Application of composition in medicine preparation

Abstract

The present application relates to the use of a composition for the preparation of a medicament for the treatment of autism spectrum disorders, wherein the composition comprises taurine and a beta-receptor blocker.

Description

Technical Field

[0001] This application relates to the field of biomedicine, and specifically relates to a composition and its application in the treatment of autism spectrum disorder. Background Art

[0002] Autism spectrum is usually simply referred to as autism, that is, autism spectrum disorder (English: autism spectrum disorders, ASD; or autism spectrum conditions, ASC) under professional diagnosis, which belongs to the neurodevelopmental disorder syndrome. Its main clinical manifestations are abnormal nature of social interaction and communication patterns, limited, stereotyped and repetitive interests and activities. Some patients are also accompanied by intellectual deficiency, delayed or retarded cognitive development, and loss of acquired developmental skills after a certain period of normal development.

[0003] Currently, there is no specific drug for ASD. The main treatment methods are to improve the patient's social interaction ability through education and training, master life skills and learning skills, and supplemented with drugs to reduce co-morbid symptoms. Antipsychotic drugs have been approved for the treatment of autism. The US FDA approved risperidone in 2006 and aripiprazole in 2009 for the treatment of young ASD patients. Such drugs mainly regulate dopamine in the brain to improve the irritable response and aggressive behavior related to ASD patients. However, recent studies have shown that such drugs can cause metabolic abnormalities, extrapyramidal reactions, gastrointestinal symptoms.

[0004] Therefore, there is still a need in this field for methods to treat and reduce the severity and symptom incidence related to autism spectrum disorder. Summary of the Invention

[0005] This application provides a combination therapy of taurine and β-blockers, which can treat autism spectrum disorder or improve the related symptoms of its patients. Moreover, the combination therapy of taurine and β-blockers is superior to their respective single use in improving the symptoms of autism spectrum disorder.

[0006] On the one hand, this application provides the use of a composition in the preparation of a drug, wherein the composition contains taurine and a β-blocker.

[0007] In certain embodiments, the β-blocker is selected from β1 receptor selective β-blockers, β2 receptor selective β-blockers, mixed α and β-blockers and / or non-selective β-blockers.

[0008] In certain embodiments, the β-blocker is selected from the following: Atenolol, Metoprolol, Carvedilol, Labetalol, Propranolol, Bisoprolol, Propafenone, and pharmaceutically acceptable salts thereof.

[0009] In certain embodiments, the β-blocker is Atenolol or a pharmaceutically acceptable salt thereof. In certain embodiments, the β-blocker is Metoprolol or a pharmaceutically acceptable salt thereof. In certain embodiments, the β-blocker is selected from Metoprolol succinate and Metoprolol tartrate. In certain embodiments, the β-blocker is Carvedilol or a pharmaceutically acceptable salt thereof. In certain embodiments, the β-blocker is Carvedilol phosphate. In certain embodiments, the β-blocker is Labetalol or a pharmaceutically acceptable salt thereof. In certain embodiments, the β-blocker is Labetalol hydrochloride. In certain embodiments, the β-blocker is Propranolol or a pharmaceutically acceptable salt thereof. In certain embodiments, the β-blocker is Propranolol hydrochloride. In certain embodiments, the β-blocker is Bisoprolol or a pharmaceutically acceptable salt thereof. In certain embodiments, the β-blocker is Bisoprolol fumarate. In certain embodiments, the β-blocker is Propafenone or a pharmaceutically acceptable salt thereof. In certain embodiments, the β-blocker is Propafenone hydrochloride.

[0010] In certain embodiments, the mass ratio of the taurine and its derivatives to the β-blocker is from 80:1 to 2:1. In certain embodiments, the mass ratio of the taurine and its derivatives to the β-blocker is from 40:1 to 1:1. In certain embodiments, the mass ratio of the taurine and its derivatives to the β-blocker is 80:1, 40:1, 20:1, 200:15, 8:1, 100:15, 4:1, 16:5, 2:1, or 1:1.

[0011] In certain embodiments, the composition has one or more of the following functions: improving memory impairment, improving social impairment, improving speech communication impairment, reducing repetitive stereotyped behaviors, improving sensory ability defects, and improving motor ability defects.

[0012] In certain embodiments, the composition has one or more of the following functions: improving memory impairment in patients with autism spectrum disorder, improving social impairment in patients with autism spectrum disorder, improving speech communication impairment in patients with autism spectrum disorder, reducing repetitive stereotyped behaviors in patients with autism spectrum disorder, improving sensory ability deficits in patients with autism spectrum disorder, improving motor ability deficits in patients with autism spectrum disorder, and improving self-care ability in patients with autism spectrum disorder.

[0013] In certain embodiments, the composition has one or more of the following functions: rescuing social preference in patients with autism spectrum disorder, rescuing social memory in patients with autism spectrum disorder, rescuing empathy ability in patients with autism spectrum disorder, rescuing spatial memory in patients with autism spectrum disorder.

[0014] In certain embodiments, the drug is used to improve memory impairment, improve social impairment, improve speech communication impairment, reduce repetitive stereotyped behaviors, improve sensory ability deficits, and / or improve motor ability deficits.

[0015] In certain embodiments, the drug is used to treat autism spectrum disorder.

[0016] In certain embodiments, the drug is used to improve memory impairment in patients with autism spectrum disorder, improve social impairment in patients with autism spectrum disorder, improve speech communication impairment in patients with autism spectrum disorder, reduce repetitive stereotyped behaviors in patients with autism spectrum disorder, improve sensory ability deficits in patients with autism spectrum disorder, improve motor ability deficits in patients with autism spectrum disorder, and / or improve self-care ability in patients with autism spectrum disorder.

[0017] In certain embodiments, the drug comprises a pharmaceutical composition, and the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0018] On the other hand, the present application provides a composition comprising taurine and a β-blocker.

[0019] In certain embodiments, the β-blocker is selected from the following: Atenolol, Metoprolol, Carvedilol, Labetalol, Propranolol, Bisoprolol, and their medicinal salts.

[0020] In certain embodiments, the beta-blocker is atenolol or a pharmaceutically acceptable salt thereof. In certain embodiments, the beta-blocker is metoprolol or a pharmaceutically acceptable salt thereof. In certain embodiments, the beta-blocker is selected from metoprolol succinate and metoprolol tartrate. In certain embodiments, the beta-blocker is carvedilol or a pharmaceutically acceptable salt thereof. In certain embodiments, the beta-blocker is carvedilol phosphate. In certain embodiments, the beta-blocker is labetalol or a pharmaceutically acceptable salt thereof. In certain embodiments, the beta-blocker is labetalol hydrochloride. In certain embodiments, the beta-blocker is propranolol or a pharmaceutically acceptable salt thereof. In certain embodiments, the beta-blocker is propranolol hydrochloride. In certain embodiments, the beta-blocker is bisoprolol or a pharmaceutically acceptable salt thereof. In certain embodiments, the beta-blocker is bisoprolol fumarate. In certain embodiments, the beta-blocker is propafenone or a pharmaceutically acceptable salt thereof. In certain embodiments, the beta-blocker is propafenone hydrochloride.

[0021] In certain embodiments, the mass ratio of the taurine and its derivatives to the beta-blocker is from 100:1 to 1:10. In certain embodiments, the mass ratio of the taurine and its derivatives to the beta-blocker is from 80:1 to 2:1. In certain embodiments, the mass ratio of the taurine and its derivatives to the beta-blocker is from 40:1 to 1:1. In certain embodiments, the mass ratio of the taurine and its derivatives to the beta-blocker is 80:1, 40:1, 20:1, 200:15, 8:1, 100:15, 4:1, 16:5, 2:1 or 1:1.

[0022] In certain embodiments, the composition has one or more of the following functions: improving memory impairment, improving social impairment, improving speech communication impairment, reducing repetitive stereotyped behavior, improving sensory ability defects, and improving motor ability defects.

[0023] In certain embodiments, the composition has one or more of the following functions: improving memory impairment in patients with autism spectrum disorder, improving social impairment in patients with autism spectrum disorder, improving speech communication impairment in patients with autism spectrum disorder, reducing repetitive stereotyped behavior in patients with autism spectrum disorder, improving sensory ability defects in patients with autism spectrum disorder, improving motor ability defects in patients with autism spectrum disorder, and improving self-care ability in patients with autism spectrum disorder.

[0024] In certain embodiments, the composition has one or more of the following functions: rescuing the social preference of patients with autism spectrum disorder, rescuing the social memory of patients with autism spectrum disorder, rescuing the empathy ability of patients with autism spectrum disorder, rescuing the spatial memory of patients with autism spectrum disorder.

[0025] In certain embodiments, the composition is a pharmaceutical composition and comprises a pharmaceutically acceptable carrier.

[0026] In certain embodiments, it includes administering taurine and a β-blocker to a subject.

[0027] In certain embodiments, it includes administering the composition described in the present application to a subject.

[0028] On the other hand, the present application provides the use of taurine and a β-blocker in the treatment of autism spectrum disorder.

[0029] On the other hand, the present application provides the use of the composition described in the present application in the treatment of autism spectrum disorder.

[0030] Those skilled in the art can easily insight into other aspects and advantages of the present application from the following detailed description. Only exemplary embodiments of the present application are shown and described in the following detailed description. As those skilled in the art will recognize, the content of the present application enables those skilled in the art to make changes to the disclosed specific embodiments without departing from the spirit and scope of the invention involved in the present application. Accordingly, the description in the drawings and the specification of the present application is merely exemplary and not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The specific features of the invention involved in the present application are shown in the appended claims. The features and advantages of the invention involved in the present application can be better understood by referring to the exemplary embodiments and the drawings described in detail below. A brief description of the drawings is as follows:

[0032] Figure 1 Shows a schematic diagram of the three-chamber experiment for the mouse social memory test.

[0033] Figure 2 Shows a schematic diagram of the mouse pain transfer experiment.

[0034] Figure 3 Shows a schematic diagram of the water maze device used in the mouse water maze memory test.

[0035] Figure 4 Shows a flow chart of the social experiment of the autism mouse model.

[0036] Figure 5It shows the flow chart of the social behavior experiment.

[0037] Figure 6 It shows the rescue effect of propafenone on the social function of VPA model mice. The mice underwent a three-chamber social experiment to test their social ability. From left to right are the wild control group, the VPA model group, and the propafenone group. Figure 6 A, Comparison of the exploration time of mice for strange mice and empty restraint cages. Two-way ANOVA was used to statistically analyze the variance. Figure 6 B, Comparison of the exploration time of mice for strange mice and familiar mice. Two-way ANOVA was used to statistically analyze the variance. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, **** represents p < 0.0001. N = 6).

[0038] Figure 7 It shows the rescue effect of taurine on the social function of VPA model mice. The mice underwent a three-chamber social experiment to test their social ability. From left to right are the wild control group, the VPA model group, and the taurine group. Figure 7 A, Comparison of the exploration time of mice for strange mice and empty restraint cages. Two-way ANOVA was used to statistically analyze the variance. Figure 7 B, Comparison of the exploration time of mice for strange mice and familiar mice. Two-way ANOVA was used to statistically analyze the variance. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, **** represents p < 0.0001. N = 6).

[0039] Figure 8 It shows the rescue effect of propranolol on the social function of VPA model mice. The mice underwent a three-chamber social experiment to test their social ability. From left to right are the wild control group, the VPA model group, and the propranolol group. Figure 8 A, Comparison of the exploration time of mice for strange mice and empty restraint cages. Two-way ANOVA was used to statistically analyze the variance. Figure 8 B, Comparison of the exploration time of mice for strange mice and familiar mice. Two-way ANOVA was used to statistically analyze the variance. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, **** represents p < 0.0001. N = 5 - 6).

