Use of a traditional Chinese medicine composition in treating herpes skin diseases

Abstract

The present application belongs to the technical field of traditional Chinese medicine, and relates to a traditional Chinese medicine composition and application thereof, in particular to application of the traditional Chinese medicine composition in preparation of a medicine for treating herpes skin diseases. The traditional Chinese medicine composition is mainly prepared from ginseng, rehmannia glutinosa, prepared rehmannia root, dogwood fruit, Chinese yam, cortex moutan, alisma orientalis, poria cocos, radix asparagi and radix ophiopogonis. The present application is further development of a new application of the marketed product ginseng oral liquid for consolidating the body. Pharmacological experiments show that the ginseng oral liquid for consolidating the body prepared from the traditional Chinese medicine composition can significantly shorten the time for swelling, scabbing and healing of herpes; can reduce damage to the nervous system and stimulation to inflammatory cells, and eliminate or improve neuralgia caused by herpes zoster.

Description

Technical Field

[0001] This invention relates to a novel use of a traditional Chinese medicine composition, specifically its use in the preparation of drugs for treating herpetic skin diseases, belonging to the field of traditional Chinese medicine technology. Background Technology

[0002] Herpes refers to localized, lacunar lesions containing fluid that are raised above the skin surface. Those less than 1 cm in diameter are called vesicles, and those greater than 1 cm are called bullae. There are many causes of herpes symptoms, mainly including the following: 1. Infectious causes, such as herpes simplex, herpes zoster, chickenpox, hand-foot-mouth disease, tinea pedis, tinea corporis, erysipelas, and toxic epidermal necrolysis; 2. Allergic causes, such as papular urticaria, contact dermatitis, autosensitization dermatitis, pompholyx, drug eruption, and bullous erythema multiforme; 3. Hereditary causes, such as familial chronic benign pemphigus, bullous epidermal necrolysis, pigmentary incontinence, and enteropathic acrodermatitis; 4. Autoimmune causes, such as pemphigus, bullous pemphigoid, herpes gestationis, dermatitis herpetiformis, and pemphigus herpetiformis; 5. Parasitic causes, such as wax beetle dermatitis, rove beetle dermatitis, and scabies; 6. Physical causes, such as frostbite, burns, and prickly heat; 7. Metabolic causes, such as porphyria.

[0003] Herpes simplex and herpes zoster are herpesvirus skin diseases. Herpes simplex is caused by the human herpes simplex virus (HSV), which mainly infects any part of the body, including the skin and damaged skin, especially the skin and mucous membranes of the mouth, eyes, and other oral cavities. The disease is prone to recurrence. Herpes zoster is an acute herpetic skin disease caused by the varicella-zoster virus. The initial infection manifests as chickenpox or a latent infection. Later, the virus enters the sensory nerve endings in the skin and gradually moves along the nerve fibers towards the center, eventually remaining dormant in the ganglia of the dorsal root of the spinal cord for a long time. Once the body's resistance decreases or cellular immunity weakens, the virus can be reactivated, causing inflammation and necrosis of the affected ganglia, resulting in neuralgia.

[0004] Modern medicine treats shingles primarily with ganciclovir, mecobalamin, and vitamins, with definite efficacy, but often leaves postherpetic neuralgia as a sequela. Shingles falls under the category of "snake-like sores" or "waist-encircling fire rash" in traditional Chinese medicine. Traditional Chinese medicine believes it is related to dietary imbalances, spleen dysfunction, and emotional distress; its pathogenesis mainly involves liver qi stagnation, internal damp-heat in the spleen and stomach, overflowing to the skin, combined with external pathogenic factors, leading to dampness, heat, and fire toxins in the skin.

[0005] Pemphigus is a group of autoimmune vesicular diseases of the skin and mucous membranes. Patients have autoantibodies against adhesion molecules in the desmosomes of epidermal spinous cells in their serum. There are two main types of pemphigus, classified into four typical subtypes: pemphigus vulgaris, pemphigus vesicola, pemphigus foliaceus, and pemphigus erythematosus. All types of pemphigus share common characteristics in their skin and mucous membrane lesions. Vesicles and bullae occur on erythematous or seemingly normal skin, with loose vesicle walls and a positive Nikolsky sign (epidermal dissociation). The vesicle walls are thin and easily rupture, forming erosions covered with pale yellow crusts. In addition to affecting the skin throughout the body, the mucous membranes of the mouth, pharynx, larynx, esophagus, vulva, and anus are also frequently involved, manifesting as vesicles and erosions.

