A low-toxicity and high-efficiency composition for preventing and treating depression

Abstract

The present application relates to the low-toxicity and high-efficiency composition for preventing and treating depression, which can effectively solve the problem of preparing the low-toxicity and high-efficiency medicine for preventing and treating depression, and the composition is composed of rehmannia extract and fluoxetine, wherein the rehmannia extract is one of rehmannia water extract, rehmannia alcohol extract, rehmannia glycoside D and catalpol. The rehmannia water extract, rehmannia alcohol extract, catalpol and rehmannia glycoside D in rehmannia are selected for the first time, and are matched with fluoxetine to form the composition, so as to provide the safe and high-efficiency anti-depression composition, greatly improve the drug advantage, partially solve the hidden danger of liver toxicity of the current anti-depression drug to the clinical safe drug use, help to improve the compliance of the depression patients, maintain the body health of the depression patients, promote the recovery of the patients, improve the life quality of the patients, and have significant economic and social benefits.

Description

TECHNICAL FIELD

[0001] The present application relates to medicine, in particular to a low-toxicity and high-efficiency composition for preventing and treating depression. BACKGROUND

[0002] Depression is a disease with high incidence, high recurrence rate, high mortality and high disability rate worldwide, and is the root cause of great harm and burden to human health, family and society. However, the efficacy of the first-line traditional clinical antidepressants is not satisfactory, and some of these drugs gradually reveal their limitations such as side effects, which is more detrimental to the treatment adherence, cure and prognosis of patients with depression. It is urgent to find safe and effective antidepressants.

[0003] Fluoxetine, also known as "Prozac", is a selective serotonin reuptake inhibitor, and is one of the most effective drugs for treating depression. Although fluoxetine has been widely used as a first-line treatment for depression and other mental disorders, its widely reported potential hepatotoxicity hinders the safe use of fluoxetine in clinical practice. The liver is the main site of drug metabolism, so the effect of drugs on the integrity of the liver is very important. The liver is the largest internal organ in the human body and is the main organ for the metabolism and detoxification of exogenous substances. Liver damage can cause an increase in liver enzymes in the liver, and the damage is often related to insufficient detoxification of exogenous toxic substances or excessive production of toxic metabolites during metabolism.

[0004] Traditional Chinese medicine can resist oxidative damage to the liver through the characteristics of "multiple components, multiple links, multiple pathways and multiple targets", such as regulating liver metabolism, detoxification and promoting liver cell proliferation, etc., and has become an important target for the prevention and treatment of liver damage. Recent studies have shown that traditional Chinese medicine has a potential role in improving liver damage. Rehmannia glutinosa Libosch. is the fresh or dried tuber of the plant Rehmannia glutinosa Libosch. and is one of the famous "four major medicinal herbs" in China. It has a history of over a thousand years as a medicinal herb in China. Rehmannia glutinosa Libosch. enters the heart, liver and kidney channels, and has the functions of clearing heat and cooling blood, nourishing yin and generating fluid. Its main active ingredients include sugars, iridoid glycosides and amino acids, etc. The 2015 edition of the Chinese Pharmacopoeia specifies that catalpol and rehderin D are the index components of Rehmannia glutinosa Libosch. quality standards. Modern research has shown that Rehmannia glutinosa Libosch. has various pharmacological activities such as anti-depression, anti-oxidation and anti-inflammation, etc. Catalpol has related effects such as anti-depression, anti-inflammation, anti-oxidation and improvement of insulin resistance, etc. Rehderin D has activities such as anti-cancer and anti-inflammation, etc. Rehmannia glutinosa Libosch. and its main active ingredient catalpol have protective effects in various tissue or cell damage including liver damage. Some studies have shown that Rehmannia glutinosa Libosch. and catalpol both have hepatoprotective effects and can have different degrees of attenuation effect on liver damage of animals induced by lipopolysaccharide (LPS) / D-galactosamine (D-gal), carbon tetrachloride, triptolide, etc., showing good protective effects.