[0040] Figure 9Shown is the rescue effect of atenolol on the social function of VPA model mice. The mice underwent a three-chamber social experiment to test their social ability. From left to right are the wild control group, the VPA model group, and the atenolol group. A, Comparison of the exploration time of mice for unfamiliar mice and empty restraint cages. Two-way ANOVA was used to analyze the variance. B, Comparison of the exploration time of mice for unfamiliar mice and familiar mice. Two-way ANOVA was used to analyze the variance. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, **** represents p < 0.0001. N = 4, 6).

[0041] Figure 10 Shown is the rescue effect of aripiprazole and carvedilol on the social function of VPA model mice. The mice underwent a three-chamber social experiment to test their social ability. From left to right are the wild control group, the VPA model group, the aripiprazole group, and the carvedilol group. Figure 10 A, Comparison of the exploration time of mice for unfamiliar mice and empty restraint cages. Two-way ANOVA was used to analyze the variance. Figure 10 B, Comparison of the exploration time of mice for unfamiliar mice and familiar mice. Two-way ANOVA was used to analyze the variance. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, **** represents p < 0.0001. N = 3, 6).

[0042] Figure 11 Shown is the rescue effect of the combination of aripiprazole and atenolol, and the combination of aripiprazole and labetalol on the social function of VPA model mice. The mice underwent a three-chamber social experiment to test their social ability. From left to right are the wild control group, the VPA model group, the aripiprazole + atenolol group, and the aripiprazole + labetalol group. Figure 11 A, Comparison of the exploration time of mice for unfamiliar mice and empty restraint cages. Two-way ANOVA was used to analyze the variance. Figure 11 B, Comparison of the exploration time of mice for unfamiliar mice and familiar mice. Two-way ANOVA was used to analyze the variance. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, **** represents p < 0.0001. N = 4, 6).

[0043] Figure 12 Shown is the rescue effect of the combination of atenolol and taurine, and the combination of propafenone and taurine on the social function of VPA model mice. The mice underwent a three-chamber social experiment to test their social ability. From left to right are the wild control group, the VPA model group, the atenolol + taurine group, and the propafenone + taurine group. Figure 12A, Comparison of the exploration time of mice towards unfamiliar mice and an empty restraint cage. Two-way ANOVA was used to statistically analyze the variance. Figure 12 B, Comparison of the exploration time of mice towards unfamiliar mice and familiar mice. Two-way ANOVA was used to statistically analyze the variance. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, **** represents p < 0.0001. N = 4, 6).

[0044] Figure 13 Shown are the rescue effects of the combination of metoprolol and taurine, and metoprolol and taurine on the social function of VPA model mice. Mice underwent a three-chamber social experiment to test their social ability. From left to right are the wild control group, VPA model group, metoprolol + taurine group, metoprolol group, and taurine group. Figure 13 A, Comparison of the exploration time of mice towards unfamiliar mice and an empty restraint cage. Two-way ANOVA was used to statistically analyze the variance. Figure 13 B, Comparison of the exploration time of mice towards unfamiliar mice and familiar mice. Two-way ANOVA was used to statistically analyze the variance. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, **** represents p < 0.0001. N = 6).

[0045] Figure 14 Shown is the rescue effect of metoprolol, the combination of metoprolol and taurine on the social function of VPA model mice when administered the drug twice a day. Mice underwent a three-chamber social experiment to test their social ability. From left to right are the wild control group, VPA model group, metoprolol + taurine group, and metoprolol group. Figure 14 A, Comparison of the exploration time of mice towards unfamiliar mice and an empty restraint cage. Two-way ANOVA was used to statistically analyze the variance. Figure 14 B, Comparison of the exploration time of mice towards unfamiliar mice and familiar mice. Two-way ANOVA was used to statistically analyze the variance. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001, **** represents p < 0.0001. N = 5).

[0046] Figure 15 Shown is the rescue of the social function of Shank3 model mice by 10 mg / kg metoprolol compound, etc. Mice underwent a three-chamber social experiment to test their social ability. From left to right are the wild control group, VPA model group, aripiprazole group, metoprolol + taurine group, and metoprolol group. Figure 15 A, Comparison of the exploration time of mice towards unfamiliar mice and an empty restraint cage. Two-way ANOVA was used to statistically analyze the variance. Figure 15B, Comparison of exploration time of mice towards unfamiliar and familiar mice. Two-way ANOVA was used to analyze the variance. (* indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001, **** indicates p < 0.0001. N = 5).

[0047] Figure 16 Shown is the experimental flow chart of the autistic model mice.

[0048] Figure 17 Shown is the rescue of empathic function of 20 mg / kg metoprolol compound etc. on VPA model mice. After the mice underwent the empathy paradigm, the pain thresholds of the mice before and after interaction were tested. From left to right were the control group, VPA model group, metoprolol + taurine group, and taurine group. Two-way ANOVA was used to analyze the variance. (* indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001, **** indicates p < 0.0001. N = 6).

[0049] Figure 18 Shown is the rescue of empathic function of 20 mg / kg metoprolol compound etc. on Shank3 model mice. After the mice underwent the empathy paradigm, the pain thresholds of the mice before and after interaction were tested. From left to right were the wild control group, VPA model group, metoprolol + taurine group, and metoprolol group. Two-way ANOVA was used to analyze the variance. (* indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001, **** indicates p < 0.0001. N = 6).

[0050] Figure 19 Shown is the rescue of spatial memory of 20 mg / kg metoprolol compound on VPA model mice. After 5 days of water maze training, the memory ability of the mice was tested. Figure 19 A, Time for the mice to reach the platform during training. Multiple variance comparison analysis was used. Figure 19 B, Proportion of time for the mice to swim in the platform quadrant during the adaptation and test phases. One-way ANOVA was used to analyze the variance. Figure 19 C, Number of times the mice crossed the platform position during the adaptation and test phases. (* indicates p < 0.05, ** indicates p < 0.01, *** indicates p < 0.001. N = 6).

[0051] Figure 20 Shown is the rescue of spatial memory of 10 mg / kg metoprolol compound on VPA model mice. After 5 days of water maze training, the memory ability of the mice was tested. Figure 20 A, Time for the mice to reach the platform during training. Multiple variance comparison analysis was used. Figure 20B. Number of times the mice crossed the platform position during the adaptation and testing phases. One-way ANOVA was used to statistically analyze the variance. Figure 20 C. Proportion of time the mice swam in the platform quadrant during the adaptation and testing phases. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001. N = 6).

[0052] Figure 21 Shown is the spatial memory rescue of the Shank3 mice by the 20 mg / kg metoprolol compound. After 6 days of water maze training, the memory ability of the tested mice was measured. Figure 21 A. Time taken for the mice to reach the platform during training. Multiple variance comparison analysis was used. Figure 21 B. Number of times the mice crossed the platform position during the adaptation and testing phases. One-way ANOVA was used to statistically analyze the variance. Figure 21 C. Proportion of time the mice swam in the platform quadrant during the adaptation and testing phases. (* represents p < 0.05, ** represents p < 0.01, *** represents p < 0.001. N = 6). Detailed implementation manners

[0053] The following specific embodiments illustrate the implementation manners of the invention of the present application. Those skilled in the art can easily understand other advantages and effects of the invention of the present application from the content disclosed in this specification.

[0054] Term definitions

[0055] In the present application, the term "taurine" also known as 2-aminoethanesulfonic acid (IUPAC nomenclature) is a sulfonic acid with an amino group. The CAS number of taurine is 107-35-7 and its molecular formula is C2H7NO3S. The interchangeable use of "taurine" and "L-taurine" refers to the same organic compound.

[0056] In the present application, the term "beta-blocker" also known as Beta receptor blocking drug, β receptor blocker, β receptor antagonist or β blocker, beta-blocking agent, generally refers to a class of substances that can inhibit the activity of β-receptors. Beta-blockers can bind to β-receptors and thus inhibit their activity. For example, beta-blockers can block the binding of β-receptors to adrenaline and noradrenaline, thereby inhibiting their activity. Beta-blockers can have effects such as slowing heart rate, reducing blood pressure, decreasing cardiac contractility, controlling arrhythmias, reducing myocardial oxygen consumption, and controlling hyperthyroidism.

[0057] β receptors are mainly divided into three subtypes: β1 receptors, β2 receptors, and β3 receptors, which have different distributions and functions in different tissues and organs. β1 receptors are mainly distributed in the heart and adrenal tissues, regulating the contractility and heart rate of the heart, as well as the release of adrenaline. β2 receptors are widely distributed in various tissues, such as bronchial smooth muscle, vascular smooth muscle, hepatocytes, and muscle tissues, etc., and are involved in regulating physiological processes such as bronchial dilation, vasodilation, and glycogenolysis. β3 receptors are mainly present in adipocytes and the digestive system, regulating fat metabolism and energy consumption. β-blockers can be divided into 4 categories: ① non-selective β-blockers, which can block both β1 and β2 receptors simultaneously; ② β1 receptor-selective β-blockers, which mainly act on β1 receptors; ③ β2 receptor-selective β-blockers, which mainly act on β2 receptors; ④ mixed α and β-blockers, which can act on both β-receptors and α-receptors.

[0058] In the present application, the term "pharmaceutically acceptable salt" generally refers to a salt suitable for contact with human and animal tissues. Pharmaceutically acceptable salts include acid and base addition salts. The term "pharmaceutically acceptable acid addition salt" generally refers to such a pharmaceutically acceptable salt formed by using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, alicyclic, aromatic, aralkyl, heterocyclic, carboxylic acid, and sulfonic acid types, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. The term "pharmaceutically acceptable base addition salt" generally refers to those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of available inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of the following: primary amines, secondary amines, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. These salts can be formed by processes known and described in the art.

[0059] In the present application, the term "pharmaceutical composition" generally refers to a preparation in a form that permits the biological activity of the active ingredient to be effective, and which does not contain additional ingredients that are unacceptably toxic to the subject to which the preparation is to be administered. These preparations can be sterile. The pharmaceutical composition can also contain one or more pharmaceutically acceptable carriers. The acceptable ingredients of the pharmaceutical composition are preferably non-toxic to the recipient at the dosages and concentrations used.

[0060] In the present application, the term "pharmaceutically acceptable carrier" generally refers to any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, etc. that are compatible with the administration of a drug. The use of such media and agents for active pharmaceutical substances is well known in the art. Any conventional media or agent can be considered for use in the pharmaceutical compositions of the present application, unless it is incompatible with the active compound.

[0061] In the present application, the term "treatment" generally includes: (1) preventing a subject from developing adverse symptoms and pathological conditions that the subject is predisposed to develop but has not yet been diagnosed with; (2) inhibiting adverse symptoms and pathological conditions, i.e., controlling their development; or (3) improving or alleviating adverse symptoms or pathological conditions, even if the above adverse symptoms or pathological conditions regress. For example, the treatment of autism spectrum disorder as described in the present application can include the alleviation of symptoms associated with autism spectrum disorder, regardless of whether the subject is diagnosed with autism spectrum disorder.

[0062] In the present application, the term "autism spectrum disorders (ASD)" is also referred to as "Autism spectrum" or "Autism", and generally refers to a neurodevelopmental disorder syndrome and its related symptoms. According to the fifth edition, revised (DSM-5-TR) of the Diagnostic and Statistical Manual of Mental Disorders and the eleventh edition (ICD-11) of the International Classification of Diseases, autism is generally understood as a spectrum disorder. For example, the autism spectrum disorder described in the present application may include a certain level of autism spectrum disorder (ASD), level 1 ASD, level 2 ASD, level 3 ASD, autism ("classical autism"), Asperger syndrome ("high-functioning autism"), pervasive developmental disorder (PDD "atypical autism"), pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, developmental disorders related to autism spectrum disorder, speech and language delay (SLD), obsessive-compulsive disorder (OCD), social disorder, intellectual disability, learning disability, sensory processing, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), speech disorder, language disorder, social deficit, social interaction deficit, repetitive stereotyped behavior (RBB), repetitive stereotyped interest, repetitive stereotyped activity, global developmental delay or one or more of other behaviors, intellectual or developmental delays.

