Use of Sixteen-flavor Azalea Pills in preventing and treating insomnia

Abstract

The present invention provides a new use of the Sixteen-Ingredient Azalea Pill in the prevention and treatment of insomnia. Animal experimental studies have shown that the Sixteen-Ingredient Azalea Pill can increase the levels of neurotransmitters 5-hydroxytryptamine (5-HT), dopamine (DA), and hydroxybutyric acid (GABA) in brain tissue, thereby reducing sleep latency, prolonging sleep duration, and improving sleep. A summary of a large number of clinical cases found that the Sixteen-Ingredient Azalea Pill can quickly and effectively cure insomnia without withdrawal reactions. The Sixteen-Ingredient Azalea Pill of the present invention treats insomnia with a short treatment course, high efficacy, and is not prone to relapse after cure. The present invention expands the disease field for the application of the Sixteen-Ingredient Azalea Pill and provides a direction for the development of new indications for it.

Description

Technical Field

[0001] The present invention relates to the field of traditional Chinese medicine, and in particular to application of Sixteen-flavor Azalea Pills in preparing medicines for preventing and treating insomnia. Background Art

[0002] Insomnia is the most common sleep disorder in clinical practice, with up to 10% to 15% of adults meeting diagnostic criteria. Insomnia often develops over a chronic course, with nearly half of cases of severe insomnia persisting for more than 10 years. Insomnia severely impairs patients' physical and mental health, impacting their quality of life and even leading to accidents such as traffic accidents, endangering personal and public safety. It poses a significant burden on both individuals and society.

[0003] Insomnia is a sleep disorder characterized by frequent and persistent difficulty falling asleep and / or maintaining sleep, leading to unsatisfactory sleep. According to the International Classification of Sleep Disorders, Third Edition (ICSD-3), insomnia can be categorized as chronic insomnia, short-term insomnia, and other types of insomnia.

[0004] The 2017 Chinese Guidelines for the Diagnosis and Treatment of Insomnia recommend both psychotherapy and medication. Regarding medication, the guidelines recommend the use of hypnotic medications, as appropriate, in addition to psychotherapy, to achieve the goals of relieving symptoms, improving sleep quality, prolonging effective sleep time, and improving the patient's quality of life. Commonly used medications are short- and medium-acting benzodiazepine receptor agonists (BzRAs) or melatonin receptor agonists (such as ramelteon) and sedative antidepressants (such as trazodone, mirtazapine, fluvoxamine, and doxepin). However, long-term medication use can lead to drug tolerance or severe adverse reactions. Once patients feel they can control their sleep, the gradual reduction and discontinuation of medication can take weeks to months, significantly reducing patient compliance.

[0005] The Tibetan medical text "Detailed Explanation of the Four Medical Classics" states that when Lung is predominant, it can cause a range of symptoms, including tremors, dizziness, and insomnia. Therefore, Tibetan medicine further categorizes insomnia into Lung-predominant and Triba-predominant. Based on their clinical characteristics, treatment focuses on regulating Lung and treating Triba-predominant symptoms to improve clinical efficacy.

[0006] The Tibetan medicine "Tibetan Medicine Clinical Notes" records: Insomnia is a common symptom of many diseases such as Nianglong, Suolong, depression, and mania. At the same time, long-term decline in sleep quality or reduction in sleep time can also cause Nianglong and Suolong. Severe cases can cause mania, seriously affecting the patient's social function and quality of life, and causing great trauma to the family and society.

[0007] Sixteen-Ingredient Azalea Pill, also known as Daliju Zhouribu in Tibetan medicine, is a compound Tibetan medicinal preparation made from sixteen herbs, including Rhododendron australis, pomegranate seeds, cardamom, safflower, and Ligadu. It is listed in the standard issued by the Ministry of Tibetan Medicine (WS3-BC-0202-95). According to the ancient Tibetan medical text "Diagnosis and Treatment of Tibetan Medicine" by Gongzhu Yuandan Gyatso, its main functions are to invigorate qi and aid digestion, act as a diuretic, and relieve coughs. It is used for edema, indigestion, abdominal distension and pain, hoarseness in cough, dizziness, and water and soil discomfort. The dosage is 4-5 pills (approximately 2-2.5g) three times daily. Sixteen-Ingredient Azalea Pill has a history of clinical use spanning thousands of years, and has been a staple health remedy for generations of Tibetans living on the plateau. Summary of the Invention

[0008] The invention provides a new use of the sixteen-flavor azalea pill in treating insomnia.

