Drug combination composition for treating or / and improving attention impairment and application thereof

Abstract

The invention provides a drug combination composition for treating or / and improving attention impairment and application thereof, and relates to the technical field of biological medicine, the drug combination composition comprises isorhynchophylline and ginsenoside Rg1, and the isorhynchophylline and ginsenoside Rg1 are creatively combined to be used as a drug for treating or / and improving attention impairment. Researches show that the combination of isorhynchophylline and ginsenoside Rg1 has a more significant effect of treating or / and improving attention impairment than single isorhynchophylline or ginsenoside Rg1, provides a new strategy and idea for treating or / and improving attention impairment, and has very significant significance.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a combined pharmaceutical composition for treating and / or improving attention impairment and its application. Background Art

[0002] The mechanisms of attention impairment include neurophysiological mechanisms and psychological mechanisms. Neurophysiological mechanisms include changes in neurotransmitters, changes in brain region function, and changes in gene expression. Psychological mechanisms include attention allocation disorders, cognitive resource depletion, and emotional interference.

[0003] Current interventions include psychological and pharmacological interventions. Pharmacological interventions include neurotransmitter modulators, which improve attention impairment by regulating neurotransmitter levels, and anti-stress drugs, which alleviate stress responses and thus indirectly improve attention. However, neurotransmitter modulators and anti-stress drugs have strong adverse reactions. For example, dopamine receptor agonists may cause movement disorders, psychiatric symptoms (such as hallucinations and delusions), and cardiovascular problems. Central nervous system stimulants (such as methylphenidate) can increase dopaminergic neurotransmission, but may also cause adverse reactions such as appetite suppression, sleep disorders, increased heart rate and blood pressure, and irritability. Antidepressants (such as SSRIs) can regulate serotonin levels, but may also cause adverse reactions such as nausea, headache, and sexual dysfunction.

[0004] In view of this, the present invention is proposed. Summary of the Invention

[0005] One of the purposes of the present invention is to provide a combined pharmaceutical composition for treating and / or improving attention impairment, and proposes a combined treatment and / or improvement of attention impairment by isorhynchophylline and ginsenoside Rg1.

[0006] A second object of the present invention is to provide the use of the above-mentioned combined drug composition in the preparation of drugs for treating and / or improving attention impairment.

[0007] A third object of the present invention is to provide the use of the above-mentioned combined drug composition in the preparation of a drug for treating and / or improving vigilance impairment.

[0008] A fourth object of the present invention is to provide the use of the above-mentioned combined drug composition in the preparation of a drug for treating and / or improving orientation impairment.

[0009] A fifth object of the present invention is to provide the use of the above-mentioned combined drug composition in the preparation of drugs for treating and / or improving executive control impairment.

[0010] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are adopted: In a first aspect, the present invention provides a combined pharmaceutical composition for treating and / or improving attention impairment, wherein the combined pharmaceutical composition comprises isorhynchophylline and ginsenoside Rg1.

[0011] Furthermore, the combination drug composition is a single compound preparation or a combination of two separate preparations.

[0012] Furthermore, the combination composition is a combination of two separate preparations, and the two separate preparations are administered simultaneously or sequentially.

[0013] Furthermore, the preparation is in any pharmaceutically acceptable dosage form; Preferably, the dosage form includes at least one of granules, tablets, oral liquids, injections, capsules, powders, syrups, lozenges, pills, injections or transdermal absorption preparations.

[0014] Furthermore, the combination composition also includes pharmaceutically acceptable excipients.

[0015] Preferably, the pharmaceutically acceptable excipients include at least one of a carrier, an excipient, a diluent, a lubricant, an emulsifier, a preservative, a sweetener, a suspension stabilizer or a flavoring.

[0016] In a second aspect, the present invention provides use of the above-mentioned combination drug composition in the preparation of a drug for treating and / or improving attention impairment.

[0017] Furthermore, the attention impairment includes attention impairment caused by stress; Preferably, the attention impairment further includes attention impairment caused by at least one of childhood / adult attention deficit hyperactivity disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease or depression.

[0018] Preferably, the stress includes trauma and stress-related disorders; Preferably, the trauma and stress-related disorder comprises at least one of acute stress disorder, post-traumatic stress disorder, adjustment disorder, specified trauma and stress-related disorder or unspecified trauma and stress-related disorder.

