Use of lithium salt in preparation of drug for treating autism spectrum disorder

Abstract

The present invention relates to the technical field of medicine, and in particular to the use of a lithium salt in the preparation of a drug for treating autism spectrum disorder, wherein the lithium salt is applied in a pharmaceutical composition or formulation for preventing or treating autism.

Description

Application of a lithium salt in the preparation of a drug for treating autism spectrum disorder

[0001] Priority Declaration

[0002] This disclosure claims priority from Chinese patent application No. 202410257063.9, filed on March 6, 2024. This disclosure incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0003] The present disclosure belongs to the field of medical technology, and particularly relates to the use of a lithium salt in preparing a drug for treating autism spectrum disorder. Background Art

[0004] Autism spectrum disorder (ASD), also known as autism and synonymous with autism, is a neurodevelopmental disorder characterized by social communication impairments, a narrow range of interests or activities, and repetitive, stereotyped behaviors. With the rapid increase in the prevalence of ASD, treatment outcomes for ASD patients are poor, and the cost of treating each child with ASD is increasing. Clinical treatment for children with ASD primarily relies on rehabilitation training and educational interventions, with a lack of medications specifically designed to improve core symptoms (such as behavioral disorders, social interaction impairments, cognitive impairments, imitation impairments, or emotional expression impairments).

[0005] Lithium is a monovalent cation that is primarily used clinically to treat bipolar disorder. Numerous in vitro and in vivo evidence suggests that lithium exerts its neuroprotective / neurotrophic effects primarily by inhibiting apoptosis, inflammation, mitochondrial dysfunction, and oxidative stress.

[0006] Although lithium salts are currently mainly used as clinical drugs for affective disorders, they have not been effectively used in the treatment of autism caused by non-genetic factors.

[0007] Magda Campbel et al. reported in "Lithium and chlorpromazine: A controlled crossover study of hyperactive severely disturbed young children" that a 5-year-old autistic patient was treated with high-dose lithium salts (450–900 mg / day) and had slight behavioral improvements, but the improvement was not therapeutic.

[0008] In order to solve the above problems, we provide a use of a lithium salt in the preparation of a drug for treating autism spectrum disorder. Summary of the Invention

[0009] To address the above issues, the present disclosure provides the use of a lithium salt in the preparation of a drug for treating autism spectrum disorder, specifically the use of a lithium salt in the preparation of a pharmaceutical composition or formulation for preventing or treating autism. The disclosed low-dose lithium salt has significant therapeutic efficacy and good safety in treating autistic patients aged 3-6 years.

[0010] Furthermore, the pharmaceutical composition or preparation is configured as an oral dosage form.

[0011] Furthermore, the lithium salt is set to lithium chloride or lithium carbonate.

[0012] Furthermore, the lithium salt contains Li + , Li + The mass ratio of PEG-1 in oral dosage form is 0.00045%-0.00055%.

[0013] Furthermore, the lithium salt is prepared into a pharmaceutical preparation by means of pharmaceutical excipients, and the administration routes of the pharmaceutical preparation include intravenous administration, oral administration, gavage and enema.

[0014] Furthermore, the pharmaceutical excipients include diluents, binders, disintegrants, lubricants, wetting agents, buffers and preservatives.

[0015] Furthermore, the pharmaceutical excipients also include a coating material or a dispersion medium, and the coating material is set to hydroxypropyl methylcellulose or ethyl cellulose; the dispersion medium is set to one of water, ethanol and propylene glycol.

[0016] Furthermore, the diluent is set to be one of lactose, microcrystalline cellulose, starch and mannitol.

[0017] Furthermore, the binder is set to be one of povidone, gelatin and hydroxypropyl methylcellulose.

[0018] Furthermore, the disintegrant is set to be one of cross-linked polyvinylpyrrolidone, sodium carbonate, and sodium bicarbonate.

[0019] The present disclosure also provides a method for preventing or treating autism spectrum disorder, comprising administering a therapeutically effective amount of a lithium salt, preferably lithium carbonate, to a subject.

[0020] In some embodiments, the autism spectrum disorder may be autism spectrum disorder with intellectual developmental disorder, accompanied by mild functional language disorder or no functional language disorder, or autism spectrum disorder with intellectual developmental disorder, accompanied by functional language loss.

[0021] In some embodiments, the autism spectrum disorder to be prevented or treated may be autism spectrum disorder with reduced or alleviated behavioral disorders, autism spectrum disorder with reduced or alleviated social interaction disorders, autism spectrum disorder with reduced or alleviated cognitive ability disorders, autism spectrum disorder with reduced or alleviated imitation ability disorders, autism spectrum disorder with reduced or alleviated emotional expression disorders, or autism spectrum disorder with reduced or alleviated language expression disorders.

[0022] In some embodiments, the autism spectrum disorder to be prevented or treated is an autism spectrum disorder caused by non-genetic factors.

[0023] In some embodiments, the lithium salt is administered at a dose of 10-12 mg / kg / d.

[0024] In some embodiments, the lithium salt is administered at a dose of 10 mg / kg / d or 12 mg / kg / d.

[0025] In some embodiments, the single administration dose of the lithium salt is 5-6 mg / kg / time.

[0026] In some embodiments, the single administration dose of the lithium salt is, for example, 5 mg / kg / time or 6 mg / kg / time.

[0027] In some embodiments, the lithium salt is administered 1-3 times per day.

[0028] In some embodiments, the lithium salt is administered twice daily.

[0029] In some embodiments, the blood concentration of the lithium salt in the subject is 0.1-0.3 mmol / L.

[0030] In some embodiments, the subject of the lithium salt is a pediatric population aged 2 to 8 years old.

[0031] In some embodiments, the subject of the lithium salt is a pediatric population aged 3-6 years.

[0032] The present disclosure also provides a kit, wherein the content of lithium salt in the kit is 50-240 mg, preferably 50-180 mg.

