC, oxiracetam, meclofen axetil, GV971; Most preferred is donepezil, memantine or NAMZARIC.
- the active substance consists of modafinil, acetaminophen and donepezil; or consists of modafinil, acetaminophen and memantine; or consists of modafinil, acetaminophen and memantine Consists of acetaminophen, memantine, and donepezil.
- the medicament or kit comprises one or more medicaments.
- the active substances in the combination are present together in the same medicament, or separately in different medicaments.
- the medicament is an oral preparation, an intraoral preparation, an injection preparation, an inhalation preparation, or a topical preparation.
- the drug is a constant-release formulation, a delayed-release formulation, a sustained-release formulation or a directed-release formulation.
- the medicament further includes a pharmaceutically acceptable adjuvant.
- a second aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising an active substance, the active substance comprising modafinil and acetaminophen, wherein the weight ratio of modafinil to acetaminophen 100:1 to 1:50.
- the active substance consists of modafinil and acetaminophen.
- the weight ratio of modafinil to acetaminophen is 50:1 to 1:20.
- weight ratios are 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3 :1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12 , 1:15 or 1:20.
- some preferred solutions can achieve better effects.
- the pharmaceutical composition is for the treatment of Alzheimer's disease.
- the treatment of Alzheimer's disease includes improving cognitive dysfunction, sleep disturbance, stress or anxiety, cholinergic dysfunction, and cerebral metabolic disorder caused by Alzheimer's disease Or one or more symptoms of beta amyloid disorder; preferably improve cognitive dysfunction caused by Alzheimer's disease, and improve sleep disturbance, nervousness or anxiety, cholinergic dysfunction caused by Alzheimer's disease , one or more symptoms of cerebral metabolic disorder or beta amyloid disorder.
- the active substance further includes other active ingredients that can be used to treat Alzheimer's disease.
- the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from the group consisting of cholinesterase inhibitors, beta amyloid inhibitors, Tau protein aggregation inhibitors, N- One or more of methyl-D-aspartate receptor antagonists, cerebral metabolism promoters, and intestinal flora regulators; more preferably, the other activities that can be used to treat Alzheimer's disease
- the ingredients are selected from one or more of tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromolyn, LMTX, memantine, NAMZARIC, oxiracetam, meclofen axetil, GV971 species; most preferably donepezil, memantine or NAMZARIC.
- the active substance consists of modafinil, acetaminophen and other active ingredients useful in the treatment of Alzheimer's disease.
- the active substance consists of modafinil, acetaminophen and donepezil; or modafinil, acetaminophen and memantine; or modafinil acetaminophen, donepezil, and memantine.
- the pharmaceutical composition further includes a pharmaceutically acceptable adjuvant.
- the pharmaceutically acceptable adjuvant can be selected from any pharmaceutically acceptable adjuvant known in the art according to actual needs.
- the pharmaceutically acceptable excipients are selected from fillers, binders, bases, disintegrants, lubricants, solvents, solubilizers, flavoring agents, colorants, taste-masking agents, pH adjusting agents , isotonic agents, suspending agents, thickening agents, preservatives, stabilizers, antioxidants, wetting agents, surfactants, suspending agents, propellants, absorption enhancers, absorption delaying agents and coating materials at least one.
- the pharmaceutical composition is an oral formulation, an intraoral formulation, an injection formulation, an inhalation formulation, or a topical formulation.
- the oral formulation is selected from tablets, capsules, granules, powders, pills, drops, syrups, oral solutions, oral suspensions, or oral emulsions;
- the intraoral formulation is selected from tongue Substance preparations, buccal preparations or buccal preparations;
- the injection preparations are selected from powders for injection, emulsions for injections or solutions for injections;
- the inhalation preparations are solutions for inhalation, powders for inhalation, etc.;
- the topical preparations Selected from patches, creams, ointments, ointments, gels or topical solutions.
- the pharmaceutical composition is a constant-release formulation, a delayed-release formulation, a sustained-release formulation or a directed-release formulation.
- a third aspect of the present invention provides a kit for treating Alzheimer's disease, comprising active substances including modafinil and acetaminophen, wherein modafinil and acetaminophen The weight ratio of phenol is 100:1 to 1:50.
- the weight ratio of modafinil and paracetamol is 50:1-1:20.
- weight ratios are 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3 :1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12 , 1:15 or 1:20.
- the treatment of Alzheimer's disease comprises improving cognitive dysfunction, sleep disturbance, stress or anxiety, cholinergic dysfunction, brain metabolic disorder or One or more symptoms of beta amyloid disorders; preferably improve cognitive dysfunction caused by Alzheimer's disease, and improve sleep disturbance, nervousness or anxiety, cholinergic dysfunction, Alzheimer's disease caused by Alzheimer's disease One or more symptoms of cerebral metabolic disorder or beta amyloid disorder.
- the active substance further comprises other active ingredients useful for the treatment of Alzheimer's disease.
- the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from the group consisting of cholinesterase inhibitors, beta amyloid inhibitors, tau protein aggregation inhibitors, N-methyl methacrylates One or more of base-D-aspartate receptor antagonists, brain metabolism promoters, and intestinal flora regulators; more preferably, the other active ingredients that can be used for the treatment of Alzheimer's disease One or more selected from tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromolyn, LMTX, memantine, NAMZARIC, oxiracetam, meclofen axetil, GV971 ; most preferably donepezil, memantine or NAMZARIC.
- a fourth aspect of the invention provides a method of treating Alzheimer's disease comprising administering to a subject in need thereof a therapeutically effective amount of the combination of any of the first aspects of the invention or of any of the second aspects of the invention.
- the pharmaceutical composition of item, or treatment using the kit of any item of the third aspect of the present invention is provided.
- Some embodiments of methods according to the present invention comprise administering to a subject in need thereof a therapeutically effective amount of an active substance comprising modafinil and acetaminophen, wherein modafinil and acetaminophen The weight ratio of 100:1 ⁇ 1:50.
- the weight ratio of modafinil to acetaminophen is 50:1 to 1:20.
- weight ratios are 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3 :1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12 , 1:15 or 1:20.
- the subject is an Alzheimer's disease patient.
- the present invention can be used to treat any patient at any stage of the disease, ameliorating the symptoms of said patient.
- the subject has one or more symptoms of cognitive dysfunction, sleep disturbance, stress or anxiety, cholinergic dysfunction, cerebral metabolic disturbance, or beta amyloid disturbance;
- the subject has cognitive dysfunction and one or more symptoms of sleep disturbance, stress or anxiety, cholinergic dysfunction, cerebral metabolic disturbance, or beta amyloid disturbance.
- the active substance further comprises other active ingredients useful in the treatment of Alzheimer's disease.
- the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from cholinesterase inhibitors, beta amyloid inhibitors, tau protein aggregation inhibitors, N-methyl methacrylates One or more of base-D-aspartate receptor antagonists, brain metabolism promoters, and intestinal flora regulators; more preferably, the other active ingredients that can be used for the treatment of Alzheimer's disease One or more selected from tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromolyn, LMTX, memantine, NAMZARIC, oxiracetam, meclofen axetil, GV971 ; most preferably donepezil, memantine or NAMZARIC.
- the therapeutically effective amount of modafinil may be a daily dosage of 10 mg to 1000 mg, preferably 20 mg to 800 mg, more preferably 50 mg to 500 mg.
- the amount is 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg.
- the therapeutically effective amount of acetaminophen may be 1 mg to 2000 mg per day, preferably 5 mg to 2000 mg, and more preferably 20 mg to 1200 mg.
- the dosage is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg , 800mg, 900mg, 1000mg, 1200mg, 1500mg or 2000mg.
- the doses of other active ingredients that can be used for the treatment of Alzheimer's disease may be the doses conventionally used in clinical practice, or may be lower than the doses conventionally used in clinical practice in order to obtain the best therapeutic effect.
- the doses routinely used in clinical practice are well known in the art and can be found in numerous treatises.
- the need for dosage adjustment of the other active ingredients useful in the treatment of Alzheimer's disease can be readily determined by clinicians in the art based on their clinical experience.
- the daily dose may be 0.5-50 mg, preferably 1-20 mg, such as 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15mg, 20mg, 30mg, 40mg and 50mg.
- the specific dosage of the active substances described in the present invention may need to be adjusted accordingly due to various factors, including but not limited to: the severity of the subject's condition, the subject's age, sex, weight, administration route and drug dosage form, etc.
- the active substances may be administered simultaneously or separately.
- Alzheimer's disease refers to Alzheimer's disease as determined by clinical diagnostic criteria. Diagnostic criteria and diagnostic methods for Alzheimer's disease are well known in the art.
- active substance refers to a compound that is medically or pharmaceutically capable of exerting a certain desired pharmacological activity.
- Active substance includes not only the compound molecule itself, but also pharmaceutically acceptable salts, polymorphs, solvates, hydrates, derivatives, active metabolites, prodrugs, steric isomers thereof in any chemical purity.
- “Pharmaceutically acceptable salt” refers to a pharmaceutically acceptable and relatively non-toxic inorganic/organic acid or base addition salt of a compound.
- Polymorph refers to a substance formed by microscopically different ordered arrangements of multiple compound molecules without changing the molecular structure of a single compound.
- Solvate refers to a substance formed by non-covalent bonding of compound molecules with a solvent. When the solvent is water, it can also be called “hydrate”.
- “Derivatives” include new compounds that retain the core structure of the compound and are substituted on certain groups to form new compounds related to the function of the compound, such as the acid, amide, ester, ether, acetylated variant, hydroxyl of the compound. variant, glycosylation variant or alkylation (C1-C6) variant, etc.
- Derivatives also include active metabolites and prodrugs of the compound.
- Stepoisomer refers to the substance formed by changing the three-dimensional spatial structure of the molecule under the condition that the plane structure of the compound molecule remains unchanged.
- modafinil includes at least the molecule with the chemical name 2-[(diphenylmethyl)sulfinyl]acetamide, which also includes any chemically pure pharmaceutically acceptable salt, polymorph, Solvates, hydrates, active metabolites, prodrugs, steric isomers.
- modafinil in the present invention can be R chiral isomer 2-[(R)-(diphenylmethyl)sulfinyl]acetamide, S chiral isomer 2- [(S)-(diphenylmethyl)sulfinyl]acetamide, or racemic 2-[(R,S)-(diphenylmethyl)sulfinyl]acetamide.
- the racemate of modafinil, 2-[(R,S)-(diphenylmethyl)sulfinyl]acetamide, is marketed under the trade names of PROVIGIL (USA) and Great (China).
- the R isomer 2-[(R)-(diphenylmethyl)sulfinyl]acetamide is marketed under the trade name NUVIGIL (USA).
- the S isomer can be prepared according to the methods disclosed in the existing literature.
- the global marketed dosage forms of Modafinil include capsules, tablets, orally disintegrating tablets, suspensions, oral solutions, etc., which can be obtained through legal commercial channels.
- acetaminophen includes at least the molecule with the chemical name N-acetyl-p-aminophenol, which also includes pharmaceutically acceptable salts, polymorphs, solvates, hydrates of any chemical purity , active metabolites, prodrugs, steric isomers.
- Acetaminophen is a non-steroidal anti-inflammatory drug widely used in the world for antipyretic and anti-inflammatory.
- the global marketed dosage forms of acetaminophen include capsules, tablets, sustained-release tablets, orally disintegrating tablets, sublingual tablets, enemas, granules, sustained-release granules, injections, drops, solutions, lozenges, patches , powder, suppository, suspension, etc., can be obtained through legal commercialization.
- LMTX refers to: a Tau protein aggregation inhibitor developed by TauRx Company, as a potential therapeutic drug for Alzheimer's disease, currently in clinical phase III.
- Donepezil includes at least the chemical name ( ⁇ ) 2,3-dihydro-5,6-dimethylchloro-2- ⁇ [(1-benzyl)-4-piperidinyl]methane yl ⁇ -1H-inden-1-one, which also includes pharmaceutically acceptable salts, polymorphs, solvates, hydrates, active metabolites, prodrugs, steric isomers of any chemical purity, such as Donepezil hydrochloride.
- Donepezil is a marketed cholinesterase inhibitor for the treatment of Alzheimer's disease.
- Memantine includes at least the molecule with the chemical name 1-amino-3,5-dimethyladamantanamine, which also includes pharmaceutically acceptable salts, polymorphs, solvates of any chemical purity , hydrates, active metabolites, prodrugs, steric isomers such as memantine hydrochloride. Memantine is a marketed N-methyl-D-aspartate receptor antagonist for the treatment of Alzheimer's disease.
- NAMZARIC refers to a combination of donepezil and memantine, marketed in the United States under the trade name NAMZARIC.
- GV971 refers to: mannooligosaccharide, which may be a gut microbiota regulator, and was launched in China in 2019 for the treatment of Alzheimer's disease.
- treating includes delaying or reducing symptoms caused by a given disease.
- treatment specifically includes controlling the progression of the disease and associated symptoms.
- the term "combination therapy” refers to a therapy in which more than one active substance is co-administered to a subject to cause a biological effect.
- the active substances can be administered simultaneously or separately. "At the same time” means at about the same time, and “separately” means at different times.
- terapéuticaally effective amount refers to an amount sufficient to cure, alleviate or partially inhibit the clinical manifestations of a given disease.
- An amount suitable for accomplishing this purpose is defined as a “therapeutically effective amount”.
- the effective amount for each purpose depends on the severity of the disease or injury as well as factors such as the subject's weight and general state of health.
- the term “combination” refers to an association between more than one component.
- the components can be physically mixed together or physically separated from each other.
- the active ingredients may be present in the same pharmaceutical agent at the same time, or separately in multiple different pharmaceutical agents.
- composition refers to a mixture of one or more components.
- one or more active ingredients may be included in the composition, and one or more inert ingredients may optionally be included.
- pharmaceutical refers to a finished pharmaceutical preparation that contains an active substance and is intended for immediate use by a patient or physician.
- kits refers to a container that holds a medicament for storage, transportation, formulation, and use of the medicament.
- a “kit” may be a single container or multiple containers.
- the “kit” may include one drug or multiple drugs, so as to be used alone or in combination in clinical practice.
- multiple active substances such as modafinil, acetaminophen or other active ingredients that can be used to treat Alzheimer's disease, can be present in a kit in separate dosage forms for simultaneous or sequential administration medicine.
- pharmaceutically acceptable generally means available in the pharmaceutical art and is not harmful to the product or to mammals.
- excipient may be any conventional excipient in the pharmaceutical field.
- the choice of specific excipients depends on the form of the pharmaceutical formulation or/and the mode of administration.
- the present invention provides combinations for the treatment of Alzheimer's disease. More specifically, after combining modafinil and acetaminophen in the present invention, it is found that the two can synergize, reduce adverse reactions, and significantly improve the symptoms related to Alzheimer's disease.
- the present invention combines modafinil and acetaminophen, significantly improves the cholinergic dysfunction and brain energy metabolism disorder of Alzheimer's disease patients, reduces the level of beta amyloid in the brain, and effectively improves learning Cognitive functions such as ability, memory ability, autonomous behavior ability, and exploration ability reduce tension and anxiety, and can treat Alzheimer's disease from multiple levels and improve clinical efficacy.
- the modafinil and paracetamol of the present invention can also be combined with other existing drugs that can be used for the treatment of Alzheimer's disease, so as to further improve the curative effect of the existing drugs.