[0019] In a third aspect, the present invention provides use of the above-mentioned combination drug composition in the preparation of a drug for treating and / or improving vigilance impairment.

[0020] In a fourth aspect, the present invention provides use of the above-mentioned combined drug composition in the preparation of a drug for treating and / or improving orientation impairment.

[0021] In a fifth aspect, the present invention provides the use of the above-mentioned combination drug composition in the preparation of a drug for treating and / or improving executive control impairment.

[0022] The present invention provides a combination drug composition for treating and / or improving attention impairment, creatively combining isorhynchophylline and ginsenoside Rg1 as a drug for treating and / or improving attention impairment. Research in the present invention demonstrates that the combination of isorhynchophylline and ginsenoside Rg1 is more effective in treating and / or improving attention impairment than either isorhynchophylline or ginsenoside Rg1 alone, providing a new strategy and approach for treating and / or improving attention impairment, which is of great significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0024] Figure 1 This is an experimental process for the effect of a combined drug composition for treating and / or improving attention impairment provided by the present invention on the attention of mice subjected to plantar electric shock stress; Figure 2 The present invention provides the effect of the combined use of isorhynchophylline and ginsenoside Rg1 on the attention of mice subjected to plantar electric shock stress under the condition of a stimulation duration of 2s; wherein A is the correct rate of mouse touch screen under the condition of a stimulation duration of 2s; B is the omission rate of mouse touch screen under the condition of a stimulation duration of 2s; C is the completion time of the mouse touch screen 30 trials under the condition of a stimulation duration of 2s; Figure 3 The present invention provides the effect of the combined use of isorhynchophylline and ginsenoside Rg1 on the attention of mice subjected to plantar electric shock stress under the condition of a stimulation duration of 1.8 s; wherein A is the correct rate of mouse screen touch under the condition of a stimulation duration of 1.8 s; B is the screen touch omission rate of mice under the condition of a stimulation duration of 1.8 s; C is the completion time of the mouse to touch the screen 30 times under the condition of a stimulation duration of 1.8 s; Figure 4 The present invention provides the effect of the combined use of isorhynchophylline and ginsenoside Rg1 on the attention of mice subjected to foot shock stress under the condition of a stimulation duration of 1.6 s; wherein A is the correct rate of mouse touch screen under the condition of a stimulation duration of 1.6 s; B is the omission rate of mouse touch screen under the condition of a stimulation duration of 1.6 s; C is the completion time of the mouse touch screen 30 trials under the condition of a stimulation duration of 1.6 s; Figure 5The present invention provides the effects of the combined use of isorhynchophylline and ginsenoside Rg1 on the attention of mice subjected to plantar electric shock stress under the conditions of a stimulation delay time of 2s, 3s, 4s, and 5s, respectively; wherein A is the correct rate of touch screen of mice under the condition of a short stimulation delay time (2s, 3s, 4s, 5s); B is the touch screen omission rate of mice under the condition of a short stimulation delay time (2s, 3s, 4s, 5s); C is the completion time of 30 touch screen trials of mice under the condition of a short stimulation delay time (2s, 3s, 4s, 5s); Figure 6 The present invention provides the effects of the combined use of isorhynchophylline and ginsenoside Rg1 on the attention of mice subjected to foot shock stress under conditions of 5s, 6s, 7s, and 8s, respectively. A represents the correct touch rate of mice under conditions of long stimulus delays (5s, 6s, 7s, and 8s); B represents the touch omission rate of mice under conditions of long stimulus delays (5s, 6s, 7s, and 8s); and C represents the time it takes for mice to complete 30 touch trials under conditions of long stimulus delays (5s, 6s, 7s, and 8s). DETAILED DESCRIPTION

[0025] Unless otherwise defined herein, scientific and technical terms used in conjunction with the present invention shall have the meanings commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear; however, in the event of any potential ambiguity, the definitions provided herein take precedence over any dictionary or external definitions. In this application, the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "including" and other forms is non-limiting.

[0026] Generally, the nomenclature used in conjunction with cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization as described herein and its technology are those well-known and commonly used in this area.Unless otherwise indicated, the methods and techniques of the present invention are generally according to those well-known in the art, and are carried out as described in various general and more specific references, which are cited and discussed throughout this specification.Enzymatic reactions and purification techniques are carried out according to the manufacturer's specifications, as commonly achieved in this area, or as described herein.The nomenclature used in conjunction with analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry as described herein and its laboratory procedures and technology are those well-known and commonly used in this area.