[0005] However, there is no report on whether rehmannia or components in rehmannia (such as catalpol and rehderian D) can enhance the antidepressant efficacy of fluoxetine and reduce fluoxetine-induced liver injury. SUMMARY

[0006] In view of the above, the present application aims to provide a low-toxicity and high-efficiency composition for preventing and treating depression, which can effectively solve the problem of preparing a low-toxicity and high-efficiency drug for preventing and treating depression.

[0007] The technical solution of the present application is a low-toxicity and high-efficiency composition for preventing and treating depression, which is composed of rehmannia extract and fluoxetine, and the rehmannia extract is one of rehmannia water extract, rehmannia alcohol extract, rehderian D and catalpol.

[0008] The present application first selects components in rehmannia, such as rehmannia water extract, rehmannia alcohol extract, catalpol and rehderian D, and combines them with fluoxetine to form a composition, aiming to provide a safe and efficient antidepressant composition, greatly improve the advantages of the drug, partially solve the hidden troubles caused by liver toxicity of the current antidepressant drugs to the safety of clinical drug use, help to improve the compliance of patients with depression, maintain the health of patients with depression, promote the rehabilitation of patients, improve the quality of life of patients, and have significant economic and social benefits. DETAILED DESCRIPTION

[0009] The specific embodiments of the present application will be described in detail below in combination with the examples.

[0010] In the specific implementation of the present application, the following examples can be given.

[0011] Example 1

[0012] The low-toxicity and high-efficiency composition for preventing and treating depression of the present application is composed of rehmannia water extract and fluoxetine, and the rehmannia water extract is as follows: 3g of rehmannia decoction pieces are soaked in 6-8 times the weight volume of water for 30-60min, boiled with a strong fire, then boiled with a weak fire for 30min, filtered to obtain the first filtrate; the residue is added with 6-8 times the weight volume of water, boiled with a strong fire, then boiled with a weak fire for 20-25min, filtered to obtain the second filtrate; the two filtrates are combined, concentrated, dried to obtain the rehmannia water extract, which is then mixed with 10mg of fluoxetine with a purity of ≥99% to form the composition.

[0013] The weight volume refers to the solid in g and the liquid in mL (hereinafter the same).

[0014] Example 2

[0015] The low-toxicity and high-efficiency composition for preventing and treating depression is composed of radix rehmanniae alcohol extract and fluoxetine, wherein the radix rehmanniae alcohol extract is obtained by extracting radix rehmanniae decoction pieces 3 g by reflux extraction with 6-8 times of 90% ethanol by weight and volume for 2-3 times, wherein the first extraction is performed after soaking at room temperature for 40-60 min, the extraction liquids of 2-3 times are combined, ethanol is recovered by distillation, and the combined extraction liquid is dried to obtain the radix rehmanniae alcohol extract, which is then mixed with 10 mg of fluoxetine with a purity of greater than or equal to 99% to obtain the composition.

[0016] Example 3

[0017] The low-toxicity and high-efficiency composition for preventing and treating depression is composed of 10 mg of catalpol with a purity of greater than or equal to 99% and 10 mg of fluoxetine with a purity of greater than or equal to 99%.

[0018] The catalpol is extracted from fresh radix rehmanniae (a known commercially available product), and the molecular structural formula is as follows:

[0019]

[0020] Example 4

[0021] The low-toxicity and high-efficiency composition for preventing and treating depression is composed of 10 mg of radix rehmanniae glycoside D with a purity of greater than or equal to 99% and 10 mg of fluoxetine with a purity of greater than or equal to 99%.

