Combination drug for treating depression and use thereof

Abstract

The application belongs to the technical field of medicine, and discloses a combined medicine for treating depression and application thereof. The combined medicine provided by the application comprises an antidepressant and artemisia indica simultaneously administered and / or sequentially administered. The application realizes the antidepressant effect of the combined use of the antidepressant and artemisia indica, effectively prevents and reduces liver injury caused by the antidepressant, expands the user group of the antidepressant, and has important significance in the clinical treatment of depression.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a combination drug for treating depression and its application. Background Technology

[0002] Depression, also known as depressive disorder, is a mental disorder with a high incidence, high clinical cure rate, but low treatment acceptance rate and high relapse rate. Its main characteristic is a significant and persistent low mood. Some patients may exhibit self-harm or suicidal behavior, and may even experience psychotic symptoms such as delusions and hallucinations. Clinically, depressive disorders can be classified into mild, moderate, and severe based on the number, type, and severity of symptoms, and are referred to as geriatric depression, childhood depression, postpartum depression, etc., depending on the specific group, such as the elderly, children, or postpartum women. Depression is not contagious, but it is strongly associated with stressful life events, pessimistic personality traits, a history of other mental illnesses, serious chronic diseases, alcoholism, and drug abuse.

[0003] Treatment for depression primarily includes medication, psychotherapy, and physical therapy. Medication is the main treatment method. Antidepressants include tricyclic antidepressants, tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRISs), norepinephrine-specific serotonin reuptake inhibitors (NaSSAs), and norepinephrine-dopamine reuptake inhibitors (NDRISs).

[0004] Research indicates that the cure rate for depression treated with monotherapy is 30%, and approximately two-thirds of patients who do not respond to treatment must have their treatment regimen changed. A course of treatment with an antidepressant lasts at least six weeks, and a three-month course is required after switching medications. About half of the patients relapse during this period, making the initial treatment phase crucial for the effectiveness of depression treatment. Approximately 60% of patients with depression are treated with selective serotonin reuptake inhibitors (SSRIs). Studies have shown that combination therapy is more effective than monotherapy in the initial stages of depression treatment.

[0005] Most medications used to treat depression are excreted through the liver and kidneys. Furthermore, treatment with these medications can lead to liver and kidney damage, including elevated liver enzymes, impaired liver function, drug-induced hepatitis, kidney damage, and drug-induced nephropathy. While the risk of severe liver damage or even liver failure is significantly lower than with some other medications (analgesics, antibiotics, traditional Chinese medicine, etc.), there are certain limitations on the suitable patient population for treatment.

[0006] For example, Chinese patent CN115300571A discloses an antidepressant drug composition, its preparation method, and its application. This application provides an antidepressant drug composition comprising an aqueous extract of the traditional Chinese medicine Chaihu Shugan San and a Bifidobacterium solution. The aqueous extract of Chaihu Shugan San combined with the Bifidobacterium solution can significantly improve depressive behavioral indicators in rats with chronic unpredictable mild stress depression, protect hippocampal neurons, and synergistically regulate the intestinal microbiota balance in the depressed rat model, achieving a synergistic effect. Compared with existing antidepressants, the aqueous extract of Chaihu Shugan San combined with Bifidobacterium has better efficacy, no toxic side effects, and no addictive properties in regulating depression. There is a synergistic effect between the aqueous extract of Chaihu Shugan San and Bifidobacterium; their combined use can better regulate the intestinal flora balance in depressed rat models, providing a new method for antidepressant treatment. However, the composition of this application is complex and not suitable for large-scale production.

[0007] For example, Chinese patent CN104435298B provides an antidepressant pharmaceutical composition, which is a preparation made from the following raw materials in parts by weight: Bupleurum chinense 3-10 parts, Nardostachys jatamansi 3-9 parts, Schisandra chinensis 6-12 parts, and Glycyrrhiza uralensis 2-10 parts. The pharmaceutical composition prepared by this invention has antidepressant efficacy and is used to treat depression, especially for depression of the liver qi stagnation type and liver qi stagnation suppressing spleen type, showing clear efficacy and providing a new medication option for clinical use. However, this application also has the aforementioned problems.

[0008] Therefore, it is particularly important to study a pharmaceutical composition that can be used to treat depression and prevent and reduce liver damage caused by antidepressants. Summary of the Invention

[0009] To address the problems existing in the prior art, this invention provides a combination drug for treating depression and its application. This invention achieves its antidepressant effect by combining an antidepressant with Artemisia capillaris, while effectively preventing and reducing liver damage caused by antidepressants, thus expanding the user base for antidepressants and having significant implications for the clinical treatment of depression.