[0027] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0028] In one aspect, the present invention provides a combined pharmaceutical composition for treating and / or improving attention impairment, wherein the combined pharmaceutical composition comprises isorhynchophylline and ginsenoside Rg1.

[0029] The combination drug composition described herein innovatively combines isorhynchophylline and ginsenoside Rg1 as a drug for treating and / or improving attention impairment. Research in this invention demonstrates that the combination of isorhynchophylline and ginsenoside Rg1 is more effective in treating and / or improving attention impairment than either isorhynchophylline or ginsenoside Rg1 alone, providing a novel strategy and approach for treating and / or improving attention impairment, which is of significant significance.

[0030] In some specific embodiments, the combination composition is a single compound preparation or a combination of two separate preparations; in some specific embodiments, the combination composition is a combination of two separate preparations, and the two separate preparations are administered simultaneously or sequentially.

[0031] In some specific embodiments, the preparation is any pharmaceutically acceptable dosage form; in some specific embodiments, the dosage form includes at least one of granules, tablets, oral liquids, injections, capsules, powders, syrups, lozenges, pills, injections or transdermal absorption preparations.

[0032] In some specific embodiments, the combination composition further comprises a pharmaceutically acceptable excipient.

[0033] Among them, "pharmaceutically acceptable excipients" are basically synonymous with "pharmaceutically usable excipients" or "excipients commonly used in the pharmaceutical process" understood in the art. Those skilled in the art can select conventional excipients according to actual conditions and preparation requirements.

[0034] In some specific embodiments, the pharmaceutically acceptable excipient includes at least one of a carrier, an excipient, a diluent, a lubricant, an emulsifier, a preservative, a sweetener, a suspension stabilizer or a flavoring.

[0035] Wherein, the isorhynchophylline and isorhynchophylline derivatives are obtained by plant extraction or chemical synthesis.

[0036] It should be noted that the drug is administered orally, sublingually, transdermally, intramuscularly, subcutaneously, etc. The preparation processes and equipment for various dosage forms of drug preparations are conventional techniques in the pharmaceutical field and are not limited in the present invention.

[0037] According to another aspect of the present invention, there is also provided use of the above-mentioned combined pharmaceutical composition in the preparation of a drug for treating and / or improving attention impairment.

[0038] The present study showed that intraperitoneal injection of isorhynchophylline and ginsenoside Rg1 for 7 consecutive days significantly improved the accuracy, omission rate, and completion time of mice subjected to foot shock. This suggests that the combination of isorhynchophylline and ginsenoside Rg1 improves attention by regulating alertness, orientation, and executive control.

[0039] In some specific embodiments, said attention impairment comprises stress-induced attention impairment.

[0040] Stress and attention deficit hyperactivity disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, and depression cause attention impairment through the following common mechanisms: First, hypothalamic-pituitary-adrenal axis (HPA axis) dysregulation Stress activates the HPA axis, leading to elevated levels of glucocorticoids such as cortisol. This imbalance is common in disorders such as ADHD and depression. For example, patients with ADHD exhibit a delayed circadian rhythm of cortisol, while patients with depression often exhibit HPA axis hyperactivation. Long-term HPA axis imbalance can damage the hippocampus and prefrontal cortex, impairing attention and cognitive function.

[0041] Second, neurotransmitter dysfunction Dopamine (DA): Dopamine plays a key role in attention regulation. Dysfunction in dopamine is associated with stress and a variety of neuropsychiatric disorders, including ADHD, schizophrenia, drug addiction, Parkinson's disease, and Huntington's disease. For example, in ADHD, dysregulation of dopaminergic neurotransmission is thought to be associated with attention deficits and impulsive behavior. In Parkinson's disease, degeneration of dopaminergic neurons leads to impairments in attention and motor function.

[0042] Norepinephrine (NE): Norepinephrine is also involved in attention regulation, and its dysfunction is associated with stress, ADHD, depression, and other diseases. For example, ADHD patients show dysregulation of noradrenergic neurotransmission, leading to inattention.