- test methods used in the examples are conventional methods unless otherwise specified; the materials, reagents, etc. used, unless otherwise specified, can be obtained from commercial sources.
- Example 1 Effects of Modafinil in combination with acetaminophen on Alzheimer's disease model animals with aging and sleep disturbance
- Drugs Modafinil (provided by Xiangbei Wellman Pharmaceutical Co., Ltd.), ibuprofen (commercially available), paracetamol (commercially available).
- Grouping After one week of adaptive feeding, experimental animals were randomly divided into blank control group, model control group, modafinil group (MDF), ibuprofen group (IBU), acetaminophen group (APAP), and modafinil group. Finil + ibuprofen group (MDF/IBU-1), modafinil + ibuprofen group (MDF/IBU-2), modafinil + acetaminophen group (MDF/APAP- 1) Modafinil + acetaminophen two groups (MDF/APAP-2), modafinil + acetaminophen three groups (MDF/APAP-3), 12 animals in each group.
- MDF modafinil group
- IBU ibuprofen group
- APAP acetaminophen group
- Modeling Animals in each group were fed in heat-resistant rat cages, placed under natural light, and given a normal diet. In the blank control group, 0.5 mL of normal saline was injected intraperitoneally every day for 6 weeks. Except for the blank control group, the other groups were intraperitoneally injected with D-galactose 50 mg/kg daily for 6 consecutive weeks, during which artificial light was added every night (19:00 to 7:00 the next day) from the 4th week onwards ( Strength 600lx).
- mice were administered by continuous intragastric administration for 2 weeks.
- Modafinil was administered at 5 mg/kg per day in the MDF group
- ibuprofen was administered at 100 mg/kg per day in the IBU group
- acetaminophen at 100 mg/kg per day in the APAP group
- the MDF/IBU-1 group was administered Modafinil 5 mg/kg and ibuprofen 0.1 mg/kg daily
- MDF/IBU-2 group received daily modafinil 5 mg/kg and ibuprofen 100 mg/kg
- MDF The /APAP-1 group was given 5 mg/kg of modafinil and 0.1 mg/kg of acetaminophen daily
- the MDF/APAP-2 group was given 5 mg/kg of modafinil and 100 mg/kg daily
- the MDF/APAP-3 group received 5 mg/kg of modafinil and 200 mg/kg of acetaminophen daily.
- the blank control group and the model control group were given the same
- Open field test put the animal into a square box with a length of 25cm, a width of 25cm and a height of 40cm. The bottom of the box is divided into 25 small squares on average, and the number of times of passing, standing, urinating and defecation and grooming are recorded within 5 minutes. Times (the times of modification refers to the times of scratching, washing face, licking feet, etc.).
- Morris water maze test Morris water maze test is performed after completion of the open field test. First, placenavigation training: set a platform somewhere in the fourth quadrant of the circular pool of the water maze, the platform is set at 1 cm underwater, and the animals are placed in the water facing the pool wall from other quadrants. Train animals to find platforms in 60 seconds. Train 2 times a day for 5 consecutive days. On the 6th day, the spatial probe test was performed, the platform was removed, the animal was placed in the water facing the pool wall, tested for 60 seconds, and the number of times the animal reached the original platform position within 60 seconds (the number of passes) was recorded, and in the fourth quadrant Sojourn time as a percentage of total swimming time (fourth quadrant time share).
- Table 1 lists the main results of the open field test.
- Table 2 lists the main results of the Morris water maze test.
- the open field test detects the autonomous behavior and mental state of animals. The more times of crossing and standing, the stronger the autonomous behavior and exploration ability of the animal, and the more times of urination and modification, the stronger the sense of tension and anxiety of the animal.
- Morris water maze test can detect the learning and memory ability of animals.
- the effect of modafinil in combination with acetaminophen was investigated in this experiment. It was found that acetaminophen can significantly enhance the effect of modafinil, and the combination of the two can significantly improve the autonomous behavior, exploration ability, learning and memory ability of model animals, which is statistically significant compared with the model group.
- mice Male Kunming mice, half male and half male, weighing 30-40g.
- Drugs Modafinil (provided by Xiangbei Wellman Pharmaceutical Co., Ltd.), paracetamol (commercially available), donepezil (commercially available).
- Grouping Animals were randomly divided into 8 groups after one week of adaptive feeding: blank control group, model control group, modafinil group (MDF), paracetamol group (APAP), donepezil group (DNP), modafinil group + acetaminophen low-dose group (MDF/APAP-l), modafinil + acetaminophen high-dose group (MDF/APAP-h), modafinil + acetaminophen + donepezil group (MDF /APAP/DNP), 12 in each group.
- MDF modafinil group
- APAP paracetamol group
- DNP donepezil group
- MDF/APAP-l modafinil group + acetaminophen low-dose group
- MDF/APAP-h modafinil + acetaminophen + donepezil group
- 12 in each group 12 in each group.
- MDF group was given 5 mg/kg of modafinil daily
- APAP group was given 30 mg/kg of acetaminophen daily
- DNP group was given 1 mg/kg of donepezil daily
- MDF/APAP-1 The group was given 5 mg/kg of modafinil and 30 mg/kg of acetaminophen daily
- the MDF/APAP-h group was given 10 mg/kg of modafinil and 60 mg/kg of acetaminophen daily
- MDF/APAP/DNP group was given 10 mg/kg of modafinil, 60 mg/kg of acetaminophen and 1 mg/kg of donepezil daily.
- the blank control group and the model control group were given the same volume of normal saline every day. Each group was given continuous intragastric administration for 1 week.
- Test One hour after the modeling is completed, perform the avoidance platform jumping reflex experiment: put the animals into the platform jumping reaction box (the bottom of the box is a copper grid that can be energized, and a plastic safety platform is set in the box), after 3 minutes of adaptation, turn on 36V AC , recording the time (reaction time) between the time the animal received the shock and jumped onto the safety platform. After 24 hours, the animals were put into the platform jumping reaction box again, and 36V alternating current was applied, and the time between the animals jumping on the safety platform and the first jumping off the safety platform (platform jumping latency) was recorded.
- mice were decapitated and the brains were removed. The brain tissue was quickly separated on ice, and normal saline was added to make a 10% concentration of brain tissue homogenate. , the content of acetylcholinesterase was determined with a microplate reader.
- Table 3 lists the main results of the avoidance platform jumping reflex experiment, and Table 4 lists the main results of the cholinergic index measurement.
- Acetylcholinesterase activity (U/mgprot) blank 12 0.34 ⁇ 0.10 Model comparison 12 0.80 ⁇ 0.08 ##
- scopolamine was used to cause cholinergic disorders in animals, which can be manifested as increased acetylcholinesterase activity, and thus decreased acetylcholine content.
- the activity of acetylcholinesterase in the model group was significantly increased, and the reaction time in the avoidance platform jumping reflex test was longer, and the platform jumping latency was shortened, indicating that the animals had cholinergic disorders and cognitive decline.
- Donepezil a positive drug for Alzheimer's disease, is a known acetylcholinesterase inhibitor. This experiment shows that it can reduce the activity of acetylcholinesterase in animals and improve learning and memory ability. It shows that this model can be used to evaluate the effect of Alzheimer's disease drugs.
- the avoidance platform reflex test can reflect the animal's learning ability and memory ability by testing the animal's response to electric shock injury. Among them, the shorter the time (reaction time) between the time the animal received the electric shock and the jump on the safety platform, the better the learning ability. After 24 hours of learning, the animals were tested again from the time they jumped on the safety platform to the first time they jumped off the safety platform. The longer the platform jump latency, the better the memory ability of the animal. In this experiment, modafinil combined with acetaminophen also showed positive effects. Both low and high doses showed that it could reduce the activity of acetylcholinesterase, protect the cholinergic disorders caused by scopolamine, and improve the ability of learning and memory.
- donepezil, modafinil and acetaminophen were used in combination in this experiment.
- the effect of the combination of the three was significantly better than that of donepezil, showing that the combination of modafinil and acetaminophen has the advantages of Potential for drug synergists in Alzheimer's disease.
- Animals Wister rats, half male and half female, weighing 250-300 g.
- Drugs Modafinil (provided by Xiangbei Wellman Pharmaceutical Co., Ltd.), paracetamol (commercially available), memantine (commercially available).
- Grouping Animals were randomly divided into 8 groups: blank group, model group, modafinil group (MDF), paracetamol group (APAP), memantine group (MEM), modafinil + paracetamol a group (MDF/APAP-a), modafinil + acetaminophen b group (MDF/APAP-b), modafinil + acetaminophen + memantine group (MDF/APAP/MEM). 18 animals per group.
- MDF modafinil group
- APAP paracetamol group
- MEM memantine group
- MDF/APAP-a modafinil + paracetamol a group
- MDF/APAP-b modafinil + acetaminophen + memantine group
- 18 animals per group 18 animals per group.
- Administration was started the next day after the modeling was completed.
- the MDF group was given 20 mg/kg of modafinil daily
- the APAP group was given 10 mg/kg of paracetamol daily
- the MEM group was given 0.5 mg/kg of memantine daily
- the MDF/APAP-a group was given Modafinil 20mg/kg and acetaminophen 10mg/kg daily
- MDF/APAP-b group 20mg/kg modafinil and acetaminophen 120mg/kg daily
- the MEM group was administered 20 mg/kg modafinil, 120 mg/kg acetaminophen and 0.5 mg/kg memantine daily.
- the blank group and the model group were given the same volume of normal saline every day. Each group was given continuous intragastric administration for 1 week.
- Test Morris water maze test was performed the day after the last dose. In the training of place navigation, a platform was set in the circular pool of the water maze, and the platform was set at 1 cm underwater, and the animals were placed in the water facing the pool wall. Start timing and record the time for the animals to find the platform (platform-finding latency). Animals that find the platform within 60 seconds are guided to stand on the platform for 15 seconds. Animals that do not find the platform within 60 seconds are guided by the experimenter to find the platform. Training was performed twice a day for 5 consecutive days, and the average of the 5 days was used as the platform-seeking incubation period. On the 6th day, a spatial probe test was performed, the platform was removed, and the animals were placed in the water facing the pool wall for 60 seconds.
- Count of cells positive for beta amyloid expression After the completion of the Morris water maze test, the rest of the animals except those used for the energy metabolism assay were perfused with paraformaldehyde after anesthesia, the brains were taken and the hippocampus was isolated, histological sections were stained with HE and Immunohistochemical staining. Observe the sections under a 400-fold microscope, and record the number of light yellow or brown cells in 5 randomly selected areas, that is, the number of cells that express amyloid-beta positive. Two slices were made for each animal, the observation was repeated, and the average was taken.
- Table 5 lists the main results of the Morris water maze test
- Table 6 lists the main results of the energy metabolism assay
- Table 7 lists the counts of cells positive for beta amyloid expression.
- the combination of memantine, modafinil and acetaminophen is more effective than memantine, indicating that the combination of modafinil and acetaminophen can be used as an alternative to existing Alzheimer's disease drugs. Use of synergists.
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Abstract
A combination for treating Alzheimer's disease and a use thereof, specifically, a combination based on Modafinil and acetaminophen, and a use thereof for preparing a drug to treat Alzheimer's disease. According to research, when combining Modafinil and acetaminophen for treating Alzheimer's disease, the effect of Modafinil is significantly enhanced by acetaminophen, and test results show that the combination of the two has a synergistic effect; also, acetaminophen eliminates certain adverse reactions to Modafinil, such as anxiety and tension.
Description
本发明涉及医药技术领域，特别涉及治疗阿尔茨海默病的组合及其应用。The present invention relates to the technical field of medicine, in particular to a combination for treating Alzheimer's disease and its application.
阿尔茨海默病(Alzheimer’s Disease，AD)是一种神经退行性疾病，其病因不明，临床表现主要是持续进行性的认知功能减退及其伴随的社会生活功能减退和人格行为改变和精神异常。其中认知功能减退主要表现为记忆障碍、失语、失用、失认和执行功能障碍等，精神异常主要表现为激越、妄想、幻觉、抑郁、淡漠等。病理改变主要有脑皮质萎缩、沟回增宽、脑室扩大、神经元大量减少、β淀粉样蛋白聚集形成老年斑、Tau蛋白高度磷酸化形成神经元纤维缠结、胆碱乙酰化酶及乙酰胆碱含量显著减少等。Alzheimer's disease (AD) is a neurodegenerative disease whose etiology is unknown. The clinical manifestations are mainly persistent cognitive decline and its accompanying social life dysfunction, personality behavior changes, and mental disorders. . Among them, cognitive dysfunction is mainly manifested as memory impairment, aphasia, apraxia, agnosia and executive dysfunction, etc., and mental disorders are mainly manifested as agitation, delusions, hallucinations, depression, and apathy. The pathological changes mainly include cerebral cortical atrophy, widening of sulci and gyri, enlargement of ventricle, massive reduction of neurons, accumulation of β-amyloid to form senile plaques, hyperphosphorylation of Tau protein to form neurofibrillary tangles, and significant content of choline acetylase and acetylcholine. reduce etc.
阿尔茨海默病的发病人群主要是65岁以上的老年人，患者生活功能的减退以及人格行为的改变，给社会和患者家庭带来了非常沉重的负担。自1906年阿尔茨海默病被发现以来，科学家们进行了大量的相关研究。特别是近10年以来，β淀粉样蛋白抑制剂类药物的开发非常热门。但是遗憾的是，目前对于阿尔茨海默病的发病原因仍然不清楚，多款β淀粉样蛋白抑制剂的失败为后续药物的研发蒙上了阴影。目前批准上市的治疗阿尔茨海默病的药物数量较少并且治疗效果有限。现有上市药物主要有胆碱酯酶抑制剂、N-甲基-D-天冬氨酸受体拮抗剂、脑代谢促进剂、肠道菌群调节剂几类；在研的药物主要还有β淀粉样蛋白抑制剂、Tau蛋白聚集抑制剂等。这些药物有的是对症治疗，有的仅能改善少数病理指标，很少能够真正改善阿尔茨海默病导致的认知功能障碍，并且存在许多不良反应。The incidence of Alzheimer's disease is mainly the elderly over 65 years old. The decline of patients' living functions and changes in personality and behavior have brought a very heavy burden to the society and the patient's family. Since the discovery of Alzheimer's disease in 1906, scientists have conducted a lot of related research. Especially in the past 10 years, the development of β-amyloid inhibitor drugs has been very popular. Unfortunately, the cause of Alzheimer's disease is still unclear, and the failure of several amyloid beta inhibitors has cast a shadow over the development of subsequent drugs. The number of drugs currently approved for the treatment of Alzheimer's disease is small and the therapeutic effect is limited. The existing listed drugs mainly include cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, brain metabolism promoters, and intestinal flora regulators; the drugs under development mainly include β-amyloid inhibitor, Tau protein aggregation inhibitor, etc. Some of these drugs are symptomatic treatment, some can only improve a few pathological indicators, few can really improve the cognitive dysfunction caused by Alzheimer's disease, and there are many adverse reactions.