[0010] Artemisia capillaris grows in the high-altitude Qinghai-Tibet Plateau region of my country. It is an annual, low-growing herbaceous medicinal plant belonging to the Gentianaceae family. It is one of the most distinctive medicinal plants in Tibetan medicine, used to treat liver and gallbladder diseases, fever, and blood disorders. It has antipyretic and diuretic effects. This patent includes, but is not limited to, Artemisia capillaris as a raw material, as well as various preparations containing the effective components of Artemisia capillaris prepared from it, such as Artemisia capillaris tablets, Artemisia capillaris capsules, Artemisia capillaris dripping pills, and Artemisia capillaris granules.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0012] Firstly, this application provides a combination drug for treating depression, characterized in that: the combination drug includes an antidepressant and a traditional Chinese medicine administered simultaneously and / or sequentially, the traditional Chinese medicine including Artemisia capillaris.

[0013] Preferably, the antidepressant in the combination drug composition for treating depression is one or more of the following: melatonin receptor agonists, selective serotonin reuptake inhibitors (SSRIs), or serotonin and norepinephrine reuptake inhibitors (SNRIs).

[0014] Preferably, the mass ratio of the antidepressant to Artemisia capillaris is 0.01-0.02:6.38-19.14;

[0015] More preferably, when the antidepressant is a melatonin receptor agonist, the mass ratio of the antidepressant to Artemisia capillaris is 0.01:6.38-19.14; when the antidepressant is a selective serotonin reuptake inhibitor (SSRI), the mass ratio of the antidepressant to Artemisia capillaris is 0.015:6.38-19.14; and when the antidepressant is a serotonin and norepinephrine reuptake inhibitor (SNRI), the mass ratio of the antidepressant to Artemisia capillaris is 0.02:6.38-19.14.

[0016] Preferably, the melatonin receptor agonist mainly includes agomelatine;

[0017] Preferably, the selective serotonin reuptake inhibitors include, but are not limited to: fluvoxamine, fluoxetine, paroxetine, escitalopram, or sertraline hydrochloride.

[0018] Preferably, the 5-hydroxytryptamine and norepinephrine reuptake inhibitors include, but are not limited to, duloxetine, mirtazapine, or venlafaxine hydrochloride.

[0019] More preferably, the selective serotonin reuptake inhibitor mainly includes sertraline hydrochloride.

[0020] More preferably, the 5-hydroxytryptamine and norepinephrine reuptake inhibitors mainly include venlafaxine hydrochloride.

[0021] In addition, this application also provides the use of combination drugs for treating depression in the preparation of pharmaceutical formulations for the prevention and / or treatment of depression.

[0022] This application also provides a pharmaceutical preparation for treating depression, characterized in that: the pharmaceutical preparation comprises: a combination drug for treating depression and pharmaceutically acceptable excipients.

[0023] Preferably, the pharmaceutically acceptable excipients include one or more of the following: fillers, wetting agents, binders, disintegrants, and lubricants.

[0024] Preferably, the dosage form of the pharmaceutical preparation is: powder, granules, capsules, tablets, oral liquid or pills.

[0025] This application also provides the use of combination drugs in the preparation of drugs for treating liver damage caused by antidepressants.

[0026] This application also provides the use of Artemisia capillaris as described in the combination drug in the preparation of a drug for treating liver damage caused by antidepressants.

[0027] Preferably, the antidepressant is selected from one of melatonin receptor agonists, selective serotonin reuptake inhibitors (SSRIs), or serotonin and norepinephrine reuptake inhibitors (SNRIs).

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] (1) This application adopts the method of combining traditional Chinese and Western medicine, and uses antidepressants in combination with Tibetan Artemisia capillaris, which has a synergistic effect.

[0030] (2) The application proposes that the combined use of antidepressants and Artemisia capillaris can effectively prevent and reduce liver damage caused by antidepressants.

[0031] (3) The combination drug provided in this application can effectively expand the population of antidepressant users and is of great significance in the clinical treatment of depression. Attached Figure Description

[0032] Figure 1 The latency time for mice in each group to jump off the platform is plotted.

[0033] Figure 2 This is a graph showing the percentage of time mice spent in the open arm in each group.

[0034] Figure 3 The graph shows the immobility time of mice in each group during forced swimming.

[0035] Figure 4 The graph shows the immobility time of mice in each group during tail suspension.

[0036] Figure 5 The graph shows the serum AST levels in mice from each group.