[0043] Serotonin (5-HT): Serotonin plays an important role in mood and cognitive function, and its abnormal function is associated with diseases such as stress, depression, ADHD and drug addiction.

[0044] Third, neuroinflammation and oxidative stress Neuroinflammation: Neuroinflammation plays an important role in multiple neuropsychiatric disorders, including stress, ADHD, Alzheimer's disease, Parkinson's disease, and depression. For example, patients with ADHD show evidence of neuroinflammation, which may be associated with attention deficits.

[0045] Oxidative stress: Oxidative stress is common in stress and various neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease) and psychiatric disorders (such as ADHD and depression). Oxidative stress can damage nerve cells, affect the synthesis and release of neurotransmitters, and thus lead to attention deficit.

[0046] Fourth, neuroplasticity changes Neurogenesis and synaptic plasticity: Neurogenesis and synaptic plasticity play a crucial role in attention regulation. Stress and various disorders (such as ADHD, depression, and Alzheimer's disease) can lead to changes in neuroplasticity, impairing attention and cognitive function. For example, ADHD patients have reduced volume in the prefrontal cortex and basal ganglia, impairing attention and executive function.

[0047] Fifth, stress and various diseases can lead to dysfunction in brain regions such as the prefrontal cortex, hippocampus, and amygdala: The prefrontal cortex (PFC): The PFC plays a key role in attention and executive function. A variety of disorders (such as ADHD, schizophrenia, and depression) can lead to abnormal PFC function, impairing attention. For example, individuals with ADHD show reduced activation of the PFC during attention tasks.

[0048] Basal ganglia: These organs play an important role in motor control and attention regulation. Disorders such as Parkinson's disease and Huntington's disease can lead to malfunction of the basal ganglia, which in turn affects attention.

[0049] Hippocampus: The hippocampus plays an important role in learning and memory. Stress and diseases (such as Alzheimer's disease and depression) can cause the hippocampus to atrophy, affecting attention and memory.

[0050] Stress and attention deficits caused by various neuropsychiatric diseases (such as ADHD, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, and depression) share common mechanisms, including neurotransmitter dysfunction, neuroinflammation and oxidative stress, changes in neuroplasticity, and abnormal brain region function.

[0051] In some specific embodiments, the attention impairment further comprises attention impairment caused by at least one of childhood / adult attention deficit hyperactivity disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, or depression.

[0052] Specifically, patients with attention deficit hyperactivity disorder (ADHD) often exhibit symptoms such as inattention, impulsivity, and hyperactivity. Schizophrenia is associated with inattention. Drug addiction has a significant impact on attention and impulse control abilities. Attention and executive control abilities of patients with Alzheimer's disease (AD) are impaired in the early stages of AD. Patients with Parkinson's disease often exhibit inattention and slow reaction. Huntington's disease is associated with attention deficits, particularly the ability to maintain attention in visual-spatial areas. Other studies have also shown that patients with Huntington's disease have deficits in selective attention, shifting and directing attention, and tasks that disengage attention. Patients with depression often exhibit inattention and slow reaction.

[0053] In some specific embodiments, the stress includes trauma and stress-related disorders; in some specific embodiments, the trauma and stress-related disorders include at least one of acute stress disorder, post-traumatic stress disorder, adjustment disorder, specific trauma and stress-related disorder or unspecified trauma and stress-related disorder.

[0054] According to another aspect of the present invention, there is also provided the use of the above-mentioned combined drug composition in the preparation of a drug for treating and / or improving vigilance impairment.

[0055] According to another aspect of the present invention, there is also provided use of the above-mentioned combined drug composition in the preparation of a drug for treating and / or improving orientation impairment.

[0056] According to another aspect of the present invention, there is also provided use of the above-mentioned combined drug composition in the preparation of a drug for treating and / or improving executive control impairment.

[0057] The present invention is further described below by way of examples. Unless otherwise specified, the materials in the examples were prepared according to existing methods or directly purchased from the market.

[0058] Isorhynchophyline (IRN, CAS: 6859-01-4) was purchased from Chengdu Mansite Biotechnology Co., Ltd.

[0059] Ginsenoside Rg1 (CAS: 22427-39-0) was purchased from Yuanye Biotechnology Co., Ltd.