[0033] The beneficial effects of the present disclosure are:

[0034] (1) The present disclosure applies lithium salts to pharmaceutical compositions or preparations for preventing or treating autism, wherein the pharmaceutical compositions or preparations are provided as oral preparations, the lithium salts are prepared into pharmaceutical preparations by means of pharmaceutical excipients, and the administration routes of the pharmaceutical preparations include intravenous administration, oral administration, gavage and enema. In addition, actual treatment verification is conducted by injecting lithium salts into autism model rats, and the verification results show that lithium salts can effectively eliminate or alleviate the symptoms of autism model rats. Therefore, the application of lithium salts in the preparation of drugs for treating autism spectrum disorders can effectively eliminate or alleviate the symptoms of autism model.

[0035] (2) The low-dose lithium carbonate (10 mg / kg / day or 12 mg / kg / day) disclosed herein has significant therapeutic effects and good safety in treating patients with autism aged 3-6 years, especially in the following areas: improvement of stereotyped and repetitive behaviors, emotional expression and mood regulation, small muscle movements, large muscle movements and behavior management, social interaction ability, imitation ability, mood swings and irritability, etc.

[0036] (3) In clinical practice, lithium carbonate has an excellent therapeutic effect on individualized intervention for patients with autism, further improving patients' social, cognitive, behavioral and language abilities and improving their quality of life.

[0037] Other features and advantages of the present disclosure will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present disclosure. The purposes and other advantages of the present disclosure can be realized and obtained by the structures indicated in the description, claims and drawings.

[0038] It should be understood that within the scope of the present disclosure, the above-mentioned technical features of the present disclosure and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the embodiments of the present disclosure or the technical solutions in the prior art, a brief introduction will be given below to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present disclosure. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.

[0040] FIG1 shows the scores of each energy region of ATEC for the lithium carbonate treatment group and the control group according to an embodiment of the present disclosure;

[0041] FIG2 shows the CARS score results of the lithium carbonate treatment group and the control group according to an embodiment of the present disclosure;

[0042] FIG3 shows the Wechsler Intelligence Test results of the lithium carbonate treatment group and the control group according to an embodiment of the present disclosure;

[0043] Figures 4-1 and 4-2 show the scores of each energy region of PEP-3 of the treatment group and the control group after treatment with lithium carbonate according to an embodiment of the present disclosure;

[0044] FIG5 shows the changes in stereotypic behaviors of autism model VPA rats after lithium chloride treatment according to an embodiment of the present disclosure;

[0045] FIG6-1 and FIG6-2 show the social behavior test results of autism model VPA rats after lithium chloride treatment according to an embodiment of the present disclosure;

[0046] FIG7-1 and FIG7-2 show the anxiety behavior test results of autism model VPA rats after lithium chloride treatment according to an embodiment of the present disclosure;

[0047] FIG8 shows the immunofluorescence results of autism model VPA rats after lithium chloride treatment according to an embodiment of the present disclosure;

[0048] FIG9 shows the action potential results of pyramidal neurons in the mPFC brain region of autism model VPA rats after lithium chloride treatment according to an embodiment of the present disclosure;

[0049] FIG10 shows the dendritic structure and dendritic spine morphology of neurons in autism model VPA rats after lithium chloride treatment according to an embodiment of the present disclosure. DETAILED DESCRIPTION

[0050] To make the objectives, technical solutions, and advantages of the embodiments of the present disclosure more clear, the technical solutions in the embodiments of the present disclosure will be clearly and completely described below in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present disclosure, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present disclosure without making any creative efforts shall fall within the scope of protection of the present disclosure.

[0051] The present disclosure provides an application of a lithium salt in preparing a drug for treating autism spectrum disorder, specifically the application of a lithium salt in preparing a pharmaceutical composition or preparation for preventing or treating autism.

[0052] Wherein, the pharmaceutical composition or preparation is provided as an oral dosage form.

[0053] The lithium salt is set to lithium chloride or lithium carbonate.

[0054] The lithium salt contains Li + , Li +The mass ratio of Li in oral dosage form is 0.00045%-0.00055%. For example, 1 kg of oral dosage form contains 5 mg of Li. + .

[0055] The lithium salt is prepared into a pharmaceutical preparation by pharmaceutical excipients, and the administration routes of the pharmaceutical preparation include intravenous administration, oral administration, gavage and enema.

[0056] The pharmaceutical excipients include diluents, binders, disintegrants, lubricants, wetting agents, buffers and preservatives.

[0057] The pharmaceutical excipients also include a coating material or a dispersion medium. The coating material is configured as hydroxypropyl methylcellulose or ethyl cellulose and is used to coat the pharmaceutical preparation to change the release characteristics of the drug, improve stability, or mask an unpleasant taste. The dispersion medium is configured as one of water, ethanol, and propylene glycol to facilitate the dissolution or dispersion of the lithium salt in the preparation, thereby facilitating the preparation of a solution, suspension, or emulsion.

[0058] The diluent is set to be one of lactose, microcrystalline cellulose, starch and mannitol, and is used to increase the volume of the preparation or the release rate of the high-speed drug.

[0059] The binder is configured as one of povidone, gelatin and hydroxypropyl methylcellulose, and is used to bind the drug particles together to form tablets or pills.

[0060] The disintegrant is set to be one of cross-linked polyvinylpyrrolidone, sodium carbonate, and sodium bicarbonate, and is used to promote the disintegration and release of the drug preparation in the body.

[0061] The lubricant is set to magnesium stearate or talc, which is used to reduce friction during the preparation and packaging of the pharmaceutical preparation and improve fluidity.

[0062] The wetting agent is set to Tween-80 or sodium lauryl sulfate to improve the water solubility and wettability of the drug and enhance the stability and bioavailability of the preparation.

[0063] The embodiments of the present disclosure also provide a use of a lithium salt in the preparation of a drug for treating autism spectrum disorder with intellectual development disorder, mild functional language disorder or no functional language disorder, or autism spectrum disorder with intellectual development disorder and functional language loss.