莫达非尼(Modafinil)是1990年代上市的一种治疗嗜睡症的药物，可促进嗜睡症患者的清醒。由于莫达非尼被认为具有精神兴奋作用并且具有较低的滥用可能性，自上市以来许多研究开始关注莫达非尼对于认知功能的改善。但直到目前，本领域还没有形成统一一致的观点。例如：有研究表明在健康受试者中，莫达非尼可增强数字跨度测试、视觉模式识别记忆、空间规划和停止信号反应时间测试中的能力[1]。多项研究表明莫达非尼可改善一些认知领域的功能，包括工作记忆和情景记忆以及其它依赖前额叶皮层和认知控制的过程[2]。但也有研究指出，莫达非尼不影响健康年轻志愿者的认知功能，并且产生了更多不良情绪如心理焦虑、攻击性等[3]。一项双盲试验结果表明，莫达非尼对人体运 动神经元没有兴奋作用，不能提高注意力、敏捷性和警觉性[4]。在精神分裂症患者中，莫达非尼不能提高认知功能、减轻疲劳、增强活动能力、改善阴性症状[5]。一项III期临床试验中，莫达非尼未能改善阿尔茨海默氏病患者的冷漠症状、日常生活活动功能[6]。有研究报道在基因敲除的Df(h22q11)/+雄性小鼠中(这些基因敲除小鼠与野生型小鼠相比，额叶前额皮质-海马振荡同步性降低，可作为一种认知功能障碍动物模型)，观察到莫达非尼加剧了小鼠认知障碍[7]。目前没有试验表明莫达非尼是否可以改善阿尔茨海默病导致的认知功能障碍。赛福伦(Cephalon)公司于2003年的专利申请CN03816595.3提到莫达非尼可治疗阿尔茨海默病，但仅为断言或推测并无相关试验数据。因此，多年以来，业界对莫达非尼是否能改善认知并没有形成一致的观点，无论是对于健康人群，还是神经系统疾病的患者，有的研究显示可以增强认知功能，有的研究显示并未达到认知改善作用。Modafinil, a drug introduced in the 1990s to treat narcolepsy, promotes wakefulness in people with narcolepsy. Since modafinil is considered to have psychostimulant effects and has a low potential for abuse, many studies have focused on the improvement of cognitive function with modafinil since its launch. But so far, there is no unified view in this field. For example, studies have shown that in healthy subjects, modafinil enhances performance on tests of digit span, visual pattern recognition memory, spatial planning, and stop-signal reaction time [1]. Multiple studies have shown that modafinil improves function in several cognitive domains, including working and episodic memory and other processes that depend on the prefrontal cortex and cognitive control [2]. However, some studies have pointed out that modafinil does not affect the cognitive function of healthy young volunteers, and produces more negative emotions such as psychological anxiety, aggression, etc. [3]. The results of a double-blind trial showed that modafinil had no excitatory effect on human motor neurons and could not improve attention, agility and alertness [4]. In patients with schizophrenia, modafinil does not improve cognitive function, reduce fatigue, enhance mobility, or improve negative symptoms [5]. In a phase III clinical trial, modafinil failed to improve symptoms of apathy and activities of daily living in patients with Alzheimer's disease [6]. Studies have reported that in knockout Df(h22q11)/+ male mice (these knockout mice have reduced frontal prefrontal cortex-hippocampal oscillation synchrony compared with wild-type mice, which may serve as a cognitive functional impairment animal model), it was observed that modafinil exacerbated cognitive impairment in mice [7]. There are currently no trials to show whether modafinil improves cognitive impairment caused by Alzheimer's disease. The patent application CN03816595.3 of Cephalon Company in 2003 mentioned that modafinil can treat Alzheimer's disease, but it is only an assertion or speculation without relevant experimental data. Therefore, for many years, the industry has not reached a consensus on whether modafinil can improve cognition. Whether it is for healthy people or patients with neurological diseases, some studies have shown that it can enhance cognitive function, and some studies have shown that modafinil can improve cognition. No cognitive improvement was achieved.
对乙酰氨基酚(Acetaminophen，APAP)属于非甾体抗炎药(Nonsteroidal anti-inflammatory drugs，NSAIDs)，主要用于小儿普通感冒或流行性感冒引起的发热，以及缓解轻至中度疼痛。对乙酰氨基酚具有一定的中枢神经保护作用。有人认为对乙酰氨基酚对神经炎症的缓解作用可能有助于治疗神经系统疾病。神经炎症在AD发病机制中的作用一直备受关注，大量的临床和实验室研究证实，AD的发生、发展存在炎症过程，但炎症是AD发生、发展的有益因素还是有害因素，是AD的致病因素还是病理结果目前仍不清楚。有关NSAIDs与AD关系的研究文献，结果并不一致。迄今，多项流行病学研究显示，NSAIDs能够显著降低AD的风险性或推迟AD的发病(即预防)，但也有NSAIDs的使用与痴呆的发生及认知功能的下降没有关联性的研究结论。与大多数的流行病学研究结果不同，NSAIDs治疗AD的临床研究结果未显示其对AD有治疗作用[8]。另外，专利EP0946162提出对乙酰氨基酚可治疗阿尔茨海默病，其体外试验表明对乙酰氨基酚可降低脑胶质瘤细胞T98G中多种炎性因子的表达，但缺乏动物试验或人体试验进一步证明有效性。许多其它研究仍出现相反结论，例如动物试验中对乙酰氨基酚使小鼠记忆产生损伤[9]，回顾性临床研究表明对乙酰氨基酚可增加阿尔茨海默病的风险[10]，权威循证医学机构Cochrane对604项人体研究进行的Meta分析认为无法证明包括对乙酰氨基酚在内等非甾体抗炎药可用于治疗阿尔茨海默病[11]。Acetaminophen (APAP) belongs to the nonsteroidal anti-inflammatory drugs (NSAIDs), which is mainly used for fever and mild to moderate pain caused by common cold or influenza in children. Acetaminophen has a certain central nervous system protective effect. It has been suggested that the neuroinflammation-modifying effects of acetaminophen may help treat neurological disorders. The role of neuroinflammation in the pathogenesis of AD has always attracted much attention. A large number of clinical and laboratory studies have confirmed that there is an inflammatory process in the occurrence and development of AD, but inflammation is a beneficial or harmful factor in the occurrence and development of AD, and is the cause of AD. The pathogenic factor or the pathological result is still unclear. The research literature on the relationship between NSAIDs and AD is inconsistent. So far, a number of epidemiological studies have shown that NSAIDs can significantly reduce the risk of AD or delay the onset of AD (ie, prevention), but there are also research conclusions that the use of NSAIDs is not associated with the occurrence of dementia and cognitive decline. Unlike most epidemiological studies, clinical studies of NSAIDs in AD have not shown that they have a therapeutic effect on AD [8]. In addition, the patent EP0946162 proposes that acetaminophen can treat Alzheimer's disease, and its in vitro tests show that acetaminophen can reduce the expression of various inflammatory factors in glioma cells T98G, but there is a lack of animal experiments or human experiments to further Prove validity. Numerous other studies have come to the opposite conclusion, such as acetaminophen in animal experiments impairs memory in mice [9], and retrospective clinical studies have shown that acetaminophen increases the risk of Alzheimer's disease [10], authoritative follow-up According to a meta-analysis of 604 human studies conducted by Cochrane, a medical institution, it was found that non-steroidal anti-inflammatory drugs, including acetaminophen, could not be used to treat Alzheimer's disease [11].
因此，现有的治疗阿尔茨海默病的药物仍然存在疗效不确切、不良反应多等问题。Therefore, the existing drugs for the treatment of Alzheimer's disease still have problems such as inaccurate efficacy and many adverse reactions.
发明内容SUMMARY OF THE INVENTION
本发明旨在至少解决现有技术中存在的技术问题之一。为此，本发明提供了一种用于阿尔茨海默病的组合、组合物、药盒、应用、治疗方法等。更具体地，提供了一种包括莫达非尼和对乙酰氨基酚 的组合。The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the present invention provides a combination, composition, kit, application, treatment method and the like for Alzheimer's disease. More specifically, a combination comprising modafinil and acetaminophen is provided.
本发明人在研究中令人惊讶地发现，将莫达非尼和对乙酰氨基酚组合治疗阿尔茨海默病时，莫达非尼的作用可被对乙酰氨基酚显著增强，在多项试验中表明二者组合发挥了协同作用；并且对乙酰氨基酚还消除了莫达非尼的某些不良反应，如焦虑、紧张等。The inventors have surprisingly found in their research that the effect of modafinil can be significantly enhanced by acetaminophen when combined modafinil and acetaminophen are used to treat Alzheimer's disease. It shows that the combination of the two plays a synergistic effect; and acetaminophen also eliminates some of the adverse reactions of modafinil, such as anxiety, nervousness, etc.
因此，本发明的技术方案如下文所示。Therefore, the technical solutions of the present invention are as follows.
本发明的第一方面提供了一种组合在制备治疗阿尔茨海默病的药物或药盒中的应用，所述组合中包括活性物质，所述活性物质包括莫达非尼和对乙酰氨基酚，其中莫达非尼和对乙酰氨基酚的重量比为100:1～1:50。A first aspect of the present invention provides the use of a combination in the preparation of a drug or kit for treating Alzheimer's disease, the combination comprising active substances, the active substances comprising modafinil and acetaminophen , wherein the weight ratio of modafinil and paracetamol is 100:1 to 1:50.
根据本发明的应用的一些实施方式，所述治疗阿尔茨海默病包括改善阿尔茨海默病引起的认知功能障碍、睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状；优选改善阿尔茨海默病引起的认知功能障碍，并且改善阿尔茨海默病引起的睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状。According to some embodiments of the application of the present invention, the treatment of Alzheimer's disease comprises amelioration of cognitive dysfunction, sleep disturbance, stress or anxiety, cholinergic dysfunction, cerebral metabolic disorder or beta caused by Alzheimer's disease One or more symptoms of amyloid disorders; preferably amelioration of cognitive dysfunction caused by Alzheimer's disease, and improvement of sleep disturbance, nervousness or anxiety, cholinergic dysfunction, brain dysfunction caused by Alzheimer's disease One or more symptoms of metabolic disorder or beta amyloid disorder.
根据本发明的应用的一些实施方式，所述莫达非尼和对乙酰氨基酚的重量比为50:1～1:20，例如重量比为50:1、40:1、30:1、20:1、10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:12、1:15或1:20。According to some embodiments of the application of the present invention, the weight ratio of modafinil to acetaminophen is 50:1 to 1:20, for example, the weight ratio is 50:1, 40:1, 30:1, 20 :1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3 , 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, or 1:20.
根据本发明的应用的一些实施方式，所述活性物质由莫达非尼和对乙酰氨基酚组成。According to some embodiments of the use of the present invention, the active substance consists of modafinil and acetaminophen.
根据本发明的应用的一些实施方式，所述组合中的活性物质还包括其它可用于治疗阿尔茨海默病的活性成分。According to some embodiments of the application of the present invention, the active substances in the combination also include other active ingredients that are useful in the treatment of Alzheimer's disease.
根据本发明的应用的一些实施方式，所述活性物质由莫达非尼、对乙酰氨基酚以及其它可用于治疗阿尔茨海默病的活性物质组成。According to some embodiments of the use of the present invention, the active substance consists of modafinil, acetaminophen and other active substances useful in the treatment of Alzheimer's disease.
根据本发明的应用的一些实施方式，所述其它可用于治疗阿尔茨海默病的活性成分选自胆碱酯酶抑制剂、β淀粉样蛋白抑制剂、Tau蛋白聚集抑制剂、N-甲基-D-天冬氨酸受体拮抗剂、脑代谢促进剂、肠道菌群调节剂中的一种或多种；更优选地，所述其它可用于治疗阿尔茨海默病的活性成分选自他克林、加兰他敏、多奈哌齐、卡巴拉汀、石杉碱甲、色甘酸、LMTX、美金刚、NAMZARIC、奥拉西坦、甲氯芬酯、GV971中的一种或多种；最优选为多奈哌齐、美金刚或NAMZARIC。According to some embodiments of the application of the present invention, the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from the group consisting of cholinesterase inhibitors, beta amyloid inhibitors, tau protein aggregation inhibitors, N-methyl - One or more of D-aspartate receptor antagonists, brain metabolism promoters, and intestinal flora regulators; more preferably, the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from One or more of tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromolyn, LMTX, memantine, NAMZARIC, oxiracetam, meclofen axetil, GV971; Most preferred is donepezil, memantine or NAMZARIC.
根据本发明的应用的一些实施方式，所述活性物质由莫达非尼、对乙酰氨基酚和多奈哌齐组成；或者由莫达非尼、对乙酰氨基酚和美金刚组成；或者由莫达非尼、对乙酰氨基酚、美金刚和多奈哌齐组成。According to some embodiments of the application of the present invention, the active substance consists of modafinil, acetaminophen and donepezil; or consists of modafinil, acetaminophen and memantine; or consists of modafinil, acetaminophen and memantine Consists of acetaminophen, memantine, and donepezil.
根据本发明的应用的一些实施方式，所述药物或药盒包括一个或多个药剂。According to some embodiments of the use of the invention, the medicament or kit comprises one or more medicaments.
根据本发明的应用的一些实施方式，所述组合中的活性物质共同存在于同一药剂中，或者分别存在于不同的药剂中。According to some embodiments of the use of the present invention, the active substances in the combination are present together in the same medicament, or separately in different medicaments.
根据本发明的应用的一些实施方式，所述的药物为口服制剂、口腔内制剂、注射制剂、吸入制剂，或者局部用制剂。According to some embodiments of the application of the present invention, the medicament is an oral preparation, an intraoral preparation, an injection preparation, an inhalation preparation, or a topical preparation.
根据本发明的应用的一些实施方式，所述药物为常释制剂、迟释制剂、缓释制剂或定向释放制剂。According to some embodiments of the application of the present invention, the drug is a constant-release formulation, a delayed-release formulation, a sustained-release formulation or a directed-release formulation.
根据本发明的应用的一些实施方式，所述药物还包括药学上可接受的辅料。According to some embodiments of the application of the present invention, the medicament further includes a pharmaceutically acceptable adjuvant.
本发明第二方面提供了一种药物组合物，所述药物组合物包括活性物质，所述活性物质包括莫达非尼和对乙酰氨基酚，其中莫达非尼和对乙酰氨基酚的重量比为100:1～1:50。A second aspect of the present invention provides a pharmaceutical composition comprising an active substance, the active substance comprising modafinil and acetaminophen, wherein the weight ratio of modafinil to acetaminophen 100:1 to 1:50.
根据本发明的药物组合物的一些实施方式，所述活性物质，由莫达非尼和对乙酰氨基酚组成。According to some embodiments of the pharmaceutical composition of the present invention, the active substance consists of modafinil and acetaminophen.
根据本发明的药物组合物的一些实施方式，优选地，所述莫达非尼和对乙酰氨基酚的重量比为50:1～1:20。例如，重量比为50:1、40:1、30:1、20:1、10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:12、1:15或1:20。根据本发明的一些实施方式，一些优选方案可以起到更好的效果。According to some embodiments of the pharmaceutical composition of the present invention, preferably, the weight ratio of modafinil to acetaminophen is 50:1 to 1:20. For example, weight ratios are 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3 :1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12 , 1:15 or 1:20. According to some embodiments of the present invention, some preferred solutions can achieve better effects.
根据本发明的药物组合物的一些实施方式，所述药物组合物用于治疗阿尔茨海默病。According to some embodiments of the pharmaceutical composition of the present invention, the pharmaceutical composition is for the treatment of Alzheimer's disease.