[0022] The radix rehmanniae glycoside D is extracted from radix rehmanniae (a known commercially available product), and the molecular formula is C27H 42 O 20 , and the structural formula is as follows:

[0023]

[0024] The present application first selects the components of radix rehmanniae, such as radix rehmanniae water extract, radix rehmanniae alcohol extract, catalpol and radix rehmanniae glycoside D, and combines them with fluoxetine to obtain a composition, which has the effects of safe and efficient anti-depression, greatly improves the advantages of fluoxetine and radix rehmanniae extract, prevents the hidden dangers of liver toxicity of anti-depression drugs to safe medication, improves the curative effect, and achieves very good beneficial technical effects through experiments. The relevant experimental data are as follows:

[0025] 1. Experimental materials

[0026] 1.1 Source of experimental animals

[0027] ICR mice, male, SPF level, body weight 16-18 g, provided by Jinan Pengyue Experimental Animal Breeding Co., Ltd. [SYXK (YU) 2020-0004].

[0028] 1.2 Experimental drugs: The composition for preventing and treating depression is obtained according to the operation method of examples 1-4.

[0029] 2. Test of antidepressant effect of the composition for preventing and treating depression

[0030] 2.1 Test of antidepressant effect of the composition in physiological state

[0031] After 100 male ICR mice are adaptively fed for one week, they are randomly divided into blank control group, fluoxetine group, Rehmannia glutinosa water extract group, Rehmannia glutinosa alcohol extract group, catalpol group, Rehmannia glutinosa glycoside D group, Rehmannia glutinosa water extract combined with fluoxetine group, Rehmannia glutinosa alcohol extract combined with fluoxetine group, catalpol combined with fluoxetine group, Rehmannia glutinosa glycoside D combined with fluoxetine group, 10 groups in total, 10 mice per group. The dosage of fluoxetine is 10 mg / kg, the dosage of Rehmannia glutinosa water extract and alcohol extract is 3 mg / kg, and the dosage of catalpol and Rehmannia glutinosa glycoside D is 10 mg / kg. The drugs are administered once a day for 25 consecutive days. Fluoxetine, Rehmannia extract, catalpol and Rehmannia glycoside D are dissolved in 0.5% sodium carboxymethyl cellulose solution. The blank control group is given the same volume of 0.5% sodium carboxymethyl cellulose solution. One hour after the last administration, the classic depression behavior test forced swimming test (FST) and tail suspension test (TST) are performed.

[0032] 2.2 Test of antidepressant effect of the composition on the classic depression model

[0033] After 110 male ICR mice are adaptively fed for one week, they are randomly divided into blank control group, negative control group, fluoxetine group, Rehmannia glutinosa water extract group, Rehmannia glutinosa alcohol extract group, catalpol group, Rehmannia glutinosa glycoside D group, Rehmannia glutinosa water extract combined with fluoxetine group, Rehmannia glutinosa alcohol extract combined with fluoxetine group, catalpol combined with fluoxetine group, Rehmannia glutinosa glycoside D combined with fluoxetine group, 11 groups in total, 10 mice per group. Except for the blank group, the rest of the groups are induced into depression state by the classic depression model replication method, i.e. chronic unpredictable mild stress method. Except for the blank control group, the rest of the mice are arranged for CUMS stress, including deprivation of water source for 24 hours, cage inclined at 45° along the vertical axis for 24 hours, deprivation of food for 24 hours, wet bedding for 24 hours, 100HZ noise for 2 hours, horizontal oscillation for 10 minutes, tail clamping for 1 minute, restraint for 2 hours, 45℃ heat stimulation for 15 minutes, 4℃ cold stimulation for 15 minutes, and all the stimulation methods are randomly applied without repetition within 3 days. The dosage of fluoxetine, Rehmannia glutinosa water extract, Rehmannia glutinosa alcohol extract, catalpol and Rehmannia glycoside D is referred to item 2.1. The blank control group and negative control group are given the same volume of 0.5% sodium carboxymethyl cellulose solution. One hour after the last administration, the classic depression behavior test sugar water preference test (SPT) and FST are performed.

