Application of Jianjing bezoar heart-fire-clearing pill in treatment of general anxiety disorder

Abstract

The invention provides an application of a Jianjing bezoar heart-fire-clearing pill in treatment of a wide anxiety disorder, and discovers that the marketed drug Jianjing bezoar heart-fire-clearing pill can effectively treat the wide anxiety disorder. After the traditional Chinese medicine composition is continuously taken for 4 weeks, the average score of a Hamilton anxiety scale HAMA is reduced from 22.22 to 8.22 after 300 patients with general anxiety disorder are treated, and the total effective rate reaches 93%; the average score of a traditional Chinese medicine syndrome scale is reduced from 36.62 to 14.29, and the total effective rate reaches 96%; only 12 cases of adverse reactions are concentrated on the digestive system and are rapidly relieved after drug withdrawal. According to the invention, new indications of the Lianjing bezoar heart-fire-clearing pill are found, the application field of the Lianjing bezoar heart-fire-clearing pill is expanded, and the Lianjing bezoar heart-fire-clearing pill can also play a role in treatment of general anxiety disorder.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicines, and in particular to application of Tongren Niuhuang Qingxin Pills in treating generalized anxiety disorder. Background Art

[0002] Generalized anxiety disorder is a common and disabling mental illness that is often underdiagnosed and undertreated. Patients with generalized anxiety disorder have an increased risk of suicide, cardiovascular-related events, and death. Common symptoms include chronic, generalized anxiety and worry, accompanied by non-specific physical and psychological symptoms (restlessness, fatigue, difficulty concentrating, irritability, muscle tension, or sleep disorders). More than one-third of patients with generalized anxiety disorder have reduced work productivity, an average of 6.3 days of absenteeism per month, and higher healthcare utilization and costs, which have a serious negative impact on patients' life satisfaction and quality of life.

[0003] Currently, conventional treatments include psychotherapy and medication, but these still have shortcomings, such as inconsistent results, significant side effects, and drug dependency. In particular, patients with anxiety due to phlegm-heat disturbing the heart syndrome often suffer from chronic negative emotional stimulation, which leads to liver wood disorder. This wood stagnation overwhelms earth, and spleen deficiency is unable to transport and transform water and dampness. This water and dampness accumulate and form phlegm, which gradually transforms into heat. Traditional treatments often fail to achieve ideal results.

[0004] The marketed drug Tongren Niuhuang Qingxin Wan is typically used to treat stroke symptoms caused by Qi and blood deficiency and phlegm-heat disturbance. It is commonly used clinically for cerebral infarction, hypertension, and vertigo. Its effects include nourishing Qi and blood, calming the mind, and resolving phlegm and extinguishing wind. It is commonly used to treat chest heat, dizziness, aphasia, facial paralysis, hemiplegia, slurred speech, coma, and excessive phlegm caused by Qi and blood deficiency and phlegm-heat disturbance. However, there is currently no clear indication for its use in treating generalized anxiety disorder (phlegm-heat disturbance of the heart syndrome). Summary of the Invention

[0005] The present invention provides the use of Tongren Niuhuang Qingxin Pills in treating generalized anxiety disorder. The present invention finds that oral Tongren Niuhuang Qingxin Pills can treat generalized anxiety disorder with high efficacy and minimal toxic and side effects, and exhibits significant effectiveness in both the Hamilton Anxiety Scale (HAMA) and the Traditional Chinese Medicine Syndrome Rating Table for Generalized Anxiety Disorder evaluation indicators.

[0006] The present invention provides a use of Tongren Niuhuang Qingxin Pills in preparing a drug for treating generalized anxiety disorder. The Tongren Niuhuang Qingxin Pills are marketed drugs, including Tongren Niuhuang Qingxin Pills produced by Beijing Tongrentang Development Co., Ltd. Pharmaceutical Factory, which have a drug approval number of National Medicine Standard Z11020001 and a drug standard code of 86900166004075 or 86900166005546; Or the Tongren Niuhuang Qingxin Pills produced by Beijing Tongrentang Development Co., Ltd. Pharmaceutical Factory, with the drug approval number of National Medicine Standard Z11020025, whose drug standard code is 86900166003146; Or the Tongren Niuhuang Qingxin Pills produced by Beijing Tongrentang Technology Development Co., Ltd. Pharmaceutical Factory, with the drug approval number Z11020490, whose drug code is 86900169000609.