[0063] Autism spectrum disorder and / or its related symptoms can be evaluated by a variety of methods known in the art. The Autism Behavior Checklist (ABC scale) is one of the most widely used autism assessment scales in China at present. The ABC scale (Autism Behavior Checklist) was developed by Krug in 1978. The table lists 57 behavioral characteristics of children with autism, including five aspects: Sensory, Relating, Body and object use, Language, and Social and self-help, and is used for children aged 2-14. Commonly used scales also include the Autism Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview-Revised (ADI-R), the Childhood Autism Rating Scale (CARS), the Social Responsiveness Scale (SRS), the Vineland Adaptive Behavior Scales (Vineland-II), the Ohio Autism Clinical Global Impression Scale (OACIS), the Repetitive Behavior Scale-Revised (RBS-R), and the Yale-Brown Obsessive Compulsive Scale for Children with Autism Spectrum Disorder (CYBOSC-ASD).

[0064] In this application, the term "memory disorder" generally refers to a condition where an individual has problems in acquiring, storing, recalling, or using information. Such problems can be temporary or long-term and may be caused by various factors, including brain injury, neurological diseases, drugs or drug abuse, emotional or mental health problems, etc. The social impairments in individuals with autism spectrum disorder can manifest as one or more of the following: social memory disorder, including difficulty in remembering others' names, faces, emotional states, or social rules; non-verbal memory disorder, such as disorders in spatial memory, visual memory, or motor memory, forgetting specific figures, positions, sequences, or actions; excessive attention to details and difficulty in integrating information into a meaningful whole; perseverative interests and attention, being overly engaged in specific interests or activities, resulting in interference with attention and memory for other information or events; emotional memory disorder, for example, difficulty in recalling past emotional experiences or difficulty in understanding and expressing emotions. Memory disorders can be evaluated by methods known in the art, such as cognitive function tests, standardized memory assessment tools, etc. Commonly used standardized memory assessment tools can include the Wechsler Memory Scale, the Brief Assessment of Cognition in Schizophrenia (BACS), the Rey Complex Figure Delayed Recall Test, etc.

[0065] In this application, the term "social impairment" generally refers to an individual's avoidance or strong aversion to social interaction. Social impairments can include social psychological disorders, social functional impairments, and / or social anxiety disorders. The social impairments in individuals with autism spectrum disorder can manifest as one or more of the following: lack of use of body language or other non-verbal communication skills, such as lack of eye contact; inability to develop appropriate peer relationships with peers of the same age; weaker interpersonal communication ability compared to normal individuals, lacking the motivation and ability to actively share things, interests, and emotions when communicating with peers; less response in communication, unable to initiate social interactions, difficult to maintain two-way conversations, and even establish friendships; lack of motivation to actively participate in social or group activities, preferring to be alone; failure to perceive, understand, and respond to others' feelings and needs, and to perceive the presence of others; inability to participate in pretend or social imitation games. Social impairments can be evaluated by methods known in the art, such as the Autism Behavior Checklist (ABC) and the Childhood Autism Rating Scale (CARS).

[0066] In the present application, the term "speech communication disorder" generally refers to a neurodevelopmental disorder that affects language ability. It is manifested as an individual having difficulties in language comprehension, expression, or speech, which go beyond the scope of normal language development. Speech communication disorders may involve multiple aspects, including pronunciation of language, use of vocabulary, understanding and application of grammar, understanding of semantics, as well as problems with speech and fluency. The speech communication disorders of autistic patients can be manifested as one or more of the following: delayed language development or complete lack of ability to understand and express; weak understanding ability, only understanding the literal meaning of speech or words, unable to understand the underlying meaning; unable to understand or misinterpreting puns, jokes, idioms, metaphors, or sarcastic remarks; when others ask questions, unable to understand the meaning and key points of the questions, resulting in inappropriate answers; unable to understand abstract concepts and complex instructions; the expression shows stereotyped, repetitive, direct, or parrot-like speech; stereotypically adhering to some words or content of speech, such as parrot-like conversations, or even talking to oneself; using more direct words or sentences when communicating with others, unable to use euphemistic words, giving the impression of being impolite and straightforward; abnormal ability to organize sentence or sentence structure, such as confusing the use of pronouns like "you", "I", "he", etc.; the sentences fail to convey the intended meaning, lack context, and are repetitive and redundant; the content of speech and writing has no focus; abnormal intonation control; flat or strange intonation; not strengthening the tone on important words; speaking too loudly or too softly, too fast or too slow; showing a one-way communication style during a conversation with others, lacking communication skills; not being interested in others' topics, only focusing on and constantly repeating one's own interested topics; inappropriate timing of speaking, inappropriate response to others' speech; saying inappropriate things in a specific environment; not knowing when to start, join, or continue a conversation at the appropriate time, not knowing how to take turns speaking, and having difficulty maintaining a conversation with others; interrupting others during a conversation. Speech communication disorders can be evaluated by methods known in the art, such as using standardized language assessment tools, such as language development tests, language comprehension and expression tests, to evaluate the language ability level of an individual.

[0067] In this application, the term "repetitive stereotyped behavior" generally refers to a persistent, frequent, and stereotyped pattern, lacking flexibility and variability, and usually not affected by environmental or social feedback. Repetitive stereotyped behavior may include one or more of the following: repetition of object or body movements, including swinging, rocking, spinning, rubbing, patting, waving; repetition of verbal speech: including repeating a word, phrase, sentence, song, or part of a conversation, sometimes even repeating one's own or others' words (also known as echolalia); repetition of interests or activities: for example, a strong interest in specific items or activities, such as flipping objects, arranging items neatly, constantly disassembling and assembling toys, etc.; insistence on a fixed schedule or routine: a stubborn insistence on certain activities, environments, or behaviors in daily life, which may cause anxiety or challenges if disrupted; strong pursuit of a special interest: an abnormal interest and investment in a specific topic, activity, or theme, which may occupy a large amount of time and energy. Repetitive stereotyped behavior can be evaluated by methods known in the art, such as standardized questionnaires and scales, such as the RBS-R (Repetitive Behavior Scale-Revised), etc.

[0068] In this application, the term "sensory ability deficit" generally refers to difficulties and abnormalities in the process of reflecting individual attributes of stimuli, and can also be called "sensory disorder" or "sensory integration disorder". Sensory ability deficits may include sensory hyperesthesia, hypoesthesia and anesthesia, paresthesia, and / or visceral discomfort. Sensory hyperesthesia generally refers to an abnormally increased ability to perceive external stimuli. Hypoesthesia or anesthesia generally refers to a decreased ability to perceive external stimuli. Paresthesia generally refers to a wrong perception of the nature of external stimuli. Visceral discomfort generally refers to an abnormal discomfort or pain caused by internal somatic stimuli. The assessment of sensory ability can be carried out by methods known in the art, such as standardized questionnaires and scales, such as the sensory integration and praxis tests (SIPT), sensory profile (SP), evaluation of sensory processing (ESP), sensory processing measure (SPM), etc.

[0069] In the present application, the term "motor ability defect" generally refers to difficulties or abnormalities in motor control. Motor ability defects can include difficulties in motor coordination, abnormal muscle tone, delayed development of motor skills, abnormal motor perception, and / or motor stereotypies. Difficulties in motor coordination generally refer to a lack of coordination when performing complex movements or motions, which may be manifested as clumsy movements or an unsteady gait. Abnormal muscle tone generally refers to abnormal muscle tension, including over-tension or over-relaxation of muscles. This may result in incoordination and instability during movement. Delayed development of motor skills generally refers to slow progress in learning and mastering basic motor skills. Abnormal motor perception generally refers to an affected ability to perceive and understand motion. Motor stereotypies generally refer to repetitive or stereotyped movement patterns. The assessment of motor ability can be carried out by methods known in the art, such as motor assessment tools and behavioral observations, etc. Motor assessment tools can include standardized motor development assessment scales, motion analysis, muscle strength tests, and balance assessments, etc.

[0070] In the present application, the term "self-care agency" generally refers to the ability of an individual to independently complete basic daily life activities and personal hygiene activities, including but not limited to dressing, eating, toileting, moving and transferring, household chores, etc. The assessment of self-care ability can be carried out by methods known in the art, such as daily observations and standardized questionnaires and scales. Standardized questionnaires and scales can include the Barthel Index, the Katz Index, etc.

[0071] In the present application, the terms "co-administering with", "combination medication", "combination therapy", "combination treatment", or "combined treatment" generally refer to, for example, administering the taurine and its derivatives described in the present application and the β-blockers described in the present application as separate formulations / applications (or as a single formulation / application). Co-administration can be simultaneous administration or sequential administration in any order, but preferably during a period when the two (or all) active agents exert their biological activities simultaneously. The dosage and timing of co-administration depend on the type of patient being treated (species, gender, age, weight, etc.) and the severity of the condition.

[0072] In the present application, the term "rescue" or "save" generally refers to recovering from a severely adverse state or avoiding more severe consequences. In the present application, the term "improve" or "enhance" generally refers to elevating an existing state to make it better. In certain situations, the improvement includes the rescue. In the present application, the terms "rescue" and "improve" may be relative, which means their effects are measured according to the specific context and baseline situation. Different reference points may lead to different evaluation criteria. For example, it can be compared with the same subject before administering the composition, such as before and after treatment. If certain performances of the subject show significant improvement after administering the composition described in the present application, then it can be said that the composition "rescues" or "improves" these performances. In the present application, the term "effective amount" or "therapeutically effective amount" generally refers to the amount of a reagent sufficient to provide the desired biological result. This result can be a reduction and / or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system. For example, the "effective amount" for therapeutic use refers to the amount of the composition containing the compound as the active ingredient that is clinically significant for reducing the disease. In any case, the appropriate "effective" amount can be determined by those of ordinary skill in the art using routine experiments. Therefore, the expression "effective amount" generally refers to the amount when the active substance has a therapeutic effect.

[0073] As used in the specification and claims, the singular forms "a", "an" and "the" include plural forms unless the context clearly dictates otherwise.

[0074] The term "subject" as used in the present application generally refers to the object to which the composition, the pharmaceutical composition, the combination therapy and / or the treatment method described in the present application is administered. For example, the subject can include a human or a non-human animal in need of prognosis, improvement, prevention and / or treatment of a disease. For example, the subject can include mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, etc. Examples of non-mammals include, but are not limited to, fruit flies, birds, fish, etc. In certain embodiments, the mammal is a human. In certain embodiments, the subject described in the present application is a child.

[0075] All numerical values or statements involving components, etc. used in this application should be understood to be modified by "about" in all cases. When the term "about" refers to a quantity or numerical range, it means that the indicated quantity or numerical range is an approximation within the experimental variability (or within the statistical experimental error), so the quantity or numerical range can vary, for example, between ±5 of the stated quantity or numerical range. All ranges involving the same component or property include the endpoints, and these endpoints can be combined independently. Since these ranges are continuous, they include every value between the minimum and maximum values. It should also be understood that any numerical range cited in this application is expected to include all sub-ranges within that range.

[0076] When this application defines a range for a physical property such as molecular weight or for a chemical property, all combinations and sub-combinations of the range and the specific embodiments within it should be included. The term "comprising" (and related terms such as "containing" or "having" or "including") includes embodiments that, for example, are any combination of substances, compositions, methods, or processes, etc., that "consist of the described features" or "consist essentially of the described features".

[0077] As used in this application, "and / or" should be understood to mean "either or both" of the associated components, i.e., the components are present jointly in some cases and separately in other cases. Multiple components listed with "and / or" should be understood in the same way, i.e., "one or more" of the associated components. Except for the components specifically determined by the "and / or" clause, other components can optionally be present, whether related or unrelated to those specifically determined components. Thus, as a non-limiting example, when referring to "A and / or B" and used to connect open-ended language such as "comprising", in one embodiment, it can refer only to A (optionally including components other than B); in another embodiment, it can refer only to B (optionally including components other than A); in yet another embodiment, it refers to A and B (optionally including other components), etc.