[0034] 2.3 FST test

[0035] The mice were individually placed in a cylindrical plastic bucket (height 25 cm x diameter 10 cm) with water depth of 15 cm and water temperature of about 23-25°C, and kept calm during the experiment. The mice were slowly placed in the bucket and allowed to swim freely for 2 min, and the time of immobility of the mice within 4 min was recorded with a stopwatch, i.e. the time of immobility of the mice with only the head out of the water to breathe or the limbs slightly sliding to keep the body balanced without sinking, and the mice were taken out, dried and put back into the cage after 4 min.

[0036] 2.4 TST test

[0037] The mice were suspended with adhesive tape at a height of 15 cm above the ground about 1 cm from the tip of the tail, and timing was started for 6 min. After the mice were suspended for 2 min, the time of immobility of the mice within 4 min was recorded by the experimenter, and the standard of immobility of the mice was that the mice stopped struggling and hung passively and completely still.

[0038] 2.5 SPT test

[0039] Each mouse was individually raised, and on day 1, 2 bottles of 1% sucrose water were provided for each mouse, and the bottles were exchanged in position every 8 h. After 24 h, 1 bottle of 1% sucrose water and 1 bottle of pure water were provided for the mice to drink freely for 24 h. Then the mice were deprived of water for 12 h. 1 bottle of 1% sucrose water and 1 bottle of pure water were provided for each mouse to drink freely for 24 h, and the sucrose preference of each mouse was calculated by weighing the change in mass of the bottles (each bottle of sucrose water and pure water was 50 mL). Sucrose preference = sucrose drinking amount (g) / [sucrose drinking amount (g) + pure water drinking amount (g)] x 100%.

[0040] 2.6 Liver function index test

[0041] Immediately after the completion of the behavior test, all the mice were enucleated and blood was taken, and after standing at room temperature for 2 h, the blood was centrifuged at 4°C and 3500 r / min for 10 min, and the upper serum was separated, and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of the mice were determined according to the instructions of the kit.

[0042] 3. Test results

[0043] 3.1 Test of the composition for enhancing the antidepressant efficacy on mice in a physiological state

[0044] The abnormal increase of the immobility time of the mice in the FST and the TST shows that the despair behavior of the mice is enhanced, which generally characterizes the depressive behavior of the mice. The decrease of the immobility time in the FST and the TST characterizes the antidepressant effect of the drug. The present application proves that the Rehmannia glutinosa L. water extract combination fluoxetine group, the catalpol combination fluoxetine group, the rehderianoside D combination fluoxetine group can reverse the increase of the immobility time of the mice in the FST and the TST more than fluoxetine, and the increase rate of the drug efficacy of the three combinations in the FST is 25.2%, 24.3% and 17.9% in turn, and the increase rate of the drug efficacy of the three combinations in the TST is 26.7%, 3.9%, 27.9% and 14.2% in turn. The increase rate of the drug efficacy of the Rehmannia glutinosa L. water extract, the Rehmannia glutinosa L. alcohol extract, the catalpol and the rehderianoside D in the FST test without combination of fluoxetine is 29.1%, 13.2%, 29.5% and 24.2% in turn, and the increase rate of the drug efficacy in the TST test without combination of fluoxetine is 35.7%, 14.9%, 38.8% and 32.0% in turn. It is comprehensively explained that the antidepressant drug efficacy of the combination on the mice in the physiological state is enhanced. The results are shown in Table 1.

[0045] Table 1 Influence test of the combination on the immobility time of the mice in the FST and the TST in the physiological state

[0046]

[0047] Note: compared with the blank control group, * P<0.05, ** P<0.01; compared with the fluoxetine group, # P<0.05, ## P<0.01; compared with the Rehmannia glutinosa L. water extract group, ■ P<0.05, ■■ P<0.01; compared with the Rehmannia glutinosa L. alcohol extract group, □ P<0.05, □□ P<0.01; compared with the catalpol group, ▲ P<0.05, ▲▲ P<0.01; compared with the rehderianoside D group, △P<0.05, △△P<0.01

[0048] 3.2 Test of the combination on the decrease of the liver toxicity of the mice in the physiological state