[0009] The prescription composition of the Sixteen-flavor Azalea Flower Pill of the present invention is as follows:

[0010] 400g of Rhododendron azalea, 100g of pomegranate seeds, 20g of cardamom, 50g of cinnamon, 75g of travertine, 80g of safflower, 50g of costus root, 10g of nutmeg, 50g of camphor tree, 30g of grapes, 35g of processed crab, 50g of ligado, 30g of longan, 20g of cloves, 40g of jujube, and 50g of licorice. Grind these 16 ingredients into a fine powder, sieve, mix thoroughly, and make into pills with water. Dry to obtain the product. This product is a brown, watery pill with a fragrant aroma and a pungent, slightly sweet taste. Each pill weighs 0.5g.

[0011] The inventors have found that the Sixteen-Ingredient Azalea Pill can quickly and effectively cure insomnia without withdrawal reactions during the long-term clinical application of the Sixteen-Ingredient Azalea Pill, through scientific experimental design, systematic research, and summary of a large number of clinical cases. The inventors have found in long-term clinical practice that taking 2 to 2.5 g of the Sixteen-Ingredient Azalea Pill once a day before bed for 7 to 14 consecutive days can effectively treat insomnia without withdrawal reactions, is safe and convenient, and has high patient compliance.

[0012] Animal experiments have shown that Sixteen-flavor Azalea Pills can increase the levels of neurotransmitters serotonin (5-HT), dopamine (DA), and gamma-hydroxybutyric acid (GABA) in brain tissue, thereby reducing sleep latency, prolonging sleep duration, and improving sleep.

[0013] The sixteen-ingredient azalea flower pill of the present invention treats insomnia, has a short treatment course, a high efficacy rate, and is unlikely to relapse after being cured. The present invention expands the disease field in which the sixteen-ingredient azalea flower pill is applied and provides a direction for the development of new indications for the pill. DETAILED DESCRIPTION

[0014] The following examples are given to further explain the present invention, but are not intended to limit the present invention in any way.

[0015] Example 1 Parachlorophenylalanine (PCPA)-induced insomnia in rats

[0016] Model Establishment: Seventy-two Wistar rats were housed for three days and then randomly divided into a normal group (12 rats) and a model group (60 rats). The model group was treated with PCPA to induce insomnia according to the literature. PCPA (300 mg / kg) was injected intraperitoneally once daily for three consecutive days. The rats showed loss of circadian rhythm, continued daytime activity, increased excitability and aggression, decreased appetite, and matted fur, indicating successful model establishment. The model rats were then randomly divided into a model group, a Twenty Flavors Nutmeg Pill group, and low-, medium-, and high-dose Sixteen Flavors Azalea Pill groups, with 12 rats in each group. Both the normal and model groups were administered 0.5% CMC-Na by gavage. The Twenty Flavors Nutmeg Pill group was administered 0.6 g / kg of Twenty Flavors Nutmeg Pill, and the low-, medium-, and high-dose Sixteen Flavors Azalea Pill groups were administered 0.5 g / kg, 1 g / kg, and 2 g / kg of Sixteen Flavors Azalea Pill, respectively. Each group was gavaged with 10 mL / kg for 7 days.

[0017] Sodium pentobarbital righting test: One hour after the last administration, 6 rats were randomly selected from each group and injected intraperitoneally with 35 mg / kg sodium pentobarbital. The sleep latency and sleep duration were calculated.

[0018] Open field test: 12 h after the last administration, 6 rats were randomly selected from each group, and behavioral software was used to analyze the total activity distance, time spent in the center area, and number of times the rats entered the center area within 300 s.