[0078] It should be understood that, unless explicitly indicated to the contrary, in any method claimed herein that includes more than one step or act, the order of the steps and acts of the method need not be limited to the order of the steps and acts recited in the method. Detailed Description of the Invention

[0080] Composition

[0081] On the one hand, this application provides a composition comprising taurine and a β-blocker.

[0082] In certain embodiments, the mass ratio of taurine to the β-blocker in the composition can be 100:1 - 1:10, 90:1 - 1:10, 80:1 - 1:10, 70:1 - 1:10, 60:1 - 1:10, 50:1 - 1:10, 40:1 - 1:10, 30:1 - 1:10, 20:1 - 1:10, or 10:1 - 1:10. In certain embodiments, the mass ratio of taurine to the β-blocker in the composition can be 100:1 - 1:10, 80:1 - 2:1, or 40:1 - 1:1. In certain embodiments, the mass ratio of taurine to the β-blocker in the composition can be 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 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, or 1:5. In certain embodiments, the mass ratio of taurine to the β-blocker in the composition can be 400:15, 200:15, 100:15, or 16:5.

[0083] The composition described in the present application can have one or more of the following functions: improving memory impairment, improving social impairment, improving speech communication impairment, reducing repetitive stereotyped behaviors, improving sensory ability defects, and improving motor ability defects.

[0084] Compared with using each preparation alone, providing a composition combining taurine and a β-blocker can have better functions and / or reduce side effects. In some cases, the functions of the composition described in the present application can be additive (for example, the function of the composition is approximately equal to the sum of the effects of taurine and the β-blocker alone). In some cases, the functions of the composition described in the present application can be synergistic (for example, the function of the composition is greater than the sum of the effects of taurine and the β-blocker alone). In some cases, the better functions of the composition described in the present application can be an increase in the types of functions (for example, the types of functions of the composition are greater than those of taurine and the β-blocker alone; for example, the composition can improve multiple symptoms, while taurine and the β-blocker can only improve one symptom). In some cases, the better functions of the composition described in the present application can be an enhancement in the intensity of functions (for example, the intensity of the combined function is greater than that of taurine and the β-blocker alone).

[0085] The composition described in the present application may have one or more of the following functions: improving the social impairment of patients with autism spectrum disorder, improving the speech communication impairment of patients with autism spectrum disorder, reducing the repetitive stereotyped behaviors of patients with autism spectrum disorder, improving the sensory ability defects of patients with autism spectrum disorder, improving the motor ability defects of patients with autism spectrum disorder, and improving the self-care ability of patients with autism spectrum disorder. The pharmaceutical composition described in the present application may also have one or more of the following functions: rescuing the social preference of patients with autism spectrum disorder, rescuing the social memory of patients with autism spectrum disorder, rescuing the empathy ability of patients with autism spectrum disorder, rescuing the spatial memory of patients with autism spectrum disorder.

[0086] The composition described in the present application may have a therapeutic effect on autism spectrum disorder. The composition described in the present application may have an improving effect on one or more related symptoms of patients with autism spectrum disorder.

[0087] The functions of the composition described in the present application can be detected by methods known in the art. For example, the therapeutic effect of the composition described in the present application on patients with autism spectrum disorder can be detected by methods known in the art for diagnosing and / or symptom assessing patients with autism spectrum disorder. For example, the therapeutic effect of the composition described in the present application on patients with autism spectrum disorder may include reducing the score of the Autism Behavior Checklist (ABC) of patients with autism spectrum disorder by more than 5 points, reducing the score of the Childhood Autism Rating Scale (CARS) of patients with autism spectrum disorder by more than 5 points. For example, the therapeutic effect of the composition described in the present application on patients with autism spectrum disorder may include reducing the score of the Autism Behavior Checklist (ABC) of patients with autism spectrum disorder to below 67 points, reducing the score of the Childhood Autism Rating Scale (CARS) of patients with autism spectrum disorder to below 30 points. Compared with the individual effects of taurine and β-blockers, the composition described in the present application may have a better therapeutic effect on autism spectrum disorder. For example, the better therapeutic effect may be reflected in an increase in the types of autism spectrum disorder-related symptoms improved. For example, the better therapeutic effect may be reflected in an improvement in the degree of improvement of a certain autism spectrum disorder-related symptom.

[0088] Taurine and β-blockers

[0089] The present application relates to the use of taurine and β-blockers.

[0090] Polymorphic forms of different β-blockers and their salts, solvates, esters, and prodrugs are intended to be included in the present application. The β-blockers described in the present application can be any conventional β-blockers known in the art. Preferably, the β-blocker is selected from the group of compounds that are known in the art and can be commercially available under different trade names, or can be obtained as described in the literature.

[0091] Non-selective β-blockers

[0092] In certain embodiments, the β-blocker can be a non-selective β-blocker. Examples of non-selective β-blockers include, but are not limited to, propranolol or its pharmaceutically acceptable salts.

[0093] In certain embodiments, the β-blocker can be propranolol or its pharmaceutically acceptable salts. For example, the β-blocker can be propranolol hydrochloride. Propranolol as described in the present application generally refers to a drug with a CAS number of 525-66-6 and a molecular formula of C 16 H 21 NO2, which can also be referred to as naphtholol, Inderal, naphthyloxypropanolamine, propranolol, or 1-isopropylamino-3-(naphthalen-1-yloxy)propan-2-ol. Propranolol hydrochloride as described in the present application generally refers to the hydrochloride salt of propranolol. For example, the CAS number of propranolol hydrochloride can be 3506-09-0, and its molecular formula can be C 16 H 21 NO2·HCl, which can also be referred to as 1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride.

[0094] In certain embodiments, the composition described in the present application can contain taurine and propranolol or its pharmaceutically acceptable salts.

[0095] In certain embodiments, the composition described in the present application can contain taurine and propranolol. In certain embodiments, the composition described in the present application can contain taurine and propranolol hydrochloride.

[0096] In certain embodiments, the composition described in the present application may comprise taurine and propranolol or a pharmaceutically acceptable salt thereof. The mass ratio of taurine to propranolol or a pharmaceutically acceptable salt thereof in the composition may be 100:1 - 1:10, 90:1 - 1:10, 80:1 - 1:10, 70:1 - 1:10, 60:1 - 1:10, 50:1 - 1:10, 40:1 - 1:10, 30:1 - 1:10, 20:1 - 1:10 or 10:1 - 1:10. In certain embodiments, the mass ratio of taurine to propranolol or a pharmaceutically acceptable salt thereof in the composition may be 100:1 - 1:10, 80:1 - 2:1 or 40:1 - 1:1. In certain embodiments, the mass ratio of taurine to propranolol or a pharmaceutically acceptable salt thereof in the composition may be 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 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 or 1:5. In certain embodiments, the mass ratio of taurine to propranolol or a pharmaceutically acceptable salt thereof in the composition may be 400:15, 200:15, 100:15 or 16:5.

[0097] β1 receptor selective β-blockers

[0098] In certain embodiments, the β-blocker may be a β1 - receptor selective β-blocker.

[0099] Examples of β1 - receptor selective β-blockers include, but are not limited to, atenolol, bisoprolol and metoprolol.

[0100] In certain embodiments, the β-blocker may be selected from atenolol or a pharmaceutically acceptable salt thereof, bisoprolol or a pharmaceutically acceptable salt thereof, and metoprolol or a pharmaceutically acceptable salt thereof.

[0101] In certain embodiments, the β-blocker may be metoprolol or a pharmaceutically acceptable salt thereof. For example, the β-blocker may be selected from metoprolol succinate and metoprolol tartrate. Metoprolol as described in the present application generally refers to a drug with a CAS number of 51384 - 51 - 1 and a molecular formula of C 15 H 25 NO3, which may also be referred to as metoprolol, metoxyphenolamine, metolol or (±)-1 - isopropylamino - 3 - [p-(2 - methoxyethyl)phenoxy]-2 - propanol. Metoprolol succinate as described in the present application generally refers to the succinate salt of metoprolol. For example, the CAS number of metoprolol succinate may be 98418 - 47 - 4, and its molecular formula may be (C 15 H 25NO3)2·C4H6O4, which can also be referred to as 1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol succinate. The metoprolol tartrate described in this application generally refers to the tartrate salt of metoprolol. For example, the CAS number of metoprolol tartrate can be 56392-17-7, and its molecular formula can be (C 15 H 25 NO3)2·C4H6O6, which can also be referred to as 1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol tartrate.

[0102] In certain embodiments, the composition described in this application may contain taurine, and metoprolol or its pharmaceutically acceptable salt.

[0103] In certain embodiments, the composition described in this application may contain taurine and metoprolol. In certain embodiments, the composition described in this application may contain taurine and a pharmaceutically acceptable salt of metoprolol. In certain embodiments, the composition described in this application may contain taurine and metoprolol succinate. In certain embodiments, the composition described in this application may contain taurine and metoprolol tartrate.

[0104] In certain embodiments, the composition described in this application may contain taurine and metoprolol or its pharmaceutically acceptable salt, and the mass ratio of taurine to metoprolol or its pharmaceutically acceptable salt in the composition may be 100:1 - 1:10, 90:1 - 1:10, 80:1 - 1:10, 70:1 - 1:10, 60:1 - 1:10, 50:1 - 1:10, 40:1 - 1:10, 30:1 - 1:10, 20:1 - 1:10, or 10:1 - 1:10. In certain embodiments, the mass ratio of taurine to metoprolol or its pharmaceutically acceptable salt in the composition may be 100:1 - 1:10, 80:1 - 2:1, or 40:1 - 1:1. In certain embodiments, the mass ratio of taurine to metoprolol or its pharmaceutically acceptable salt in the composition may be 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 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, or 1:5. In certain embodiments, the mass ratio of taurine to metoprolol or its pharmaceutically acceptable salt in the composition may be 400:15, 200:15, 100:15, or 16:5.

[0105] In some embodiments, the β-blocker can be bisoprolol or a pharmaceutically acceptable salt thereof. For example, the β-blocker can be bisoprolol fumarate. Bisoprolol as described in the present application generally refers to a drug with a CAS number of 66722-44-9 and a molecular formula of C 18 H 31 NO4, which can also be referred to as 1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]-2-propanol. Bisoprolol fumarate as described in the present application generally refers to the fumarate salt of bisoprolol. For example, the CAS number of bisoprolol fumarate can be 104344-23-2, and its molecular formula can be (C 18 H 31 NO4)2·C4H4O4, which can also be referred to as 1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]-2-propanol fumarate.

[0106] In some embodiments, the composition described in the present application can contain taurine, and bisoprolol or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the composition described in the present application can contain taurine and bisoprolol. In some embodiments, the composition described in the present application can contain taurine and a pharmaceutically acceptable salt of bisoprolol. In some embodiments, the composition described in the present application can contain taurine and bisoprolol fumarate.

[0108] In certain embodiments, the composition described in the present application may comprise taurine and bisoprolol or a pharmaceutically acceptable salt thereof, and the mass ratio of taurine to bisoprolol or a pharmaceutically acceptable salt thereof in the composition may be 100:1 - 1:10, 90:1 - 1:10, 80:1 - 1:10, 70:1 - 1:10, 60:1 - 1:10, 50:1 - 1:10, 40:1 - 1:10, 30:1 - 1:10, 20:1 - 1:10 or 10:1 - 1:10. In certain embodiments, the mass ratio of taurine to bisoprolol or a pharmaceutically acceptable salt thereof in the composition may be 100:1 - 1:10, 80:1 - 2:1 or 40:1 - 1:1. In certain embodiments, the mass ratio of taurine to bisoprolol or a pharmaceutically acceptable salt thereof in the composition may be 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 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 or 1:5. In certain embodiments, the mass ratio of taurine to bisoprolol or a pharmaceutically acceptable salt thereof in the composition may be 400:15, 200:15, 100:15 or 16:5.