[0049] Abnormal increase of the levels of serum liver function indicators AST and ALT of mice generally indicates that the liver function of mice is impaired, and further indicates the hepatotoxicity of the drug. It can be seen from the results that long-term administration of fluoxetine can cause abnormal increase of the levels of liver function indicators AST and ALT of mice, reflecting the hepatotoxicity of long-term administration of fluoxetine. The compositions (Radix Rehmanniae water extract combined with fluoxetine group, Radix Rehmanniae alcohol extract combined with fluoxetine group, catalpol combined with fluoxetine group, Radix Rehmanniae glycosides D combined with fluoxetine group) in the application can all significantly reduce the hepatotoxicity after administration of fluoxetine alone. The efficacy increase rates of fluoxetine for reducing the AST level of mice are 38.0%, 13.5%, 38.3% and 37.3% in turn, and the efficacy increase rates of fluoxetine for reducing the ALT level of mice are 46.2%, 8.6%, 45.1% and 44.9% in turn, indicating that the compositions in the application weaken the liver function damage of mice in physiological state, i.e. the hepatotoxicity of the compositions is reduced, and the results are shown in Table 2.

[0050] Table 2 Effects of the compositions on the levels of serum AST and ALT of mice in physiological state

[0051]

[0052]

[0053] Note: compared with the blank control group, * P<0.05, ** P<0.01; compared with the fluoxetine group, # P<0.05, ## P<0.01.

[0054] 3.3 Results of the anti-depression efficacy enhancement test of the compositions on mice in depression state

[0055] The abnormal increase of the immobility time of the mice in the FST shows that the despair behavior of the mice is enhanced and characterizes the depressive behavior of the mice, and the abnormal decrease of the sugar water preference degree of the mice in the SPT shows that the sensitivity of the mice to the reward is reduced, thereby characterizing the increase of the depressive degree of the mice. The increase of the immobility time of the mice in the FST and the decrease of the sugar water preference degree of the mice in the SPT after the administration show the antidepressant effect of the drug. The present application proves that the Rehmannia glutinosa L. water extract combined with fluoxetine group, the Rehmannia glutinosa L. alcohol extract combined with fluoxetine group, the catalpol combined with fluoxetine group and the rehderianoside D combined with fluoxetine group can more reversely change the increase of the immobility time of the CUMS depressive state mice in the FST and the decrease of the sugar water preference degree of the CUMS depressive state mice in the SPT compared with fluoxetine, and the increase rates of the drug efficacy of the combination in the FST are 32.2%, 11.9%, 35.1% and 29.7% respectively, and the increase rates of the drug efficacy of the combination in the TST are 80.4%, 24.9%, 63.5% and 59.9% respectively. The increase rates of the drug efficacy of the Rehmannia glutinosa L. water extract, the Rehmannia glutinosa L. alcohol extract, the catalpol and the rehderianoside D in the FST test without the combination of fluoxetine are 34.2%, 15.6%, 37.3% and 31.6% respectively, and the increase rates of the drug efficacy in the TST test without the combination of fluoxetine are 92.6%, 42.8%, 66.2% and 92.0% respectively. It is comprehensively explained that the antidepressant efficacy of the combination in the present application is enhanced on the depressive state mice. The results are shown in Table 3.

[0056] Table 3 Influence of the combination on the immobility time of the depressive state mice in the FST and the TST

[0057]

[0058] Note: compared with the blank control group, * P<0.05, ** P<0.01; compared with the fluoxetine group, # P<0.05, ## P<0.01; compared with the Rehmannia glutinosa L. water extract group, ■ P<0.05, ■■ P<0.01; compared with the Rehmannia glutinosa L. alcohol extract group, □ P<0.05, □□ P<0.01; compared with the catalpol group, ▲ P<0.05, ▲▲ P<0.01; compared with the rehderianoside D group, △P<0.05, △△P<0.01

[0059] 3.4 Test results of the combination on the liver toxicity of the depressive state mice

