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

Abstract

The present invention relates to the use of Sixteen-Ingredient Azalea Pill in the prevention and treatment of neuralgia. Animal experiments have shown that Sixteen-Ingredient Azalea Pill can significantly increase the pain threshold of mice to thermal stimulation and the mechanical pain threshold of rats with primary trigeminal neuralgia, inhibit inflammatory responses, and increase the levels of the neurotransmitters 5-HT and GABA in brain tissue. Clinical study results show that the drug treatment of the present invention is highly effective and is not prone to recurrence after cure. The present invention provides a direction for the new application and development of Sixteen-Ingredient Azalea Pill, broadening its clinical application.

Description

Technical Field

[0001] The invention relates to the field of traditional Chinese medicine, and in particular to application of Sixteen-flavor Azalea Pill in preventing and treating trigeminal neuralgia. Background Art

[0002] Trigeminal neuralgia can be divided into primary and secondary types. Primary trigeminal neuralgia (PTN), also known as idiopathic trigeminal neuralgia, is a paroxysmal, severe pain in the head, face, and oral cavity within the distribution area of ​​the trigeminal nerve. Its etiology and pathogenesis remain unclear. Secondary trigeminal neuralgia, also known as symptomatic trigeminal neuralgia, is often a clinical symptom of a specific disease and is caused by tumors, inflammation, trauma, or lesions in the cerebellopontine angle and its adjacent areas, as well as lesions in the trigeminal nerve branches.

[0003] According to domestic and international literature, the incidence of PTN is approximately 47.8 to 182 per 100,000 people. It is most common in middle-aged and elderly people, with 70% to 80% occurring in adults over 40 years old, peaking between 48 and 69 years old, and predominantly in women. This disease is stubborn, recurrent, and difficult to completely cure, negatively impacting patients' physiological functions, physical and mental health, and quality of life while also placing a significant financial burden on families and society.

[0004] Primary trigeminal neuralgia lacks a specific name in ancient Chinese medical texts. Based on its clinical symptoms, it falls under the categories of "facial pain," "jaw pain," "oral pain," "cheek pain," "facial wind," and "head wind." The description of "jue ni" in the "Huangdi Neijing Suwen," dating back over 2,000 years, is similar to the symptoms of trigeminal neuralgia. Similar symptoms have since been described in over 20 ancient texts, including the "Nanjing," "Zhangshi Yitong," "Benshi Fang," "Rumen Shiqin," and "Zhengzhi Zhunsheng."

[0005] In his "Continuation of Famous Doctors' Cases", Wei Zhixiu, a doctor in the Qing Dynasty, described the disease as "suddenly one day, the patient suffers from pain in the lips, cheeks, and hairline. He cannot open his mouth and has difficulty speaking. Eating and drinking are also affected. The forehead and cheeks are often painful and feel sticky when touched." These symptoms are very similar to what we call PTN in modern times.

[0006] According to Traditional Chinese Medicine (TCM), the causes of PTN are often linked to exogenous pathogenic factors and emotional imbalance. Wind-cold pathogens can invade the Yangming, Taiyang, and Shaoyang meridians of the face, leading to stagnation of tendons and blood vessels and obstruction of Qi and blood. Alternatively, wind-heat toxic pathogens can invade the face, stagnate Qi and blood in the meridians, and prevent smooth flow. Emotional imbalance, trauma, or prolonged illness can also lead to obstruction of Qi and blood in the facial meridians, resulting in "facial pain."

[0007] The main drugs used to treat PTN include antiepileptic drugs, benzodiazepine tranquilizers, antispasmodics, and neurotrophic drugs. However, these drugs are dose-dependent and have related complications when used for a long time. In addition, the analgesic effect weakens as the duration of use increases. In addition, these drugs should not be stopped suddenly after use, so as to avoid the need for a larger dose to achieve the therapeutic effect before stopping the drug when the pain recurs. Therefore, research on alternative drugs is very necessary.

