Application of orifice-opening and deafness-removing pill in preparation of anti-dizziness drug

Abstract

The invention relates to the technical field of medicines, in particular to novel application of orifice-opening and deafness-removing pills in preparation of anti-dizziness medicines. Experiments prove that the administration group can remarkably shorten the standing time consumption of a vertigo mouse caused by movement on the horizontal rod and reduce the vertigo response index, so that the movement vertigo model mouse can stand stably on the horizontal rod more quickly; abnormal changes of indexes such as ACTH, NE and CREB in mouse serum and BDNF, CREB, 5-HT and DA in brain caused by motion vertigo can be remarkably reversed. Therefore, the orifice-opening and deafness-removing pill has an obvious anti-dizziness effect, can be used as an active ingredient for preparing the anti-dizziness medicine, and is an effective treatment medicine especially for dizziness induced by movement. According to the invention, new indications of the orifice-opening and deafness-removing pill except deafness, tinnitus and otitis media are expanded. In anti-dizziness treatment, compared with dizziness stop, the traditional Chinese medicine composition can avoid digestive system reaction, cardiovascular reaction, central nervous system reaction and other side effects caused by dizziness stop.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a new application of Tongqiao Erlong Pills in the preparation of anti-vertigo medicines. Background Art

[0002] Vertigo is a kind of motion or positional illusion caused by the body's spatial positioning disorder. The maintenance of human balance requires information input from the vestibular, visual and proprioceptive systems, as well as the complex connection and integration between the peripheral and central nervous systems, and the vestibular system plays a leading role in maintaining body balance. The causes of vertigo may involve lesions in various parts of the body. In addition to organic lesions such as ear-related, neurogenic, and central lesions, the vestibular system causes a series of reactions such as dizziness, nausea, vomiting, and sweating under external stimulation, which are also common causes of vertigo, such as motion sickness and benign paroxysmal positional vertigo. Motion sickness is a series of physiological reactions of the human body to the wrong perception of the state of motion, mainly caused by the conflict of information from the vestibular, visual and proprioceptive systems, and is common when riding in a boat, car, airplane or other means of transportation. Benign paroxysmal positional vertigo is a peripheral vestibular disease induced by changes in the head position relative to the direction of gravity, manifested by repeated episodes of transient vertigo.

[0003] Tongqiao Erlong Pills are a traditional Chinese medicine preparation, which originated from the famous ancient prescription "Xuanming Lunfang" written by Liu Wansu of the Jin Dynasty. It belongs to the national basic medicine for ear diseases and the national medical insurance Class A medicine. Tongqiao Erlong Pills produced by Hebei Yongfeng Pharmaceutical Co., Ltd., with approval number Z13020411, contains 12 kinds of Chinese medicine ingredients: Bupleurum chinense, Gentiana scabra, Aloe vera, Rhubarb, Scutellaria baicalensis, Indigo naturalis, Arisaema consanguineum (fried with alum), Aucklandia lappa, Citrus aurantium (fried with vinegar), Tangerine peel, Angelica sinensis, Gardenia jasminoides (fried with ginger). This medicine has the effects of clearing the liver and purging fire, clearing the orifices and moistening the bowels. At present, it is mainly used in clinical practice to treat ear symptoms caused by liver and gallbladder damp-heat and liver yang hyperactivity. No research has shown the efficacy of Tongqiao Erlong Pills in motion sickness and benign paroxysmal positional vertigo. Summary of the invention

[0004] 1. Technical issues to be resolved

[0005] In view of the above-mentioned shortcomings and deficiencies of the prior art, the present invention provides the use of Tongqiao Erlong Pills in the preparation of anti-vertigo drugs, thereby expanding the application scope of Tongqiao Erlong Pills.

[0006] (II) Technical solution

[0007] The invention relates to the use of Tongqiao Erlong Pills as an active ingredient in the preparation of an anti-vertigo drug, wherein the vertigo is motion-induced vertigo.

[0008] According to a preferred embodiment of the present invention, the vertigo includes motion sickness and benign paroxysmal positional vertigo.

[0009] According to a preferred embodiment of the present invention, the vertigo is motion sickness induced by riding in a car, boat or plane, and benign paroxysmal positional vertigo induced by changes in head position.