根据本发明的药物组合物的一些实施方式，所述治疗阿尔茨海默病包括改善阿尔茨海默病引起的认知功能障碍、睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状；优选改善阿尔茨海默病引起的认知功能障碍，并且改善阿尔茨海默病引起的睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状。According to some embodiments of the pharmaceutical composition of the present invention, the treatment of Alzheimer's disease includes improving cognitive dysfunction, sleep disturbance, stress or anxiety, cholinergic dysfunction, and cerebral metabolic disorder caused by Alzheimer's disease Or one or more symptoms of beta amyloid disorder; preferably improve cognitive dysfunction caused by Alzheimer's disease, and improve sleep disturbance, nervousness or anxiety, cholinergic dysfunction caused by Alzheimer's disease , one or more symptoms of cerebral metabolic disorder or beta amyloid disorder.
根据本发明的药物组合物的一些实施方式，所述活性物质还包括其它可用于治疗阿尔茨海默病的活性成分。According to some embodiments of the pharmaceutical composition of the present invention, the active substance further includes other active ingredients that can be used to treat Alzheimer's disease.
根据本发明的药物组合物的一些实施方式，所述其它可用于治疗阿尔茨海默病的活性成分选自胆碱酯酶抑制剂、β淀粉样蛋白抑制剂、Tau蛋白聚集抑制剂、N-甲基-D-天冬氨酸受体拮抗剂、脑代谢促进剂、肠道菌群调节剂中的一种或多种；更优选地，所述其它可用于治疗阿尔茨海默病的活性成分选自他克林、加兰他敏、多奈哌齐、卡巴拉汀、石杉碱甲、色甘酸、LMTX、美金刚、NAMZARIC、奥拉西坦、甲氯芬酯、GV971中的一种或多种；最优选为多奈哌齐、美金刚或NAMZARIC。According to some embodiments of the pharmaceutical composition of the present invention, the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from the group consisting of cholinesterase inhibitors, beta amyloid inhibitors, Tau protein aggregation inhibitors, N- One or more of methyl-D-aspartate receptor antagonists, cerebral metabolism promoters, and intestinal flora regulators; more preferably, the other activities that can be used to treat Alzheimer's disease The ingredients are selected from one or more of tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromolyn, LMTX, memantine, NAMZARIC, oxiracetam, meclofen axetil, GV971 species; most preferably donepezil, memantine or NAMZARIC.
根据本发明的药物组合物的一些实施方式，所述活性物质由莫达非尼、对乙酰氨基酚和其它可用于治疗阿尔茨海默病的活性成分组成。According to some embodiments of the pharmaceutical composition of the present invention, the active substance consists of modafinil, acetaminophen and other active ingredients useful in the treatment of Alzheimer's disease.
根据本发明的药物组合物的一些实施方式，所述活性物质由莫达非尼、对乙酰氨基酚和多奈哌齐组成；或者由莫达非尼、对乙酰氨基酚和美金刚组成；或者由莫达非尼、对乙酰氨基酚、多奈哌齐和美金刚组成。According to some embodiments of the pharmaceutical composition of the present invention, the active substance consists of modafinil, acetaminophen and donepezil; or modafinil, acetaminophen and memantine; or modafinil acetaminophen, donepezil, and memantine.
根据本发明的药物组合物的一些实施方式，所述药物组合物还包括药学上可接受的辅料。所述药学上可接受的辅料可以根据实际需要，选择本领域公知的任何药学上可接受的辅料。在一些实例中，所述药学上可接受的辅料选自填充剂、粘合剂、基质、崩解剂、润滑剂、溶剂、增溶剂、矫味剂、着色剂、掩味剂、pH调节剂、等渗剂、助悬剂、增稠剂、防腐剂、稳定剂、抗氧剂、润湿剂、表面活性剂、悬浮剂、抛射剂、吸收增强剂、吸收延迟剂和包衣材料中的至少一种。According to some embodiments of the pharmaceutical composition of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable adjuvant. The pharmaceutically acceptable adjuvant can be selected from any pharmaceutically acceptable adjuvant known in the art according to actual needs. In some examples, the pharmaceutically acceptable excipients are selected from fillers, binders, bases, disintegrants, lubricants, solvents, solubilizers, flavoring agents, colorants, taste-masking agents, pH adjusting agents , isotonic agents, suspending agents, thickening agents, preservatives, stabilizers, antioxidants, wetting agents, surfactants, suspending agents, propellants, absorption enhancers, absorption delaying agents and coating materials at least one.
根据本发明的药物组合物的一些实施方式，所述药物组合物为口服制剂、口腔内制剂、注射制剂、吸入制剂，或者局部用制剂。在一些实例中，所述口服制剂选自片剂、胶囊剂、颗粒剂、散剂、丸剂、滴剂、糖浆剂、口服溶液剂、口服混悬剂或口服乳剂；所述口腔内制剂选自舌下用制剂、口颊用制剂或者口含制剂；所述注射制剂选自注射用粉末、注射用乳剂或注射用溶液；所述吸入制剂为吸入用溶液、吸入用粉末等；所述局部用制剂选自贴剂、乳膏、软膏、油膏、凝胶或外用溶液。According to some embodiments of the pharmaceutical composition of the present invention, the pharmaceutical composition is an oral formulation, an intraoral formulation, an injection formulation, an inhalation formulation, or a topical formulation. In some instances, the oral formulation is selected from tablets, capsules, granules, powders, pills, drops, syrups, oral solutions, oral suspensions, or oral emulsions; the intraoral formulation is selected from tongue Substance preparations, buccal preparations or buccal preparations; the injection preparations are selected from powders for injection, emulsions for injections or solutions for injections; the inhalation preparations are solutions for inhalation, powders for inhalation, etc.; the topical preparations Selected from patches, creams, ointments, ointments, gels or topical solutions.
根据本发明的药物组合物的一些实施方式，所述药物组合物为常释制剂、迟释制剂、缓释制剂或定向释放制剂。According to some embodiments of the pharmaceutical composition of the present invention, the pharmaceutical composition is a constant-release formulation, a delayed-release formulation, a sustained-release formulation or a directed-release formulation.
本发明第三方面提供了一种用于治疗阿尔茨海默病的药盒，包括活性物质，所述活性物质包括莫达非尼和对乙酰氨基酚，其中，莫达非尼和对乙酰氨基酚的重量比为100:1～1:50。A third aspect of the present invention provides a kit for treating Alzheimer's disease, comprising active substances including modafinil and acetaminophen, wherein modafinil and acetaminophen The weight ratio of phenol is 100:1 to 1:50.
根据本发明的药盒的一些实施方式，其中莫达非尼和对乙酰氨基酚的重量比为50:1～1:20。例如，重量比为50:1、40:1、30:1、20:1、10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:12、1:15或1:20。According to some embodiments of the kit of the present invention, the weight ratio of modafinil and paracetamol is 50:1-1:20. For example, weight ratios are 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3 :1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12 , 1:15 or 1:20.
根据本发明的药盒的一些实施方式，所述治疗阿尔茨海默病包括改善阿尔茨海默病引起的认知功能障碍、睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状；优选改善阿尔茨海默病引起的认知功能障碍，并且改善阿尔茨海默病引起的睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状。According to some embodiments of the kit of the present invention, the treatment of Alzheimer's disease comprises improving cognitive dysfunction, sleep disturbance, stress or anxiety, cholinergic dysfunction, brain metabolic disorder or One or more symptoms of beta amyloid disorders; preferably improve cognitive dysfunction caused by Alzheimer's disease, and improve sleep disturbance, nervousness or anxiety, cholinergic dysfunction, Alzheimer's disease caused by Alzheimer's disease One or more symptoms of cerebral metabolic disorder or beta amyloid disorder.
根据本发明的药盒的一些实施方式，所述活性物质还包括其它可用于治疗阿尔茨海默病的活性成分。According to some embodiments of the kit of the present invention, the active substance further comprises other active ingredients useful for the treatment of Alzheimer's disease.
根据本发明的药盒的一些实施方式，所述其它可用于治疗阿尔茨海默病的活性成分选自胆碱酯酶抑制剂、β淀粉样蛋白抑制剂、Tau蛋白聚集抑制剂、N-甲基-D-天冬氨酸受体拮抗剂、脑代谢促进 剂、肠道菌群调节剂中的一种或多种；更优选地，所述其它可用于治疗阿尔茨海默病的活性成分选自他克林、加兰他敏、多奈哌齐、卡巴拉汀、石杉碱甲、色甘酸、LMTX、美金刚、NAMZARIC、奥拉西坦、甲氯芬酯、GV971中的一种或多种；最优选为多奈哌齐、美金刚或NAMZARIC。According to some embodiments of the kit of the present invention, the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from the group consisting of cholinesterase inhibitors, beta amyloid inhibitors, tau protein aggregation inhibitors, N-methyl methacrylates One or more of base-D-aspartate receptor antagonists, brain metabolism promoters, and intestinal flora regulators; more preferably, the other active ingredients that can be used for the treatment of Alzheimer's disease One or more selected from tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromolyn, LMTX, memantine, NAMZARIC, oxiracetam, meclofen axetil, GV971 ; most preferably donepezil, memantine or NAMZARIC.
本发明的第四方面提供了一种治疗阿尔茨海默病的方法，其包括向有此需要的对象施用治疗有效量的本发明第一方面任一项的组合或本发明第二方面任一项的药物组合物，或采用本发明第三方面任一项的药盒进行治疗。A fourth aspect of the invention provides a method of treating Alzheimer's disease comprising administering to a subject in need thereof a therapeutically effective amount of the combination of any of the first aspects of the invention or of any of the second aspects of the invention The pharmaceutical composition of item, or treatment using the kit of any item of the third aspect of the present invention.
根据本发明的方法的一些实施方式，包括向有此需要的对象施用治疗有效量的活性物质，所述活性物质包括莫达非尼和对乙酰氨基酚，其中莫达非尼和对乙酰氨基酚的重量比为100:1～1:50。Some embodiments of methods according to the present invention comprise administering to a subject in need thereof a therapeutically effective amount of an active substance comprising modafinil and acetaminophen, wherein modafinil and acetaminophen The weight ratio of 100:1 ~ 1:50.
根据本发明的方法的一些实施方式，其中莫达非尼和对乙酰氨基酚的重量比为50:1～1:20。例如，重量比为50:1、40:1、30:1、20:1、10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:12、1:15或1:20。According to some embodiments of the method of the present invention, the weight ratio of modafinil to acetaminophen is 50:1 to 1:20. For example, weight ratios are 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3 :1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12 , 1:15 or 1:20.
根据本发明的方法的一些实施方式，其中莫达非尼和对乙酰氨基酚同时施用或分开施用。Some embodiments of the method according to the invention, wherein modafinil and acetaminophen are administered simultaneously or separately.
根据本发明的方法的一些实施方式，所述对象为阿尔茨海默病患者。本发明可以用于在该疾病的任何阶段治疗任何患者，改善所述患者的症状。According to some embodiments of the methods of the invention, the subject is an Alzheimer's disease patient. The present invention can be used to treat any patient at any stage of the disease, ameliorating the symptoms of said patient.
根据本发明的方法的一些实施方式，所述对象存在认知功能障碍、睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状；优选所述对象存在认知功能障碍，还存在睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状。According to some embodiments of the methods of the invention, the subject has one or more symptoms of cognitive dysfunction, sleep disturbance, stress or anxiety, cholinergic dysfunction, cerebral metabolic disturbance, or beta amyloid disturbance; Preferably, the subject has cognitive dysfunction and one or more symptoms of sleep disturbance, stress or anxiety, cholinergic dysfunction, cerebral metabolic disturbance, or beta amyloid disturbance.
根据本发明的方法的一些实施方式，所述活性物质还包括其它可用于治疗阿尔茨海默病的活性成分。According to some embodiments of the method of the present invention, the active substance further comprises other active ingredients useful in the treatment of Alzheimer's disease.
根据本发明的方法的一些实施方式，所述的其它可用于治疗阿尔茨海默病的活性成分选自胆碱酯酶抑制剂、β淀粉样蛋白抑制剂、Tau蛋白聚集抑制剂、N-甲基-D-天冬氨酸受体拮抗剂、脑代谢促进剂、肠道菌群调节剂中的一种或多种；更优选地，所述其它可用于治疗阿尔茨海默病的活性成分选自他克林、加兰他敏、多奈哌齐、卡巴拉汀、石杉碱甲、色甘酸、LMTX、美金刚、NAMZARIC、奥拉西坦、甲氯芬酯、GV971中的一种或多种；最优选为多奈哌齐、美金刚或NAMZARIC。According to some embodiments of the method of the present invention, the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from cholinesterase inhibitors, beta amyloid inhibitors, tau protein aggregation inhibitors, N-methyl methacrylates One or more of base-D-aspartate receptor antagonists, brain metabolism promoters, and intestinal flora regulators; more preferably, the other active ingredients that can be used for the treatment of Alzheimer's disease One or more selected from tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromolyn, LMTX, memantine, NAMZARIC, oxiracetam, meclofen axetil, GV971 ; most preferably donepezil, memantine or NAMZARIC.
根据本发明的研究结果，本领域技术人员可以容易地确定活性物质的治疗有效量。根据本发明的方法的一些实施方式，治疗有效量的莫达非尼可以是每日用量10mg～1000mg，优选20mg～800mg，更优选50mg～500mg。例如用量为10mg、15mg、20mg、30mg、40mg、50mg、60mg、70mg、80 mg、90mg、100mg、120mg、150mg、200mg、250mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg或1000mg。治疗有效量的对乙酰氨基酚可以为每日用量1mg～2000mg，优选5mg～2000mg，更优选20mg～1200mg。例如用量为1mg、2mg、3mg、4mg、5mg、8mg、10mg、15mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、150mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg、1200mg、1500mg或2000mg。Based on the findings of the present invention, those skilled in the art can easily determine the therapeutically effective amount of the active substance. According to some embodiments of the methods of the invention, the therapeutically effective amount of modafinil may be a daily dosage of 10 mg to 1000 mg, preferably 20 mg to 800 mg, more preferably 50 mg to 500 mg. For example, the amount is 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg. The therapeutically effective amount of acetaminophen may be 1 mg to 2000 mg per day, preferably 5 mg to 2000 mg, and more preferably 20 mg to 1200 mg. For example, the dosage is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg , 800mg, 900mg, 1000mg, 1200mg, 1500mg or 2000mg.
其它可用于治疗阿尔茨海默病的活性成分的剂量可以是临床常规使用的剂量，或者低于临床常规使用剂量，以便获得最佳的治疗效果。其中，临床常规使用剂量是本领域公知的，并且可以从许多论著中找到。在需要对所述其它可用于治疗阿尔茨海默病的活性成分的剂量调整时，本领域的临床医生根据其临床经验是容易确定的。根据本发明的方法一些实施方式，其每日剂量可以为0.5～50mg，优选1～20mg，例如0.5mg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、12mg、15mg、20mg、30mg、40mg和50mg。The doses of other active ingredients that can be used for the treatment of Alzheimer's disease may be the doses conventionally used in clinical practice, or may be lower than the doses conventionally used in clinical practice in order to obtain the best therapeutic effect. Among them, the doses routinely used in clinical practice are well known in the art and can be found in numerous treatises. The need for dosage adjustment of the other active ingredients useful in the treatment of Alzheimer's disease can be readily determined by clinicians in the art based on their clinical experience. According to some embodiments of the method of the present invention, the daily dose may be 0.5-50 mg, preferably 1-20 mg, such as 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 15mg, 20mg, 30mg, 40mg and 50mg.