[0064] The embodiments of the present disclosure also provide a use of a lithium salt in the preparation of autism spectrum disorder drugs for reducing or alleviating behavioral disorders, reducing or alleviating social interaction disorders, reducing or alleviating cognitive impairment, reducing or alleviating imitation ability impairment, reducing or alleviating emotional expression impairment, or reducing or alleviating language expression impairment.

[0065] The present disclosure provides a method for preventing or treating autism spectrum disorder, comprising administering a therapeutically effective amount of a lithium salt, preferably lithium carbonate, to a subject.

[0066] In some embodiments, the autism spectrum disorder may be autism spectrum disorder with intellectual developmental disorder, accompanied by mild functional language disorder or no functional language disorder, or autism spectrum disorder with intellectual developmental disorder, accompanied by functional language loss.

[0067] In some embodiments, the autism spectrum disorder to be prevented or treated may be autism spectrum disorder with reduced or alleviated behavioral disorders, autism spectrum disorder with reduced or alleviated social interaction disorders, autism spectrum disorder with reduced or alleviated cognitive ability disorders, autism spectrum disorder with reduced or alleviated imitation ability disorders, autism spectrum disorder with reduced or alleviated emotional expression disorders, or autism spectrum disorder with reduced or alleviated language expression disorders.

[0068] In some embodiments, the lithium salt is administered at a dose of 10-12 mg / kg / d.

[0069] In some embodiments, the lithium salt is administered at a dose of 10 mg / kg / d or 12 mg / kg / d.

[0070] In some embodiments, the single administration dose of the lithium salt is 5-6 mg / kg / time.

[0071] In some embodiments, the single administration dose of the lithium salt is, for example, 5 mg / kg / time or 6 mg / kg / time.

[0072] In some embodiments, the lithium salt is administered 1-3 times per day.

[0073] In some embodiments, the lithium salt is administered twice daily.

[0074] In some embodiments, the blood concentration of the lithium salt in the subject is 0.1-0.3 mmol / L.

[0075] In some embodiments, the subject of the lithium salt is a pediatric population aged 2 to 8 years old.

[0076] In some embodiments, the subject of the lithium salt is a pediatric population aged 3-6 years.

[0077] In some embodiments, the autism spectrum disorder to be prevented or treated is an autism spectrum disorder caused by non-genetic factors.

[0078] The present disclosure also provides a kit, wherein the content of lithium salt in the kit is 50-240 mg, preferably 50-180 mg.

[0079] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0080] The term "non-genetic factors" refers to diseases whose pathogenesis is mainly caused by external factors such as environment, lifestyle, infection, chemicals, physical factors, etc., rather than directly caused by gene mutations or genetic variations.

[0081] The term "autism spectrum disorder with intellectual developmental disability and mild functional language impairment or no functional language impairment" refers to individuals who meet all the definitional requirements of autism spectrum disorder and intellectual developmental disability and have only mild or no functional impairment in the ability to use functional language (spoken or written) for instrumental purposes, such as expressing personal needs and desires.

[0082] The term "autism spectrum disorder with intellectual developmental disability and functional language impairment" refers to individuals who meet the full definition of autism spectrum disorder and intellectual developmental disability, with a complete or near-complete loss of the ability to use functional language (oral or written) for instrumental purposes, such as expressing personal needs and desires, compared to their peers.

[0083] The term "comprising" is inclusive of "containing," "consisting essentially of," and "consisting of.

[0084] The kit described in the present disclosure may also include instructions for use to facilitate those skilled in the art to use it in the correct manner.

[0085] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0086] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0087] The term "subject" refers to any animal, preferably a mammal, and most preferably a human, that is about to be or has been administered a compound according to the embodiments of the present disclosure. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0088] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present disclosure.

[0089] The reagents and raw materials used in the present disclosure are commercially available.

[0090] Example 1

[0091] In order to verify the effectiveness of lithium carbonate in preventing or treating autism, the present disclosure provides a clinical lithium carbonate therapy for treating the core symptoms of autism, comprising the following steps:

[0092] S1. Children with ASD who meet the criteria of the Diagnostic and Statistical Manual of Mental Disorders (5th edition) or the Autism Diagnostic Observation Scale (2nd edition), and whose families give informed consent and voluntarily sign the informed consent form, will be randomly divided into a control group and an experimental group;

[0093] S2. Exclusion criteria: ① inherited metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsions; ⑤ taking any medication that may cause cognitive changes or damage to important organs within 1 month before medication; ⑥ any other physical or mental illness that may cause brain dysfunction;

[0094] S3, control group: received oral placebo calcium carbonate in addition to conventional rehabilitation training. The rehabilitation training mainly focused on language comprehension, language expression, social emotions, gross motor skills, fine motor skills, self-care, and behavior management;

[0095] S4, experimental group received oral sustained-release lithium carbonate treatment on the basis of conventional rehabilitation training, 5 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months;

[0096] S5. One course of rehabilitation training is 28 days, followed by a 2-week break for the second course, and three courses of rehabilitation are required.

[0097] S6. Monitor blood lithium concentration, liver, kidney, and thyroid function before treatment (M0 stage) and after treatment (M3 stage) to assess toxic and side effects.

[0098] S7. Before treatment (M0 phase) and after treatment (M3 phase), the subjects' five major ability areas, including gross motor skills, fine motor skills, cognitive ability, language ability, emotional and social behavior ability, were evaluated using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale and Psychoeducational Profile version 3 (PEP-3).

[0099] ATEC is a tool developed by the Autism Spectrum Disorders Institute in the United States. The difference between the initial (baseline) ATEC score and the subsequent ATEC score is used to assess and track treatment effectiveness. ATEC consists of four subscales: Speech / Language Communication (14 items, scores ranging from 0 to 28), Social Ability (20 items, scores ranging from 0 to 40), Sensory / Cognitive Awareness (18 items, scores ranging from 0 to 36), and Health / Physical Behavior (25 items, scores ranging from 0 to 75). Scores on subscales I-III range from 0 to 2, with a score of 2 indicating lower developmental abilities and higher severity of autism and behavioral problems. Items on the Health / Physical Behavior subscale are scored from 0 (no problems) to 3 (severe problems). The sum of the scores for each subscale represents the total ATEC score. The maximum total score is 179 (range 0-179), with higher scores indicating more severe and / or serious symptoms.