[0060] 1.1 Reagents and materials used in the experiment: SPF male C57BL / 6J mice were purchased from Beijing Sibeifu Biotechnology Co., Ltd. and acclimated for one week with free access to food and water. The enclosure temperature was 25 ± 2°C, humidity was 40%–60%, and the light–dark cycle was 7:00 AM to 7:00 PM with a 12-hour light–dark cycle. Two days before and during the experiment, the mice were placed on a restricted diet and water schedule: free access to food and water for one hour each morning or after the experiment, with no food or water available for the remainder of the time to maintain motivation. Cardboard tubes and ping-pong balls were placed in each cage to provide environmental enrichment for the mice. Animal care, experimental protocols, and experimental procedures strictly adhered to the guidelines of the Animal Care and Use Committee of the National Center for Drug Safety Evaluation, Beijing.

[0061] Touch screen operating platform experimental box (Campden Instruments Limited, UK); Touch screen operating system (Bussey Saksida Touch Screen); Software: Whisker Server, used to run the experimental environment system; 89540-Pairwise (Visual) Discrimination (PD) Task for Mouse Touch Screen Systems, used to run the experimental program; 5-Choice Serial Reaction Time Task for Mouse Touch Screen Systems (895435-Choice Serial Reaction Time Task for Mouse Touch Screen Systems); ABET II Touch for data acquisition, export, and analysis.

[0062] 1.2 Experimental Procedure After mice experience acute stress stimulation, their attention will be damaged to a certain extent. After being given isorhynchophylline and ginsenoside Rg1, the animals' damaged attention is significantly improved and the effect is better than using either alone.

[0063] Experimental Example 1: Effects of Isorhynchophylline and Ginsenoside Rg1 on Attention Impairment in Stress-Induced Mice The method used includes the following steps: (1) Environmental adaptation During the 7-day acclimatization period, mice were gently handled for 3 minutes daily to minimize the impact of irrelevant stress stimuli on subsequent experimental procedures. During the experiment, the experimental environment was kept relatively quiet.

[0064] (2) Experimental groups After weighing, mice were randomly divided into control, model (foot shock), and drug intervention groups. Behavioral experiments were conducted with 8-11 animals per group. The control and model groups received intraperitoneal injections of normal saline. Three drug intervention groups (including isorhynchophylline, ginsenoside Rg1, and a combination) were administered intraperitoneally for seven consecutive days before foot shock induction. Attention testing was performed 0.5 hours after foot shock. The dose of isorhynchophylline was 40 mg / kg, the dose of ginsenoside Rg1 was 30 mg / kg, and the combined dose of the two drugs was 40 mg / kg isorhynchophylline plus 30 mg / kg ginsenoside Rg1.

[0065] (3) Touchscreen paradigm pre-training Two days before the experiment, the subjects were restricted from eating and drinking for one hour each day. Pre-training was also started: Habituation 1: Place the mice in the touch-screen operant chamber for 20 minutes to acclimate them to the chamber for 2 days. Habituation 2: 3 days in total. On the first day, the rats were placed in the operating room for 20 minutes to adapt and eat. On the next two days, the rats were placed in the operating room for 40 minutes to adapt and eat. Initial Touch Training: The touchscreen device was functioning normally, and a pattern stimulus appeared on the screen. The mouse received a triple reward for touching the pattern. If the mouse did not touch the pattern, it would receive a single reward after the pattern disappeared. The food reward was accompanied by a tray light and an audible sound. The training standard was to touch the pattern 30 times within 60 minutes.

[0066] Must Touch Stimuli: During this phase, mice must touch the stimulus pattern (one stimulus at a time, displayed on one side of the screen. The other side is blank. The left or right position is pseudo-randomly chosen; for example, no pattern will appear on the same side more than three times in a row). The mouse must touch the stimulus to elicit a tone / food response. If the mouse touches a blank portion of the screen, there is no response. A tray light illuminates and a tone is played during food delivery. The training criterion is 30 pattern touches within 60 minutes.

[0067] Must Initiate: During this phase, mice were required to initiate the experiment at the start of the experiment by touching the light on the food tray. The screen then displayed a pattern, one stimulus at a time, while the other remained blank. The left and right positions of the stimulus were pseudo-randomized. The mouse had to touch the pattern to elicit a tone / food response. The training criterion was 30 trials within 60 minutes.