[0019] Sampling and Index Measurement: Rats were fasted for 12 hours and sacrificed by decapitation. Brain tissue was immediately dissected on ice and frozen in liquid nitrogen at -80°C until analysis. A 10% brain homogenate was prepared, and ELISA was used to measure 5-HT, γ-GABA, and DA levels in the brain tissue.

[0020] Data statistics: SPSS 22.0 was used for data analysis. ± s The comparison among the groups was performed using one-way analysis of variance. P The difference was statistically significant when the value was <0.05.

[0021] Experimental results:

[0022] 1. Impact on sleep latency and sleep duration

[0023] Compared with the normal group, the sleep latency of rats in the model group and the positive drug group was delayed, and the sleep duration was significantly shortened (P < 0.01). There was no significant difference among the low, medium and high dose groups of Sixteen Azalea Pills. Compared with the model group, Twenty Nutmeg Pills and Sixteen Azalea Pills could significantly shorten the sleep latency and prolong the sleep duration (P < 0.01). Compared with the positive drug group, the Sixteen Azalea Pill group could shorten the sleep latency and prolong the sleep duration to varying degrees (P < 0.05, P < 0.01).

[0024] Table 1. Pentobarbital sodium righting test

[0025]

[0026] Compared with the normal group, * P<0.05, ** P<0.01; compared with the model group, △ P < 0.05; △△ P<0.01; compared with the positive drug group, ▲ P < 0.05; ▲▲ P<0.01.

[0027] 2. Behavioral results

[0028] In the open field test of rats with PCPA-induced insomnia, total movement distance decreased, while the number of entries into the central region and modifications increased. Treatment with Twenty Flavors Nutmeg Pills and Sixteen Flavors Azalea Pills increased movement distance, while the number of entries into the central region and modifications decreased.

[0029] Table 2. Open field test

[0030]

[0031] Compared with the normal group, * P<0.05, ** P<0.01; compared with the model group, △ P < 0.05; △△ P<0.01; compared with the positive drug group, ▲ P < 0.05; ▲▲ P<0.01.

[0032] 3. Effects on neurotransmitters in brain tissue

[0033] Compared with the normal group, the levels of 5-HT, γ-GABA, and DA in the brain tissue of rats in the model group were significantly decreased ( P <0.01). Compared with the model group, the 5-HT, γ-GABA, and DA levels in the brain tissue of rats in the Ershiwei Roudouku Pill and Shiliuwei Dujuanhua Pill treatment groups were significantly increased ( PCompared with the positive control drug Ershiwei Roudoukou pill group, the levels of 5-HT, γ-GABA and DA in the brain tissue of rats in the middle and high dose groups of Shiliuwei Dujuanhua pill were statistically significant.

[0034] Table 3. Effects on neurotransmitters in brain tissue of insomnia model rats

[0035]

[0036] Compared with the normal group, * P<0.05, ** P<0.01; compared with the model group, △ P < 0.05; △△ P<0.01; compared with the positive drug group, ▲ P < 0.05; ▲▲ P<0.01.

[0037] Conclusion: Treatment with Sixteen-flavor Azalea Pill (0.5g / kg, 1g / kg, and 2g / kg) significantly shortened sleep latency and prolonged sleep duration in rats with PCPA-induced insomnia, and alleviated the nervous behavior of insomnia rats. Sixteen-flavor Azalea Pill may promote sleep and improve sleep quality by increasing 5-HT, γ-GABA, and DA levels in insomnia rats.

[0038] Example 2

[0039] Clinical data

[0040] The diagnostic criteria refer to the diagnostic criteria of the International Classification of Sleep Disorders (3rd Edition) (ICSD-3).

[0041] (1) Symptom criteria for sleep difficulties: meeting one or more of the following symptoms: ① Difficulty falling asleep; ② Difficulty maintaining sleep; ③ Waking up earlier than the desired time; ④ Refusing to go to bed at the appropriate time; ⑤ Difficulty falling asleep without caregiver intervention.