[0037] Figure 6 The graph shows the serum ALT levels in mice from each group. Detailed Implementation

[0038] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0039] The manufacturers and specifications of the reagents used in the following examples are as follows:

[0040] drug factory Specification Agomelatin Jiangsu Hansoh Pharmaceutical Group Co., Ltd. 25mg Sertraline hydrochloride Zhejiang Huahai Pharmaceutical Co., Ltd. 50mg Venlafaxine Hydrochloride Xi'an Yuanda Detian Pharmaceutical Co., Ltd. 75mg Silymarin capsules MEDAPHARMAGMBH&CO.KG 140mg Tibetan Artemisia capillaris capsules Xi'an Yuanda Detian Pharmaceutical Co., Ltd. 0.35g

[0041] 1. The effect of Artemisia capillaris on the efficacy of various antidepressants.

[0042] Example 1: A combination drug for treating depression

[0043] Including the following raw materials:

[0044] Agomelatine 10mg / Kg, and the contents of Artemisia capillaris capsules 6.38g / Kg.

[0045] Example 2: A combination drug for treating depression

[0046] Including the following raw materials:

[0047] Agomelatine 10mg / Kg, and the contents of Artemisia capillaris capsules 19.14g / Kg.

[0048] Comparative Example 1: A combination drug for treating depression

[0049] Including the following raw materials:

[0050] Agomelatine 10mg / Kg, silymarin 800mg / Kg.

[0051] Comparative Example 2: A combination drug for treating depression

[0052] Including the following raw materials:

[0053] Agomelatine 10mg / Kg.

[0054] Example 3: A combination drug for treating depression

[0055] Including the following raw materials:

[0056] Sertraline hydrochloride 15mg / Kg, and the contents of Artemisia capillaris capsules 6.38g / Kg.

[0057] Example 4: A combination drug for treating depression

[0058] Including the following raw materials:

[0059] Sertraline hydrochloride 15mg / Kg, and the contents of Artemisia capillaris capsules 19.14g / Kg.

[0060] Comparative Example 3: A combination drug for treating depression

[0061] Including the following raw materials:

[0062] Sertraline hydrochloride 15 mg / kg, silymarin 800 mg / kg.

[0063] Comparative Example 4: A combination drug for treating depression

[0064] Including the following raw materials:

[0065] Sertraline hydrochloride 15mg / Kg.

[0066] Example 5: A combination drug for treating depression

[0067] Including the following raw materials:

[0068] Venlafaxine hydrochloride 20 mg / kg, and the contents of Artemisia capillaris capsules 6.38 g / kg.

[0069] Example 6: A combination drug for treating depression

[0070] Including the following raw materials:

[0071] Venlafaxine hydrochloride 20 mg / kg, and the contents of Artemisia capillaris capsules 19.14 g / kg.

[0072] Comparative Example 5: A combination drug for treating depression

[0073] Including the following raw materials:

[0074] Venlafaxine hydrochloride 20 mg / kg, silymarin 800 mg / kg.

[0075] Comparative Example 6: A combination drug for treating depression

[0076] Including the following raw materials:

[0077] Venlafaxine hydrochloride 20 mg / kg.

[0078] Effect Experiment

[0079] (1) Experimental animals: 6-7 week old SPF grade C57BL / 6 mice (purchased from the Animal Experiment Center of Xi'an Jiaotong University), with an average weight of 18-20g. These mice were housed in a controlled environment with the room temperature maintained at 22±2℃ and the humidity at 55%±5%, following a 12h light / dark cycle. They were allowed free access to food and water. All experimental procedures involving mice were performed in accordance with the National Institutes of Health's guidelines for laboratory animal care and use.

[0080] (2) Grouping of animals:

[0081] Animals were placed in a controlled environment for 7 days to acclimatize, and their body weight and sucrose preference rates were tested. Mice with abnormal values ​​were excluded. Animals were randomly assigned to groups of 10 each: control group, model group, implementation example group, and comparative example group.

[0082] (3) Animal modeling and intervention methods:

[0083] The model group, the example group, and the control group were used to establish mouse models of depression and anxiety by administering chronic unpredictable mild stimuli (CUMS) for 5 weeks. The CUMS included the following eight different types of stimuli:

[0084] 4.1 Mandatory Swimming

[0085] Pour water at 23±2℃ into a 22cm deep glass jar, place the mouse in the jar for 10 minutes, and carefully cover it with a heavy lid to prevent it from escaping. Then put the mouse back in a clean, dry cage and line it with fresh bedding to prevent it from getting cold and catching a cold.

[0086] 4.2 Constraint Force

[0087] The mouse was placed in a 50mL plastic tube and secured with plastic tape to prevent it from moving. There was a hole at the far end of the tube to allow for normal breathing.

[0088] 4.3 Water scarcity

[0089] Remove the water bottle from the cage within 24 hours and put it back after the time is up.

[0090] 4.4 Isolation

[0091] The mice were placed alone in a new cage for 24 hours, and then returned to the cage with their companions.

[0092] 4.5 Food shortage

[0093] Remove the food from the cage for 24 hours, then put the food back in.