[0007] The present invention has been verified by both traditional Chinese and Western medicine clinical diagnostic standards and found that, in addition to its existing function of treating stroke symptoms caused by qi and blood deficiency and phlegm-heat disturbance, the Tongren Niuhuang Qingxin Pill also has the effects of clearing the heart and resolving phlegm, calming the mind and strengthening the spleen, and calming the nerves and dispelling wind. It is mainly used to treat mental confusion, slurred speech, dizziness, convulsions, epilepsy, etc. It has therapeutic effects on many mental illnesses, especially when used in combination with antipsychotics and antianxiety drugs, it can improve anxiety and somatic symptoms and correct toxic side effects. It is a traditional Chinese patent medicine for treating mental illness that deserves in-depth study.

[0008] Preferably, the prescription composition of Tongren Niuhuang Qingxin Pills in the application includes: bezoar, donkey-hide gelatin, musk, buffalo horn concentrated powder, antelope horn angelica, Chuanxiong, licorice, yam, scutellaria, white peony root, ophiopogon, Atractylodes (fried with bran), pollen (fried), Poria, jujube (pitted), ginseng, siler, dried ginger, bupleurum, cinnamon, white ampelopsis, platycodon, bitter almond (fried), Liushenqu (fried with bran), soybean yellow roll, and borneol.

[0009] Preferably, the preparation method of Tongren Niuhuang Qingxin Pills in the application is as follows: angelica, Chuanxiong, liquorice, Chinese yam, scutellaria, white peony root, ophiopogon, atractylodes (fried with bran), Liushenqu (fried with bran), pollen (fried), jujube (pitted), donkey-hide gelatin, poria, ginseng, siler, dried ginger, bupleurum, cinnamon, white peony root, platycodon, soybean yellow roll, bitter almond (fried) are crushed into fine powder, antelope horn is filed into fine powder, buffalo horn concentrated powder, musk, borneol, and bezoar are finely ground, mixed with the above powders, sieved, and mixed. For every 100g of powder, 30-40g of refined honey and an appropriate amount of water are added, and the pills are made into water-honey pills, dried or coated with gold; or Add 120-130g of refined honey to make large honey pills.

[0010] Preferably, the dosage of Niuhuang Qingxin Pills in the application is 2-4 g of water-honeyed pills twice a day for 4 weeks; Or take large honey pills twice a day, 1-2 pills each time, for 4 weeks.

[0011] Preferably, the generalized anxiety disorder in the application comprises the following symptoms: (1) Fear and anxiety; (2) Feeling upset; (3) Impatient and talkative; (4) Easily startled during sleep; (5) Dizziness and headache; (6) Bitter and dry mouth; (7) Red tongue with yellow greasy coating; (8) Sliding and rapid pulse.

[0012] The present invention also provides a pharmaceutical composition for treating generalized anxiety disorder, wherein the pharmaceutical composition contains Tongren Niuhuang Qingxin Pills, which are marketed drugs and have a drug approval number of National Medicine Standard Z11020001. Or the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020025; Or the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020490.

[0013] The present invention further provides a method for preparing a pharmaceutical composition for treating generalized anxiety disorder, comprising mixing an antianxiety drug with Tongren Niuhuang Qingxin Pills, wherein the Tongren Niuhuang Qingxin Pills are a marketed drug with a drug approval number of National Medicine Standard Z11020001. Or the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020025; Or the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020490.

[0014] It should be noted that depression can also have some anxiety-like symptoms, but its etiology and pathogenesis are different from the generalized anxiety disorder described in this application. The typical symptoms of depression are low mood, loss of interest, lack of energy, impaired cognitive function, etc. The generalized anxiety disorder described in the present invention is a type of anxiety disorder, which is characterized by widespread and persistent anxiety and worry, and is a chronic anxiety disorder accompanied by motor tension and autonomic hyperactivity. The new application of Tongren Niuhuang Qingxin Pills in the present invention is only used to treat generalized anxiety disorder. For detailed discrimination between the two, please refer to the "Guidelines for the Diagnosis and Treatment of Mental Disorders" (2020 edition) issued by the National Health Commission of the People's Republic of China.

[0015] The use of Tongren Niuhuang Qingxin Pills in the treatment of generalized anxiety disorder (GAD) has identified a new indication for the marketed drug. Clinical trials have verified their efficacy for GAD (phlegm-heat disturbing the heart syndrome) using both the Western medicine Hamilton Anxiety Rating Scale (HAMA) and Traditional Chinese Medicine (TCM) syndrome criteria. In a study of 300 GAD patients taking Tongren Niuhuang Qingxin Pills for 28 days, the average HAMA score decreased from 22.22 to 8.22, with an overall efficacy rate of 93%. The average score on the TCM syndrome scale decreased from 36.62 to 14.29, with an overall efficacy rate of 96%. There were only 12 cases of adverse reactions, primarily affecting the digestive system, which all resolved rapidly after discontinuation of the medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In order to more clearly illustrate the technical solutions in the present invention or the prior art, a brief introduction is given below to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0017] Figure 1 This is a HAMA scale score trend chart for all subjects provided by the present invention.