本发明中所述活性物质的具体使用剂量可因多种因素而需要作出相应的调整，这些因素包括但不限于：受试者病况的严重程度，受试者的年龄、性别、体重、给药途径和药物剂型等。The specific dosage of the active substances described in the present invention may need to be adjusted accordingly due to various factors, including but not limited to: the severity of the subject's condition, the subject's age, sex, weight, administration route and drug dosage form, etc.
根据本发明的方法一些实施方式，其中所述活性物质可以同时施用或分开施用。According to some embodiments of the method of the present invention, the active substances may be administered simultaneously or separately.
定义definition
如本文所用，术语“阿尔茨海默病”是指：按照临床诊断标准确定的阿尔茨海默病。阿尔茨海默病的诊断标准和诊断方法是领域内公知的。As used herein, the term "Alzheimer's disease" refers to Alzheimer's disease as determined by clinical diagnostic criteria. Diagnostic criteria and diagnostic methods for Alzheimer's disease are well known in the art.
如本文所用，术语“活性物质”指医学或药学上可发挥一定的所期望的药理活性的化合物。“活性物质”不仅包括化合物分子本身，还包括其任何化学纯度的可药用盐、多晶型物、溶剂合物、水合物、衍生物、活性代谢物、前药、空间异构体。“可药用盐”是指化合物的药学上可接受的且相对无毒的无机/有机的酸加成盐或碱加成盐。“多晶型物”是指在不改变单个化合物分子结构的情况下，多个化合物分子在微观上通过不同有序排列方式所形成的物质。“溶剂合物”是指化合物分子与溶剂进行非共价结合所形成的物质，当溶剂为水时，也可称“水合物”。“衍生物”包括保留化合物母核结构，并在某些基团上进行取代所形成的与该化合物功能相关的新化合物，如该化合物的酸、酰胺、酯、醚、乙酰化变体、羟基化变体、糖基化变体或烷基化(C1-C6)变体等。“衍生物”还包括该化合物的活性代谢物和前药。“空间异构体”指化合物分子在平面结构不变的情况下，通过改变分子的三维空间结构所形成的物质。As used herein, the term "active substance" refers to a compound that is medically or pharmaceutically capable of exerting a certain desired pharmacological activity. "Active substance" includes not only the compound molecule itself, but also pharmaceutically acceptable salts, polymorphs, solvates, hydrates, derivatives, active metabolites, prodrugs, steric isomers thereof in any chemical purity. "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable and relatively non-toxic inorganic/organic acid or base addition salt of a compound. "Polymorph" refers to a substance formed by microscopically different ordered arrangements of multiple compound molecules without changing the molecular structure of a single compound. "Solvate" refers to a substance formed by non-covalent bonding of compound molecules with a solvent. When the solvent is water, it can also be called "hydrate". "Derivatives" include new compounds that retain the core structure of the compound and are substituted on certain groups to form new compounds related to the function of the compound, such as the acid, amide, ester, ether, acetylated variant, hydroxyl of the compound. variant, glycosylation variant or alkylation (C1-C6) variant, etc. "Derivatives" also include active metabolites and prodrugs of the compound. "Stereoisomer" refers to the substance formed by changing the three-dimensional spatial structure of the molecule under the condition that the plane structure of the compound molecule remains unchanged.
基于本发明的描述，本领域技术人员可以理解，由于“活性物质”的可药用盐、多晶型物、溶剂 合物、水合物、衍生物、活性代谢物、前药、空间异构体等也具有“活性物质”的核心结构，从而具有相似的药理活性，因此可以按照本发明描述的规律通过与本发明类似的方式实现本发明目的。Based on the description of the present invention, those skilled in the art can understand that due to the pharmaceutically acceptable salts, polymorphs, solvates, hydrates, derivatives, active metabolites, prodrugs, steric isomers of "active substances" etc. also have the core structure of "active substances", so they have similar pharmacological activities, so the object of the present invention can be achieved in a manner similar to that of the present invention according to the rules described in the present invention.
如本文所用，“莫达非尼”至少包括化学名称为2-[(二苯甲基)亚磺酰基]乙酰胺的分子，其还包括任何化学纯度的可药用盐、多晶型物、溶剂合物、水合物、活性代谢物、前药、空间异构体。在一些具体实施方式中，本发明中莫达非尼可以为R手性异构体2-[(R)-(二苯甲基)亚磺酰基]乙酰胺、S手性异构体2-[(S)-(二苯甲基)亚磺酰基]乙酰胺，或消旋体2-[(R,S)-(二苯甲基)亚磺酰基]乙酰胺。莫达非尼的消旋体2-[(R,S)-(二苯甲基)亚磺酰基]乙酰胺以PROVIGIL(美国)、伟大(中国)等商品名上市。R异构体2-[(R)-(二苯甲基)亚磺酰基]乙酰胺以NUVIGIL(美国)的商品名上市。S异构体可以按照现有文献公开的方法进行制备。莫达非尼全球上市的剂型有胶囊剂、片剂、口崩片、混悬剂、口服溶液等，可通过合法的商业化途径获得。As used herein, "modafinil" includes at least the molecule with the chemical name 2-[(diphenylmethyl)sulfinyl]acetamide, which also includes any chemically pure pharmaceutically acceptable salt, polymorph, Solvates, hydrates, active metabolites, prodrugs, steric isomers. In some specific embodiments, modafinil in the present invention can be R chiral isomer 2-[(R)-(diphenylmethyl)sulfinyl]acetamide, S chiral isomer 2- [(S)-(diphenylmethyl)sulfinyl]acetamide, or racemic 2-[(R,S)-(diphenylmethyl)sulfinyl]acetamide. The racemate of modafinil, 2-[(R,S)-(diphenylmethyl)sulfinyl]acetamide, is marketed under the trade names of PROVIGIL (USA) and Great (China). The R isomer 2-[(R)-(diphenylmethyl)sulfinyl]acetamide is marketed under the trade name NUVIGIL (USA). The S isomer can be prepared according to the methods disclosed in the existing literature. The global marketed dosage forms of Modafinil include capsules, tablets, orally disintegrating tablets, suspensions, oral solutions, etc., which can be obtained through legal commercial channels.
如本文所用，“对乙酰氨基酚”至少包括化学名称为N-乙酰-对-氨基苯酚的的分子，其还包括任何化学纯度的可药用盐、多晶型物、溶剂合物、水合物、活性代谢物、前药、空间异构体。对乙酰氨基酚是全球广泛使用的一种非甾体类抗炎药，用于退热和抗炎等。对乙酰氨基酚全球已上市的剂型有胶囊剂、片剂、缓释片、口崩片、舌下片、灌肠剂、颗粒剂、缓释颗粒、注射剂、滴剂、溶液、锭剂、贴剂、粉末、栓剂、混悬剂等，可通过合法商业化途径获得。As used herein, "acetaminophen" includes at least the molecule with the chemical name N-acetyl-p-aminophenol, which also includes pharmaceutically acceptable salts, polymorphs, solvates, hydrates of any chemical purity , active metabolites, prodrugs, steric isomers. Acetaminophen is a non-steroidal anti-inflammatory drug widely used in the world for antipyretic and anti-inflammatory. The global marketed dosage forms of acetaminophen include capsules, tablets, sustained-release tablets, orally disintegrating tablets, sublingual tablets, enemas, granules, sustained-release granules, injections, drops, solutions, lozenges, patches , powder, suppository, suspension, etc., can be obtained through legal commercialization.
如本文所用，“LMTX”是指：TauRx公司开发的一种Tau蛋白聚集抑制剂，作为阿尔茨海默病的潜在治疗药物，目前处于临床III期阶段。As used herein, "LMTX" refers to: a Tau protein aggregation inhibitor developed by TauRx Company, as a potential therapeutic drug for Alzheimer's disease, currently in clinical phase III.
如本文所用，“多奈哌齐”至少包括化学名称为(±)2,3-二氢-5,6-二甲氯基-2-{[(1-苯甲基)-4-哌啶基]甲基}-1H-茚-1-酮的分子，其还包括任何化学纯度的可药用盐、多晶型物、溶剂合物、水合物、活性代谢物、前药、空间异构体，例如盐酸多奈哌齐。多奈哌齐是一种已上市的治疗阿尔茨海默病的胆碱酯酶抑制剂。As used herein, "Donepezil" includes at least the chemical name (±) 2,3-dihydro-5,6-dimethylchloro-2-{[(1-benzyl)-4-piperidinyl]methane yl}-1H-inden-1-one, which also includes pharmaceutically acceptable salts, polymorphs, solvates, hydrates, active metabolites, prodrugs, steric isomers of any chemical purity, such as Donepezil hydrochloride. Donepezil is a marketed cholinesterase inhibitor for the treatment of Alzheimer's disease.
如本文所用，“美金刚”至少包括化学名称为1-氨基-3,5-二甲基金刚烷胺的分子，其还包括任何化学纯度的可药用盐、多晶型物、溶剂合物、水合物、活性代谢物、前药、空间异构体，例如盐酸美金刚。美金刚是一种已上市的治疗阿尔茨海默病的N-甲基-D-天冬氨酸受体拮抗剂。As used herein, "Memantine" includes at least the molecule with the chemical name 1-amino-3,5-dimethyladamantanamine, which also includes pharmaceutically acceptable salts, polymorphs, solvates of any chemical purity , hydrates, active metabolites, prodrugs, steric isomers such as memantine hydrochloride. Memantine is a marketed N-methyl-D-aspartate receptor antagonist for the treatment of Alzheimer's disease.
如本文所用，“NAMZARIC”是指一种多奈哌齐和美金刚的复方药物，其以NAMZARIC的商品名在美国上市。As used herein, "NAMZARIC" refers to a combination of donepezil and memantine, marketed in the United States under the trade name NAMZARIC.
如本文所用，“GV971”是指：甘露寡糖二酸，可能是一种肠道菌群调节剂，于2019年在中国上市用于治疗阿尔茨海默病。As used herein, "GV971" refers to: mannooligosaccharide, which may be a gut microbiota regulator, and was launched in China in 2019 for the treatment of Alzheimer's disease.
如本文所用，术语“治疗”包括延迟或减少由给定疾病引发的症状。术语治疗特别包括控制疾病和相关症状的进展。As used herein, the term "treating" includes delaying or reducing symptoms caused by a given disease. The term treatment specifically includes controlling the progression of the disease and associated symptoms.
如本文所用，术语“组合治疗”是指将一种以上活性物质共同给药受试者以引起生物作用的治疗。在组合治疗中，活性物质可以同时给药，也可以分开给药。“同时”是指在大致相同的时间内，“分开”是指在不同的时间内。As used herein, the term "combination therapy" refers to a therapy in which more than one active substance is co-administered to a subject to cause a biological effect. In combination therapy, the active substances can be administered simultaneously or separately. "At the same time" means at about the same time, and "separately" means at different times.
如本文所用，术语“治疗有效量”是指足以治愈、减轻或者部分抑制给定疾病的临床表现的量。将适于完成该目的的量定义为“治疗有效量”。对于每个目的的有效量取决于疾病或者损伤的严重度以及受试者的体重和一般的健康状态等因素。As used herein, the term "therapeutically effective amount" refers to an amount sufficient to cure, alleviate or partially inhibit the clinical manifestations of a given disease. An amount suitable for accomplishing this purpose is defined as a "therapeutically effective amount". The effective amount for each purpose depends on the severity of the disease or injury as well as factors such as the subject's weight and general state of health.
如本文所用，术语“组合”是指一种以上的组分之间的联合。组分之间可以是在物理上混合在一起的，也可以是在物理上相互分离的。对于一种以上活性组分的“组合”而言，这些活性组分可以是同时存在于同一个药剂中，也可以是分别存在于多个不同的药剂中。As used herein, the term "combination" refers to an association between more than one component. The components can be physically mixed together or physically separated from each other. For a "combination" of more than one active ingredient, the active ingredients may be present in the same pharmaceutical agent at the same time, or separately in multiple different pharmaceutical agents.
如本文所用，术语“组合物”是指一种或多种组分所形成的混合物。对于药物组合物而言，组合物中可以包括一种或多种活性组分，还可任选包括一种或者多种惰性组分。As used herein, the term "composition" refers to a mixture of one or more components. For pharmaceutical compositions, one or more active ingredients may be included in the composition, and one or more inert ingredients may optionally be included.
如本文所用，术语“药剂”是指含有活性物质，并可供患者或医生直接使用的成品药物制剂。As used herein, the term "pharmaceutical" refers to a finished pharmaceutical preparation that contains an active substance and is intended for immediate use by a patient or physician.
如本文所用，术语“药盒”是指装有药剂的容器，以便药剂的存储、运输、配制和使用。“药盒”可以是一个容器，也可以是多个容器。“药盒”中可以包括一种药剂，也可以包括多种药剂，以便于临床上单独用药或联合用药。本发明中，多种活性物质，如莫达非尼、对乙酰氨基酚或其它可用于治疗阿尔茨海默病的活性成分，可以以单独的剂型存在于药盒中，用于同时或依次给药。As used herein, the term "kit" refers to a container that holds a medicament for storage, transportation, formulation, and use of the medicament. A "kit" may be a single container or multiple containers. The "kit" may include one drug or multiple drugs, so as to be used alone or in combination in clinical practice. In the present invention, multiple active substances, such as modafinil, acetaminophen or other active ingredients that can be used to treat Alzheimer's disease, can be present in a kit in separate dosage forms for simultaneous or sequential administration medicine.
如本文所用，术语“药学上可接受的”通常是指制药领域可使用，对产品或者对哺乳动物无害。As used herein, the term "pharmaceutically acceptable" generally means available in the pharmaceutical art and is not harmful to the product or to mammals.
如本文所用，术语“辅料”可以是制药领域中任何常规的辅料。具体的辅料的选择取决于药物制剂的形式或/和给药的方式。As used herein, the term "excipient" may be any conventional excipient in the pharmaceutical field. The choice of specific excipients depends on the form of the pharmaceutical formulation or/and the mode of administration.
如本文所用，术语“一个”、“一种”和“该”和类似术语应该理解为涵盖单数和复数，除非在本申请另作说明或者上下文明显矛盾。As used herein, the terms "a", "an" and "the" and similar terms should be construed to encompass both the singular and the plural unless otherwise indicated in this application or clearly contradicted by context.
本发明的有益效果：Beneficial effects of the present invention:
本发明提供了用于治疗阿尔茨海默病的组合。更具体地，本发明将莫达非尼和对乙酰氨基酚组合后，发现两者能够协同增效，降低不良反应，明显改善阿尔茨海默病的相关症状。The present invention provides combinations for the treatment of Alzheimer's disease. More specifically, after combining modafinil and acetaminophen in the present invention, it is found that the two can synergize, reduce adverse reactions, and significantly improve the symptoms related to Alzheimer's disease.
本发明将莫达非尼和对乙酰氨基酚进行组合，显著改善了阿尔茨海默病患者的胆碱能功能障碍、脑能量代谢障碍、降低了脑内β淀粉样蛋白水平，有效提高了学习能力、记忆能力、自主行为能力、 探究能力等认知功能，降低了紧张感和焦虑感，可以从多个层面治疗阿尔茨海默病，提高临床疗效。另外本发明的莫达非尼和对乙酰氨基酚还可以与现有的其它可用于治疗阿尔茨海默病的药物进行组合，以进一步提高现有药物的疗效。The present invention combines modafinil and acetaminophen, significantly improves the cholinergic dysfunction and brain energy metabolism disorder of Alzheimer's disease patients, reduces the level of beta amyloid in the brain, and effectively improves learning Cognitive functions such as ability, memory ability, autonomous behavior ability, and exploration ability reduce tension and anxiety, and can treat Alzheimer's disease from multiple levels and improve clinical efficacy. In addition, the modafinil and paracetamol of the present invention can also be combined with other existing drugs that can be used for the treatment of Alzheimer's disease, so as to further improve the curative effect of the existing drugs.