[0109] In certain embodiments, the β-blocker may be atenolol or a pharmaceutically acceptable salt thereof. The atenolol described in the present application generally refers to a drug with a CAS number of 29122 - 68 - 7 and a molecular formula of C 14 H 22 N2O3, which may also be referred to as 4 - [3 - [(1 - methylethyl)amino - 2 - hydroxy]propoxy]benzeneacetamide. The salts of atenolol described in the present application, such as the hydrochloride salt of atenolol, generally refer to the complex formed by the combination of atenolol and hydrochloric acid. The CAS number of atenolol hydrochloride is 65277 - 36 - 3, and its molecular formula is C 14 H 22 N2O3·HCl, which may also be referred to as 4 - [3 - [(1 - methylethyl)amino - 2 - hydroxy]propoxy]benzeneacetamide hydrochloride.

[0110] In certain embodiments, the composition described in the present application may comprise taurine, and atenolol and its pharmaceutically acceptable salts.

[0111] In certain embodiments, the composition described in the present application may comprise taurine and atenolol. In certain embodiments, the composition described in the present application may comprise taurine and a pharmaceutically acceptable salt of atenolol. In certain embodiments, the composition described in the present application may comprise taurine and hydrochloric acid atenolol.

[0112] In certain embodiments, the composition described in the present application may comprise taurine and atenolol or a pharmaceutically acceptable salt thereof, and the mass ratio of taurine to atenolol or a pharmaceutically acceptable salt thereof in the composition may be 100:1 - 1:10, 90:1 - 1:10, 80:1 - 1:10, 70:1 - 1:10, 60:1 - 1:10, 50:1 - 1:10, 40:1 - 1:10, 30:1 - 1:10, 20:1 - 1:10 or 10:1 - 1:10. In certain embodiments, the mass ratio of taurine to atenolol or a pharmaceutically acceptable salt thereof in the composition may be 100:1 - 1:10, 80:1 - 2:1 or 40:1 - 1:1. In certain embodiments, the mass ratio of taurine to atenolol or a pharmaceutically acceptable salt thereof in the composition may be 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 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 or 1:5. In certain embodiments, the mass ratio of taurine to atenolol or a pharmaceutically acceptable salt thereof in the composition may be 400:15, 200:15, 100:15 or 16:5.

[0113] β2 receptor selective β-blockers

[0114] In certain embodiments, the β-blocker may be a β2 receptor selective β-blocker.

[0115] Mixed α and β-blockers

[0116] In certain embodiments, the β-blocker may be a mixed α and β-blocker. Examples of the mixed α and β-blocker include but are not limited to carvedilol and labetalol.

[0117] In certain embodiments, the β-blocker may be selected from carvedilol and its pharmaceutically acceptable salts, and labetalol and its pharmaceutically acceptable salts.

[0118] In certain embodiments, the β-blocker may be carvedilol or a pharmaceutically acceptable salt thereof. For example, the β-blocker may be carvedilol phosphate. Carvedilol as described in the present application generally refers to a drug with a CAS number of 72956 - 09 - 3 and a molecular formula of C 24 H 26N2O4, which may also be referred to as (±)-1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]-2-propanol. The carvedilol phosphate described in this application generally refers to the phosphate of carvedilol, for example, carvedilol dihydrogen phosphate. For example, the CAS number of carvedilol phosphate may be 610309-89-2, and its molecular formula may be C 24 H 26 N2O4·H3PO4·1 / 2H2O.

[0119] In certain embodiments, the composition described in this application may contain taurine, and carvedilol or its pharmaceutically acceptable salt.

[0120] In certain embodiments, the composition described in this application may contain taurine and carvedilol. In certain embodiments, the composition described in this application may contain taurine and a pharmaceutically acceptable salt of carvedilol. In certain embodiments, the composition described in this application may contain taurine and carvedilol phosphate.

[0121] In certain embodiments, the composition described in this application may contain taurine and carvedilol or its pharmaceutically acceptable salt, and the mass ratio of taurine to carvedilol or its pharmaceutically acceptable salt in the composition may be 100:1 - 1:10, 90:1 - 1:10, 80:1 - 1:10, 70:1 - 1:10, 60:1 - 1:10, 50:1 - 1:10, 40:1 - 1:10, 30:1 - 1:10, 20:1 - 1:10, or 10:1 - 1:10. In certain embodiments, the mass ratio of taurine to carvedilol or its pharmaceutically acceptable salt in the composition may be 100:1 - 1:10, 80:1 - 2:1, or 40:1 - 1:1. In certain embodiments, the mass ratio of taurine to carvedilol or its pharmaceutically acceptable salt in the composition may be 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 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, or 1:5. In certain embodiments, the mass ratio of taurine to carvedilol or its pharmaceutically acceptable salt in the composition may be 400:15, 200:15, 100:15, or 16:5.

[0122] In certain embodiments, the β-blocker may be labetalol or its pharmaceutically acceptable salt. For example, the β-blocker may be labetalol hydrochloride. The labetalol described in this application generally refers to a drug, its CAS number is 36894-69-6, and its molecular formula is C 19 H 24N2O3, which may also be referred to as Labenatalol. The labetalol hydrochloride described in this application generally refers to the hydrochloride salt of labetalol. For example, the CAS number of labetalol hydrochloride may be 32780-64-6, and its molecular formula may be C 19 H 24 N2O3·HCl, which may also be referred to as 5-[1-hydroxy-2-(1-methyl-3-phenylpropylamino)ethyl]salicylamide hydrochloride.

[0123] In certain embodiments, the composition described in this application may comprise taurine, and labetalol or a pharmaceutically acceptable salt thereof.

[0124] In certain embodiments, the composition described in this application may comprise taurine and labetalol. In certain embodiments, the composition described in this application may comprise taurine and a pharmaceutically acceptable salt of labetalol. In certain embodiments, the composition described in this application may comprise taurine and labetalol hydrochloride.

[0125] In certain embodiments, the composition described in this application may comprise taurine and labetalol or a pharmaceutically acceptable salt thereof, and the mass ratio of taurine to labetalol or a pharmaceutically acceptable salt thereof in the composition may be 100:1 - 1:10, 90:1 - 1:10, 80:1 - 1:10, 70:1 - 1:10, 60:1 - 1:10, 50:1 - 1:10, 40:1 - 1:10, 30:1 - 1:10, 20:1 - 1:10 or 10:1 - 1:10. In certain embodiments, the mass ratio of taurine to labetalol or a pharmaceutically acceptable salt thereof in the composition may be 100:1 - 1:10, 80:1 - 2:1 or 40:1 - 1:1. In certain embodiments, the mass ratio of taurine to labetalol or a pharmaceutically acceptable salt thereof in the composition may be 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 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 or 1:5. In certain embodiments, the mass ratio of taurine to labetalol or a pharmaceutically acceptable salt thereof in the composition may be 400:15, 200:15, 100:15 or 16:5.

[0126] Substances capable of inhibiting β-receptor activity

[0127] The β-blockers described in this application may also include substances that can inhibit β-receptor activity and / or can block β-receptors. For certain reasons, they are not referred to as "β-blockers" in the art. For example, inhibiting β-receptor activity is not their main function, but as long as they have an inhibitory effect on β-receptor activity, they are included within the scope of the β-blockers described in this application.

[0128] The inhibition of β - receptor activity may include blocking the binding of the β - receptor to its ligand. For example, the inhibition may include a reduction of at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% in the binding of the β - receptor to its ligand relative to the absence of a β - blocker.

[0129] In certain embodiments, the β - blocker may include an anti - arrhythmic drug having an inhibitory effect on β - receptor activity.

[0130] In certain embodiments, the β - blocker may be propafenone or a pharmaceutically acceptable salt thereof. For example, the β - blocker may be propafenone hydrochloride. Propafenone as described in the present application generally refers to a drug with a CAS number of 54063 - 53 - 5 and a molecular formula of C 21 H 27 NO3, which may also be referred to as 1 - [2 - [2 - hydroxy - 3 - (propylamino) - propoxy]phenyl] - 3 - phenyl - 1 - propanone. Propafenone hydrochloride as described in the present application generally refers to the hydrochloride salt of propafenone. For example, its CAS number may be 34183 - 22 - 7 and its molecular formula may be C 21 H 27 NO3·HCl, which may also be referred to as 3 - phenyl - 1 - [2 - 3 - (propylamino) - 2 - hydroxypropoxy]phenyl - 1 - propanone hydrochloride.

[0131] In certain embodiments, the composition described in the present application may comprise taurine, and propafenone or a pharmaceutically acceptable salt thereof.

[0132] In certain embodiments, the composition described in the present application may comprise taurine and propafenone. In certain embodiments, the composition described in the present application may comprise taurine and a pharmaceutically acceptable salt of propafenone. In certain embodiments, the composition described in the present application may comprise taurine and propafenone hydrochloride.

[0133] In certain embodiments, the composition described in the present application may comprise taurine and propafenone or a pharmaceutically acceptable salt thereof. The mass ratio of taurine to propafenone or a pharmaceutically acceptable salt thereof in the composition may be 100:1 - 1:10, 90:1 - 1:10, 80:1 - 1:10, 70:1 - 1:10, 60:1 - 1:10, 50:1 - 1:10, 40:1 - 1:10, 30:1 - 1:10, 20:1 - 1:10, or 10:1 - 1:10. In certain embodiments, the mass ratio of taurine to propafenone or a pharmaceutically acceptable salt thereof in the composition may be 100:1 - 1:10, 80:1 - 2:1, or 40:1 - 1:1. In certain embodiments, the mass ratio of taurine to propafenone or a pharmaceutically acceptable salt thereof in the composition may be 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 15:1, 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, or 1:5. In certain embodiments, the mass ratio of taurine to propafenone or a pharmaceutically acceptable salt thereof in the composition may be 400:15, 200:15, 100:15, or 16:5.

[0134] Pharmaceutical composition

[0135] On the other hand, the present application provides a pharmaceutical composition comprising taurine and a β - blocker. For example, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

[0136] The pharmaceutical composition described in the present application may include a pharmaceutical product suitable for pharmaceutical use (e.g., treating autism spectrum disorder or improving related symptoms). The pharmaceutical composition described in the present application may be a composition comprising multiple active ingredients (e.g., taurine and a β - blocker) and one or more inert ingredients; and any product directly or indirectly obtained by the combination, compounding, or aggregation of any two or more ingredients.

[0137] The pharmaceutical composition described in the present application may have one or more of the following functions: improving memory impairment, improving social impairment, improving speech communication impairment, reducing repetitive stereotyped behaviors, improving sensory ability defects, and improving motor ability defects.

[0138] The pharmaceutical composition described in the present application may have one or more of the following functions: improving the social impairment of patients with autism spectrum disorder, improving the speech communication impairment of patients with autism spectrum disorder, reducing the repetitive stereotyped behaviors of patients with autism spectrum disorder, improving the sensory ability defects of patients with autism spectrum disorder, improving the motor ability defects of patients with autism spectrum disorder, and improving the self-care ability of patients with autism spectrum disorder. The pharmaceutical composition described in the present application may also have one or more of the following functions: rescuing the social preference of patients with autism spectrum disorder, rescuing the social memory of patients with autism spectrum disorder, rescuing the empathy ability of patients with autism spectrum disorder, rescuing the spatial memory of patients with autism spectrum disorder.

[0139] The pharmaceutical composition described in the present application may have a therapeutic effect on autism spectrum disorder. The pharmaceutical composition described in the present application may have an improving effect on one or more related symptoms of patients with autism spectrum disorder.

[0140] Treatment methods and uses

[0141] On the other hand, the present application provides the use of a composition in the preparation of a drug, wherein the composition comprises taurine and a β-blocker.