[0094] 4.6 Wet litter

[0095] The mice were placed individually in a new cage with 200 ml of water per 100 grams of bedding for 24 hours. The mice were then returned to their cages along with their companions.

[0096] No bedding: The mice were placed alone in a new cage without bedding for 24 hours, and then returned to the cage with their companions.

[0097] 4.7 Inclined Cage

[0098] Tilt the cage at a 45° angle for 24 hours, then return the cage to its normal position.

[0099] Tail clamping: Clamp a plastic clamp 2 cm from the end of the tail for 3 minutes each time, 3 times a day, and return the animal and its companions to the cage.

[0100] 4.8 Crowded Space

[0101] Place a plastic partition in the cage to reduce the activity area by half. Remove the partition after 24 hours.

[0102] To avoid animal adaptation to specific stimuli, which could affect the accuracy of experimental results, one or two stimuli were randomly applied daily, six days a week. Furthermore, to ensure the unpredictability of the experiment, each stimulus was used no more than three times cumulatively throughout the entire experimental period. This method aims to create a complex and variable stress environment to induce behavioral and physiological responses in mice similar to human depression and anxiety.

[0103] Throughout the experiment, the blank group and the model group were fed in a routine manner, while the example group and the comparative group were fed in a routine manner and began to be administered drugs by gavage on day 36. The dosage was the same as the dosage of the corresponding combination drugs in the example and the comparative examples. Except for comparative examples 2, 4 and 6, the other groups were administered drugs simultaneously.

[0104] (5) Behavioral evaluation:

[0105] Behavioral evaluations of all mice began in week seven, including the jumping platform test, elevated cross maze test, forced swimming test, and tail suspension test.

[0106] 5.1 Diving Platform Experiment

[0107] Mice were placed on a platform and trained with an electric grid (0.2 mA). When a mouse jumped off the platform, it received an electric shock, thus generating pain memory. The training lasted for three minutes. If a mouse did not jump off the platform within three minutes, it was removed. After training, all mice returned to their original cages. A 24-hour memory retrieval phase followed: mice were placed on the platform for a three-minute test. This test was conducted without electricity, and the latency for each group of mice to jump off the platform was recorded.

[0108] Table 1-1 Latency time of mice jumping off the platform in each group

[0109] Grouping mean ± standard deviation blank 12.81±6.76 Model group <![CDATA[40.84±9.20 a*** ]]> Example 1 <![CDATA[19.21±6.66 b***,c**,d* ]]> Example 2 <![CDATA[16.55±7.52 b***,c**,d** ]]> Comparative Example 1 <![CDATA[29.54±9.41 b** ]]> Comparative Example 2 <![CDATA[28.26±10.43 b** ]]>

[0110] a vs. blank group, b vs. model group, c vs. comparative example 1, d vs. comparative example 2.

[0111] *P<0.05, **P<0.01, ***P<0.001

[0112] Table 1-2 Latency time of mice jumping off the platform in each group

[0113] Grouping mean ± standard deviation blank 12.81±6.76 Model group <![CDATA[40.84±9.20 a*** ]]> Example 3 <![CDATA[18.97±4.44 b***,c*,d* ]]> Example 4 <![CDATA[15.81±7.88 b***,c**,d** ]]> Comparative Example 3 <![CDATA[27.68±10.25 b** ]]> Comparative Example 4 <![CDATA[27.81±8.73 b** ]]>

[0114] a vs. blank group, b vs. model group, c vs. comparative example 3, d vs. comparative example 4.

[0115] *P<0.05, **P<0.01, ***P<0.001

[0116] Table 1-3 Latency time of mice jumping off the platform in each group

[0117] Grouping mean ± standard deviation blank 12.81±6.76 Model group <![CDATA[40.84±9.20 a*** ]]> Example 5 <![CDATA[22.14±8.22 b***,c*,d* ]]> Example 6 <![CDATA[18.66±10.16 b***,c**,d** ]]> Comparative Example 5 <![CDATA[29.87±9.14 b** ]]> Comparative Example 6 <![CDATA[30.33±6.46 b** ]]>

[0118] a vs. blank group, b vs. model group, c vs. control group 5, d vs. control group 6.

[0119] *P<0.05, **P<0.01, ***P<0.001

[0120] The results are shown in Table 1 and Figure 1 As shown, compared with the blank group, the latency time of the model group mice to jump off the platform in the platform test was longer, which suggests that the mice have hesitant and anxious behaviors. The latency time of the example group and the comparative group was significantly reduced compared with the model group, indicating that agomelatine, sertraline hydrochloride and venlafaxine hydrochloride have significant therapeutic effects on depression. After adding Artemisia capillaris and silymarin respectively, the latency time was further shortened. Compared with Artemisia capillaris and silymarin, the antidepressant effect of Artemisia capillaris combined with antidepressants is stronger.