[0008] In Tibetan medicine, trigeminal neuralgia is called "Yamagosen." The primary cause is the blockage of Qi and blood circulation. In Tibetan medicine, "Qi" is equivalent to "Qi" and "Wind" in Traditional Chinese Medicine, but its actual role is broader. Physiologically, Qi and Wind govern respiration, limb movement, sensory perception, circulation, and excretion, serving as the driving force behind normal human function. Clinically, various illnesses arise from an imbalance of Qi within and without the body's internal and external Qi. Trigeminal neuralgia is associated with the development of head Qi. Long-term dietary and lifestyle issues, as well as emotional distress, can lead to Qi imbalances, resulting in the formation of "Yamagosen worms," ​​or bloodworms, in the blood. Tibetan medicine considers Yamagosen, or "Yama worms," ​​to be malignant bacteria that invade the brain. In Tibetan medicine, "worms" are categorized as external and internal. Yama worms belong to the category of internal worms, parasitic within human blood vessels and circulate throughout the body. Yama worm disease is more likely to occur in the head, upper palate, cheeks, gums, ears, nose and other parts of the body, which is consistent with the distribution of the trigeminal nerve. White Yama worm, that is, the imbalance of Qi and blood caused by the imbalance of Long; Black Yama worms are mainly caused by blood worms in the blood circulation; Flower yama is caused by a combination of vascular imbalance and bloodworms. Medically, the symptoms of yama include cerebral neuritis and trigeminal neuralgia. Symptoms include restlessness, tooth and cheek pain, yellow nasal discharge, itchy and painful eyes, blurred vision, swelling between skull sutures, severe chronic pain, and migraines.

[0009] 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 due to 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

[0010] The present invention aims to provide a new use of Sixteen-flavor Azalea Flower Pill in treating neuralgia, especially in preventing and treating trigeminal neuralgia.

[0011] The prescription composition of the Sixteen-flavor Azalea Flower Pill of the present invention is as follows:

[0012] 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.

[0013] The inventors found that the Sixteen-Ingredient Azalea Pill can quickly and effectively cure trigeminal neuralgia without withdrawal reactions and is safe and convenient 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.

[0014] Animal experimental studies have shown that Sixteen-flavor Azalea Pills can significantly increase the pain threshold of thermal stimulation in mice, and significantly increase the mechanical pain threshold of rats with primary trigeminal neuralgia model, inhibit inflammatory response, and increase the levels of neurotransmitters 5-HT and GABA in brain tissue.

[0015] The inventors have found in long-term clinical practice that taking 16-flavor azalea pills 2g / time, three times a day, for 7 consecutive days can effectively treat trigeminal neuralgia, especially primary trigeminal neuralgia, and has excellent efficacy without withdrawal reaction.

[0016] The present invention provides a new development direction for the Sixteen-flavor Azalea Pill and broadens its clinical application. Secondly, the present invention has a short treatment course, high efficacy, and is not prone to recurrence after cure. DETAILED DESCRIPTION

[0017] Example 1 Painful tail-flick experiment in mice

[0018] SPF male ICR mice weighing 20-25g were acclimated for 3 days. The tail tip was marked with a marker 4 cm from the tip of the mouse's tail. The marked area on the tail was placed over the light source hole on the illumination board. The lamp power was set to 36.0W. A YLS-12A tail light analgesia meter automatically recorded the time from light onset to tail flicking due to pain. Baseline values ​​were measured before dosing. Two measurements were taken, with a 30-minute interval between the two, and the average was calculated. If the time from light onset to tail flicking due to pain exceeded 5 seconds, the mice were considered unqualified and eliminated. Qualified mice were randomly divided into 10 groups. The mice were randomly divided into a normal control group (0.5% CMC-Na 10 ml / kg), a positive control group (peach leaf 675 mg / kg), a low-dose Sixteen-Ingredient Azalea Pill group (450 mg / kg), a medium-dose Sixteen-Ingredient Azalea Pill group (900 mg / kg), and a high-dose Sixteen-Ingredient Azalea Pill group (1800 mg / kg), with 10 mice in each group. Mice were gavage-administered for three consecutive days. One hour after the last dose, pain threshold testing was performed using the same method as above. The duration of tail-flicking in pain was recorded, and the percentage increase in pain threshold was calculated as (pain threshold of mice in the treatment group - pain threshold of mice in the control group) / pain threshold of mice in the control group × 100%.