[0100] As shown in Figure 1, Figures 1a and 1b show the scores of each ATEC domain for the lithium carbonate treatment group and the control group. Figure 1a shows the scores of stereotyped behavior, physiological behavior, and impulsive behavior for the lithium carbonate treatment group and the control group; Figure 1b shows the scores of sensory, perceptual, and cognitive abilities for the lithium carbonate treatment group and the control group; Figure 1c shows the scores of language expression, communication, and other abilities for the lithium carbonate treatment group and the control group; Figure 1d shows the scores of social ability for the lithium carbonate treatment group and the control group; and Figure 1e shows the total scores of the ATEC scale for the lithium carbonate treatment group and the control group. The autism efficacy evaluation table provided in Figure 1 shows that the improvement effects of the ATEC behavioral disorder, cognitive disorder, and ATEC total score in the lithium carbonate treatment group increased by 3.75 times, 1.61 times, and 1.60 times, respectively.

[0101] To evaluate the effect of lithium carbonate treatment on disease severity, the Childhood Autism Rating Scale (CARS) was used to assess the severity of autism in children before and after treatment. The CARS is a 15-item rating scale used by professional physicians. Each item is scored on a scale of 1 to 4. A total score of 30 or higher is considered a diagnosis of ASD, 30 or lower is considered mild to moderate, and a total score of 36 or higher is considered severe. Figure 2 shows the CARS scores for the lithium carbonate treatment group and the control group. The scores indicate that the lithium carbonate treatment group improved the severity of autism by 1.29 times. This data did not show a statistically significant difference.

[0102] The Wechsler Intelligence Scale, developed by American psychologist David Wechsler, is internationally recognized as the most authoritative and widely used diagnostic intelligence test. The scale consists of two sections, verbal and operational, each composed of several subtests. Test results are presented as three composite scores: verbal IQ, operational IQ, and total IQ. Using the Wechsler Intelligence Scale, we assessed the changes in intelligence in children with autism before and after treatment. As shown in Figure 3, Figures 3a to 3c show the Wechsler Intelligence Scale results for the lithium carbonate treatment group and the control group. Figure 3a shows the verbal IQ for the lithium carbonate treatment group and the control group; Figure 3b shows the operational IQ for the lithium carbonate treatment group and the control group; and Figure 3c shows the total IQ for the lithium carbonate treatment group and the control group. The results shown in Figure 3 indicate that lithium carbonate treatment significantly improved the level of intelligence in autism, with a 2.23-fold improvement in verbal IQ and a 1.28-fold improvement in operational IQ. These data were not statistically significant.

[0103] To avoid systematic errors, the five major domains of autistic children were reassessed using the Psychoeducational Assessment of Autism (Third Edition). This scoring system, developed by E. Schoplerh and R.J. Reichler in the United States, is widely used in clinical practice. It encompasses ten components: cognition (verbal / preverbal), language comprehension, language expression, fine motor skills, gross motor skills, imitation (visual / motor), emotional expression, social interaction, behavioral characteristics—nonverbal, and behavioral characteristics—verbal. Higher scores indicate greater development of the corresponding domain. As shown in Figures 4-1 and 4-2, (a) and (b) show the scores for each domain of the PEP-3 for the lithium carbonate-treated and control groups. Figure 4-1a shows the cognitive scores of the lithium carbonate treatment group and the control group; Figure 4-1b shows the language expression scores of the lithium carbonate treatment group and the control group; Figure 4-1c shows the language comprehension scores of the lithium carbonate treatment group and the control group; Figure 4-1d shows the communication scores of the lithium carbonate treatment group and the control group; Figure 4e shows the small muscle scores of the lithium carbonate treatment group and the control group; Figure 4-1f shows the large muscle scores of the lithium carbonate treatment group and the control group; Figure 4-1g shows the imitation scores of the lithium carbonate treatment group and the control group; Figure 4-1h shows the total physical fitness scores of the lithium carbonate treatment group and the control group. Figure 4-2i shows the emotional expression scores of the lithium carbonate treatment group and the control group; Figure 4-2j shows the behavioral characteristics (non-verbal) scores of the lithium carbonate treatment group and the control group; Figure 4-2k shows the behavioral characteristics (verbal) scores of the lithium carbonate treatment group and the control group; Figure 4-2l shows the total social interaction scores of the lithium carbonate treatment group and the control group; Figure 4-2m shows the total behavioral scores of the lithium carbonate treatment group and the control group; From the data in Figures 4-1 and 4-2, it can be seen that after lithium carbonate intervention, the gross muscle score increased significantly, and the improvement effect increased by 1.56 times, indicating an improvement in gross motor skills. In addition, the improvement effects of the lithium carbonate treatment group on social interaction, language comprehension, cognition and total scores increased by 3.79 times, 2.71 times, 47.67 times and 4.10 times, respectively.

[0104] In order to monitor the toxic and side effects of lithium carbonate, blood lithium concentration monitoring, liver function, kidney function, and thyroid function examinations were performed during the treatment period (before medication, i.e., M0, one month after medication, i.e., M1, and three months after medication, i.e., M3). The results are shown in Table 1. The data in the figure indicate that after medication, except for the increase in lithium ion concentration, no abnormalities occurred in other ions of the electrolytes in the blood, and no toxic and side effects were observed in the liver, kidney, thyroid and other organs.

[0105] Table 1

[0106] Example 2

[0107] The present disclosure also provides a method for reducing or alleviating stereotyped repetitive behaviors, social disorders, and synaptic transmission disorders in autism model rats by intervening with lithium chloride, comprising the following steps:

[0108] A1. On days 5-32 after birth, 1 mmol / kg of lithium chloride was intraperitoneally injected into autistic VPA rats daily for 28 consecutive days.