[0121] 5.2 Elevated Cross Maze Experiment

[0122] Mice were placed in the center of the maze, facing an open arm, and allowed to move freely for 6 minutes. The percentage of time each group of mice spent in the open arm was recorded.

[0123] Table 2-1 Percentage of time spent in open arm for each group of mice

[0124] Grouping mean ± standard deviation blank 43.61±7.65 Model group <![CDATA[26.94±10.94 a** ]]> Example 1 <![CDATA[41.68±15.56 b** ]]> Example 2 <![CDATA[45.23±8.82 b** ]]> Comparative Example 1 <![CDATA[43.47±10.34 b** ]]> Comparative Example 2 <![CDATA[41.84±13.36 b** ]]>

[0125] a vs. blank group, b vs. model group

[0126] *P<0.05, **P<0.01, ***P<0.001

[0127] Table 2-2 Latency time of mice jumping off the platform in each group

[0128] Grouping mean ± standard deviation blank 43.61±7.65 Model group <![CDATA[26.94±10.94 a** ]]> Example 3 <![CDATA[39.03±14.35 b* ]]> Example 4 <![CDATA[38.49±12.36 b* ]]> Comparative Example 3 35.24±11.27 Comparative Example 4 37.22±11.78

[0129] a vs. blank group, b vs. model group

[0130] *P<0.05, **P<0.01, ***P<0.001

[0131] Table 2-3 Latency time of mice jumping off the platform in each group

[0132] Grouping mean ± standard deviation blank 43.61±7.65 Model group <![CDATA[26.94±10.94 a** ]]> Example 5 <![CDATA[40.29±14.30 b* ]]> Example 6 <![CDATA[44.67±14.90 b* ]]> Comparative Example 5 <![CDATA[40.17±10.15 b** ]]> Comparative Example 6 <![CDATA[39.16±11.85 b* ]]>

[0133] a vs. blank group, b vs. model group

[0134] *P<0.05, **P<0.01, ***P<0.001

[0135] The results are shown in Table 2 and Figure 2 As shown, compared with the blank group, the mice in the model group spent less time in the open arm of the elevated cross maze test, which suggests that the mice have hesitant and anxious behaviors. After intervention with antidepressant drugs, the behavioral indicators of the example group and the control group improved significantly. Adding Artemisia capillaris and silymarin to the antidepressant drugs did not affect their antidepressant effect, but had a synergistic effect. Moreover, the antidepressant effect of the example group was better than that of the control group.

[0136] 5.3 Forced Swimming Experiment

[0137] A 30 cm glass tank filled with water at 23-25°C was used. On the first day, all mice were forced to swim for 15 minutes as a training exercise. On the second day, the mice were placed in the same environment for 10 minutes. Motion activity was monitored using a video tracking system, and the immobility time of each animal during the test was calculated (immobility was defined as inactivity other than the floating action required to keep the head above the water surface).

[0138] Table 3-1 Immobility time of mice in each group during forced swimming

[0139] Grouping mean ± standard deviation blank 39.64±11.88 Model group <![CDATA[121.04±13.95 a*** ]]> Example 1 <![CDATA[60.36±13.30 b***,c***,d* ]]> Example 2 <![CDATA[55.12±15.15 b***,c***,d** ]]> Comparative Example 1 <![CDATA[82.71±11.34 b*** ]]> Comparative Example 2 <![CDATA[74.37±12.56 b*** ]]>

[0140] a vs. blank group, b vs. model group, c vs. comparative example 1, d vs. comparative example 2.

[0141] *P<0.05, **P<0.01, ***P<0.001

[0142] Table 3-2 Immobility time of mice in each group during forced swimming

[0143] Grouping mean ± standard deviation blank 39.64±11.88 Model group <![CDATA[121.04±13.95 a*** ]]> Example 3 <![CDATA[69.69±13.00 b***,c**,d** ]]> Example 4 <![CDATA[68.62±14.17 b***,c**,d** ]]> Comparative Example 3 <![CDATA[90.18±15.71 b*** ]]> Comparative Example 4 <![CDATA[89.35±15.93 b*** ]]>

[0144] a vs. blank group, b vs. model group, c vs. comparative example 3, d vs. comparative example 4.

[0145] *P<0.05, **P<0.01, ***P<0.001

[0146] Table 3-3 Immobility time of mice in each group during forced swimming

[0147] Grouping mean ± standard deviation blank 39.64±11.88 Model group <![CDATA[121.04±13.95 a*** ]]> Example 5 <![CDATA[63.84±11.20 b***,d* ]]> Example 6 <![CDATA[57.52±18.27 b***,c**,d** ]]> Comparative Example 5 <![CDATA[75.59±12.21 b*** ]]> Comparative Example 6 <![CDATA[79.33±12.97 b*** ]]>

[0148] a vs. blank group, b vs. model group, c vs. control group 5, d vs. control group 6.