[0010] According to a preferred embodiment of the present invention, the medicine includes Tongqiao Erlong Pills, Tongqiao Erlong Pills powder or a water dispersion of Tongqiao Erlong Pills powder.

[0011] According to a preferred embodiment of the present invention, the drug is an oral preparation.

[0012] In terms of disease-inducing factors, motion sickness and benign paroxysmal positional vertigo are both motion-induced vertigo. Movement factors include riding in a car, boat, or plane, and also include being in a certain specific body position, such as lying down, sitting up, looking up to pick up objects, lowering the head, turning the head, or turning over. The vertigo induced by riding in a car, boat, or plane is called motion sickness, and the short-term vertigo induced by a certain specific body position is called benign paroxysmal positional vertigo. Motion sickness and benign paroxysmal positional vertigo may be related to abnormal stimulation or signal processing of the vestibular system.

[0013] (III) Beneficial effects

[0014] The mouse motion vertigo model was used to investigate the anti-vertigo effect of Tongqiao Erlong Pills on vertigo caused by motion stimulation in mice. The mouse motion vertigo model was established by low-speed centrifuge. Before the low-speed centrifugation to establish the motion vertigo model in mice, Tongqiao Erlong Pills powder water dispersion was used for gavage to healthy mice. High, medium and low dose groups were set up, and the dosages were 1, 2 and 4 g crude drug / kg.day, respectively. After 7 consecutive days of administration, the mice were placed in a low-speed centrifuge and centrifuged at 250r / min for 5min. The mice were immediately placed on a horizontal rod with a length of 60cm and a diameter of 0.8cm. The shortest time from the end of centrifugation to the end of standing on the rod and the dizziness reaction index within 2min after the end of rotation were recorded. Experiments have shown that each drug group can significantly shorten the time it takes for dizzy mice to stand on the horizontal rod, allowing the motion dizziness model mice to stand on the horizontal rod faster, and can significantly reduce the dizziness reaction index; each drug dosage group can reverse the abnormal changes in ACTH, NE, CREB in mouse serum and BDNF, CREB, 5-HT, DA and other indicators in the brain to varying degrees. Experiments have shown that the anti-vertigo effect of the Tongqiao Erlong Pills group is equivalent to that of the commercially available drug Xuanyunting (Difenidol Hydrochloride Tablets). This proves that Tongqiao Erlong Pills can be used as an active ingredient to prepare drugs for anti-vertigo, especially motion sickness and benign paroxysmal positional vertigo.

[0015] The invention expands the new indications of the traditional Chinese medicine Tongqiao Erlong Pills in addition to deafness, tinnitus and otitis media. In anti-vertigo treatment, compared with Xuanyunting, the invention can avoid the side effects of digestive system reaction, cardiovascular reaction and central nervous system reaction that Xuanyunting easily induces. DETAILED DESCRIPTION

[0016] In order to better explain the present invention and facilitate understanding, the present invention is described in detail below through specific implementation methods. The experimental materials used in the following embodiments are described as follows:

[0017] 1. Experimental Materials

[0018] (1) Experimental drugs

[0019] Tongqiao Erlong Pills, abbreviated as TQEL. This product is a white, shiny water pill, which turns green-brown after removing the coating; bitter. Intended clinical indications: clearing the liver and purging fire, clearing the orifices and moistening the bowels. It is used for liver meridian heat, dizziness, deafness, ear swelling and pain, red eyes and bitter mouth, chest fullness and stuffiness, and dry stool. Content and specifications: Each 100 pills weigh 6g, containing 13.62mg / g of baicalin. Provided by Hebei Yongfeng Pharmaceutical Co., Ltd., drug batch number: 10423020214.

[0020] (2) Positive control drug

[0021] Difenidol hydrochloride tablets (Vertigo stop): This product is a film-coated tablet, which appears white after removing the coating. It is used to prevent and treat dizziness, nausea, and vomiting caused by various reasons or diseases, such as motion sickness when riding in a car, ship, or plane. Specifications: 25mg / tablet, 24 tablets / box, oral, adult, 25mg-50mg once for the treatment of motion sickness, 3 times a day. To prevent motion sickness, it should be taken 30 minutes before departure. Store in a sealed container. Batch number: 230206, production date: 2023.02.27, valid until: 2026.01. Provided by Hunan Qianjin Xiangjiang Pharmaceutical Co., Ltd.