[0109] A2. Conduct behavioral tests such as grooming, bead burying, three-box social interaction, and open field tests within 33-42 days, and use in vitro patch clamp whole-cell recording to detect action potentials of pyramidal neurons in the mPFC.

[0110] A3. On the 44th day after birth, brain tissue samples were collected from rats in each group. After fixation, dehydration, and frozen sectioning, immunofluorescence staining was performed for the neuronal marker NeuN, the microglial marker IBA1, the astrocyte marker GFAP, the excitatory postsynaptic density marker PSD-95, the excitatory presynaptic marker VGluT1, and the membrane protein Synaptophysin closely related to synaptic function. HALO pathology analysis software was then used to count and analyze the morphology of different types of nerve cells in the autism model VPA rats and after lithium chloride treatment.

[0111] A4. On the 44th day after birth, brain tissue samples were collected from rats in each group. Golgi staining was used to analyze the dendritic structure and dendritic spine morphology of neurons and to assess their synaptic plasticity.

[0112] To verify that lithium chloride intervention can reduce or alleviate behavioral and social issues in autistic VPA rats, we conducted further validation based on the clinical treatment effect. The experiment mainly included: establishment of autistic VPA rats, lithium chloride treatment, and behavioral assessment. The specific plan is as follows:

[0113] (1) Construction of the VPA rat model of autism

[0114] 1) Based on previous studies and literature reports, we established a VPA rat model of autism. Specifically, 8-week-old SPF-grade female and male Sprague-Dawley (SD) rats were acclimated to the breeding environment for one week and then co-housed overnight at 5:1 at 5:00 PM on the first day. Vaginal smears were performed the following day. Successful mating and conception were considered on the afternoon of the day sperm was detected under microscopic examination during estrus, designated as embryonic day 0.5 (E0.5). Pregnant female rats were housed individually.

[0115] 2) On E12.5, pregnant female mice were randomly divided into two groups. The model group received an intraperitoneal injection of 600 mg / kg b.wt. sodium valproate solution (sodium valproate powder dissolved in 0.9% saline to make a 250 mg / ml solution), while the control group received an equal volume of saline. Pups born to females in the model group were designated the valproate group (VPA group), while pups born to females in the control group were designated the saline group. Pups were weaned on postnatal day (PND) 21 and housed separately.

[0116] (2) Treatment with lithium chloride

[0117] The treatment plan is: on the 5th to 32th day after birth of the autism model VPA rats, 1mmol / kg of lithium chloride is injected intraperitoneally for 28 consecutive days.

[0118] (3) Behavioral assessment

[0119] During the 33-42 days after birth, the autism model VPA rats were tested for stereotypic behaviors through grooming test and bead burying test, their anxiety behavior was assessed through open field test, and their social interaction ability was assessed through three-box social interaction.

[0120] B1. Grooming experiment: After the two groups of test mice were placed in the breeding cage and adapted for 10 minutes, their grooming behavior was recorded for 30 minutes using EthoVisionXT16 software, and the differences in the duration of grooming behavior of each group were analyzed.

[0121] As shown in Figure 5, Figures 5a-b show changes in stereotypic behaviors in autistic VPA rats after lithium chloride treatment. Figure 5a shows the number of beads buried by rats in different groups, and Figure 5b shows the grooming time of rats in different groups. The results in Figure 5a show that the grooming time of autistic VPA rats was significantly higher than that of the normal control group, and that this time was significantly reduced after lithium chloride treatment, indicating that the stereotypic behaviors of autistic VPA rats were significantly reduced after lithium chloride treatment.

[0122] B2. Bead Burying Test: Place 5 cm thick corncob bedding in a standard rat cage and flatten it. First, place the test rats in the test room to acclimate for at least 30 minutes. Then, place 12 glass beads (16 mm diameter) in a 6 × 2 pattern on the bedding. After 30 minutes, remove the rats from the cage and record the number of buried glass beads (>50% buried volume). The bedding can be flattened and reused. As shown in Figure 5b, the number of buried beads in VPA rats with autism was significantly higher than that in the normal control group. This number was significantly reduced after lithium chloride treatment. These results suggest that lithium chloride treatment reduces or alleviates the stereotyped behaviors of VPA rats with autism.

[0123] B3. Three-box social experiment:

[0124] The experiment consisted of three phases. ① Three boxes were separated by transparent acrylic panels, and the test mouse was placed in the middle box. The mouse was allowed to freely move in and out of the three boxes for 10 minutes of exploration. ② A stranger mouse (Stranger 1) of the same age and sex from a different cage was placed in the left box. The cage in the right box was left empty, and the resin door separating the boxes was removed, allowing the test mouse to move freely in all three boxes for 10 minutes. ③ A second stranger mouse (Stranger 2) of the same species was placed in the empty cage from the first phase of the experiment and recorded for 10 minutes. Statistical indicators: EthoVision XT16 software was used to track and record the contact duration between the test mouse and Stranger 1, the empty cage, and Stranger 2, and ANY-Maze software was used to analyze and calculate the social preference index: (time spent in the left cage - time spent in the right cage) / (time spent in the left cage + time spent in the right cage).

[0125] Figures 6-1 and 6-2 (a, b) show the results of social behavior testing in autistic VPA rats after lithium chloride treatment. Figure 6-1 (a) shows the movement trajectories of rats in different groups; Figure 6-1 (b) shows the results of the second phase of social preference in the three-chamber social experiment in autistic VPA rats after lithium chloride treatment; and Figure 6-2 (c) shows the results of the third phase of social preference in the three-chamber social experiment in autistic VPA rats after lithium chloride treatment. The experimental results (Figures 6-1 and 6-2 (ac)) show that the social preference of autistic VPA rats was significantly reduced compared to the control group, but their social interaction level was significantly improved after lithium chloride treatment. These results suggest that lithium chloride treatment alleviates the social impairments in autistic VPA rats.