[0149] *P<0.05, **P<0.01, ***P<0.001

[0150] The results are shown in Table 3 and Figure 3 As shown, compared with the control group, the model group mice exhibited a significantly increased immobility time during the forced swimming test, reflecting higher levels of hopeless behavior, a typical manifestation of depression. After intervention with antidepressants, this behavioral indicator was significantly improved. Compared with the control group, the example group showed that *Artemisia capillaris* had no effect on the efficacy of antidepressant treatment and even had a certain improving effect, surpassing the efficacy of silymarin.

[0151] 5.4 Tail Suspension Experiment:

[0152] The tip of the mouse's tail (2 cm from the tail tip) was taped to a suspension bar (30 cm above the ground). The mouse was then allowed to touch the suspension. Initially, the mouse instinctively struggled violently to escape, but if unable to escape, it became immobile in a state of despair, exhibiting depressive-like behavior. The longer the immobility, the more depressed the mouse became. Movement was monitored using a video tracking system for 6 minutes, and the immobility time for each animal during the test was calculated (immobility was defined as movement without voluntary or escapist intent).

[0153] Table 4-1 Immobility time of mice in each group during tail suspension

[0154] Grouping mean ± standard deviation blank 105.33±12.8 Model group <![CDATA[191.71±14.85 a*** ]]> Example 1 <![CDATA[126.92±10.72 b***,c* ]]> Example 2 <![CDATA[112.78±10.11 b***,c***,d*** ]]> Comparative Example 1 <![CDATA[140.75±16.06 b*** ]]> Comparative Example 2 <![CDATA[138.26±12.76 b*** ]]>

[0155] a vs. blank group, b vs. model group, c vs. comparative example 1, d vs. comparative example 2.

[0156] *P<0.05, **P<0.01, ***P<0.001

[0157] Table 4-2 Immobility time (s) of mice in each group during tail suspension

[0158] Grouping mean ± standard deviation blank 105.33±12.8 Model group <![CDATA[191.71±14.85 a*** ]]> Example 3 <![CDATA[130.31±14.28 b***,c**,d* ]]> Example 4 <![CDATA[117.62±11.83 b***,c***,d*** ]]> Comparative Example 3 <![CDATA[146.79±12.68 b*** ]]> Comparative Example 4 <![CDATA[142.67±10.51 b*** ]]>

[0159] a vs. blank group, b vs. model group, c vs. comparative example 3, d vs. comparative example 4.

[0160] *P<0.05, **P<0.01, ***P<0.001

[0161] Table 4-3 Immobility time of mice in each group during tail suspension

[0162] Grouping mean ± standard deviation blank 105.33±12.8 Model group <![CDATA[191.71±14.85 a*** ]]> Example 5 <![CDATA[121.83±15.43 b***,d* ]]> Example 6 <![CDATA[117.12±13.4 b***,c*,d** ]]> Comparative Example 5 <![CDATA[130.12±13.44 b*** ]]> Comparative Example 6 <![CDATA[136.75±14.23 b*** ]]>

[0163] a vs. blank group, b vs. model group, c vs. control group 5, d vs. control group 6.

[0164] *P<0.05, **P<0.01, ***P<0.001

[0165] The results are shown in Table 4 and Figure 4 As shown, compared with the blank group, the model group mice had a significantly increased immobility time in the tail suspension test, which reflects a higher level of hopelessness behavior, a typical manifestation of depression. After intervention with antidepressant drugs, this behavioral indicator tended to normalize. Comparing the test group and the control group, Artemisia capillaris had no effect on the therapeutic effect of antidepressant drugs and even had a certain improving effect, which was better than that of silymarin.

[0166] Based on the experimental data above, Artemisia capillaris has no effect on the efficacy of antidepressants and even has a certain synergistic effect, with its overall effect being superior to silymarin.

[0167] 2. The therapeutic effect of Artemisia capillaris on liver damage caused by various antidepressants.

[0168] Example 7: A combination drug for treating depression

[0169] Including the following raw materials:

[0170] Agomelatine 400mg / Kg, and the contents of Artemisia capillaris capsules 6.38g / Kg.

[0171] Example 8: A combination drug for treating depression

[0172] Including the following raw materials:

[0173] Agomelatine 400mg / Kg, and the contents of Artemisia capillaris capsules 19.14g / Kg.

[0174] Comparative Example 7: A combination drug for treating depression

[0175] Including the following raw materials:

[0176] Agomelatine 400mg / Kg, silymarin 800mg / Kg.