[0142] In certain embodiments, the drug described in the present application may include a pharmaceutical composition. For example, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

[0143] On the other hand, the present application provides a treatment method, which comprises administering taurine and a β-blocker to a subject.

[0144] On the other hand, the present application provides a treatment method, which comprises administering the composition described in the present application, the drug described in the present application, and / or the pharmaceutical composition described in the present application to a subject.

[0145] On the other hand, the present application provides the use of taurine and the β-blocker in the treatment of autism spectrum disorder.

[0146] On the other hand, the present application provides the use of the composition described in the present application and / or the pharmaceutical composition described in the present application in the treatment of autism spectrum disorder.

[0147] The treatment method described in the present application may include combination therapy of taurine and a β-blocker. For example, combination therapy for autism spectrum disorder or related symptoms.

[0148] Compared with the individual effects of taurine and β-blockers, the treatment method described in the present application may have a better therapeutic effect on autism spectrum disorder. For example, the better therapeutic effect may be reflected in an increase in the types of symptoms related to autism spectrum disorder that are improved. For example, the better therapeutic effect may be reflected in an increase in the degree of improvement of a certain symptom related to autism spectrum disorder.

[0149] The combination therapy described in the present application may include simultaneously administering the taurine described in the present application and the β-blocker described in the present application in the same or different dosage forms, or separately administering the taurine described in the present application and the β-blocker described in the present application (e.g., sequentially). Thus, taurine and the β-blocker may be simultaneously administered in a single formulation. Alternatively, taurine and the β-blocker may be formulated for separate administration and administered simultaneously or sequentially (e.g., taurine is administered within about 30 minutes before the β-blocker is administered).

[0150] For example, the taurine described in the present application may be administered first, and then (e.g., immediately thereafter) the β-blocker described in the present application may be administered, or vice versa. In certain embodiments, the β-blocker described in the present application is administered before the taurine is administered. In certain embodiments, the β-blocker described in the present application is administered after the taurine is administered. In certain embodiments, the taurine described in the present application and the β-blocker described in the present application are administered simultaneously.

[0151] In certain embodiments, the dosages of the taurine and / or β-blocker described in the present application are calculated according to body weight, such as mg / kg body weight. For example, the dosages of the taurine and / or β-blocker described in the present application may be 5 mg / kg - 500 mg / kg.

[0152] In certain embodiments, based on the dose administered to a murine animal model, the total dose of taurine and the β-blocker can be 55 mg / kg - 1000 mg / kg. In certain embodiments, based on the dose administered to a murine animal model, the total dose of taurine and the β-blocker can be 205 mg / kg - 505 mg / kg. In certain embodiments, based on the dose administered to a murine animal model, the dose of taurine can be 50 mg / kg - 500 mg / kg, and the dose of the β-blocker can be 5 mg / kg - 200 mg / kg. In certain embodiments, based on the dose administered to a murine animal model, the dose of taurine can be 500 mg / kg, 450 mg / kg, 400 mg / kg, 350 mg / kg, 300 mg / kg, 250 mg / kg, 200 mg / kg, 150 mg / kg, 100 mg / kg, or 50 mg / kg; the dose of the β-blocker can be 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 150 mg / kg, or 200 mg / kg.

[0153] The administration doses for different subjects, such as between humans and non-human animals, can be converted according to methods known in the art. A conventional method for extrapolating the human dose based on the dose administered to a murine animal model can be used with a conversion factor for converting the mouse dose to the human dose: human dose / kg = mouse dose / kg × 12. See Freireich et al., Cancer Chemother Rep. 50, 219 - 244 (1966). The drug dose can also be given in mg per square meter of body surface area because this method has a better correlation with certain metabolic and excretion functions than body weight. In addition, body surface area can be used as a common characteristic for drug doses in adults, children, and different animal species. See Freireich et al., Cancer Chemother Rep. 50, 219 - 244 (1966).

[0154] Suitable methods for administering the compositions of the subject matter disclosed herein to an individual include, but are not limited to, systemic administration, parenteral administration, oral delivery, buccal delivery, subcutaneous administration, inhalation, intratracheal instillation, transdermal delivery, and local injection. The mode of administration used according to the methods of the present application depends on various factors, including but not limited to the drug and / or carrier used, the severity of the condition being treated, and the metabolic or elimination mechanism of the active agent after administration.

[0155] Without intending to be bound by any theory, the following examples are merely intended to illustrate the methods, compositions, and uses of the present application, and are not intended to limit the scope of the invention of the present application.

[0156] Example

[0157] Instruments, equipment, reagents and consumables

[0158] Mouse spatial memory test pool, mouse foot mechanical pricking device, three-box experimental device, ANY-maze mouse behavior automatic recording software, camera.

[0159] Test subjects

[0160]

[0161] -Autism model mice

[0162] 2-month-old C57BL6 / J mice were subcutaneously injected with 600 mg / kg of VPA at E12.5. Male mice among the pups were valproate-treated autistic mice, and they began to show autistic symptoms 40 days after birth. The experiment was conducted after feeding for 11 days.

[0163] -Shank3 transgenic mice

[0164] Shank family genes are congenital ASD pathogenic genes, and the mutation rate of Shank3 gene is about 2%. The genotype of Shank3 mouse is B6.129-Shank3 tm2Gfng / J, JAX number is 017688. Knockout of the Shank3 gene leads to abnormal protein expression, and the animals show symptoms of autism. Experiments were started at 1 month of age.

[0165] Operation procedures

[0166] 1. Mouse Modeling and Drug Administration

[0167] 1.1 Purchase and use of VPA

[0168] Sodium valproate, CAS No. 1069-66-5, was purchased from Aladdin. Weigh 0.594 g of VPA powder, add 9.94 ml of 0.9% NaCl and vortex until clear to obtain a 59.76 mg / ml VPA solution. The pregnant mice were subcutaneously injected at E12.5 with an injection volume of 600 mg / kg.

[0169] 1.2 Test drug source

[0170] Propranolol was purchased from Selleck. Carvedilol, Labetalol, Propafenone, Taurine, and Atenolol were purchased from Aladdin. Metoprolol was purchased from MCE. Bisoprolol was purchased from Beijing Huasu Pharmaceutical Co., Ltd. The solvent PBS was purchased from Baird.

[0171] 1.3 Method for preparing drugs

[0172] Weigh an appropriate amount of the drug and place it in a mortar. Add a small amount of the solvent (PBS), grind it, and then pour it out. After rinsing the grinder three times with the solvent, make up the volume to the required concentration with the solvent. After aliquoting, store it in the dark at -20°C in a refrigerator.

[0173] 1.4 Administration method and administration time

[0174] According to the body weights of the rats and mice and the experimental purpose, administer the drug at the designed concentration. Refer to each example for the administration dose. Take out the prepared drug solution and the solvent from the -20°C refrigerator and let them return to room temperature. Use a gavage needle to orally administer the drug solution or physiological saline into the stomach of the mice. For the single-dose administration experiment, perform gavage at 9 am every day, once a day. The animals in the experimental group are given a quantitative drug, and the model group and the wild control group are given a quantitative solvent. Start the behavioral experiment after the specified administration time. Continuously administer the drug every day during the behavioral experiment until the end of the experiment.

[0175] 2. Behavioral tests

[0176] 2.1 Social memory test for mice

[0177] Divide the open field with a length of 1 m and a width of 40 cm evenly into 3 areas. Place a restraint cage (such as Figure 1 , define the left side as Cage A and the right side as Cage B) at the center of the first and third areas, within a range of 5 cm from the restraint cage (Area A-1; Area B-1).

[0178] The test environment has a room temperature maintained at 25°C, a humidity maintained at 30 - 40%, a quiet environment, no strong light irradiation, and no unauthorized personnel.

[0179] Adaptation period: On the first day, no mice are placed in Cages A and B. Place the experimental mice with their heads facing the inner wall of the open field and put them into the open field from the middle position to adapt for 30 minutes to familiarize themselves with the open field environment. After each group finishes, clean the cage and then replace it with the next group of animals for adaptation.

[0180] Social preference test: The test was conducted on the second day. A strange animal was placed in the restraint cage A, and B was an empty restraint cage (either B or A was selected to place the strange mouse based on the adaptation period data, and the strange mouse was placed in the area where the experimental animal had a weak preference). The experimental mice were placed in the middle facing the inner wall of the open field and tested for 10 minutes. The Anymaze software and camera were used to automatically record the movement trajectories and time of the mice, and the time the animals stayed within a range of 5 cm from the restraint cage was statistically analyzed. The behavior of staying within 5 cm near the restraint cage B where the strange mouse was placed was defined as prosocial behavior. After each group was tested, the cage was cleaned and the next group of animals was tested.

[0181] Social memory test: Four hours after the social preference test was completed, the social memory test was conducted. A familiar animal was placed in the restraint cage A, and a strange animal was placed in the restraint cage B. The experimental mice were placed in the middle facing the inner wall of the open field in sequence and tested for 10 minutes. The time the animals stayed within a range of 5 cm from the restraint cage was observed and recorded. After each group was tested, the cage was cleaned and the next group of animals was tested.

[0182] 2.2 Mouse pain transfer experiment

[0183] As Figure 2 shown, for the pain threshold test, Von Frey filaments of different thicknesses were used to stimulate the plantar surface of the mice, and the classical "up and down" method was used to record the experimental results, and the 50% paw withdrawal threshold of the mice was calculated according to the formula. The pain threshold test was carried out successively on a pain test stand 40 cm high, a 10*10*5 cm restraint cage, and using different fiber hairs (specifications: 0.008 g, 0.02 g, 0.04 g, 0.07 g, 0.16 g, 0.4 g, 0.6 g, 1 g).

[0184] The pain test stand was placed on the operating table, and the test mouse was fixed on the pain test stand with the restraint cage. (The bottom was illuminated with a table lamp to shine on the sole of the foot). After adapting for 2 - 3 h and waiting for the mouse to be quiet, the test was carried out. First, the fiber hair (0.07 g) suitable for the pain threshold critical weight of the mouse was selected as the first hair and tested successively. The fiber hair was continuously pricked on the plantar surface of the mouse, and the angle between the bent fiber hair and the plantar surface was 45°. If the test mouse showed a pain response within 5 s, it was marked with an "X" on the record form, otherwise with an "O". Each mouse was tested 6 times, and the interval between each test was 1 min. According to the reaction pattern of the mouse, the parameters were determined by referring to the reference table, and calculated using the formula to obtain the 50% PWT value (paw withdrawal threshold), and then statistical analysis was carried out.

[0185] After the mouse's pain threshold baseline was tested, it was co-housed with a CFA pain mouse for 24 h, and the mouse's pain threshold was tested again for comparison.

[0186] 2.3 Mouse water maze memory test

[0187] As Figure 3As shown in the figure, the water pool for the mouse spatial memory test is a circular barrel with a water maze diameter of 1.2 meters, which is divided into four quadrants A, B, C, and D. Markers of different shapes are set at the 3 o'clock, 6 o'clock, 9 o'clock, and 12 o'clock positions on the barrel wall, and a platform is set at the midpoint of the line connecting the 6 o'clock and 9 o'clock positions. The platform is 2 centimeters below the water surface. Water is injected into the barrel and whitened with milk so that the platform is invisible.

[0188] The experimental animals are trained four times a day at intervals of 1 hour, with each time lasting 1 minute. The mice are placed into the water at the 4 o'clock, 3 o'clock, 2 o'clock, and 1 o'clock positions, allowing the mice to swim in the pool to find the position of the platform. If the animal does not find the platform position within 1 minute, it is manually guided to the platform to enable it to remember the platform position. The training lasts for 4 - 6 days. A camera is used to automatically record the swimming trajectories of the mice, and the ANY-maze software is used to analyze the swimming trajectories and swimming times of the mice. On the last day, the platform is removed, and the mice swim freely for 1 minute, and their movement trajectories are recorded.