[0018] Figure 2 It is a trend chart of TCM syndrome scale scores for all subjects provided by the present invention. DETAILED DESCRIPTION

[0019] To make the objectives, technical solutions, and advantages of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in conjunction with the accompanying drawings. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.

[0020] Example This example provides a clinical trial of Tongren Niuhuang Qingxin Pills in treating generalized anxiety disorder.

[0021] 1 Clinical Data 1.1 Case Source The research cases in this project came from the Third Affiliated Hospital of Beijing University of Chinese Medicine, Dongzhimen Hospital of Beijing University of Chinese Medicine, Beijing Huilongguan Hospital, Suzhou Affiliated Hospital of Nanjing University of Chinese Medicine, Affiliated Hospital of Changchun University of Chinese Medicine, Affiliated Hospital of Shandong University of Chinese Medicine, First Affiliated Hospital of Anhui University of Chinese Medicine, Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, and Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University. 300 patients with generalized anxiety disorder (phlegm-heat disturbing the heart syndrome) who met the inclusion and exclusion criteria and visited the outpatient clinic from April 2022 to October 2023 were recruited.

[0022] 1.2 Diagnostic criteria Western medicine diagnostic standards: The diagnostic standards for generalized anxiety disorder adopt the DSM-5 standards issued by the American Mental Health Association in 2013, and the severity of the disease is determined by the Hamilton Anxiety Scale (HAMA): a total score of more than 29 points indicates severe anxiety; more than 21 points definitely indicates obvious anxiety; more than 14 points definitely indicates anxiety; more than 7 points may indicate anxiety; if less than 6 points, there are no anxiety symptoms.

[0023] TCM diagnostic criteria: TCM diagnostic criteria adopt the international standard "International TCM Clinical Diagnosis and Treatment Guidelines - Anxiety Disorders" issued by the World Federation of Chinese Medicine Societies, and select the diagnostic criteria for phlegm-heat disturbing the heart syndrome: panic and restlessness, restlessness, impatience and excessive talk, easy to be startled at night, dizziness and headache, bitter and dry mouth, red tongue with yellow greasy coating, and slippery and rapid pulse.

[0024] 1.3 Inclusion criteria ① Age 18 to 65 years old; ② Patients who meet the clinical research criteria for generalized anxiety disorder (HAMA score ≥ 14 points and < 29 points, 24-item Hamilton Depression Scale (HAMD) score < 17 points; Self-Rating Anxiety Scale (SAS) score ≥ 50 points); ③ Meet the Traditional Chinese Medicine syndrome criteria for phlegm-heat disturbing the heart syndrome; ④ Have stable vital signs, clear consciousness, and a certain degree of expression; ⑤ Sign the informed consent form and agree to participate in this study.

[0025] According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), depression and anxiety disorders are two different mental disorders, but they often co-occur and their symptoms overlap to a certain extent. The above inclusion criteria can effectively distinguish anxiety disorders from depression, and avoid judging the treatment effect of anxiety disorders by depression cases or cases suffering from both depression and anxiety disorders.

[0026] 1.4 Exclusion criteria ① Patients with physical diseases secondary to generalized anxiety disorder, such as coronary heart disease, hypertension, diabetes, etc.; ② Patients with unstable vital signs; ③ Patients with severe aphasia, agnosia and inability to communicate; ④ Patients with anxiety associated with other mental illnesses (such as depression, obsessive-compulsive disorder, schizophrenia, etc.) diagnosed by Western medicine; ⑤ Patients with known alcoholism or substance dependence; ⑥ Patients with non-anxiety psychosis diagnosed by Western medicine; ⑦ Patients using other Chinese medicine or traditional Chinese medicine treatments for anxiety during the trial; ⑧ Patients with severe liver and kidney dysfunction; ⑨ Pregnant or lactating women; ⑩ Patients who meet other syndrome criteria.

[0027] 2 Research Methods 2.1 Design A multicenter, single-arm, and self-controlled before-after study was conducted to investigate the efficacy and safety of a Chinese herbal medicine combination in treating generalized anxiety disorder (phlegm-heat disturbing the heart syndrome) by administering drug intervention to patients who met the inclusion and exclusion criteria.