[0177] Comparative Example 8: A combination drug for treating depression

[0178] Including the following raw materials:

[0179] Agomelatine 400mg / Kg.

[0180] Example 9: A combination drug for treating depression

[0181] Including the following raw materials:

[0182] Sertraline hydrochloride 300mg / Kg, and the contents of Artemisia capillaris capsules 6.38g / Kg.

[0183] Example 10: A combination drug for treating depression

[0184] Including the following raw materials:

[0185] Sertraline hydrochloride 300mg / Kg, and the contents of Artemisia capillaris capsules 19.14g / Kg.

[0186] Comparative Example 9: A combination drug for treating depression

[0187] Including the following raw materials:

[0188] Sertraline hydrochloride 300 mg / kg, silymarin 800 mg / kg.

[0189] Comparative Example 10: A combination drug for treating depression

[0190] Including the following raw materials:

[0191] Sertraline hydrochloride 300mg / Kg.

[0192] Example 11: A combination drug for treating depression

[0193] Including the following raw materials:

[0194] Venlafaxine hydrochloride 200 mg / kg, and the contents of Artemisia capillaris capsules 6.38 g / kg.

[0195] Example 12: A combination drug for treating depression

[0196] Including the following raw materials:

[0197] Venlafaxine hydrochloride 200 mg / kg, and the contents of Artemisia capillaris capsules 19.14 g / kg.

[0198] Comparative Example 11: A combination drug for treating depression

[0199] Including the following raw materials:

[0200] Venlafaxine hydrochloride 200 mg / kg, silymarin 800 mg / kg.

[0201] Comparative Example 12: A combination drug for treating depression

[0202] Including the following raw materials:

[0203] Venlafaxine hydrochloride 200 mg / kg.

[0204] Effect Experiment

[0205] (1) Experimental animals: 6-7 week old SPF grade C57BL / 6 mice (purchased from the Animal Experiment Center of Xi'an Jiaotong University), with an average weight of 18-20g. These mice were housed in a controlled environment with the room temperature maintained at 22±2℃ and the humidity at 55%±5%, following a 12h light / dark cycle. They were allowed free access to food and water. All experimental procedures involving mice were performed in accordance with the National Institutes of Health's guidelines for laboratory animal care and use.

[0206] (2) Grouping of animals:

[0207] Animals were placed in a controlled environment for 7 days to acclimatize, and their body weight and sucrose preference rates were tested. Mice with abnormal values ​​were excluded. Animals were randomly assigned to groups of 10 each: control group, implementation example group, and comparative example group.

[0208] (3) Animal modeling and intervention methods:

[0209] The blank control group was given 0.9% sodium chloride injection, 1 mL / 100 g, twice a day; comparative examples 8, 10, and 12 were given the corresponding doses of drug solution, once a day, for 14 consecutive days; the example and the other control groups were given the corresponding doses of Artemisia capillaris solution and silymarin solution in addition to the corresponding antidepressants.

[0210] (4) Indicator detection:

[0211] The patient fasted for 12 hours the night before the experiment ended. After anesthesia, the eyeballs were enucleated and blood was collected. The blood was allowed to stand at room temperature for 30 minutes, and then centrifuged at 3500 r / min for 15 minutes at 4℃. The supernatant serum was collected and tested using the Ruixin Bio ELISA kit (catalog number: RX201960M) to measure the serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities.

[0212] Table 5-1 Serum AST concentrations (U / L) in each group of mice

[0213] Grouping mean ± standard deviation Blank group 83.68±8.82 Example 7 <![CDATA[156.16±10.76 a***,b***,c*** ]]> Example 8 <![CDATA[110.37±12.38 a***,b***,c*** ]]> Comparative Example 7 <![CDATA[132.95±12.53 a*** ]]> Comparative Example 8 <![CDATA[186.24±12.6 a*** ]]>

[0214] a vs. blank group, b vs. control group (7 ratio), c vs. control group (8 ratio)

[0215] *P<0.05, **P<0.01, ***P<0.001

[0216] Table 5-2 Serum AST concentrations (U / L) in each group of mice

[0217] Grouping mean ± standard deviation Blank group 83.68±8.82 Example 9 <![CDATA[125.21±14.93 a***,b***,c*** ]]> Example 10 <![CDATA[124.32±10.83 a***,b***,c*** ]]> Comparative Example 9 <![CDATA[148.85±12.43 a*** ]]> Comparative Example 10 <![CDATA[172.26±11.03 a*** ]]>

[0218] a vs. blank group, b vs. control group (9 out of 10), c vs. control group (10 out of 10)