[0042] (2) Daytime symptom criteria: one or more of the following symptoms related to sleep difficulties: ① fatigue or listlessness; ② decreased attention, concentration, or memory; ③ impairment of social, family, occupational, or academic functions; ④ emotional instability or irritability; ⑤ daytime sleepiness; ⑥ behavioral problems (such as hyperactivity, impulsivity, or aggressiveness); ⑦ decreased motivation, energy, or work initiative; ⑧ prone to making mistakes or accidents; ⑨ very concerned about or dissatisfied with one's sleep quality.

[0043] (3) Frequency standard: ≥3 times per week.

[0044] (4) Disease course criteria: Sleep difficulties and related daytime symptoms last for ≥3 months.

[0045] Adult insomnia can be diagnosed if all four of the above criteria are met. The diagnostic criteria for short-term insomnia in adults are similar to those for chronic insomnia, but the duration of the disease is less than 3 months and there is no frequency requirement.

[0046] Inclusion criteria

[0047] (1) Meet the diagnostic criteria for chronic insomnia; (2) PSQI score ≤ 5 points ≤ 16 points; (3) Age ≤ 18 years ≤ 65 years; (4) Be able to cooperate with the completion of various scale assessments, blood tests and sample collection; (5) Sign the informed consent form. Only patients who meet the above 5 conditions can be selected.

[0048] Exclusion criteria

[0049] (1) Patients with mental disorders as indicated by the Mini Scale Interview; (2) Patients with substance use disorders (including addiction or abuse of alcohol, tobacco, caffeine, sedatives, psychoactive drugs, etc.); (3) SQ ≥ 5 points; SBQ ≥ 3 points; IRLS ≥ 10 points; (4) Use of antidepressants or other psychotropic drugs in the past 2 weeks (fluoxetine in the past 4 weeks); (5) Use of any drug that improves sleep during treatment (including Chinese medicine or health products with sedative effects); (6) Pregnant, lactating, or pregnant women; (7) HAMA ≥ 14 points; HAMD (17 items) ≥ 17 points; (8) Patients who are allergic to the test drugs and ingredients, have participated in clinical trials in the past 3 months, and are considered by the researchers to be unsuitable for participation in this trial; (9) Patients with serious primary heart, liver, lung, kidney, blood, or serious diseases that affect their survival, such as tumors or AIDS (ALT higher than 1.5 times, creatinine higher than normal; clinically significant electrocardiogram abnormalities; blood white blood cell count <3.0×10^9 / L). Subjects who met any of the above conditions were excluded.

[0050] A total of 123 outpatients were enrolled. Of these, 58 were treated with the Sixteen-Ingredient Azalea Pill (mean age, 48 years, with a history of 1-8 years, including 25 males and 33 females). The Twenty-Ingredient Nutmeg Pill group included 65 patients (mean age, 52 years, with a history of 1-10 years, including 30 males and 35 females). There were no statistically significant differences between the two groups in terms of gender, age, disease duration, or severity.

[0051] The Sixteen-Ingredient Azalea Pill group received 2.5g of Sixteen-Ingredient Azalea Pill once daily before bed with warm water; the Twenty-Ingredient Nutmeg Pill group received 3g of Twenty-Ingredient Nutmeg Pill twice daily. Both groups took the medication for four consecutive weeks, and no other medications were allowed during treatment.

[0052] Efficacy evaluation:

[0053] (1) Clinical efficacy. A marked effect is defined as sleep time increasing by 3 hours compared to before treatment or returning to normal, and sleep quality improving. A marked effect is defined as sleep time increasing by less than 3 hours compared to before treatment, and insomnia symptoms being alleviated. A treatment that does not meet the above criteria is defined as ineffective. Total effective rate = (marked effect + effective) / total number of cases × 100%

[0054] (2) PSQI score. It includes seven parts: sleep disturbance, daytime dysfunction, sleep duration, hypnotic medication, sleep efficiency, sleep onset time, and sleep quality. It is rated on a 0-3 scale with a total score of 21 points. The higher the sleep quality, the lower the score.

[0055] result:

[0056] 1. Clinical efficacy

[0057] The overall effective rate of Sixteen-flavor Azalea Pill in treating insomnia is comparable to that of Twenty-flavor Nutmeg Pill.