[0028] 2.2 Treatment methods The clinical trial used Tongren Niuhuang Qingxin Pills (approved as Z11020490), manufactured by Beijing Tongrentang Technology Development Co., Ltd. Each pill weighs 3g and is taken orally, one pill twice daily, in the morning and evening after meals. The efficacy was evaluated for four weeks.

[0029] 2.3 Observation indicators 2.3.1 Efficacy indicators: ① Improvement in clinical anxiety: The internationally recognized HAMA score reduction rate was used to assess anxiety. HAMA score reduction rate = (pre-treatment score - post-treatment score) / (pre-treatment score - lowest score on the scale) × 100%. Clinical control: score reduction rate ≥ 75%, marked efficacy: 50% ≤ score reduction rate < 75%, effective: 50% ≤ score reduction rate < 30%, and ineffective: score reduction rate < 30%.

[0030] ② Improvement in TCM syndrome efficacy: The TCM Syndrome Rating Scale for Generalized Anxiety Disorder was used for assessment. The efficacy index (n) = (pre-treatment score - post-treatment score) / pre-treatment score × 100%. Clinical control: efficacy index (n) ≥ 80%. Marked efficacy: 50% ≤ efficacy index (n) < 80%; effective: 50% ≤ efficacy index (n) < 30%; ineffective: efficacy index (n) < 30%.

[0031] 2.3.2 Safety indicators Liver and kidney function, blood, urine and stool routine tests, and electrocardiogram were tested before and after treatment.

[0032] 2.3.3 Adverse reaction evaluation ① Use the adverse reaction record form and the Treatment Effect Scale (TESS) for evaluation; ② Determine the causal relationship between the adverse reaction and the drug; ③ Record and report.

[0033] 2.4 Observation time and follow-up methods All subjects were observed and evaluated four times at the beginning of the trial, and one, two, and four weeks after the start of the trial. The observation and evaluation of the condition were conducted by two or more attending physicians of traditional Chinese medicine or integrated Chinese and Western medicine. During the observation and evaluation process, the treatment personnel, scorers, and statisticians were independent of each other in the clinical study. The average HAMA score during the treatment process was as follows: Figure 1 As shown in Figure 2, the average score changes of the TCM syndrome scale are as follows: Figure 2 The abnormal results of safety indicators are shown in Table 5, and the adverse reactions are shown in Table 6.

[0034] 2.5 Statistical methods All data were statistically analyzed using the IBM SPSS 20.0 software package. Nonparametric tests were used for enumeration data. Statistical data were analyzed using t-tests for significance. The results of the significance analysis for the HAMA scale are shown in Table 1, and the results of the significance analysis for the TCM syndrome scale are shown in Table 3. The results of the efficacy analysis for the HAMA scale are shown in Table 2, and the results of the efficacy analysis for the TCM syndrome scale are shown in Table 4.

[0035] 3 Research results 3.1 HAMA scale evaluation results (1) As shown in Table 1, the HAMA scale scores of 300 patients with generalized anxiety disorder after treatment (8.22) were lower than those before treatment (20.22), and the difference was statistically significant (P < 0.01). The clinical anxiety level was significantly improved.

[0036] (2) As shown in Table 2, in the clinical trial with 300 participants, a total of 279 cases were effective, with a total effective rate of 93%, including 75 cases (25%) under clinical control, 140 cases (46.67%) with marked effects, 64 cases (21.33%) with effectiveness, and 21 cases (7%) with ineffectiveness. This indicates that Tongren Niuhuang Qingxin Pills have a good therapeutic effect on generalized anxiety disorder.

[0037] (3) If Figure 1 As shown in the figure, in terms of the overall trend change of anxiety scores, the subjects' HAMA scores showed a significant downward trend from the first week of treatment. As the treatment time prolonged, the scale scores at the fourth week were significantly lower than those at the beginning of treatment.

[0038] 3.2 Evaluation results of TCM syndrome scale (1) As shown in Table 3, the TCM Syndrome Scale scores of 300 patients with generalized anxiety disorder after treatment (14.29) were lower than those before treatment (36.62), and the difference was statistically significant (P < 0.001). The clinical anxiety level was significantly improved.

[0039] (2) As shown in Table 4, in the clinical trial with 300 participants, the total number of effective cases was 288, with a total effective rate of 96%, including 44 cases (14.66%) under clinical control, 179 cases (59.67%) with marked effect, 65 cases (21.67%) with effect, and 12 cases (4%) with ineffectiveness.

[0040] (3) By Figure 2 It can be seen that in terms of the overall trend change of TCM syndrome scores, the subjects' TCM syndrome scale scores showed a clear downward trend from one week of treatment. As the treatment time prolonged, the scale scores were significantly lower than those at the beginning of treatment at four weeks.