以下结合具体的实施例对本发明的技术方案和技术效果做进一步说明和阐释，但本发明并不限于这些具体实施方式。实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，均可从商业途径得到的试剂和材料。The technical solutions and technical effects of the present invention will be further described and explained below in conjunction with specific embodiments, but the present invention is not limited to these specific embodiments. The test methods used in the examples are conventional methods unless otherwise specified; the materials, reagents, etc. used, unless otherwise specified, can be obtained from commercial sources.
实施例1：莫达非尼与对乙酰氨基酚联用对衰老伴随睡眠紊乱的阿尔茨海默病模型动物的作用Example 1: Effects of Modafinil in combination with acetaminophen on Alzheimer's disease model animals with aging and sleep disturbance
动物：清洁级Wister大鼠，雌雄各半，体重220～250g。Animals: Clean-grade Wister rats, half male and half male, weighing 220-250 g.
药物：莫达非尼(湘北威尔曼制药股份有限公司提供)，布洛芬(市售)，对乙酰氨基酚(市售)。Drugs: Modafinil (provided by Xiangbei Wellman Pharmaceutical Co., Ltd.), ibuprofen (commercially available), paracetamol (commercially available).
方法：method:
分组：试验动物适应性喂养一周后，随机分为：空白对照组、模型对照组、莫达非尼组(MDF)、布洛芬组(IBU)、对乙酰氨基酚组(APAP)、莫达非尼+布洛芬一组(MDF/IBU-1)、莫达非尼+布洛芬二组(MDF/IBU-2)、莫达非尼+对乙酰氨基酚一组(MDF/APAP-1)、莫达非尼+对乙酰氨基酚二组(MDF/APAP-2)、莫达非尼+对乙酰氨基酚三组(MDF/APAP-3)，每组12只动物。Grouping: After one week of adaptive feeding, experimental animals were randomly divided into blank control group, model control group, modafinil group (MDF), ibuprofen group (IBU), acetaminophen group (APAP), and modafinil group. Finil + ibuprofen group (MDF/IBU-1), modafinil + ibuprofen group (MDF/IBU-2), modafinil + acetaminophen group (MDF/APAP- 1) Modafinil + acetaminophen two groups (MDF/APAP-2), modafinil + acetaminophen three groups (MDF/APAP-3), 12 animals in each group.
造模：各组动物喂养于耐热鼠笼中，置于自然光下，给与正常饮食。空白对照组每日腹腔注射0.5mL生理盐水，连续6周。除空白对照组之外的其余各组每日腹腔注射D-半乳糖50mg/kg，连续6周，其间自第4周起每日夜晚(19:00至次日7:00)增加人工光照(强度600lx)。Modeling: Animals in each group were fed in heat-resistant rat cages, placed under natural light, and given a normal diet. In the blank control group, 0.5 mL of normal saline was injected intraperitoneally every day for 6 weeks. Except for the blank control group, the other groups were intraperitoneally injected with D-galactose 50 mg/kg daily for 6 consecutive weeks, during which artificial light was added every night (19:00 to 7:00 the next day) from the 4th week onwards ( Strength 600lx).
给药：造模完成后，连续灌胃给药2周。MDF组每日给与5mg/kg的莫达非尼，IBU组每日给与100mg/kg的布洛芬，APAP组每日给与100mg/kg的对乙酰氨基酚，MDF/IBU-1组每日给与5mg/kg的莫达非尼和0.1mg/kg的布洛芬，MDF/IBU-2组每日给与5mg/kg的莫达非尼和100mg/kg的布洛芬，MDF/APAP-1组每日给与5mg/kg的莫达非尼和0.1mg/kg的对乙酰氨基酚，MDF/APAP-2组每日给与5mg/kg的莫达非尼和100mg/kg的对乙酰氨基酚，MDF/APAP-3组每日给与5mg/kg的莫达非尼和200mg/kg的对乙酰氨基酚。空白对照组和模型对照组每日均给与相同体积的生理盐水。Administration: After the modeling was completed, the mice were administered by continuous intragastric administration for 2 weeks. Modafinil was administered at 5 mg/kg per day in the MDF group, ibuprofen was administered at 100 mg/kg per day in the IBU group, acetaminophen at 100 mg/kg per day in the APAP group, and the MDF/IBU-1 group was administered Modafinil 5 mg/kg and ibuprofen 0.1 mg/kg daily, MDF/IBU-2 group received daily modafinil 5 mg/kg and ibuprofen 100 mg/kg, MDF The /APAP-1 group was given 5 mg/kg of modafinil and 0.1 mg/kg of acetaminophen daily, and the MDF/APAP-2 group was given 5 mg/kg of modafinil and 100 mg/kg daily The MDF/APAP-3 group received 5 mg/kg of modafinil and 200 mg/kg of acetaminophen daily. The blank control group and the model control group were given the same volume of normal saline every day.
测试：给药完成后，将各组动物进行旷场测试和Morris水迷宫测试。Test: After the administration was completed, animals in each group were subjected to open field test and Morris water maze test.
旷场测试(openfieldtest)：将动物放入一个长25cm宽25cm高40cm的方箱中，箱底平均分为25个小格，记录5分钟内动物的穿格次数、站立次数、尿便次数和修饰次数(修饰次数指抓痒、洗脸、舔足等动作的次数)。Open field test (openfield test): put the animal into a square box with a length of 25cm, a width of 25cm and a height of 40cm. The bottom of the box is divided into 25 small squares on average, and the number of times of passing, standing, urinating and defecation and grooming are recorded within 5 minutes. Times (the times of modification refers to the times of scratching, washing face, licking feet, etc.).
Morris水迷宫测试：旷场测试完成后进行Morris水迷宫测试。首先进行定位航行(placenavigation)训练：在水迷宫圆形水池的第四象限某处设置一个平台，平台设置在水下1厘米处，从其它象限将动 物面向池壁放入水中。在60秒内训练动物寻找到平台。每天训练2次，连续进行5天。第6天进行空间搜索测试(spatialprobetest)，将平台去除，将动物面向池壁放入水中，测试60秒，记录60秒内动物到达原平台位置的次数(过台次数)，以及在第四象限逗留时间占总游泳时间的百分比(第四象限时间占比)。Morris water maze test: Morris water maze test is performed after completion of the open field test. First, placenavigation training: set a platform somewhere in the fourth quadrant of the circular pool of the water maze, the platform is set at 1 cm underwater, and the animals are placed in the water facing the pool wall from other quadrants. Train animals to find platforms in 60 seconds. Train 2 times a day for 5 consecutive days. On the 6th day, the spatial probe test was performed, the platform was removed, the animal was placed in the water facing the pool wall, tested for 60 seconds, and the number of times the animal reached the original platform position within 60 seconds (the number of passes) was recorded, and in the fourth quadrant Sojourn time as a percentage of total swimming time (fourth quadrant time share).
结果：表1列出了旷场测试的主要结果。表2列出了Morris水迷宫测试的主要结果。Results: Table 1 lists the main results of the open field test. Table 2 lists the main results of the Morris water maze test.
表1 旷场测试结果Table 1 Open field test results
注：与模型对照组相比，
*：P＜0.05，
**：P＜0.01。与空白组相比，
#：P＜0.05，
##：P＜0.01。
Note: Compared with the model control group, * : P<0.05, ** : P<0.01. # : P<0.05, ## : P<0.01, compared to the blank group.
表2 Morris水迷宫测试结果Table 2 Morris water maze test results
| 组别group | 动物数量number of animals | 过台次数Number of passes | 第四象限时间占比(％)The fourth quadrant time proportion (%) |
| 空白对照blank | 1212 | 3.42±1.683.42±1.68 | 42.75±11.0842.75±11.08 |
| 模型对照Model comparison | 1212 | 0.67±0.78 ## 0.67±0.78 ## | 17.83±4.95 ## 17.83±4.95 ## |
| 莫达非尼(MDF)Modafinil (MDF) | 1212 | 0.83±0.580.83±0.58 | 19.58±5.7419.58±5.74 |
| 布洛芬(IBU)ibuprofen (IBU) | 1212 | 0.75±0.450.75±0.45 | 20.42±6.4720.42±6.47 |
| 对乙酰氨基酚(APAP)Acetaminophen (APAP) | 1212 | 0.67±0.490.67±0.49 | 19.33±5.6119.33±5.61 |
| MDF/IBU-1MDF/IBU-1 | 1212 | 0.83±0.580.83±0.58 | 20.17±5.0620.17±5.06 |
| MDF/IBU-2MDF/IBU-2 | 1212 | 0.92±0.510.92±0.51 | 22.58±9.6022.58±9.60 |
| MDF/APAP-1MDF/APAP-1 | 1212 | 2.42±0.90 ** 2.42±0.90 ** | 28.67±11.56 * 28.67±11.56 * |
| MDF/APAP-2MDF/APAP-2 | 1212 | 3.08±1.24 ** 3.08±1.24 ** | 33.42±10.67 ** 33.42±10.67 ** |
| MDF/APAP-3MDF/APAP-3 | 1212 | 1.00±0.431.00±0.43 | 21.17±6.2121.17±6.21 |
注：与模型对照组相比，
*：P＜0.05，
**：P＜0.01。与空白组相比，
#：P＜0.05，
##：P＜0.01。
Note: Compared with the model control group, * : P<0.05, ** : P<0.01. # : P<0.05, ## : P<0.01, compared to the blank group.
分析：analyze:
本实验采用半乳糖造成大鼠亚急性衰老，外加人工光源进行睡眠剥夺造成大鼠睡眠紊乱。造模后的大鼠出现毛色凌乱、行动迟缓、精神萎靡等外在表现，动物自主行为能力、探究能力、学习记忆能力显著下降，表明认知能力显著降低，符合人类阿尔茨海默病的临床表现、病理特点，另外慢性发病的特征也符合人类阿尔茨海默病的进程。因此该动物模型可用于评价阿尔茨海默病药物的效果。In this experiment, galactose was used to cause subacute aging in rats, and sleep deprivation with artificial light source caused sleep disturbance in rats. After modeling, the rats showed messy coat color, slow action, lethargy and other external manifestations, and the animals' autonomous behavior ability, exploration ability, learning and memory ability were significantly reduced, indicating that cognitive ability was significantly reduced, which was in line with the clinical diagnosis of human Alzheimer's disease. Manifestations, pathological features, and chronic onset features are also consistent with the course of human Alzheimer's disease. Therefore, this animal model can be used to evaluate the effect of Alzheimer's disease drugs.
旷场测试可检测动物的自主行为和精神状态。穿格次数和站立次数越多说明动物的自主行为能力和探究能力越强，尿便次数和修饰次数越多说明动物的紧张感和焦虑感越强。Morris水迷宫测试可检测动物的学习记忆能力，过台次数越多、第四象限逗留百分比越大说明动物的学习记忆能力越好。本实验中研究了莫达非尼与对乙酰氨基酚联用的效果。发现对乙酰氨基酚可以显著增强莫达非尼的效果，二者组合能显著提高模型动物自主行为能力、探究能力、学习记忆能力，与模型组比较有统计学意义。本实验还将布洛芬和对乙酰氨基酚两种非甾体抗炎药的效果进行了对比，发现对乙酰氨基酚可以显著增强莫达非尼的效果，而布洛芬几乎不能增强莫达非尼的效果。值得注意的是，单用莫达非尼会增加动物的紧张感和焦虑感，但莫达非尼与对乙酰氨基酚联用明显减少了这种紧张感和焦虑感。The open field test detects the autonomous behavior and mental state of animals. The more times of crossing and standing, the stronger the autonomous behavior and exploration ability of the animal, and the more times of urination and modification, the stronger the sense of tension and anxiety of the animal. Morris water maze test can detect the learning and memory ability of animals. The effect of modafinil in combination with acetaminophen was investigated in this experiment. It was found that acetaminophen can significantly enhance the effect of modafinil, and the combination of the two can significantly improve the autonomous behavior, exploration ability, learning and memory ability of model animals, which is statistically significant compared with the model group. This experiment also compared the effects of two NSAIDs, ibuprofen and acetaminophen, and found that acetaminophen can significantly enhance the effect of modafinil, while ibuprofen can hardly enhance the effect of modafinil The effect of Fini. Notably, modafinil alone increased tension and anxiety in animals, but the combination of modafinil and acetaminophen significantly reduced this tension and anxiety.
实施例2：莫达非尼与对乙酰氨基酚联用对胆碱能功能障碍的阿尔茨海默病模型动物的作用Example 2: Effects of Modafinil and Paracetamol on Alzheimer's Disease Model Animals with Cholinergic Dysfunction
动物：雄性昆明种小鼠，雌雄各半，体重30-40g。Animals: Male Kunming mice, half male and half male, weighing 30-40g.
药物：莫达非尼(湘北威尔曼制药股份有限公司提供)，对乙酰氨基酚(市售)，多奈哌齐(市售)。Drugs: Modafinil (provided by Xiangbei Wellman Pharmaceutical Co., Ltd.), paracetamol (commercially available), donepezil (commercially available).
方法：method:
分组：动物适应性喂养一周后随机分为8组：空白对照组、模型对照组、莫达非尼组(MDF)、对乙酰氨基酚组(APAP)、多奈哌齐组(DNP)、莫达非尼+对乙酰氨基酚低剂量组(MDF/APAP-l)、莫达非尼+对乙酰氨基酚高剂量组(MDF/APAP-h)、莫达非尼+对乙酰氨基酚+多奈哌齐组(MDF/APAP/DNP)，每组12只。Grouping: Animals were randomly divided into 8 groups after one week of adaptive feeding: blank control group, model control group, modafinil group (MDF), paracetamol group (APAP), donepezil group (DNP), modafinil group + acetaminophen low-dose group (MDF/APAP-l), modafinil + acetaminophen high-dose group (MDF/APAP-h), modafinil + acetaminophen + donepezil group (MDF /APAP/DNP), 12 in each group.
给药：MDF组每日给与5mg/kg的莫达非尼，APAP组每日给与30mg/kg的对乙酰氨基酚，DNP组每日给与1mg/kg的多奈哌齐，MDF/APAP-l组每日给与5mg/kg的莫达非尼和30mg/kg的对乙酰氨基酚，MDF/APAP-h组每日给与10mg/kg的莫达非尼和60mg/kg的对乙酰氨基酚，MDF/APAP/DNP组每日给与10mg/kg的莫达非尼、60mg/kg的对乙酰氨基酚和1mg/kg的多奈哌齐。空白对照组和模型对照组每日均给与相同体积的生理盐水。各组连续灌胃给药1周。Administration: MDF group was given 5 mg/kg of modafinil daily, APAP group was given 30 mg/kg of acetaminophen daily, DNP group was given 1 mg/kg of donepezil daily, MDF/APAP-1 The group was given 5 mg/kg of modafinil and 30 mg/kg of acetaminophen daily, and the MDF/APAP-h group was given 10 mg/kg of modafinil and 60 mg/kg of acetaminophen daily , MDF/APAP/DNP group was given 10 mg/kg of modafinil, 60 mg/kg of acetaminophen and 1 mg/kg of donepezil daily. The blank control group and the model control group were given the same volume of normal saline every day. Each group was given continuous intragastric administration for 1 week.