[0019] Data statistical processing: Experimental data are expressed as mean ± standard deviation (± s ) indicates that the two-sample equal variance assumption is made for the variables t Inspection, with P <0.05 was considered a statistically significant difference.

[0020] Experimental results:

[0021] After drug administration, the time from light onset to pain-induced tail-flicking in mice was significantly prolonged (P < 0.001), indicating that the drug can elevate the pain threshold of mice induced by thermal stimulation. Compared with the normal control group, the percentage increase in pain threshold in all drug groups was significantly different (P < 0.001). The 450 mg / kg dose of Sixteen Azalea Pill group showed a lower percentage increase in pain threshold than the 650 mg / kg positive control group of Hantao leaf tablets (P < 0.01). With increasing doses, the 900 mg / kg and 1800 mg / kg doses of Sixteen Azalea Pill showed significantly greater percentage increases in pain threshold than the 650 mg / kg positive control group of Hantao leaf tablets (P < 0.001). However, no statistically significant differences were found between the medium and high dose groups. This suggests that Sixteen Azalea Pill has a significant inhibitory effect on pain induced by surface thermal stimulation in mice.

[0022] Table 1 Effects on the pain threshold of tail-flick in mice

[0023]

[0024] Compared with before administration, * P<0.001; compared with the normal group,△ P<0.001; compared with the positive group, ▲ P<0.05, ▲▲ P<0.01

[0025] Summary: Sixteen-flavor azalea pill can increase the pain threshold of mice's tail-flicking, indicating that it has a very significant inhibitory effect on the pain caused by thermal stimulation of the body surface in mice.

[0026] Example 2 Trigeminal neuralgia experiment in rats

[0027] SD rats were acclimated for 3 days and trained before the experiment. A Von Frey pain tester was used to continuously stimulate the whisker pads of the rats three times, with a 30-second interval between each stimulation, until the rats became calm. Sixty rats with a pain threshold greater than 15g for 3 days were randomly divided into a sham operation group (2% CMC-Na 10ml / kg), a model control group (2% CMC-Na 10ml / kg), a positive control group (peach leaf 450mg / kg), a low-dose Sixteen-Ingredient Azalea Pill group (300mg / kg), a medium-dose Sixteen-Ingredient Azalea Pill group (600mg / kg), and a high-dose Sixteen-Ingredient Azalea Pill group (1200mg / kg), with 10 rats in each group.

[0028] The ION-CCI trigeminal neuralgia model was established under sodium pentobarbital anesthesia and in the supine position. A longitudinal incision approximately 1 cm long was made along the right buccal margin of the mouth toward the nose to expose the infraorbital nerve. The surrounding tissue was separated and loosely ligated with two 4.0 chromic sutures, 2 mm apart. The ligature was tightened to only reduce the nerve diameter (visibly or microscopically) to delay nerve conduction, but not to completely block conduction and ensure unobstructed blood circulation. Postoperatively, the incision was sutured with 4.0 silk sutures. The sham group underwent the same surgery except that the infraorbital nerve was not ligated. All procedures were performed under aseptic conditions, and no antibiotics were required before or after surgery.

[0029] The corresponding drugs were administered by gavage starting on the 14th day after surgery. The sham-operated group was given 0.5% CMC-Na by gavage at a volume of 10 ml / kg, once a day for 14 consecutive days.

[0030] Mechanical pain thresholds were measured before surgery (day 0), before drug administration (day 14), and 1 hour after the last drug administration (day 28). Rats were placed in a mouse box and allowed to acclimate to the surrounding environment for 10 minutes. Von Frey hairs of varying strengths were then used to stimulate the right whisker pad area of ​​the rats at a frequency of once per second, starting with a minimum of 0.008g and progressing to a maximum of 26g. The mechanical pain threshold of the trigeminal nerve innervated facial area was defined as the minimum of three positive responses out of five stimulations. Positive responses in rats included the following: ① Rapidly scratching and biting the stimulus, exhibiting aggressive behavior; ② Rapidly retreating after being stimulated, curling up against the cage wall or hiding the head and face under the body to avoid further facial stimulation; and ③ Continuously scratching the stimulated facial area, often combined with a backward movement.