[0126] B4. Open field test:

[0127] Rats were placed in the center of an open-view box (80 cm × 80 cm × 40 cm) and allowed to explore freely for 10 minutes. A camera was installed directly above the open-view box to record the total distance the rats traveled in the box and the time they spent in the central area as indicators of locomotor activity and anxiety-like behavior.

[0128] Figures 7-1 and 7-2 ab show the results of anxiety behavior detection of autistic model VPA rats after lithium chloride treatment; Figure 7-1 a shows the results of movement trajectory of autistic model VPA rats in the open field test after lithium chloride treatment; Figure 7-2 b shows the results of total distance and central area time of autistic model VPA rats in the open field test after lithium chloride treatment; Experimental results: Compared with the control group, the total distance of movement of autistic model VPA rats in the open field test did not differ significantly, but the time they stayed in the central area was significantly lower than that of the normal control group, and the time they stayed in the central area was significantly increased after lithium chloride treatment.

[0129] (4) Nervous system development

[0130] C1. Immunofluorescence experiment:

[0131] On the 44th day after birth, brain tissue samples from each group of rats were collected. After fixation, dehydration and frozen sectioning, immunofluorescence staining was performed for neuronal marker NeuN, microglial marker IBA1, astrocyte marker GFAP, excitatory postsynaptic density marker PSD-95, excitatory presynaptic marker VGluT1, and membrane protein Synaptophysin closely related to synaptic function. Subsequently, HALO pathology analysis software was used to count and morphologically examine the cells, and the conditions of different types of nerve cells in autistic VPA rats and after lithium chloride treatment were analyzed.

[0132] Figure 8 shows immunofluorescence results of autism-model VPA rats after lithium chloride treatment. Compared with the control group, autism-model VPA rats showed increased GFAP in astrocytes and decreased NeuN in mature neurons in the prefrontal cortex (PFC) and hippocampus (CA1) regions. This suggests that VPA inhibits neurogenesis and promotes the generation or activation of astrocytes during embryonic development. After lithium chloride treatment, astrocytes decreased in the prefrontal cortex (PFC) and hippocampus (CA1) regions, while NeuN increased in mature neurons. This suggests that lithium treatment promotes neurogenesis and inhibits the generation or activation of astrocytes. Compared with the control group, autism-model VPA rats showed increased microglia in the prefrontal cortex (PFC) and hippocampus (CA1) regions. Lithium chloride treatment inhibited the generation or activation of microglia in the prefrontal cortex (PFC) and hippocampus (CA1), suggesting that lithium may play a crucial role in regulating neuronal differentiation and metabolism, as well as neuroinflammation.

[0133] C2. Patch clamp experiment:

[0134] Patch clamp was used to examine the firing of action potentials in pyramidal neurons of rats with VPA. Based on the distribution and morphology of these neurons, pyramidal neurons in layer V of the mPFC were selected. The electrode solution for recording action potentials from pyramidal neurons (in mM) consisted of 105K-gluconate, 30KCl, 10HEPES, 5EGTA, 4Mg-ATP, 0.3Na-GTP, and 10creatine phosphate. The pH was adjusted to 7.35 using KOH, and the osmotic pressure was controlled at 285mOsm / kg. To record action potentials, the voltage clamp was switched to current clamp mode, clamping the neuronal membrane potential at -70mV. Current was injected into the neurons to simulate a depolarizing burst of action potentials. The injected current ranged from -200pA to 500pA, in 50pA increments.

[0135] Figures 9a-d show the action potentials of pyramidal neurons in the mPFC of autistic VPA rats after lithium chloride treatment. Figure 9a shows example action potentials of pyramidal neurons at injection currents of 150pA, 250pA, and 350pA, respectively. Figure 9b shows the number of spikes in response to injection currents ranging from 0pA to 500pA. Figure 9c shows a comparison of resting membrane potentials. Figure 9d shows a comparison of action potential thresholds. The experimental results show that the resting potential of pyramidal neurons in male VPA rats did not change after lithium chloride treatment, but the action potentials showed statistically significant differences. The resting potentials of pyramidal neurons in female VPA rats showed significant differences, but the action potentials did not. These results suggest that lithium chloride can affect the transmission of electrical potentials between pyramidal neurons.

[0136] C3. Golgi staining:

[0137] Brain tissue samples from rats in each group were collected at P44 time point, placed in a mixture of A+B and stored in the dark at room temperature for 14 days. After 2 weeks, the tissue was transferred to solution C and stored for 3-4 days. The surface liquid was then carefully removed with filter paper, wrapped in tin foil and placed in a -80 refrigerator. One week later, the sections were stained, and the length and branch number of neuronal dendrites, dendritic spine density, and Sholl analysis were performed to evaluate the dendritic development of neurons and the effect of lithium treatment.

[0138] As shown in Figure 10, the dendritic structure and dendritic spine morphology of neurons in autistic VPA rats after lithium chloride treatment. The experimental results show that the dendritic length, branch number, and dendritic spine density of neurons in autistic VPA rats are reduced compared with the control group, but the dendritic spine density is significantly increased after lithium chloride intervention.

[0139] Example 3

[0140] Patient 001, sex: male, age: 5.3 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 5 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0141] After lithium carbonate treatment, ATEC cognition, ATEC behavior, and ATEC total scores all significantly improved, improving by 30.8%, 44.6%, and 27.3%, respectively, compared to pre-treatment. These improvements were 4.5 times, 8.5 times, and 3.8 times the average improvement in the control group (rehabilitation training only).

[0142] Example 4

[0143] Patient 003, gender: female, age: 4.42 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 5 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0144] After lithium carbonate treatment, CARs score, PEP-3 cognitive score, and PEP-3 gross muscle score improved by 22.9%, 55.3%, and 30%, respectively, compared with before treatment, which were 2.5 times, 68.2 times, and 5.2 times the average improvement of the control group (rehabilitation training treatment only).