造模：末次给药结束一小时后，除空白对照组外，其余各组动物腹腔注射东莨菪碱3mg/kg。空白对照组注射等量的生理盐水。Modeling: One hour after the last administration, except for the blank control group, animals in the other groups were intraperitoneally injected with scopolamine 3 mg/kg. The blank control group was injected with the same amount of normal saline.
测试：造模完成一小时后，进行回避性跳台反射实验：将动物放入跳台反应箱内(箱底为可通电的铜栅，箱内设置一个塑料安全平台)，适应3分钟后，通36V交流电，记录动物从受到电击到跳上安全平台之间的时间(反应时间)。24小时后再次将动物放入跳台反应箱内，通36V交流电，记录动物从跳上安全平台后到第一次跳下安全平台之间的时间(跳台潜伏期)。Test: One hour after the modeling is completed, perform the avoidance platform jumping reflex experiment: put the animals into the platform jumping reaction box (the bottom of the box is a copper grid that can be energized, and a plastic safety platform is set in the box), after 3 minutes of adaptation, turn on 36V AC , recording the time (reaction time) between the time the animal received the shock and jumped onto the safety platform. After 24 hours, the animals were put into the platform jumping reaction box again, and 36V alternating current was applied, and the time between the animals jumping on the safety platform and the first jumping off the safety platform (platform jumping latency) was recorded.
胆碱能指标测定：跳台反射实验结束后，将小鼠断头取脑，冰上迅速分离脑组织，加入生理盐水制成10％浓度的脑组织匀浆，低温离心10分钟，取上清液，用酶标仪测定乙酰胆碱酯酶含量。Determination of cholinergic indicators: After the platform reflex experiment, the mice were decapitated and the brains were removed. The brain tissue was quickly separated on ice, and normal saline was added to make a 10% concentration of brain tissue homogenate. , the content of acetylcholinesterase was determined with a microplate reader.
结果：表3列出了回避性跳台反射实验的主要结果，表4列出了胆碱能指标测定主要结果。Results: Table 3 lists the main results of the avoidance platform jumping reflex experiment, and Table 4 lists the main results of the cholinergic index measurement.
表3 回避性跳台反射实验结果Table 3 Experimental results of avoidance platform jumping reflex
| 组别group | 动物数量number of animals | 反应时间(s)Response time (s) | 跳台潜伏期(s)Platform Latency (s) |
| 空白对照blank | 1212 | 16.25±7.4616.25±7.46 | 212.00±58.69212.00±58.69 |
| 模型对照Model comparison | 1212 | 43.42±18.56 ## 43.42±18.56 ## | 123.08±22.71 ## 123.08±22.71 ## |
| 莫达非尼(MDF)Modafinil (MDF) | 1212 | 37.92±16.4437.92±16.44 | 136.08±38.36136.08±38.36 |
| 对乙酰氨基酚(APAP)Acetaminophen (APAP) | 1212 | 38.67±10.7538.67±10.75 | 131.25±33.34131.25±33.34 |
| 多奈哌齐(DNP)Donepezil (DNP) | 1212 | 27.25±8.65 ** 27.25±8.65 ** | 169.50±37.02 * 169.50±37.02 * |
| MDF/APAP-lMDF/APAP-l | 1212 | 30.75±7.96 ** 30.75±7.96 ** | 154.75±47.75154.75±47.75 |
| MDF/APAP-hMDF/APAP-h | 1212 | 26.25±9.01 ** 26.25±9.01 ** | 173.08±42.20 * 173.08±42.20 * |
| MDF/APAP/DNPMDF/APAP/DNP | 1212 | 20.08±6.46 **& 20.08±6.46 **& | 195.67±43.99 ** 195.67±43.99 ** |
注：与模型对照组相比，
*：P＜0.05，
**：P＜0.01。与空白组相比，
#：P＜0.05，
##：P＜0.01。与多奈哌齐组相比，
&：P＜0.05，
&&：P＜0.01。
Note: Compared with the model control group, * : P<0.05, ** : P<0.01. # : P<0.05, ## : P<0.01, compared to the blank group. Compared with donepezil group, &: P <0.05, && : P <0.01.
表4 胆碱能指标测试结果Table 4 Cholinergic index test results
| 组别group | 动物数量number of animals | 乙酰胆碱酯酶活性(U/mgprot)Acetylcholinesterase activity (U/mgprot) |
| 空白对照blank | 1212 | 0.34±0.100.34±0.10 |
| 模型对照Model comparison | 1212 | 0.80±0.08 ## 0.80±0.08 ## |
| 莫达非尼(MDF)Modafinil (MDF) | 1212 | 0.76±0.150.76±0.15 |
| 对乙酰氨基酚(APAP)Acetaminophen (APAP) | 1212 | 0.75±0.100.75±0.10 |
| 多奈哌齐(DNP)Donepezil (DNP) | 1212 | 0.55±0.13 ** 0.55±0.13 ** |
| MDF/APAP-lMDF/APAP-l | 1212 | 0.66±0.17 * 0.66±0.17 * |
| MDF/APAP-hMDF/APAP-h | 1212 | 0.62±0.08 ** 0.62±0.08 ** |
| MDF/APAP/DNPMDF/APAP/DNP | 1212 | 0.45±0.06 **& 0.45±0.06 **& |
注：与模型对照组相比，
*：P＜0.05，
**：P＜0.01。与空白组相比，
#：P＜0.05，
##：P＜0.01。与多奈哌齐组相比，
&：P＜0.05，
&&：P＜0.01。
Note: Compared with the model control group, * : P<0.05, ** : P<0.01. # : P<0.05, ## : P<0.01, compared to the blank group. Compared with donepezil group, &: P <0.05, && : P <0.01.
分析：analyze:
本实验采用东莨菪碱造成动物胆碱能障碍，可表现为乙酰胆碱酯酶活性升高，从而乙酰胆碱含量下降。模型组乙酰胆碱酯酶活性显著升高，并且回避性跳台反射实验中反应时间变长，跳台潜伏期变短，说明动物出现胆碱能障碍和认知能力下降。治疗阿尔茨海默病的阳性药物多奈哌齐是已知的乙酰胆碱酯酶抑制剂，本实验表明其可降低动物乙酰胆碱酯酶活性，改善学习记忆能力。说明本模型可用 于评价阿尔茨海默病药物的效果。In this experiment, scopolamine was used to cause cholinergic disorders in animals, which can be manifested as increased acetylcholinesterase activity, and thus decreased acetylcholine content. The activity of acetylcholinesterase in the model group was significantly increased, and the reaction time in the avoidance platform jumping reflex test was longer, and the platform jumping latency was shortened, indicating that the animals had cholinergic disorders and cognitive decline. Donepezil, a positive drug for Alzheimer's disease, is a known acetylcholinesterase inhibitor. This experiment shows that it can reduce the activity of acetylcholinesterase in animals and improve learning and memory ability. It shows that this model can be used to evaluate the effect of Alzheimer's disease drugs.
回避性跳台反射实验通过测试动物对电击伤害的反应，可以反映出动物的学习能力和记忆能力。其中动物从受到电击到跳上安全平台之间的时间(反应时间)越短说明学习能力越好，学习24小时之后，再测试动物从跳上安全平台后到第一次跳下安全平台之间的时间(跳台潜伏期)，跳台潜伏期越长说明动物记忆能力越好。本实验中莫达非尼联用对乙酰氨基酚同样表现出积极效果，低剂量和高剂量均显示可降低乙酰胆碱酯酶活性，保护东莨菪碱所致的胆碱能障碍，以及提高学习记忆能力。另外本实验还将多奈哌齐、莫达非尼、对乙酰氨基酚进行了三药联用，三者组合的效果明显优于多奈哌齐，显示出莫达非尼和对乙酰氨基酚的组合具有作为现有阿尔茨海默病药物增效剂的潜力。The avoidance platform reflex test can reflect the animal's learning ability and memory ability by testing the animal's response to electric shock injury. Among them, the shorter the time (reaction time) between the time the animal received the electric shock and the jump on the safety platform, the better the learning ability. After 24 hours of learning, the animals were tested again from the time they jumped on the safety platform to the first time they jumped off the safety platform. The longer the platform jump latency, the better the memory ability of the animal. In this experiment, modafinil combined with acetaminophen also showed positive effects. Both low and high doses showed that it could reduce the activity of acetylcholinesterase, protect the cholinergic disorders caused by scopolamine, and improve the ability of learning and memory. In addition, donepezil, modafinil and acetaminophen were used in combination in this experiment. The effect of the combination of the three was significantly better than that of donepezil, showing that the combination of modafinil and acetaminophen has the advantages of Potential for drug synergists in Alzheimer's disease.
实施例3：莫达非尼与对乙酰氨基酚联用对脑代谢紊乱的阿尔茨海默病模型动物的作用Example 3: Effects of Modafinil and Paracetamol on Alzheimer's Disease Model Animals with Brain Metabolic Disorders
动物：Wister大鼠，雌雄各半，体重250-300g。Animals: Wister rats, half male and half female, weighing 250-300 g.
药物：莫达非尼(湘北威尔曼制药股份有限公司提供)，对乙酰氨基酚(市售)，美金刚(市售)。Drugs: Modafinil (provided by Xiangbei Wellman Pharmaceutical Co., Ltd.), paracetamol (commercially available), memantine (commercially available).
方法：method:
分组：动物随机分为8组：空白组、模型组、莫达非尼组(MDF)、对乙酰氨基酚组(APAP)、美金刚组(MEM)、莫达非尼+对乙酰氨基酚a组(MDF/APAP-a)、莫达非尼+对乙酰氨基酚b组(MDF/APAP-b)、莫达非尼+对乙酰氨基酚+美金刚组(MDF/APAP/MEM)。每组18只动物。Grouping: Animals were randomly divided into 8 groups: blank group, model group, modafinil group (MDF), paracetamol group (APAP), memantine group (MEM), modafinil + paracetamol a group (MDF/APAP-a), modafinil + acetaminophen b group (MDF/APAP-b), modafinil + acetaminophen + memantine group (MDF/APAP/MEM). 18 animals per group.
造模：第1天，除空白组外，各组动物麻醉后，固定在定位仪上，头顶部去毛后切开头皮，分离骨膜，钻开颅骨，暴露硬脑膜。用微量注射器向右侧脑室缓慢注入链脲佐菌素3mg/kg(10μL)，处理好创口，进行常规饲养并给与抗生素抗感染。第3天进行同样操作，再重复注射一次链脲佐菌素。空白组行相同的手术，但向右侧脑室中注入的是等量的生理盐水。Modeling: On the 1st day, except for the blank group, animals in each group were anesthetized and fixed on the positioning device, the scalp was cut off after dehairing the top of the head, the periosteum was separated, the skull was drilled, and the dura mater was exposed. Streptozotocin 3 mg/kg (10 μL) was slowly injected into the right ventricle with a microsyringe, the wound was treated, and routine feeding was performed and antibiotics were given to fight infection. The same operation was carried out on the third day, and one more injection of streptozotocin was repeated. The blank group underwent the same operation, but the same volume of normal saline was injected into the right ventricle.
给药：造模完成后次日开始给药。MDF组每日给与20mg/kg的莫达非尼，APAP组每日给与10mg/kg的对乙酰氨基酚，MEM组每日给与0.5mg/kg的美金刚，MDF/APAP-a组每日给与20mg/kg莫达非尼和10mg/kg对乙酰氨基酚，MDF/APAP-b组每日给与20mg/kg莫达非尼和120mg/kg对乙酰氨基酚，MDF/APAP/MEM组每日给与20mg/kg莫达非尼、120mg/kg对乙酰氨基酚和0.5mg/kg的美金刚。空白组和模型组每日均给与相同体积的生理盐水。各组连续灌胃给药1周。Administration: Administration was started the next day after the modeling was completed. The MDF group was given 20 mg/kg of modafinil daily, the APAP group was given 10 mg/kg of paracetamol daily, the MEM group was given 0.5 mg/kg of memantine daily, and the MDF/APAP-a group was given Modafinil 20mg/kg and acetaminophen 10mg/kg daily, MDF/APAP-b group 20mg/kg modafinil and acetaminophen 120mg/kg daily, MDF/APAP/ The MEM group was administered 20 mg/kg modafinil, 120 mg/kg acetaminophen and 0.5 mg/kg memantine daily. The blank group and the model group were given the same volume of normal saline every day. Each group was given continuous intragastric administration for 1 week.
测试：末次给药后次日进行Morris水迷宫测试。定位航行(place navigation)训练中，在水迷宫圆形水池中设置一个平台，平台设置在水下1cm处，将动物面向池壁放入水中。开始计时并记录动物找到平台的时间(寻台潜伏期)，在60秒内找到平台的动物引导其在台上站立15秒，在60秒内未找到平台的动物由实验人员引导其寻找到平台。每天训练2次，连续进行5天，5天的平均值作为寻台潜伏期。第6天进行空间搜索测试(spatial probe test)，将平台去除，将动物面向池壁放入水中，测试60秒，记录60秒内动物到达原平台位置的次数(过台次数)。Test: Morris water maze test was performed the day after the last dose. In the training of place navigation, a platform was set in the circular pool of the water maze, and the platform was set at 1 cm underwater, and the animals were placed in the water facing the pool wall. Start timing and record the time for the animals to find the platform (platform-finding latency). Animals that find the platform within 60 seconds are guided to stand on the platform for 15 seconds. Animals that do not find the platform within 60 seconds are guided by the experimenter to find the platform. Training was performed twice a day for 5 consecutive days, and the average of the 5 days was used as the platform-seeking incubation period. On the 6th day, a spatial probe test was performed, the platform was removed, and the animals were placed in the water facing the pool wall for 60 seconds.
能量代谢测定：Morris水迷宫测试完成后，每组随机取9只动物，断头处死，冰面上迅速分离大脑，取100mg脑组织，加入高氯酸溶液，研磨混匀，离心，取上清液加入磷酸氢钾溶液调pH值为 6.5，再离心并取上清液备用。用高效液相色谱法(C
18柱，流动相0.05mol/L磷酸氢钾缓冲液，检测波长254nm)测定样品中三磷酸腺苷(ATP)的含量。
Determination of energy metabolism: After the completion of the Morris water maze test, 9 animals were randomly selected from each group and killed by decapitation. The brains were quickly separated on ice, and 100 mg of brain tissue was taken, added with perchloric acid solution, ground and mixed, centrifuged, and the supernatant was taken. Potassium hydrogen phosphate solution was added to the solution to adjust the pH to 6.5, then centrifuged and the supernatant was taken for use. The content of adenosine triphosphate (ATP) in the samples was determined by high performance liquid chromatography (C 18 column, mobile phase 0.05mol/L potassium hydrogen phosphate buffer, detection wavelength 254nm).
β淀粉样蛋白表达阳性细胞计数：Morris水迷宫测试完成后，除能量代谢测定使用的动物之外的其余动物，麻醉后用多聚甲醛灌注，取脑并分离海马，组织切片，用HE染色和免疫组织化学染色。在400倍显微镜下观察切片，记录随机选取的5个区域中淡黄色或棕色细胞的数量，即为β淀粉样蛋白表达阳性的细胞数量。每只动物做两张切片，重复观察，取平均值。Count of cells positive for beta amyloid expression: After the completion of the Morris water maze test, the rest of the animals except those used for the energy metabolism assay were perfused with paraformaldehyde after anesthesia, the brains were taken and the hippocampus was isolated, histological sections were stained with HE and Immunohistochemical staining. Observe the sections under a 400-fold microscope, and record the number of light yellow or brown cells in 5 randomly selected areas, that is, the number of cells that express amyloid-beta positive. Two slices were made for each animal, the observation was repeated, and the average was taken.