[0031] Target Assays: Rats were decapitated, blood was collected, and serum was separated. ELISA was used to measure the levels of the inflammatory factors TNF-α and IL-1β in serum. Rat brain tissue was dissected on ice and immediately frozen in liquid nitrogen at -80°C. The hypothalamus was isolated and homogenized, and the levels of the neurotransmitters 5-HT and γ-GABA in the hypothalamic tissue were measured by ELISA.

[0032] Experimental results:

[0033] 1. Effects on mechanical pain threshold in rats

[0034] The mechanical pain threshold of rats with ION-CCI trigeminal neuralgia model was significantly reduced 14 days after modeling (P<0.001). After drug treatment, the mechanical pain threshold of rats in each drug-treated group was significantly increased (P<0.001). Among them, the mechanical pain threshold of rats in the medium and high-dose groups of Sixteen-flavor Azalea Pill was significantly higher than that in the positive control group (P<0.05), indicating that Sixteen-flavor Azalea Pill has a significant effect on improving the mechanical pain threshold of rats with primary trigeminal neuralgia model.

[0035] Table 2 Effects on mechanical pain threshold of rats

[0036]

[0037] Compared with the sham operation group, * P < 0.01; ** P<0.001; compared with the model group, △ P<0.001; compared with the positive control group, ▲ P<0.05.

[0038] 2. Effects on serum inflammatory factors

[0039] The inflammatory factors TNF-α and IL-1β in rats with ION-CCI trigeminal neuralgia model were significantly increased. After drug treatment, the levels of TNF-α and IL-1β were significantly decreased (P < 0.001). There was no statistical difference in the inflammatory factor levels in the medium and high-dose groups of Sixteen-flavor Azalea Pill compared with the positive control group. There was no statistical difference in the inflammatory factor levels in the high-dose group of Sixteen-flavor Azalea Pill compared with the sham operation group, indicating that Sixteen-flavor Azalea Pill can inhibit the inflammatory response of rats with trigeminal neuralgia model and relieve pain.

[0040] Table 3 Effects on serum inflammatory factors

[0041]

[0042] Compared with the sham operation group, * P < 0.05; ** P<0.01; compared with the model group, △ P < 0.01, △△ P<0.001; compared with the positive control group, ▲ P<0.05, ▲▲ P<0.01.

[0043] 3. Effects on hypothalamic neurotransmitters

[0044] Compared with the sham-operated group, the hypothalamic neurotransmitter levels of 5-HT and γ-GABA in the model rats were significantly decreased, suggesting that the trigeminal neuralgia model established by ION-CCI is neurotransmitter-related. After drug treatment, 5-HT and γ-GABA levels increased in all groups. Compared with the model control group, the low, medium, and high doses of Sixteen-Ingredient Azalea Pill significantly increased 5-HT levels, while the medium and high doses significantly increased γ-GABA levels, suggesting that Sixteen-Ingredient Azalea Pill can inhibit trigeminal neuralgia by increasing neurotransmitter levels in brain tissue.

[0045] Table 4 Effects on hypothalamic neurotransmitters

[0046]

[0047] Summary: Sixteen-flavor azalea pill can inhibit inflammatory response, increase the levels of 5-HT and γ-GABA in brain tissue, increase the pain threshold of rats with primary trigeminal neuralgia model, and relieve trigeminal neuralgia.