[0145] Example 5

[0146] Patient 004, sex: male, age: 5.58 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 5 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0147] After lithium carbonate treatment, PEP-3 small muscle, PEP-3 social interaction, PEP-3 emotional expression scores and PEP-3 behavioral total scores improved by 8.6%, 250%, 125% and 72.7% respectively compared with before treatment, which were 2.6 times, 3.9 times, 18.4 times, 7.0 times and 9.6 times the average improvement effect of the control group (rehabilitation training treatment only).

[0148] Example 6

[0149] Patient 005, sex: male, age: 3.58 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 5 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0150] After lithium carbonate treatment, PEP-3 imitation ability, PEP-3 social interaction and PEP-3 total behavior scores improved by 120%, 114.3% and 43.5%, respectively, which were 5.7 times, 8.4 times and 5.7 times the average improvement of the control group (rehabilitation training treatment only).

[0151] Example 7

[0152] Patient 006, male, age: 5.25 years, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 5 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0153] After lithium carbonate treatment, ATEC social, ATEC cognitive, and ATEC total scores also improved significantly, improving by 12.2%, 15.2%, and 11.1% compared to before treatment, respectively. These improvements were 2.1 times, 2.2 times, and 3.0 times the average improvement of conventional behavioral intervention alone. In addition, the PEP-3 scores of patient 006 improved by 83.3%, 63.6%, 200%, and 128.6% in fine motor, gross motor, imitation, and cognition, respectively, which were 38.4 times, 11.1 times, 9.5 times, and 164.5 times the average improvement of the control group (rehabilitation training alone).

[0154] Example 8

[0155] Patient 008, sex: male, age: 4.17 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 5 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0156] After lithium carbonate treatment, ATEC behavior, PEP-3 emotional expression, PEP-3 social interaction and PEP-3 behavioral total scores improved by 44.9%, 116.7%, 333.3% and 82.4% respectively compared with before treatment, which were 8.5 times, 6.5 times, 24.6 times and 10.9 times the average improvement effect of the control group (rehabilitation training treatment only).

[0157] Example 9

[0158] Patient 010, sex: male, age: 5.42 years, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 5 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0159] After lithium carbonate treatment, ATEC cognition, ATEC behavior and PEP-3 emotional expression improved by 18.6%, 21.6% and 83.3% respectively compared with before treatment, which were 2.7 times, 4.1 times and 4.7 times the average improvement effect of the control group (rehabilitation training treatment only).

[0160] Example 10

[0161] Patient 012, sex: male, age: 4.25 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 5 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0162] After lithium carbonate treatment, ATEC behavior, PEP-3 emotional expression, PEP-3 social interaction, PEP-3 cognitive score, and PEP-3 behavioral total score improved by 21.6%, 83.3%, 200%, 50%, and 127.3%, respectively, compared with before treatment, which were 4.1 times, 4.7 times, 14.8 times, 64.0 times, and 16.8 times the average improvement effect of the control group (rehabilitation training treatment only).

[0163] Example 11

[0164] Patient 013, male, 4.50 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 6 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0165] After lithium carbonate treatment, ATEC's language expression improved significantly, which was 2.14 times the average improvement of the control group (rehabilitation training only).

[0166] Example 12

[0167] Patient 014, male, 3.58 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 6 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0168] After lithium carbonate treatment, ATEC's language expression improved significantly, which was 2.14 times the average improvement of the control group (rehabilitation training only).

[0169] Example 13

[0170] Patient 016, female, 4.33 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 6 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0171] After lithium carbonate treatment, ATEC language expression, ATEC behavior, ATEC total score, PEP-3 imitation and PEP-3 cognition were significantly improved, which were 2.50 times, 3.21 times, 2.06 times, 2.86 times and 50 times the average improvement of the control group (rehabilitation training treatment only).

[0172] Example 14

[0173] Patient 017, male, 5.58 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 6 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0174] After lithium carbonate treatment, CARS scores, PEP-3 cognition, and PEP-3 language expression significantly improved, reaching 3.46 times, 50 times, and 4.44 times the average improvement in the control group (rehabilitation training only). PEP-3 fine muscle scores improved by 10 points after lithium treatment, while the control group experienced a negative average score increase, indicating worsening PEP-3 fine muscle function.

[0175] Example 15

[0176] Patient 019, male, 5.42 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 6 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0177] After lithium carbonate treatment, the ATEC total score improved significantly, which was 2.25 times the average improvement of the control group (rehabilitation training treatment only).

[0178] Example 16

[0179] Patient 020, male, 3.75 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 6 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0180] After lithium carbonate treatment, the ATEC total score improved significantly, which was 2.75 times the average improvement of the control group (rehabilitation training only).

[0181] Example 17

[0182] Patient 021, male, 4.67 years old, was excluded before enrollment, namely, ① genetic metabolic disease; ② chromosomal disease; ③ epilepsy; ④ history of febrile convulsion; ⑤ taking any drug that can cause cognitive changes and damage to important organs within 1 month before medication; ⑥ any other physical and mental illness that can cause brain dysfunction; oral lithium carbonate sustained-release treatment on the basis of routine rehabilitation training, 6 mg / kg / time, twice a day, 12 hours apart, for 3 consecutive months; rehabilitation training for 28 days as a course of treatment, rest for 2 weeks for the second course of treatment, and rehabilitation for 3 consecutive courses; blood lithium concentration monitoring, liver and kidney function, and thyroid function tests were performed before treatment (M0 stage) and after treatment (M3 stage), and before treatment ( The subjects' gross motor skills, fine motor skills, cognitive abilities, language abilities, emotions, and social behaviors were evaluated before and after treatment (stage M0) and after treatment (stage M3) using the Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS), Wechsler Intelligence Scale, and Psychoeducational Profile version 3 (PEP-3).

[0183] After lithium carbonate treatment, there were significant improvements in PEP-3 cognition and PEP-3 imitation, which were 90 times and 2.86 times the average improvement of the control group (rehabilitation training treatment only).