结果：表5列出了Morris水迷宫测试的主要结果，表6列出了能量代谢测定的主要结果，表7列出了β淀粉样蛋白表达阳性的细胞计数情况。Results: Table 5 lists the main results of the Morris water maze test, Table 6 lists the main results of the energy metabolism assay, and Table 7 lists the counts of cells positive for beta amyloid expression.
表5 Morris水迷宫测试结果Table 5 Morris water maze test results
| 组别group | 动物数量number of animals | 寻台潜伏期(秒)Search latency (seconds) | 过台次数(次)Number of passes (times) |
| 空白blank | 1818 | 24.39±7.7524.39±7.75 | 3.11±1.133.11±1.13 |
| 模型Model | 1818 | 47.11±9.93 ## 47.11±9.93 ## | 0.44±0.51 ## 0.44±0.51 ## |
| 莫达非尼(MDF)Modafinil (MDF) | 1818 | 42.50±10.8942.50±10.89 | 0.50±0.620.50±0.62 |
| 对乙酰氨基酚(APAP)Acetaminophen (APAP) | 1818 | 46.72±9.4046.72±9.40 | 0.61±0.500.61±0.50 |
| 美金刚(MEM)Memantine (MEM) | 1818 | 34.56±6.88 ** 34.56±6.88 ** | 2.28±1.13 ** 2.28±1.13 ** |
| MDF/APAP-aMDF/APAP-a | 1818 | 38.61±8.16 * 38.61±8.16 * | 1.89±0.58 ** 1.89±0.58 ** |
| MDF/APAP-bMDF/APAP-b | 1818 | 32.72±8.40 ** 32.72±8.40 ** | 2.11±0.76 ** 2.11±0.76 ** |
| MDF/APAP/MEMMDF/APAP/MEM | 1818 | 29.17±5.73 **& 29.17±5.73 **& | 2.67±1.24 ** 2.67±1.24 ** |
注：与模型组相比，
*：P＜0.05，
**：P＜0.01。与空白组相比，
#：P＜0.05，
##：P＜0.01。与美金刚组相比，
&：P＜0.05，
&&：P＜0.01。
Note: compared with the model group, * : P<0.05, ** : P<0.01. # : P<0.05, ## : P<0.01, compared to the blank group. Compared with memantine, &: P <0.05, && : P <0.01.
表6 能量代谢测定结果Table 6 Determination results of energy metabolism
| 组别group | 动物数量number of animals | 三磷酸腺苷(ATP)的含量(μmol/g)Content of adenosine triphosphate (ATP) (μmol/g) |
| 空白blank | 99 | 5.19±1.025.19±1.02 |
| 模型Model | 99 | 2.56±0.75 ## 2.56±0.75 ## |
| 莫达非尼(MDF)Modafinil (MDF) | 99 | 2.95±0.552.95±0.55 |
| 对乙酰氨基酚(APAP)Acetaminophen (APAP) | 99 | 2.67±0.512.67±0.51 |
| 美金刚(MEM)Memantine (MEM) | 99 | 3.09±0.743.09±0.74 |
| MDF/APAP-aMDF/APAP-a | 99 | 3.33±0.833.33±0.83 |
| MDF/APAP-bMDF/APAP-b | 99 | 4.11±0.82 ** 4.11±0.82 ** |
| MDF/APAP/MEMMDF/APAP/MEM | 99 | 4.73±0.92 **&& 4.73±0.92 **&& |
注：与模型组相比，
*：P＜0.05，
**：P＜0.01。与空白组相比，
#：P＜0.05，
##：P＜0.01。与美金刚组相比，
&：P＜0.05，
&&：P＜0.01。
Note: compared with the model group, * : P<0.05, ** : P<0.01. # : P<0.05, ## : P<0.01, compared to the blank group. Compared with memantine, &: P <0.05, && : P <0.01.
表7 Aβ蛋白表达阳性的细胞计数情况Table 7 Counting of cells with positive Aβ protein expression
| 组别group | 动物数量number of animals | β淀粉样蛋白表达阳性细胞计数(个/mm 2) Count of amyloid-beta positive cells (cells/mm 2 ) |
| 空白blank | 99 | 9.67±1.179.67±1.17 |
| 模型Model | 99 | 30.67±2.90 ## 30.67±2.90 ## |
| 莫达非尼(MDF)Modafinil (MDF) | 99 | 28.39±2.3828.39±2.38 |
| 对乙酰氨基酚(APAP)Acetaminophen (APAP) | 99 | 27.50±2.24 * 27.50±2.24 * |
| 美金刚(MEM)Memantine (MEM) | 99 | 19.33±2.94 ** 19.33±2.94 ** |
| MDF/APAP-aMDF/APAP-a | 99 | 22.72±1.82 ** 22.72±1.82 ** |
| MDF/APAP-bMDF/APAP-b | 99 | 21.00±2.77 ** 21.00±2.77 ** |
| MDF/APAP/MEMMDF/APAP/MEM | 99 | 14.00±2.47 **&& 14.00±2.47 **&& |
注：与模型组相比，
*：P＜0.05，
**：P＜0.01。与空白组相比，
#：P＜0.05，
##：P＜0.01。与美金刚组相比，
&：P＜0.05，
&&：P＜0.01。
Note: compared with the model group, * : P<0.05, ** : P<0.01. # : P<0.05, ## : P<0.01, compared to the blank group. Compared with memantine, &: P <0.05, && : P <0.01.
分析：analyze:
本实验采用脑室局部注射链脲佐菌素造成动物脑代谢紊乱。链脲佐菌素可阻断胰岛素受体自身磷酸化和内在的酪氨酸激酶活性，导致胰岛素信号传导障碍。许多研究证实，小剂量链脲佐菌素侧脑室注射可以引起大鼠脑持久的葡萄糖代谢紊乱和能量障碍以及认知障碍，是阿尔茨海默病的一种常用动物模型。本实验中水迷宫测试发现模型组动物寻台潜伏期变长，过台次数明显减少，说明造模成功。另外还发现动物脑能量代谢明显降低(三磷酸腺苷含量明显减少)，并且β淀粉样蛋白表达明显增多。这些现象也非常符合人类阿尔茨海默病的病理表现。In this experiment, intraventricular local injection of streptozotocin was used to induce metabolic disorder of animal brain. Streptozotocin blocks insulin receptor autophosphorylation and intrinsic tyrosine kinase activity, resulting in impaired insulin signaling. Many studies have confirmed that intraventricular injection of low-dose streptozotocin can cause persistent glucose metabolism disturbance, energy disturbance and cognitive impairment in the rat brain, which is a commonly used animal model of Alzheimer's disease. In the water maze test in this experiment, it was found that the incubation period of the animals in the model group was longer, and the number of passing the platform was significantly reduced, indicating that the modeling was successful. In addition, it was found that the brain energy metabolism of animals was significantly reduced (the content of adenosine triphosphate was significantly reduced), and the expression of beta amyloid protein was significantly increased. These phenomena are also very consistent with the pathological manifestations of human Alzheimer's disease.
Morris水迷宫测试中定位航行阶段寻台潜伏期越短说明动物的学习能力越强，空间搜索测试阶段过台次数越多说明动物的记忆能力越好。本实验中研究了莫达非尼与对乙酰氨基酚联用对脑代谢紊乱的阿尔茨海默病模型动物的作用。发现莫达非尼与对乙酰氨基酚联用能降低β淀粉样蛋白表达、提高脑能量代谢、提高学习记忆能力。采用美金刚进行了对比研究，发现莫达非尼与对乙酰氨基酚联用能达到或优于美金刚的效果。另外，将美金刚、莫达非尼和对乙酰氨基酚三者联用，效果优于美金刚，说明莫达非尼和对乙酰氨基酚的组合可作为现有治疗阿尔茨海默病药物的增效剂使用。In the Morris water maze test, the shorter the platform-seeking latency in the positioning navigation phase, the stronger the animal's learning ability, and the more the number of passages in the spatial search test phase, the better the animal's memory ability. In this experiment, the effect of modafinil combined with acetaminophen on Alzheimer's disease model animals with cerebral metabolic disorders was investigated. It was found that the combination of modafinil and acetaminophen can reduce the expression of beta amyloid, improve brain energy metabolism, and improve learning and memory ability. A comparative study was conducted using memantine, and it was found that the combination of modafinil and acetaminophen could achieve or exceed the effect of memantine. In addition, the combination of memantine, modafinil and acetaminophen is more effective than memantine, indicating that the combination of modafinil and acetaminophen can be used as an alternative to existing Alzheimer's disease drugs. Use of synergists.
尽管已参照具体实施方式公开了本发明，但是显而易见的是，在不背离本发明的真正精神和范围的情况下，本领域的其它技术人员可以设计本发明的其它实施方式和变化，所附权利要求书目的在于被解释为包括所有这样的实施方式和等价的变化。此外，本文引用的所有参考文献的内容据此引入本文以供参考。Although this invention has been disclosed with reference to specific embodiments, it will be apparent that other embodiments and variations of this invention can be devised by others skilled in the art without departing from the true spirit and scope of this invention, the appended claims The claims are intended to be construed to include all such embodiments and equivalent variations. Furthermore, the contents of all references cited herein are hereby incorporated by reference.
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Claims (16)
- 一种药物组合物，包括活性物质，所述活性物质包括莫达非尼和对乙酰氨基酚，其中莫达非尼和对乙酰氨基酚的重量比为100:1～1:50。A pharmaceutical composition includes active substances, the active substances include modafinil and paracetamol, wherein the weight ratio of modafinil and paracetamol is 100:1-1:50.
- 根据权利要求1所述的药物组合物，所述药物组合物中莫达非尼和对乙酰氨基酚的重量比为50:1～1:20。The pharmaceutical composition according to claim 1, wherein the weight ratio of modafinil and paracetamol in the pharmaceutical composition is 50:1 to 1:20.
- 根据权利要求1所述的药物组合物，所述活性物质还包括其它可用于治疗阿尔茨海默病的活性成分。According to the pharmaceutical composition of claim 1, the active substance further comprises other active ingredients which can be used for the treatment of Alzheimer's disease.
- 根据权利要求3所述的药物组合物，所述其它可用于治疗阿尔茨海默病的活性成分选自胆碱酯酶抑制剂、β淀粉样蛋白抑制剂、Tau蛋白聚集抑制剂、N-甲基-D-天冬氨酸受体拮抗剂、脑代谢促进剂、肠道菌群调节剂中的一种或多种；更优选地，所述其它可用于治疗阿尔茨海默病的活性成分选自他克林、加兰他敏、多奈哌齐、卡巴拉汀、石杉碱甲、色甘酸、LMTX、美金刚、NAMZARIC、奥拉西坦、甲氯芬酯、GV971中的一种或多种；最优选为多奈哌齐、美金刚或NAMZARIC。The pharmaceutical composition according to claim 3, wherein the other active ingredients that can be used for the treatment of Alzheimer's disease are selected from cholinesterase inhibitors, beta amyloid inhibitors, Tau protein aggregation inhibitors, N-methyl methacrylates One or more of base-D-aspartate receptor antagonists, brain metabolism promoters, and intestinal flora regulators; more preferably, the other active ingredients that can be used for the treatment of Alzheimer's disease One or more selected from tacrine, galantamine, donepezil, rivastigmine, huperzine A, cromolyn, LMTX, memantine, NAMZARIC, oxiracetam, meclofen axetil, GV971 ; most preferably donepezil, memantine or NAMZARIC.
- 根据权利要求1所述的药物组合物，所述药物组合物为口服制剂、口腔内制剂、注射制剂、吸入制剂，或者局部用制剂。The pharmaceutical composition according to claim 1, which is an oral preparation, an intraoral preparation, an injection preparation, an inhalation preparation, or a topical preparation.
- 根据权利要求1所述的药物组合物，所述药物组合物为常释制剂、迟释制剂、缓释制剂或定向释放制剂。The pharmaceutical composition according to claim 1, which is a normal-release preparation, a delayed-release preparation, a sustained-release preparation or a directed-release preparation.
- 根据权利要求1所述的药物组合物，所述药物组合物还包括药学上可接受的辅料。The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable adjuvant.
- 权利要求1-7任一项所述的药物组合物在制备治疗阿尔茨海默病的药物中的应用。Application of the pharmaceutical composition according to any one of claims 1-7 in the preparation of a medicament for treating Alzheimer's disease.
- 根据权利要求8所述的应用，所述组合物中的活性物质共同存在于同一药剂中，或者分别存在于不同的药剂中。According to the use according to claim 8, the active substances in the composition are co-existed in the same medicament or separately in different medicaments.
- 根据权利要求8所述的应用，所述治疗阿尔茨海默病包括改善阿尔茨海默病引起的认知功能障碍、睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状；优选改善阿尔茨海默病引起的认知功能障碍，并且改善阿尔茨海默病引起的睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状。The use according to claim 8, wherein the treatment of Alzheimer's disease comprises improving cognitive dysfunction, sleep disturbance, tension or anxiety, cholinergic dysfunction, brain metabolic disorder or beta amyloid caused by Alzheimer's disease One or more symptoms of protein-like disorders; preferably improve cognitive dysfunction caused by Alzheimer's disease, and improve sleep disturbance, nervousness or anxiety, cholinergic dysfunction, brain metabolism caused by Alzheimer's disease Disorder or one or more symptoms of beta amyloid disorder.
- 一种用于治疗阿尔茨海默病的药盒，权利要求1-7任一项所述的药物组合物。A kit for treating Alzheimer's disease, the pharmaceutical composition of any one of claims 1-7.
- 一种治疗阿尔茨海默病的方法，包括向有此需要的对象施用权利要求1-7任一项所述的药物组合物，其特征在于，所述药物组合物中包含治疗有效量的活性物质。A method for treating Alzheimer's disease, comprising administering the pharmaceutical composition of any one of claims 1-7 to an object in need thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of activity substance.
- 根据权利要求12所述的方法，其中莫达非尼和对乙酰氨基酚同时施用或分开施用。13. The method of claim 12, wherein modafinil and acetaminophen are administered simultaneously or separately.
- 根据权利要求12所述的方法，其中所述对象为阿尔茨海默病患者。The method of claim 12, wherein the subject is an Alzheimer's disease patient.
- 根据权利要求14所述的方法，其中所述对象存在认知功能障碍、睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状；优选所述对象存在认知功能障碍，还存在睡眠紊乱、紧张或焦虑、胆碱能功能障碍、脑代谢紊乱或β淀粉样蛋白紊乱中的一种或多种症状。The method of claim 14, wherein the subject has one or more symptoms of cognitive dysfunction, sleep disturbance, stress or anxiety, cholinergic dysfunction, cerebral metabolic disorder, or beta amyloid disorder; Preferably, the subject has cognitive dysfunction and one or more symptoms of sleep disturbance, stress or anxiety, cholinergic dysfunction, cerebral metabolic disturbance, or beta amyloid disturbance.
- 根据权利要求12所述的方法，所述活性物质可以同时施用或分开施用。According to the method of claim 12, the active substances can be administered simultaneously or separately.
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