[0189] During the training stage of the mice, calculate the time required for the mice to find the platform and plot the learning curve of the mice. The shorter the time required for the mice to find the platform (Escape latency), the stronger the spatial learning and memory ability of the mice.

[0190] During the free swimming stage of the mice after the platform is removed, analyze the swimming trajectories of the mice, calculate the number of times they cross the platform position (Number of crossing) and the time they swim in the B quadrant (Time in right quadrant). The more times the mice cross the platform position and the longer the time they swim in the B quadrant, the stronger the spatial learning and memory ability of the mice.

[0191] 3. Data analysis

[0192] GraphPad 8 and SPSS 25.0 are used for data processing and graphing, and repeated measures analysis of variance and one-way analysis of variance are used to compare statistical differences. All data are expressed as mean ± standard error. *, P < 0.05, **, P < 0.01, ***, P < 0.001, ****, P < 0.0001.

[0193] Example 1: Drug rescue of social deficits in VPA-induced autistic model mice

[0194] This example shows that the combined administration of taurine and β-blocker has a better effect on rescuing the social deficits in VPA-induced autistic model mice than their separate administrations.

[0195] C57BL6 / J mice are used for VPA-induced modeling. The offspring mice start to be medicated once a day for 11 consecutive days at 40 days of age (the dose is adjusted according to the commonly used clinical dose), and then a social experiment is conducted to test the effect of the drug on rescuing the memory deficits in autistic mice.

[0196] 1.1 Single drug: Test the rescue effects of 50 mg / kg propafenone, 30 mg / kg propranolol, 200 mg / kg taurine, 200 mg / kg atenolol, 3 mg / kg aripiprazole, and 125 mg / kg carvedilol.

[0197] 1.1.1 In the social preference test, in the VPA model group (P = 0.9905), there was no significant difference in the time spent in the two restraint cages, showing social deficits; in the wild control group (P < 0.0001) and the propafenone group (P = 0.0011), the time spent by mice in the restraint cage with a strange mouse was significantly higher than that in the empty restraint cage, showing obvious social preferences. In the social memory test, in the wild control group (P < 0.0001), the time spent in the restraint cage with a strange mouse was significantly higher than that in the restraint cage with a familiar mouse, showing significant social memory; in the VPA model group (P > 0.9999) and the propafenone group (P = 0.9995), there was no significant difference in the time spent in the two restraint cages, showing social memory deficits. The results are shown in Table 1 and Figure 6 as shown, feeding 50 mg / kg propafenone for 11 days can rescue the social preference deficit of autistic mice, but cannot rescue the social memory deficit.

[0198] Table 1 Rescue effects of propafenone

[0199]

[0200]

[0201] 1.1.2 In the social preference test, in the wild control group (P < 0.0001) and the taurine group (P < 0.0001), the time spent by mice in the restraint cage with a strange mouse was significantly higher than that in the empty restraint cage, showing obvious social preferences; in the VPA model group (P = 0.9897), there was no significant difference in the time spent in the two restraint cages, showing social deficits. In the social memory test, in the wild control group (P < 0.0001), the time spent in the restraint cage with a strange mouse was significantly higher than that in the restraint cage with a familiar mouse, showing significant social memory; in the VPA model group (P = 0.3164) and the taurine group (P > 0.9999), there was no significant difference in the time spent in the two restraint cages, showing social memory deficits. The results are shown in Table 2 and Figure 7 as shown, feeding 200 mg / kg taurine for 11 days can rescue the social preference deficit of autistic mice, but cannot rescue the social memory deficit.

[0202] Table 2 Rescue effects of taurine

[0203]

[0204] 1.1.3 In the social preference test, the wild control group (P < 0.0001) and the propranolol group (P = 0.0006) showed significantly longer staying times in the restraint cage with a strange mouse than in the empty restraint cage, indicating obvious social preference; there was no significant difference in the staying times of the VPA model group (P = 0.3503) in the two restraint cages, indicating social deficit. In the social memory test, the wild control group (P = 0.0005) showed significantly longer staying time in the restraint cage with a strange mouse than in the restraint cage with a familiar mouse, indicating significant social memory. There was no significant difference in the staying times of the VPA model group (P = 0.9302) and the propranolol group (P = 0.9999) in the two restraint cages, indicating social memory deficit. The results are shown in Table 3 and Figure 8 as follows. Feeding with 30 mg / kg propranolol for 11 days could rescue the social preference deficit of autistic mice, but could not rescue the social memory deficit.

[0205] Table 3 Rescue effect of propranolol

[0206]

[0207] 1.1.4 In the social preference test, the wild control group (P < 0.0001) showed significantly longer staying times in the restraint cage with a strange mouse than in the empty restraint cage, indicating obvious social preference; there was no significant difference in the staying times of the VPA model group (P = 0.8929) and the atenolol group (P = 0.5275) in the two restraint cages, indicating social deficit. In the social memory test, the wild control group (P < 0.0001) and the atenolol group (P < 0.0001) showed significantly longer staying time in the restraint cage with a strange mouse than in the restraint cage with a familiar mouse, indicating significant social memory. There was no significant difference in the staying times of the VPA model group (P = 0.5047) in the two restraint cages, indicating social memory deficit. The results are shown in Table 4 and Figure 9 as follows. Feeding with 200 mg / kg atenolol for 11 days could rescue the social memory deficit of autistic mice, but could not rescue the social preference deficit.

[0208] Table 4 Rescue effect of atenolol

[0209]

[0210]

[0211] 1.1.5 In the social preference test, the wild control group (P < 0.0001), the aripiprazole group (P < 0.0001), and the carvedilol group (P = 0.0002) of mice spent significantly more time in the restraint cage with a strange mouse than in the empty restraint cage, showing obvious social preference; there was no significant difference in the time spent in the two restraint cages in the VPA model group (P = 0.9239), showing social deficits. In the social memory test, the wild control group (P < 0.0001) and the aripiprazole group (P = 0.0005) spent significantly more time in the restraint cage with a strange mouse than in the restraint cage with a familiar mouse, showing significant social memory. There was no significant difference in the time spent in the two restraint cages in the VPA model group (P = 0.9998) and the carvedilol group (P = 0.9975), showing social memory deficits. The results are shown in Table 5 and Figure 10 as follows. Feeding 3 mg / kg of aripiprazole for 11 days could rescue the social preference deficit and social memory deficit in autistic mice. Feeding 125 mg / kg of carvedilol for 11 days could rescue the social preference deficit in autistic mice, but could not rescue the social memory deficit.

[0212] Table 5 Rescue effects of aripiprazole and carvedilol

[0213]

[0214]

[0215] 1.2 Test the combination of two drugs: aripiprazole 3 mg / kg + atenolol 100 mg / kg, aripiprazole 3 mg / kg + labetalol 100 mg / kg.

[0216] In the social preference test, the wild control group (P < 0.0001), the aripiprazole 3 mg / kg + atenolol 200 mg / kg group (P = 0.0045), and the mice spent significantly more time in the restraint cage with a strange mouse than in the empty restraint cage, showing obvious social preference; there was no significant difference in the time spent in the two restraint cages in the VPA model group (P = 0.9995) and the aripiprazole 3 mg / kg + labetalol 100 mg / kg group (P = 0.1253), showing social deficits. In the social memory test, the wild control group (P = 0.0042), the aripiprazole 3 mg / kg + labetalol 100 mg / kg group (P < 0.0001), and spent significantly more time in the restraint cage with a strange mouse than in the restraint cage with a familiar mouse, showing significant social memory. There was no significant difference in the time spent in the two restraint cages in the VPA model group (P = 0.8776) and the aripiprazole 3 mg / kg + atenolol 200 mg / kg group (P = 0.7887), showing social memory deficits. The results are shown in Table 6 and Figure 11As shown, feeding with 3 mg / kg of aripiprazole + 100 mg / kg of atenolol for 11 days can rescue the social preference deficit in autistic mice but cannot rescue the social memory deficit. Feeding with 3 mg / kg of aripiprazole + 100 mg / kg of labetalol for 11 days can rescue the social memory deficit in autistic mice but cannot rescue the social preference deficit.

[0217] Table 6 Rescue effects of combinations of aripiprazole + atenolol and aripiprazole + labetalol

[0218]

[0219]

[0220] 1.3 Modify the social time for testing. Let the mice conduct free exploration for 20 minutes during the stage of testing social preference. Test the rescue effects of 200 mg / kg of atenolol + 200 mg / kg of taurine and 50 mg / kg of propafenone + 200 mg / kg of taurine.

[0221] In the social preference test, the residence time of mice in the restraint cage with a strange mouse in the wild control group (P < 0.0001), the group of 200 mg / kg of atenolol + 200 mg / kg of taurine (P < 0.0001), and the group of 50 mg / kg of propafenone + 200 mg / kg of taurine (P < 0.0001) was significantly higher than that in the empty restraint cage, showing obvious social preference; there was no significant difference in the residence time of the VPA model group (P = 0.9963) in the two restraint cages, showing social deficits. In the social memory test, the residence time of the wild control group (P = 0.0122), the group of 200 mg / kg of atenolol + 200 mg / kg of taurine (P = 0.0023), and the group of 50 mg / kg of propafenone + 200 mg / kg of taurine (P = 0.0035) in the restraint cage with a strange mouse was significantly higher than that in the restraint cage with a familiar mouse, showing significant social memory. The VPA model group (P = 0.9439) had no significant difference in the residence time in the two restraint cages, showing social memory deficits. The results are shown in Table 7 and Figure 12 As shown, feeding with 200 mg / kg of atenolol + 200 mg / kg of taurine and 50 mg / kg of propafenone + 200 mg / kg of taurine for 11 days can rescue the social preference deficit and social memory deficit in autistic mice.

[0222] Table 7 Rescue effects of combinations of atenolol + taurine and propafenone + taurine

[0223]

[0224]

[0225] 1.4 Modify the social time for testing. Let the mice conduct 20 minutes of free exploration during the stage of testing social preference. Test the rescue effects of 20 mg / kg metoprolol + 400 mg / kg taurine, 20 mg / kg metoprolol, and 400 mg / kg taurine

[0226] In the social preference test, the residence time of mice in the restraint cage with a strange mouse in the wild control group (P < 0.0001), 20 mg / kg metoprolol + 400 mg / kg taurine group (P < 0.0001), and 400 mg / kg taurine group (P < 0.0001) was significantly higher than that in the empty restraint cage, showing obvious social preference; there was no significant difference in the residence time of the VPA model group (P > 0.9999) and 20 mg / kg metoprolol group (P = 0.8735) in the two restraint cages, showing social deficits. In the social memory test, the residence time of mice in the restraint cage with a strange mouse in the wild control group (P = 0.0008), 20 mg / kg metoprolol + 400 mg / kg taurine group (P = 0.0003), 20 mg / kg metoprolol group (P = 0.0260), and 400 mg / kg taurine group (P = 0.0005) was significantly higher than that in the restraint cage with a familiar mouse, showing significant social memory. There was no significant difference in the residence time of the VPA model group (P = 0.9487) in the two restraint cages, showing social memory deficits. The results are shown in Table 8 and Figure 13 as follows. Feeding 20 mg / kg metoprolol + 400 mg / kg taurine and 400 mg / kg taurine for 11 days can rescue the social preference deficit and social memory deficit of autistic mice. Feeding 20 mg / kg metoprolol for 11 days can rescue the social memory deficit of autistic mice but cannot rescue the social preference deficit. 20 mg / kg metoprolol + 400 mg / kg taurine has a greater difference in the mouse-cage exploration time in the social preference test and a better rescue effect.