[0060] The results show that long-term administration of fluoxetine can aggravate the abnormal increase of liver function indicators AST and ALT of CUMS depressive state mice, which reflects that long-term administration of fluoxetine aggravates liver damage of CUMS depressive state mice. The three compositions (Radix Rehmanniae water extract combined with fluoxetine group, Radix Rehmanniae alcohol extract combined with fluoxetine group, Catalpol combined with fluoxetine group, and Radix Rehmanniae Glycosides D combined with fluoxetine group) in the application can significantly reduce the hepatotoxicity of fluoxetine alone, and the pharmacodynamic increase rates of fluoxetine for reducing the AST level of mice are 43.0%, 8.4%, 41.4% and 34.4% in turn, and the pharmacodynamic increase rates of fluoxetine for reducing the ALT level of mice are 46.9%, 10.3%, 44.1% and 37.1% in turn, which indicates that the compositions in the application can weaken the liver function damage of CUMS depressive state mice, that is, the hepatotoxicity of the compositions is reduced, and the results are shown in Table 4.

[0061] Table 4: Effects of the compositions on the AST and ALT levels of mice in depressive state

[0062]

[0063] Note: compared with the blank control group, * P < 0.05, ** P < 0.01; compared with the fluoxetine group, # P < 0.05, ## P < 0.01.

[0064] It can be seen from the above results that the compositions involved in the application have enhanced anti-depression efficacy and reduced hepatotoxicity, have great advantages of high efficiency and safety, and partially solve the hidden troubles of hepatotoxicity of the current anti-depression drugs to safe medication. The compositions are helpful to improve the compliance of patients with depression, maintain the health of patients with depression, promote the rehabilitation of patients, and improve the quality of life of patients, are a great innovation in the prevention and treatment of depression drugs, and have significant economic and social benefits.

[0065] The above only describes the preferred embodiments of the application and is not used to limit the application to other dosage forms (such as pills, powders, capsules, etc.). The application can have various modifications and changes for those skilled in the art. Any modification, equivalent replacement, improvement, etc. within the spirit and principle of the application should be included in the protection scope of the application.

Claims

1. A low-toxicity and high-efficiency composition for preventing and treating depression, characterized in that, The composition is composed of the water extract of Rehmannia glutinosa and fluoxetine, wherein the water extract of Rehmannia glutinosa is prepared by the following steps: Rehmannia glutinosa slices 3g are soaked in water with a weight-volume ratio of 6-8 for 30-60 min, and then boiled with a strong fire until boiling, and then boiled with a weak fire for 30 min, and then filtered to obtain a first filtrate; The residue is soaked in water with a weight-volume ratio of 6-8, and then boiled with a strong fire until boiling, and then boiled with a weak fire for 20-25 min, and then filtered to obtain a second filtrate; the first filtrate and the second filtrate are combined, concentrated, dried to obtain the water extract of Rehmannia glutinosa, and then mixed with fluoxetine with a purity of ≥99% and a dosage of 10 mg to obtain a low-toxicity and high-efficiency composition for preventing and treating depression; The weight-volume ratio refers to the weight of solid in g and the volume of liquid in mL.

2. A low-toxicity and high-efficiency composition for preventing and treating depression, characterized in that, The low-toxicity and high-efficiency composition for preventing and treating depression is prepared by mixing 10 mg of catalpol with a purity of ≥99% with 10 mg of fluoxetine with a purity of ≥99%.

3. A low-toxicity and high-efficiency composition for preventing and treating depression, characterized in that, The low-toxicity and high-efficiency composition for preventing and treating depression is prepared by mixing 10 mg of catalpol with a purity of ≥99% with 10 mg of fluoxetine with a purity of ≥99%. The low-toxicity and high-efficiency composition for preventing and treating depression is prepared by mixing 10 mg of catalpol with a purity of ≥99% with 10 mg of fluoxetine with a purity of ≥99%.

Images