[0184] All documents mentioned in this disclosure are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of this disclosure, those skilled in the art may make various changes or modifications to this application, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. Use of a lithium salt in the preparation of a drug for treating autism spectrum disorder, characterized in that: Use of lithium salts in preparing a pharmaceutical composition or preparation for preventing or treating autism.

2. Use of a lithium salt according to claim 1 in the preparation of a drug for treating autism spectrum disorder, characterized in that: The pharmaceutical composition or preparation is provided as an oral dosage form.

3. Use of a lithium salt according to claim 2 in the preparation of a drug for treating autism spectrum disorder, characterized in that: The lithium salt is set to lithium chloride or lithium carbonate.

4. Use of a lithium salt according to claim 3 in the preparation of a drug for treating autism spectrum disorder, characterized in that: The lithium salt contains Li+, and the mass ratio of Li+ in the oral preparation is 0.00045%-0.00055%.

5. Use of a lithium salt according to claim 4 in the preparation of a drug for treating autism spectrum disorder, characterized in that: The lithium salt is prepared into a pharmaceutical preparation by pharmaceutical excipients, and the administration routes of the pharmaceutical preparation include intravenous administration, oral administration, gavage and enema.

6. Use of a lithium salt according to claim 5 in the preparation of a drug for treating autism spectrum disorder, characterized in that: The pharmaceutical excipients include diluents, binders, disintegrants, lubricants, wetting agents, buffers and preservatives.

7. Use of a lithium salt according to claim 6 in the preparation of a drug for treating autism spectrum disorder, characterized in that: The pharmaceutical excipients further include a coating material or a dispersion medium, wherein the coating material is hydroxypropyl methylcellulose or ethyl cellulose; and the dispersion medium is one of water, ethanol and propylene glycol.

8. Use of a lithium salt according to claim 7 in the preparation of a drug for treating autism spectrum disorder, characterized in that: The diluent is set to be one of lactose, microcrystalline cellulose, starch and mannitol.

9. Use of a lithium salt according to claim 8 in the preparation of a drug for treating autism spectrum disorder, characterized in that: The binder is configured to be one of povidone, gelatin and hydroxypropyl methylcellulose.

10. Use of a lithium salt according to claim 9 in the preparation of a drug for treating autism spectrum disorder, characterized in that: The disintegrant is set to be one of cross-linked polyvinylpyrrolidone, sodium carbonate, and sodium bicarbonate.

11. The use according to any one of claims 1 to 10, characterized in that: The autism spectrum disorder may be autism spectrum disorder with intellectual development disorder, accompanied by mild functional language disorder or no functional language disorder, or autism spectrum disorder with intellectual development disorder, accompanied by functional language loss.

12. The use according to any one of claims 1 to 10, characterized in that The autism spectrum disorder to be prevented or treated may be autism spectrum disorder that reduces or alleviates behavioral disorders, autism spectrum disorder that reduces or alleviates social interaction disorders, autism spectrum disorder that reduces or alleviates cognitive ability disorders, autism spectrum disorder that reduces or alleviates imitation ability disorders, autism spectrum disorder that reduces or alleviates emotional expression disorders, or autism spectrum disorder that reduces or alleviates language expression disorders.

13. The use according to any one of claims 1 to 10, characterized in that The autism spectrum disorder to be prevented or treated is an autism spectrum disorder caused by non-genetic factors.

14. The use according to any one of claims 1 to 10, characterized in that It meets one or more of the following conditions: (1) The dosage of the lithium salt is 10-12 mg / kg / d, for example, 10 mg / kg / d, 12 mg / kg / d; (2) The single administration dose of the lithium salt is 5-6 mg / kg / time, for example, 5 mg / kg / time, 6 mg / kg / time; (3) The lithium salt is administered 1-3 times per day, for example, twice per day; (4) The blood concentration of the lithium salt in the subject is 0.1-0.3 mmol / L; (5) The subjects of the lithium salt are children aged 2-8 years old, such as children aged 3-6 years old.

15. The use according to any one of claims 1 to 14, characterized in that The autism spectrum disorder to be prevented or treated is an autism spectrum disorder caused by non-genetic factors.

16. A method for preventing or treating autism spectrum disorder, comprising administering to a subject a therapeutically effective amount of a lithium salt, preferably lithium carbonate.

17. A method for preventing or treating autism spectrum disorder, characterized in that: The autism spectrum disorder to be prevented or treated may be autism spectrum disorder with intellectual development disorder, accompanied by mild functional language disorder or no functional language disorder, or autism spectrum disorder with intellectual development disorder, accompanied by functional language loss.

18. A method for preventing or treating autism spectrum disorder, characterized in that: The autism spectrum disorder to be prevented or treated may be autism spectrum disorder that reduces or alleviates social interaction disorders, autism spectrum disorder that reduces or alleviates cognitive ability disorders, autism spectrum disorder that reduces or alleviates imitation ability disorders, autism spectrum disorder that reduces or alleviates emotional expression disorders, or autism spectrum disorder that reduces or alleviates language expression disorders.

19. A method for preventing or treating autism spectrum disorder, characterized in that: It meets one or more of the following conditions: (1) The dosage of the lithium salt is 10-12 mg / kg / d, for example, 10 mg / kg / d, 12 mg / kg / d; (2) The single administration dose of the lithium salt is 5-6 mg / kg / time, for example, 5 mg / kg / time, 6 mg / kg / time; (3) The lithium salt is administered 1-3 times per day, for example, twice per day; (4) The blood concentration of the lithium salt in the subject is 0.1-0.3 mmol / L; (5) The subjects of the lithium salt are children aged 2-8 years old, such as children aged 3-6 years old.

20. The method according to any one of claims 16 to 19, characterized in that: The autism spectrum disorder to be prevented or treated is an autism spectrum disorder caused by non-genetic factors.

21. A kit, characterized in that The kit comprises the use according to any one of claims 1 to 15 or the method according to any one of claims 16 to 20, wherein the content of lithium salt is 50-240 mg, preferably 50-180 mg.

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