[0058] Table 4. Comparison of clinical efficacy

[0059]

[0060] 2. PSQI score

[0061] The patients' sleep was significantly improved after treatment with Sixteen-flavor Azalea Pill or Twenty-flavor Nutmeg Pill (P < 0.01), and the PSQI scores showed that the degree of improvement was similar in the two groups.

[0062] Table 5. PSQI scores

[0063]

[0064] Compared with before treatment, * P<0.01

[0065] Example 3 Typical Case

[0066] Case 1: A 51-year-old female patient presented with a 6-month course of menopausal menstruation. She required 2-3 hours to fall asleep, woke easily after falling asleep, and had difficulty falling asleep again after waking. She also experienced dizziness, fatigue, and irritability during the day. After taking the Sixteen-Ingredient Azalea Flower Pill of the present invention for one week, her dizziness and fatigue symptoms significantly improved. Following another week of treatment, her sleep returned to normal. A six-month follow-up revealed no recurrence.

[0067] Case 2: male, 48 years old, 9 years of course of disease, disordered work and rest, severe insomnia. The patient was almost sleepless before 2 a.m., easily woke up after falling asleep and had many dreams. The daily sleep time was generally about 4 hours, and the patient was listless during the day. He had taken estazolam tablets for treatment, but no obvious effect was seen. After taking the 16-flavor azalea pill of the present invention for 2 weeks, the patient's deep sleep time increased, and it was easy to fall asleep again after waking up. The sleep quality was significantly improved. After continuing to use it for 2 weeks, the sleep time reached 6 hours. After using it for another 2 weeks, the total sleep time could reach more than 8 hours. The patient was in good mental state, felt energetic, and had significantly improved work efficiency. Followed up for 6 months without recurrence.

[0068] Case 3: A 63-year-old female patient with a history of coronary heart disease, diabetes, and vertigo had suffered from insomnia for nearly 10 years. She woke easily after waking and had difficulty falling asleep again, sometimes even staying awake all night. She also suffered from headaches, dizziness, and irritability. She had been taking diazepam for a long time and had sought medical attention for poor sleep quality for the past three months. After two weeks of taking the Sixteen-Ingredient Azalea Flower Pills of the present invention, her waking symptoms significantly improved. After another two weeks of treatment, her sleep time decreased, her waking symptoms improved, she could fall asleep quickly after waking, and her sleep returned to normal. Her headaches and dizziness disappeared. One-year follow-up revealed no recurrence.

[0069] The use of the sixteen-flavor azalea pill of the present invention in treating insomnia has been confirmed by animal experiments to be able to increase the secretion of sleep-promoting neurotransmitters. Clinical verification has shown that it has a good therapeutic effect on insomnia, has no withdrawal reaction, and is not prone to relapse after being cured, and is worthy of clinical promotion.

Claims

1. Use of Sixteen-flavor Azalea Pills in the preparation of medicines for preventing and treating insomnia.

2. The use according to claim 1, characterized in that The insomnia includes short-term insomnia and chronic insomnia.

3. The use according to claim 1, characterized in that The insomnia is chronic insomnia.

4. The use according to any one of claims 1 to 3, characterized in that The prescription composition of the sixteen-flavor azalea pill is: 400 parts of azalea, 100 parts of pomegranate seeds, 20 parts of cardamom, 50 parts of cinnamon, 75 parts of travertine, 80 parts of safflower, 50 parts of costus root, 10 parts of nutmeg, 50 parts of Yunnan camphor, 30 parts of grape, 35 parts of crab, 50 parts of ligado, 30 parts of longan, 20 parts of cloves, 40 parts of jujube, and 50 parts of liquorice.

5. The use according to claim 4, characterized in that The preparation method of the sixteen-ingredient azalea pill is as follows: each Chinese medicinal material is crushed into fine powder, sieved, mixed, soaked in water, and dried to obtain brown water pills, each pill weighing 0.5g.

6. The use according to claim 1, wherein The dosage of the Sixteen-flavor Azalea Pill is 2 to 2.5 g each time, once a day, before bedtime.

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