[0219] *P<0.05, **P<0.01, ***P<0.001

[0220] Table 5-3 Serum AST concentrations (U / L) in each group of mice

[0221] Grouping mean ± standard deviation Blank group 83.68±8.82 Example 11 <![CDATA[131.29±8.60 a***,b*,c*** ]]> Example 12 <![CDATA[108.74±11.46 a***,b***,c*** ]]> Comparative Example 11 <![CDATA[142.57±9.28 a*** ]]> Comparative Example 12 <![CDATA[169.35±13.22 a*** ]]>

[0222] a vs. blank group, b vs. comparison group 11, c vs. comparison group 12

[0223] *P<0.05, **P<0.01, ***P<0.001

[0224] Table 6-1 Serum ALT concentrations (U / L) in each group of mice

[0225] Grouping mean ± standard deviation Blank group 39.79±8.2 Example 7 <![CDATA[88.97±11.33 a***,b**,c*** ]]> Example 8 <![CDATA[75.61±14.21 a***,b***,c*** ]]> Comparative Example 7 <![CDATA[105.36±12.2 a*** ]]> Comparative Example 8 <![CDATA[134.39±11.88 a*** ]]>

[0226] a vs. blank group, b vs. control group (7 ratio), c vs. control group (8 ratio)

[0227] *P<0.05, **P<0.01, ***P<0.001

[0228] Table 6-2 Serum ALT concentrations (U / L) in each group of mice

[0229] Grouping mean ± standard deviation Blank group 39.79±8.2 Example 9 <![CDATA[82.29±11.7 a***,b***,c*** ]]> Example 10 <![CDATA[71.47±13.46 a***,b***,c*** ]]> Comparative Example 9 <![CDATA[102.37±8.70 a*** ]]> Comparative Example 10 <![CDATA[124.72±12.60 a*** ]]>

[0230] a vs. blank group, b vs. control group (9 out of 10), c vs. control group (10 out of 10)

[0231] *P<0.05, **P<0.01, ***P<0.001

[0232] Table 6-3 Serum ALT concentrations (U / L) in each group of mice

[0233] Grouping mean ± standard deviation Blank group 39.79±8.2 Example 11 <![CDATA[110.87±10.68 a***,c*** ]]> Example 12 <![CDATA[77.65±10.35 a***,b**,c*** ]]> Comparative Example 11 <![CDATA[111.26±12.22 a*** ]]> Comparative Example 12 <![CDATA[143.31±13.28 a*** ]]>

[0234] a vs. blank group, b vs. comparison group 11, c vs. comparison group 12

[0235] *P<0.05, **P<0.01, ***P<0.001

[0236] As shown in Table 5-6 and Figure 5-6 As shown, compared with the blank group, Comparative Examples 8, 10, and 12 all caused an increase in the corresponding enzyme indicators in the liver of mice, indicating that these antidepressants all caused certain liver damage, that is, drug-induced liver injury in mice. In Examples 7-12 and Comparative Examples 7, 9, and 11, the mice were given Artemisia capillaris and silymarin, respectively, on the basis of the corresponding antidepressants. The results showed that the activities of aspartate aminotransferase and alanine aminotransferase were reduced. In terms of alleviating liver damage caused by antidepressants, Artemisia capillaris was significantly better than silymarin.

[0237] In summary, the experimental results show that the simultaneous use of Artemisia capillaris and antidepressants not only does not affect the antidepressant effect of the drugs, but also has a synergistic effect, while alleviating drug-induced liver damage caused by antidepressants.

[0238] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A combination drug for treating depression, characterized in that: The combined medicine is composed of simultaneously or sequentially administered antidepressant western medicine and traditional Chinese medicine, wherein the traditional Chinese medicine is Bupleurum smithii; the antidepressant western medicine comprises one of melatonin receptor agonist, selective serotonin reuptake inhibitor (SSRIs) or serotonin and norepinephrine reuptake inhibitor (SNRIs); the mass ratio of the antidepressant western medicine to Bupleurum smithii is 0.01-0.02:6.38-19.14; the melatonin receptor agonist is agomelatine; the selective serotonin reuptake inhibitor (SSRIs) is sertraline hydrochloride; and the serotonin and norepinephrine reuptake inhibitor (SNRIs) is venlafaxine hydrochloride.

2. Use of the combined medicine according to claim 1 in the preparation of a medicine for treating liver injury caused by antidepressant western medicine.

3. Use according to claim 2, characterized in that: The antidepressant western medicine is selected from one of melatonin receptor agonist, selective serotonin reuptake inhibitor (SSRIs) or serotonin and norepinephrine reuptake inhibitor (SNRIs); and the mass ratio of the antidepressant western medicine to Bupleurum smithii in the combined medicine is 0.01-0.02:6.38-19.14.

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