[0022] (3) Other reagents

[0023] Sodium carboxymethyl cellulose: analytical grade, 500g, white powder or granules, hygroscopic, should be sealed and stored in a dry place, provided by Tianjin Damao Chemical Reagent Factory, batch number: 20230301.

[0024] (4) Experimental animals

[0025] The mouse strain was KM strain, SPF grade, 72 males, 3-4 weeks old, weighing 18-20 g, and the animal source was purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.

[0026] Feeding conditions: Mice were caged, 5 mice / cage, and kept in the IVC system of the Drug Quality Control and Efficacy Evaluation Laboratory of Shijiazhuang College, with 12 hours of light / day, temperature of 20-23℃, and relative humidity of 40% to 60%. The quarantine period for newly received animals is 3 days. During the quarantine period, observe the animals' drinking water, food intake, health status, and whether there are signs of disease and death. The mouse feed is a complete granular feed provided by Sibefu (Beijing) Biotechnology Co., Ltd. Sterilized purified water, free drinking water. Sterilized water is replaced 2-3 times a week. Bedding: purchased from Sibefu (Beijing) Biotechnology Co., Ltd., and replaced twice a week. The marker pen is marked with an animal marker pen.

[0027] Example 1

[0028] This example verifies the efficacy of Tongqiao Erlong Pills in anti-vertigo, and the experimental method is as follows:

[0029] (1) Preparation

[0030] Preparation of diphenhydramine solution: Grind diphenhydramine (diphenhydramine hydrochloride tablets) into powder and disperse it in a solvent to prepare a solution with a concentration of 1.25 mg / mL.

[0031] Preparation of TQEL-L low-dose solution: Grind Tongqiao Erlong Pills TQEL into powder, disperse it in a solvent to prepare a solution with a concentration of 0.05 g powder / mL.

[0032] Preparation of TQEL-M medium-dose solution: Grind Tongqiao Erlong Pills TQEL into powder, and disperse it in a solvent to prepare a solution with a concentration of 0.1 g powder / mL.

[0033] Preparation of TQEL-H high-dose group solution: Grind Tongqiao Erlong Pills TQEL into powder, disperse it in a solvent to prepare a solution with a concentration of 0.2 g powder / mL.

[0034] The above drug solutions were prepared before the experiment and stored at 2-8°C for future use. The solvents were all 0.5% CMC-Na (sodium carboxymethyl cellulose) solution. The dosage was 20 ml / kg body weight, and the average weight of mice was 20 g / mouse.

[0035] (2) Grouping and processing

[0036] The mice were randomly divided into groups according to the standing time after exercise dizziness, and the drugs were administered for 7 consecutive days according to the following administration method. The grouping of mice and the administration method are shown in Table 1. The standing time (s) of each group of mice when grouped is recorded in Table 3.

[0037] Table 1: Grouping and treatment methods for each group

[0038]

[0039] Note: All the above groups were given drugs by gavage, and the drugs were given according to body weight at 8-9 am every day, once a day, for 7 consecutive days. The normal group was fed normally every day and no modeling was performed. The model group was gavaged with the same mass of solvent every day before modeling, and the modeling was performed 7 days after gavage.

[0040] (3) Experimental methods

[0041] After administration according to the above method, 30 minutes after the last administration, except for the normal control group, the mice in the other groups were placed in a 50ml centrifuge tube with cotton pads around and at the bottom (the bottom had air holes), and the centrifuge tube was tightly covered with a plastic tube. After centrifugation at 250r / min for 5 minutes in a low-speed centrifuge, the mice were immediately placed on a horizontal rod with a length of 60cm and a diameter of 0.8cm. The shortest time taken for the mice to stand firmly on the rod after the end of centrifugation and the dizziness reaction index within 2 minutes after the end of rotation were recorded. The dizziness reaction index is based on the number of particles observed in the feces of the mice after receiving dizziness stimulation, plus other indicators such as urination, piloerection and trembling, and the dizziness reaction index is calculated. The dizziness reaction scoring standard is shown in Table 2, and the dizziness reaction index is recorded in Table 3.

[0042] Table 2: Scoring criteria for dizziness reaction

[0043]

[0044] After the horizontal rod balance experiment, the mice's eyeballs were removed to collect blood and brains, and serum and brain tissue homogenate were prepared to detect the expression levels of neurotransmitters such as ACTH, NE, DA, 5-HT and nerve growth factors BDNF and CREB. The test results are recorded in Table 4.