[0041] 3.3 Safety Results As shown in Table 5, a total of 19 patients experienced abnormal safety indicators after treatment in this study. These included 1 abnormal electrocardiogram, 3 abnormal liver function tests, 11 abnormal urinalysis results, and 4 abnormal stool tests. These abnormal safety indicators, which occurred during clinical observation, were considered by the physicians (researchers) to be unrelated to the drug itself, based on the patients' medical history.

[0042] 3.4 Adverse reaction results As shown in Table 6, a total of 12 adverse reactions occurred in this study. These included 6 cases of diarrhea, 3 cases of constipation, and 1 case each of stomachache, anorexia, and nausea. These adverse reactions were rapidly relieved after a brief discontinuation of the medication or a reduction in dosage, and have not recurred since then. The above adverse reactions, which occurred during clinical observation and were considered by the physicians (researchers) to be potentially drug-related, were considered by the physicians (researchers) to be consistent with the patient's overall medication history.

[0043] The above results show that Tongren Niuhuang Qingxin Pills have a good clinical efficacy for generalized anxiety disorder (phlegm-heat disturbing the heart syndrome), can significantly improve patients' anxiety symptoms, and improve the TCM syndrome of phlegm-heat disturbing the heart. The adverse reactions are mainly manifested in the gastrointestinal tract of the digestive system, with a low incidence rate, and the discomfort symptoms are generally mild, with good safety.

[0044] 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 aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. The use of Tongren Niuhuang Qingxin Pills in the preparation of a drug for treating generalized anxiety disorder, characterized in that: The Tongren Niuhuang Qingxin Pills are a marketed drug, and the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020001; Or the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020025; Or the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020490.

2. The use according to claim 1, characterized in that The prescription composition of Tongren Niuhuang Qingxin Pills used in the application includes: bezoar, donkey-hide gelatin, musk, buffalo horn concentrated powder, antelope horn angelica, Chuanxiong, licorice, yam, scutellaria, white peony, Ophiopogon, Atractylodes (fried with bran), Pollen Typhae (fried), Poria, jujube (pitted), ginseng, Saposhnikovia divaricata, dried ginger, bupleurum, cinnamon, white peony root, Platycodon grandiflorum, bitter almond (fried), Liushenqu (fried with bran), soybean yellow roll, and borneol.

3. The use according to claim 1, characterized in that The preparation method of Tongren Niuhuang Qingxin Pills in the application is as follows: angelica, Chuanxiong, licorice, Chinese yam, scutellaria, white peony root, ophiopogon, atractylodes (fried with bran), Liushenqu (fried with bran), pollen (fried), jujube (pitted), donkey-hide gelatin, poria, ginseng, siler, dried ginger, bupleurum, cinnamon, white peony root, platycodon, soybean yellow roll, bitter almond (fried) are crushed into fine powder, antelope horn is filed into fine powder, buffalo horn concentrated powder, musk, borneol, and bezoar are finely ground, mixed with the above powders, sieved, and mixed. For every 100g of powder, 30-40g of refined honey and an appropriate amount of water are added, and the pills are made into water-honey pills, dried or coated with gold. Add 120-130g of refined honey to make large honey pills.

4. The use according to any one of claims 1 to 3, characterized in that The dosage of Niuhuang Qingxin Pills in the application is 2-4 g of water-honeyed pills twice a day for 4 weeks. Or take large honey pills twice a day, 1-2 pills each time, for 4 weeks.

5. The use according to any one of claims 1 to 4, characterized in that Generalized anxiety disorder in this application includes the following symptoms: (1) Fear and anxiety; (2) Feeling upset; (3) Impatient and talkative; (4) Easily startled during sleep; (5) Dizziness and headache; (6) Bitter and dry mouth; (7) Red tongue with yellow greasy coating; (8) Sliding and rapid pulse.

6. A pharmaceutical composition for treating generalized anxiety disorder, characterized in that: The pharmaceutical composition contains Tongren Niuhuang Qingxin Pills, which are marketed drugs with a drug approval number of National Medicine Standard Z11020001. Or the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020025; Or the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020490.

7. A method for preparing a pharmaceutical composition for treating generalized anxiety disorder, characterized in that: An antianxiety drug is mixed with Tongren Niuhuang Qingxin Pills, which is a marketed drug with the drug approval number of National Medicine Standard Z11020001; Or the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020025; Or the drug approval number of the Tongren Niuhuang Qingxin Pills is National Medicine Standard Z11020490.

Images