[0068] Punish Incorrect: Training is identical to the previously described training, except that touching a blank stimulus (i.e., a screen without the image) results in the light in the operant chamber turning on (by default, for 5 seconds) and no food reward. After the light turns off, a 20-second delay elapses. The mouse must complete a correction trial. The image and position remain unchanged, and the same trial must be repeated until a correct response is made. The mouse then receives a tone and reward and proceeds to the next trial. The training criterion is 23 / 30 (77%) correct touches within 30 minutes on two consecutive days.

[0069] (4) 5-CSRT attention training and testing 5-CSRT Training to Baseline: Building on touchscreen training, reaction time training began after reaching the "Punish Incorrect" stage. The experiment began with a condensed milk reward, and the first trial began when the mouse left the food tray. After the mouse left the food tray, the "stimulus delay interval" (5 seconds) began. At the end of the delay interval, a stimulus was presented in one of the five stimulus grid spaces on the touchscreen. The order of stimulus presentation was pseudo-randomized. The mouse had to respond within a specified time period. Correctly touching the stimulus location triggered the appearance of a food reward in the food tray. The reward was delivered accompanied by the illumination of the tray light and a tone. The tone lasted 1000 milliseconds. When the mouse left the food tray, the ITI (5 seconds) began. After the ITI period, the tray light re-illuminated, and the mouse had to enter and exit the food tray to begin the next trial and the "stimulus delay interval" began. Incorrect responses, such as touching a location other than the stimulus location or failing to respond within the limited stimulus duration (omission), resulted in a timeout (TO, 5 seconds) and the illumination of the light. After the TO, the lights turn off and the "ITI Incorr" will begin (5 seconds). After the "Delay" period, the tray light will illuminate, and the mouse must enter and exit the food tray to begin the next trial and the "Stimulus Delay" will begin. During the Stimulus Delay, a premature response is recorded when a touch is made in one of the response grid areas and also results in a TO.

[0070] The 5-CSRT can be run by varying the duration of the stimulus, requiring mice to respond within a time limit. Initially, set a longer interval of 32 seconds to allow mice ample time to adapt to the task. Then, gradually shorten the interval to a baseline of 2 seconds to train the mice's response speed and accuracy. The training criterion is a three-day consecutive accuracy rate of >80% (omission rate <20%). In the "Execution Manager," set the appropriate touchscreen boxes to run the "5-choice Mousetouch Basic" schedule, changing the Session variable to 9, 10, 11, ..., through 13.

[0071] Testing phase: Once the mice's performance stabilized at the 2-second baseline for three consecutive days, attentional function was further assessed by manipulating basic task parameters. The mice's attention was tested by varying the stimulus duration (2.0s, 1.8s, 1.6s, i.e., sessions 13, 14, and 15) and the stimulus delay (short durations such as 2s, 3s, 4s, and 5s pseudo-randomly appearing and long durations such as 5s, 6s, 7s, and 8s pseudo-randomly appearing, i.e., SHORT and LONG). The mice were required to recognize and respond to a brief pattern stimulus in one of five stimulus grid spaces on an LCD touchscreen.

[0072] Observation indicators: accuracy rate, omission rate, and completion time.

[0073] (5) Electric shock stress in mice The drug-treated group received the drug intraperitoneally 30 minutes before each foot shock. The control and model groups received normal saline intraperitoneally. All mice, except the control group, were placed in the shock box and allowed to acclimate for 5 minutes before the shocks began. The parameters were: AC current, 1.0 mA, 6 seconds duration, 10 seconds interval, 15 shocks. Mice in the normal control group were placed in the shock box for the same period of time but were not shocked.

[0074] All data are expressed as "mean ± standard error," and all data analysis and graphics were generated using GraphPad Prism 10.3.0 software. The mean values ​​between the drug-treated and model groups were compared using a one-way analysis of variance followed by Dunnett's multiple comparison test. P A value <0.05 was considered statistically significant.