[0048] Example 3 Clinical trial study on the treatment of trigeminal neuralgia with Sixteen-flavor Azalea Pill

[0049] Diagnostic criteria: Refer to the diagnostic criteria for "classic trigeminal neuralgia" or primary trigeminal neuralgia in the International Classification of Headaches (3rd Edition) (ICHD-3) published by the Classification Committee of the International Headache Society in 2018: A. Unilateral pain that meets criteria B and C occurs at least three times. B. Occurs within the distribution area of ​​one or more branches of the trigeminal nerve, with no radiating pain outside the distribution area of ​​the trigeminal nerve. C. The pain meets at least three of the following four items: (1) Paroxysmal and recurrent, with a duration ranging from instantaneous to 2 minutes; (2) With a certain degree of severity; (3) The pain is radiating, like an electric shock or sharp stabbing pain; (4) The affected side of the face can be induced by non-noxious stimuli such as slight touch. D. There is no significant clinical evidence of neurological damage other than vascular compression factors. E. It cannot be better explained by other diagnoses in ICHD-3.

[0050] Inclusion criteria: 1. Patients who met the diagnostic criteria for primary trigeminal neuralgia; 2. Patients with recurrent pain in the past month with no obvious relief trend; 3. Aged 40-75 years; 4. Patients who signed the informed consent form.

[0051] Exclusion criteria: 1. Patients with facial pain caused by other diseases such as sinusitis, apical periodontitis, and cranial neuropathy; 2. Women who are breastfeeding or pregnant; 3. Patients with severe primary diseases or systemic failure of the cardiovascular, cerebrovascular, liver, kidney, and hematopoietic systems, as well as patients with diabetes, malignant tumors, and mental illness; 4. Patients who are participating in other medical trials; 5. Patients who have taken antibiotics within 2 months before the visit.

[0052] The trial enrolled 102 patients with trigeminal neuralgia (43 males and 59 females; mean age, 54.8 ± 9.3 years). The duration of disease ranged from 6 months to 10 years, with a mean of 3.4 ± 4.2 years. They were randomly divided into an observation group (Shiliuwei Dujuanhua Wan, 2 g, three times daily) and a control group (Hantao tablets, 5 tablets, three times daily), with 51 patients in each group. All patients received medication for one week. Pain assessment was performed after the end of treatment.

[0053] 1. NRS score

[0054] The Numerical Rating Scale (NRS) asks patients to circle an integer between 0 and 10 that best represents their pain intensity. The NRS categorizes pain intensity as 0 (no pain), 1-3 (mild pain with no sleep disruption), 4-6 (moderate pain with sleep disruption), and 7-10 (severe pain with severe sleep disruption).

[0055] 2. Traditional Chinese Medicine Symptom Scoring

[0056] The severity and frequency of pain attacks before and after treatment were evaluated using the Traditional Chinese Medicine symptom grading table developed in reference to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines for the Treatment of Trigeminal Neuralgia" issued by the former Ministry of Health.

[0057] Table 5 Quantitative table of TCM symptom classification

[0058]

[0059] 3. Efficacy evaluation

[0060] Table 6 Pain treatment efficacy evaluation criteria

[0061]

[0062] Clinical trial results:

[0063] 1. There was no statistically significant difference in NRS scores between the two groups

[0064] The NRS score of the observation group was 0.73±1.27, and the NRS score of the control group was 0.75±1.57. There was no statistically significant difference in the NRS scores between the two groups (P=0.945).

[0065] 2. Evaluation of TCM symptom efficacy

[0066] There was no significant difference in the total effective rate between the two groups.

[0067] Table 7 Clinical efficacy evaluation

[0068]

[0069] Summary: Sixteen-flavor azalea pill 2g / time, 3 times a day, for 1 week has obvious effect on primary trigeminal neuralgia, and its clinical efficacy is comparable to that of peach leaves.

Claims

1. Use of Sixteen-flavor Azalea Pills in the preparation of a drug for preventing and treating neuralgia, characterized in that: The neuralgia is trigeminal neuralgia.

2. The use according to claim 1, characterized in that The trigeminal neuralgia is primary trigeminal neuralgia.

3. The use according to any one of claims 1 to 2, 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.

4. The use according to claim 3, 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.

5. The use according to claim 1, characterized in that The dosage of the Sixteen-flavor Azalea Pill is 2g each time, 3 times a day.

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