[0045] All data are expressed as mean ± standard deviation (±s). SPSS statistical software package was used to perform normality test first. For data that conformed to normal distribution, one-way analysis of variance was used for mean comparison. If the variances were equal, the least significant difference method was used for pairwise comparison. If the variances were unequal, Dunnett's T3 test was used for pairwise comparison. If the data did not conform to normal distribution, non-parametric tests were used for statistical analysis.

[0046] (4) Experimental results

[0047] See Table 3:

[0048] The experimental results showed that after treatment with centrifuge tube, mice showed dizziness reactions such as unstable standing, erect hair, trembling, rotation, increased urination and defecation, and the time they could stand on the horizontal bar was significantly prolonged. During the experiment, there was no significant difference in the weight of mice among the groups (indicating that they were well comparable, and TQEL gavage did not have a significant adverse effect on the gastrointestinal tract of mice). Compared with the model group, Vertigo Stop could significantly shorten the time that dizzy mice caused by exercise could stand on the horizontal bar (p<0.01) and reduce the dizziness index (p<0.01). The time that mice treated with low, medium and high doses of TQEL could stand on the horizontal bar was 370.5±152.9s, 225.6±101.8s and 231.9±137.4s, respectively, and the dizziness index was 1.683±0.542, 1.400±0.490 and 1.317±0.422, respectively. By comparison, it can be seen that compared with the model group, the standing time of dizzy mice treated with each dose group of TQEL was significantly shortened on the horizontal rod, with statistically significant differences (p<0.05 or p<0.01); the dizziness reaction index was significantly reduced (p>0.05, p<0.01, p<0.01), showing a significant dose-dependent relationship. The dizziness reaction index decreased more significantly with the increase of TQEL dosage. Among them, the mice treated with the medium and high dose groups of TQEL achieved comparable effects with Vertigo Stop in shortening the standing time on the horizontal rod and reducing the dizziness reaction index.

[0049] Table 3: Effects of TQEL on body weight, standing time and dizziness index of mice with motion dizziness

[0051]

[0052] Note: Compared with the model group, ** indicates P < 0.01, * indicates P < 0.05.

[0053] Table 4: Effects of TQEL on the levels of serum ACTH, NE, CREB and brain tissue BNDF, CREB, 5-HT, and DA in dizzy mice

[0054]

[0055] Note: Compared with the model group, **: P<0.01, *: P<0.05, △△ :P<0.01.

[0056] As can be seen from Table 4, compared with the normal control group, exercise vertigo can lead to a significant increase in ACTH in the serum of mice, a significant decrease in NE and CREB, and a significant decrease in BDNF, CREB, 5-HT, and DA in the brain. Vertigo can significantly correct the changes in the above indicators. Except for CREB in serum, there are significant statistical differences compared with the model group (p<0.05); the low, medium, and high dose groups of TQEL have similar effects to Vertigo, and can reverse the abnormal changes of the above indicators to varying degrees, and have a significant dose-dependent relationship. The effect increases with the increase of dose. The effects of the high dose group on the above indicators are significantly different from those of the model group (p<0.05 or p<0.01).

[0057] 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 above embodiments, those skilled in the art should understand that the technical solutions described in the above embodiments may still be modified, or some or all of the technical features therein may be replaced by equivalents. These modifications or replacements, or the technical features in the above embodiments may be combined in the manner described in the embodiments if they do not conflict with each other, and these modifications, replacements or combinations do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of Tongqiao Erlong Pills as an active ingredient in the preparation of an anti-vertigo drug, characterized in that: The vertigo is motion-induced vertigo.

2. The use according to claim 1, characterized in that: The vertigo includes motion sickness and benign paroxysmal positional vertigo.

3. The use according to claim 2, characterized in that: The motion sickness is induced by riding in a car, boat or plane; the benign paroxysmal positional vertigo is a peripheral vestibular disease induced by changes in head position and characterized by repeated episodes of transient vertigo.

4. The use according to claim 1, characterized in that: The medicine includes Tongqiao Erlong Pills, Tongqiao Erlong Pills powder or Tongqiao Erlong Pills powder water dispersant.

5. The use according to claim 1, characterized in that: The medicine is an oral preparation.

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