[0227] Table 8 Rescue effects of metoprolol and / or taurine

[0228]

[0229]

[0230] 1.5 The rescue effects of twice-daily administration of 5 mg / kg metoprolol + 400 mg / kg taurine and 5 mg / kg metoprolol were tested. In the social preference test, the wild-type control group (P < 0.0001) and the mice in the 5 mg / kg metoprolol + 400 mg / kg taurine group spent significantly more time in the restraint cage with a strange mouse than in the empty restraint cage, showing obvious social preference; there was no significant difference in the time spent in the two restraint cages in the VPA model group (P = 0.9773) and the 5 mg / kg metoprolol group (P > 0.9999), showing social deficits. In the social memory test ( Figure 9 .19B), the wild-type control group (P = 0.0221) and the 5 mg / kg metoprolol + 400 mg / kg taurine group (P < 0.0001) spent significantly more time in the restraint cage with a strange mouse than in the restraint cage with a familiar mouse, showing significant social memory. There was no significant difference in the time spent in the two restraint cages in the VPA model group (P > 0.9999) and the 5 mg / kg metoprolol group (P = 0.8515), showing social memory deficits. The results are shown in Table 9 and Figure 14 as follows. Twice-daily administration of 5 mg / kg metoprolol for 11 days could not rescue the social preference deficit and social memory deficit of autistic mice, while twice-daily administration of 5 mg / kg metoprolol + 400 mg / kg taurine for 11 days could rescue the social preference deficit and social memory deficit of autistic mice.

[0231] Table 9 Rescue effects of metoprolol and / or taurine with twice-daily administration

[0232]

[0233] Example 2 Drug rescue of social memory deficit in Shank3 model mice

[0234] In this example, the rescue effects of 3 mg / kg aripiprazole, 10 mg / kg metoprolol + 400 mg / kg taurine, and 10 mg / kg metoprolol were tested.

[0235] In the social preference test, the wild-type control group (P < 0.0001) and the mice in the 10 mg / kg metoprolol + 400 mg / kg taurine group (P < 0.0001) spent significantly more time in the restraint cage with a strange mouse than in the empty restraint cage, showing obvious social preference; there was no significant difference in the time spent in the two restraint cages in the Shank3 model group (P = 0.9997), the 3 mg / kg aripiprazole group (P = 0.1729), and the 10 mg / kg metoprolol group (P = 0.8991), showing social deficits.

[0236] In the social memory test, the wild control group (P = 0.0003), the 10 mg / kg metoprolol + 400 mg / kg taurine group (P = 0.0006), and the 10 mg / kg metoprolol group (P = 0.0068) had significantly longer residence times in the restraint cage of unfamiliar mice than in that of familiar mice, indicating significant social memory. There were no significant differences in the residence times of the Shank3 model group (P = 0.9906) and the 3 mg / kg aripiprazole group (P = 0.7842) in the two restraint cages, indicating social memory deficits.

[0237] The results are shown in Table 10 and Figure 15 As shown, feeding with 10 mg / kg metoprolol + 400 mg / kg taurine for 11 days could rescue the social preference deficit and social memory deficit in autistic mice. Feeding with 10 mg / kg metoprolol for 11 days could rescue the social memory deficit in autistic mice but could not rescue the social preference deficit.

[0238] Table 10 10 mg / kg metoprolol, 10 mg / kg metoprolol + 400 mg / kg taurine

[0239]

[0240] Example 3 Drug rescue of the empathic ability deficit in autistic mice

[0241] After the social behavior experiment was completed, the pain transfer and water maze experiments were carried out in sequence. The experimental procedures are as Figure 16 shown.

[0242] 3.1 Test the rescue effects of 20 mg / kg metoprolol + 400 mg / kg taurine and 400 mg / kg taurine on VPA autistic mice. The pain thresholds of the wild control group (P = 0.0034), the 20 mg / kg metoprolol + 400 mg / kg taurine group (P = 0.0031), and the 400 mg / kg taurine group (P = 0.0860) were significantly lower than the baseline level after interaction, indicating obvious empathic ability; there was no significant difference in the pain threshold of the VPA model group (P = 0.1694) before and after interaction, indicating an empathic deficit.

[0243] The results are shown in Table 11 and Figure 17 As shown, feeding with 20 mg / kg metoprolol + 400 mg / kg taurine and 400 mg / kg taurine for 17 days could rescue the empathic deficit in autistic mice. The significance of the threshold reduction produced by the 20 mg / kg metoprolol + 400 mg / kg taurine compound after interaction was higher than that of the 400 mg / kg taurine group, indicating a better rescue effect.

[0244] Table 11 20 mg / kg metoprolol, 20 mg / kg metoprolol + 400 mg / kg taurine

[0245]

[0246] 3.2 Testing the rescue effect of 20 mg / kg metoprolol + 400 mg / kg taurine and 20 mg / kg metoprolol on Shank3 autistic mice. The pain thresholds of the wild control group (P = 0.0004) and the 20 mg / kg metoprolol + 400 mg / kg taurine group (P = 0.0041) were significantly lower than the baseline level after interaction, showing obvious empathy ability; there was no significant difference in the pain thresholds of the VPA model group (P = 0.8884) and the 20 mg / kg metoprolol group (P = 0.7549) before and after interaction, showing empathy defects.

[0247] As shown in Table 12 and Figure 18 feeding with 20 mg / kg metoprolol + 400 mg / kg taurine for 17 days could rescue the empathy defect of autistic mice.

[0248] Table 12 20 mg / kg metoprolol, 20 mg / kg metoprolol + 400 mg / kg taurine

[0249]

[0250]

[0251] Example 4 Drug rescue of memory defect in the water maze of autistic mice

[0252] 4.1 Testing the rescue effect of 20 mg / kg metoprolol + 400 mg / kg taurine and 400 mg / kg taurine on the VPA autistic model. As the training progressed, the time for the mice to find the platform decreased significantly over time, and there were significant differences among the groups (intra-group comparison, F = 32.112, P = 0.000; inter-group comparison, F = 2.960, P = 0.057). Compared with the wild control group, the autistic model group showed obvious memory defects (day2, P = 0.848; day3, P = 0.103; day4, P = 0.007; day5, P = 0.138).

[0253] Administering 20 mg / kg metoprolol + 400 mg / kg taurine could significantly shorten the time for the model group to find the platform (day2, P = 0.362; day3, P = 0.049; day4, P = 0.035; day5, P = 0.434), indicating that it could rescue the memory of autistic mice.

[0254] Table 13 20mg / kg Metoprolol + 400mg / kg Taurine

[0255]

[0256]

[0257] As shown in Table 13 and Figure 19 as shown, 20mg / kg Metoprolol + 400mg / kg Taurine can rescue the spatial memory deficit of VPA-induced autistic mice, while the 400mg / kg taurine group has no rescue effect.

[0258] 4.2 Test the rescue effects of 10mg / kg Metoprolol + 400mg / kg Taurine and 10mg / kg Metoprolol on the VPA-induced autistic model. As the training progresses, the time for the mice to find the platform significantly shortens over time, and there are significant differences among the groups (intra-group comparison, F = 18.839, P = 0.000; inter-group comparison, F = 14.963, P = 0.000). Compared with the wild control group, the autistic model group showed obvious memory deficits (day1, P = 0.381; day2, P = 0.072; day3, P = 0.012; day4, P = 0.000; day5, P = 0.000).

[0259] Administering 10mg / kg Metoprolol + 400mg / kg Taurine can significantly shorten the time for the model group to find the platform (day1, P = 0.427; day2, P = 0.349; day3, P = 0.003; day4, P = 0.007; day5, P = 0.000), and the swimming time in the target quadrant significantly increases (P = 0.0163), indicating that it can rescue the memory of autistic mice. Administering 10mg / kg Metoprolol can significantly shorten the time for the model group to find the platform (day1, P = 0.934; day2, P = 0.046; day3, P = 0.211; day4, P = 0.060; day5, P = 0.001), and the swimming time in the target quadrant significantly increases (P = 0.0340), indicating that it can rescue the memory of autistic mice.

[0260] Table 14 10mg / kg Metoprolol + 400mg / kg Taurine

[0261]

[0262]

[0263] As shown in Table 14 and Figure 20As shown, 10 mg / kg metoprolol + 400 mg / kg taurine and 10 mg / kg metoprolol can rescue the spatial memory deficit in VPA-induced autistic mice. 10 mg / kg metoprolol + 400 mg / kg taurine had a rescue effect from day 3 to day 5, while 10 mg / kg metoprolol only had a rescue effect on day 5. The time to reach the platform in the 10 mg / kg metoprolol + 400 mg / kg taurine group was lower than that in the 10 mg / kg metoprolol group, indicating that the compound had a better rescue effect.

[0264] 4.3 Test the rescue effects of 20 mg / kg metoprolol + 400 mg / kg taurine and 20 mg / kg metoprolol on the Shank3 autistic model. As the training progressed, the time for the mice to find the platform decreased significantly over time, and there were significant differences among the groups (intra-group comparison, F = 10.853, P = 0.000; inter-group comparison, F = 14.963, P = 0.000). Compared with the wild control group, the autistic model group showed obvious memory deficits (day1, P = 0.232; day2, P = 0.848; day3, P = 0.053; day4, P = 0.013; day5, P = 0.003; day6, P = 0.000).

[0265] Administering 20 mg / kg metoprolol + 400 mg / kg taurine could significantly shorten the time for the model group to find the platform (day1, P = 0.134; day2, P = 0.469; day3, P = 0.403; day4, P = 0.200; day5, P = 0.084; day6, P = 0.001), significantly increase the number of times of crossing the platform position (P = 0.0430), and significantly increase the swimming time in the target quadrant (P = 0.0046), indicating that it could rescue the memory of autistic mice.

[0266] Table 15 20 mg / kg metoprolol + 400 mg / kg taurine

[0267]

[0268] As shown in Table 15 and Figure 21 As shown, 20 mg / kg metoprolol + 400 mg / kg taurine can rescue the spatial memory deficit in Shank3 autistic mice.

Claims

1. Use of a composition in the preparation of a medicament for treating autism spectrum disorder, wherein the composition comprises taurine and a β-blocker, and the β-blocker is selected from the following: Atenolol, Metoprolol, Carvedilol, Labetalol, Propranolol, Bisoprolol, Propafenone, and their pharmaceutically acceptable salts.

2. The use according to claim 1, wherein the β-blocker is Metoprolol or its pharmaceutically acceptable salt.

3. The use according to claim 1, wherein the β-blocker is selected from Metoprolol succinate and Metoprolol tartrate.

4. The use according to claim 1, wherein the mass ratio of taurine to the β-blocker is 100:1 - 1:

10.

5. The use according to claim 4, wherein the mass ratio of taurine to the β-blocker is 40:1 - 1:

1.

6. The use according to claim 4, wherein the mass ratio of taurine to the β-blocker is 80:1, 40:1, 20:1, 200:15, 8:1, 100:15, 4:1, 16:5, 2:1 or 1:

1.

7. The use according to any one of claims 1 - 6, wherein the composition has one or more of the following functions: improving memory impairment, improving social impairment, improving speech communication impairment, reducing repetitive stereotyped behaviors, improving sensory ability defects, improving motor ability defects, and improving self-care ability.

8. The use according to any one of claims 1 - 6, wherein the composition has one or more of the following functions: rescuing the social preference of patients with autism spectrum disorder, rescuing the social memory of patients with autism spectrum disorder, rescuing the empathy ability of patients with autism spectrum disorder, rescuing the spatial memory of patients with autism spectrum disorder.

9. The use according to any one of claims 1 - 6, wherein the medicament is used to improve the memory impairment of patients with autism spectrum disorder, improve the social impairment of patients with autism spectrum disorder, improve the speech communication impairment of patients with autism spectrum disorder, reduce the repetitive stereotyped behaviors of patients with autism spectrum disorder, improve the sensory ability defects of patients with autism spectrum disorder, improve the motor ability defects of patients with autism spectrum disorder, and / or improve the self-care ability of patients with autism spectrum disorder.

10. The use according to any one of claims 1 - 6, wherein the medicament comprises a pharmaceutical composition, and the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

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