[0075] Analysis of test results Effects of isorhynchophylline and ginsenoside Rg1 on attention impairment in stressed mice: In Experimental Example 1, the experimental process is as follows Figure 1As shown, 40 mg / kg of isorhynchophylline and 30 mg / kg of ginsenoside Rg1 were intraperitoneally injected for 7 consecutive days, and the test was performed 0.5 hours later. The results are as follows Figures 2 to 4 As shown, where * P <0.05,** P <0.01,*** P <0.001, compared with the foot shock group, # P <0.05, compared with the combination group, one-way analysis of variance and Dunnett's test, mean ± standard error, n = 8-11. Data showed that 7 consecutive days of intraperitoneal injection of 40 mg / kg of isorhynchophylline and 30 mg / kg of ginsenoside Rg1 significantly improved attention impairment induced by foot shock. The combined effect was superior to that of isorhynchophylline or ginsenoside Rg1 alone, suggesting that the combined use of the two drugs has a more significant effect on improving attention impairment induced by foot shock than either isorhynchophylline or ginsenoside Rg1 alone.

[0076] The study demonstrated the protective effect of combined isorhynchophylline and ginsenoside Rg1 on attention impairment in mice subjected to foot shock. Seven consecutive days of intraperitoneal injection of both drugs significantly improved the accuracy, omission rate, and completion time of the foot shock mice compared to either drug alone. This suggests that this combination may enhance the intervention effect on stress-induced selective attention impairment through synergistic or additive mechanisms.

[0077] After 7 consecutive days of administration of 40mg / kg of isorhynchophylline, 30mg / kg of ginsenoside Rg1, and the combination of the two drugs, the foot shock model was established. The test was conducted 0.5h later to investigate the effect of foot shock on the attention impairment of mice. The results are as follows Figure 5 and Figure 6 As shown, where * P <0.05,** P <0.01,*** P <0.001, compared with the foot shock group, # P <0.05, ## P <0.01, compared with the combination group, one-way analysis of variance and Dunnett's test, mean ± standard error, n = 8-11. This study demonstrated that the combined use of isorhynchophylline and ginsenoside Rg1 has a superior protective effect against attention impairment induced by foot shock in mice. Seven consecutive days of intraperitoneal injection of both drugs significantly improved the accuracy, omission rate, and completion time of foot shock mice compared with either drug alone. This suggests that this combination may enhance the efficacy of interventions against stress-induced attention impairment through synergistic or additive mechanisms.

[0078] In summary, although isorhynchophylline and ginsenoside Rg1 can improve the attention of mice induced by foot shock stress alone, the combined effect is even better, suggesting that they can be used to treat stress-related attention impairment.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A combined pharmaceutical composition for treating and / or improving attention impairment, characterized in that: The combined medicinal composition comprises isorhynchophylline and ginsenoside Rg1.

2. The combined pharmaceutical composition according to claim 1, characterized in that The combination composition is a single compound preparation or a combination of two separate preparations.

3. The combined pharmaceutical composition according to claim 2, characterized in that The combination composition is a combination of two separate preparations, which are administered simultaneously or sequentially.

4. The combined pharmaceutical composition according to claim 2, characterized in that The preparation is any pharmaceutically acceptable dosage form; Preferably, the dosage form includes at least one of granules, tablets, oral liquids, injections, capsules, powders, syrups, lozenges, pills, injections or transdermal absorption preparations.

5. The combined pharmaceutical composition according to claim 4, characterized in that The combined drug composition further comprises a pharmaceutically acceptable excipient; Preferably, the pharmaceutically acceptable excipients include at least one of a carrier, an excipient, a diluent, a lubricant, an emulsifier, a preservative, a sweetener, a suspension stabilizer or a flavoring.

6. Use of the combination drug composition according to any one of claims 1 to 5 in the preparation of a medicament for treating and / or improving attention impairment.

7. The use according to claim 6, characterized in that The attention impairment includes attention impairment caused by stress; Preferably, the attention impairment further includes attention impairment caused by at least one of childhood / adult attention deficit hyperactivity disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease or depression; Preferably, the stress includes trauma and stress-related disorders; Preferably, the trauma and stress-related disorder comprises at least one of acute stress disorder, post-traumatic stress disorder, adjustment disorder, specified trauma and stress-related disorder or unspecified trauma and stress-related disorder.

8. Use of the combined drug composition according to any one of claims 1 to 5 in the preparation of a medicament for treating and / or improving vigilance impairment.

9. Use of the combined drug composition according to any one of claims 1 to 5 in the preparation of a medicament for treating and / or improving disorientation impairment.

10. Use of the combination drug composition according to any one of claims 1 to 5 in the preparation of a medicament for treating and / or improving executive control impairment.

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