[0006] In traditional Chinese medicine, pemphigus is called "fire-red sore", "infiltrating sore", or "spider sore". It is mostly caused by excessive heart fire, dampness in the spleen, and the invasion of wind-dampness-heat toxins. The internal and external evils combine and cannot be resolved, so they emerge on the skin. Alternatively, it can be caused by prolonged illness leading to damp-heat and dryness, which scorches the body fluids and depletes qi, resulting in damage to both qi and yin.

[0007] Traditional Chinese medicine has unique advantages in treating diseases such as herpes zoster and pemphigus. Guided by the principle of syndrome differentiation and treatment, it starts from the etiology and pathogenesis, takes a holistic approach, and takes into account individual differences, achieving good results in clinical practice. Summary of the Invention

[0008] This invention is a further development of new uses for the existing traditional Chinese medicine product "Ginseng Strengthening Oral Liquid" based on clinical feedback that it can alleviate the clinical symptoms of patients with pemphigus. Specifically, it is a new use of Ginseng Strengthening Oral Liquid in the treatment of herpetic skin diseases.

[0009] Ginseng Strengthening Oral Liquid is prepared from ginseng, rehmannia root, poria cocos, peony bark, prepared rehmannia root, cornus officinalis, yam, alisma plantago-aquatica, asparagus root, and ophiopogon japonicus. It has the effects of nourishing yin and replenishing qi, strengthening the body's foundation and nourishing the source. It is used for yin deficiency and qi weakness, consumptive cough, palpitations and shortness of breath, bone steaming fever, lower back pain and tinnitus, seminal emission and night sweats, and constipation. Ginseng Strengthening Oral Liquid is an exclusive product of Lunan Houpu Pharmaceutical Co., Ltd., with the approval number "National Medicine Approval Number Z10940013".

[0010] The purpose of this invention is to provide a new traditional Chinese medicine product for treating herpetic skin diseases, especially herpes zoster and pemphigus, thereby increasing patients' choice of medication.

[0011] One of the objectives of this invention is to provide the use of a traditional Chinese medicine composition mainly composed of ginseng, rehmannia root, prepared rehmannia root, cornus officinalis, yam, peony bark, alisma rhizome, poria cocos, asparagus root, and ophiopogon root in the preparation of a drug for treating herpetic skin diseases.

[0012] The herpetic dermatitis described in this invention can be caused by viral infection and / or autoimmune disease.

[0013] The herpetic skin diseases described in this invention include, but are not limited to, herpes virus skin diseases and vesicular skin diseases.

[0014] Preferably, the herpes virus skin diseases include, but are not limited to, herpes simplex, herpes zoster, and chickenpox;

[0015] More preferably, the herpes virus skin disease refers to herpes zoster.

[0016] Preferably, the vesicular skin diseases include, but are not limited to, pemphigus, subepidermal pemphigus, and other types of pemphigus.

[0017] More preferably, the pemphigus includes, but is not limited to, pemphigus vulgaris, pemphigus vesicola, pemphigus foliaceus, and pemphigus erythematosus.

[0018] Alternatively, the subepidermal pemphigus includes, but is not limited to, bullous pemphigoid, cicatricial pemphigoid, and acquired bullous epidermolysis bullosa.

[0019] The second objective of this invention is to provide the use of the above-mentioned traditional Chinese medicine composition in the preparation of a drug for treating complications of herpes zoster; preferably, the complication of herpes zoster refers to postherpetic neuralgia.

[0020] The third objective of this invention is to provide a traditional Chinese medicine preparation containing the above-mentioned traditional Chinese medicine composition, wherein the traditional Chinese medicine composition can be prepared into a clinically acceptable dosage form directly or by adding pharmaceutically acceptable excipients through conventional processes.

[0021] Preferably, the clinically acceptable dosage form is one or more of capsules, tablets, granules, pills, and oral liquids;

[0022] More preferably, the clinically acceptable dosage form is an oral liquid.

[0023] More preferably, the oral liquid is a ginseng tonic oral liquid.

[0024] Pharmacological experiments show that:

[0025] 1. The herbal composition of the present invention can reduce pain sensation in rabbits with shingles, and significantly shorten the time for swelling reduction, scab formation and healing of herpes.

[0026] 2. The traditional Chinese medicine composition of the present invention can reduce the PWT value of rats with postherpetic neuralgia, reduce the serum IL-6 and TNF-α levels, increase the serum IL-2 level, reduce damage to the nervous system and stimulation of inflammatory cells, and eliminate or improve neuralgia.

[0027] II. Pharmacological Experiments

[0028] The inventor wishes to state that the use described in the present invention is derived from the clinical use feedback of Renshen Guben Oral Liquid. During the clinical use of Renshen Guben Oral Liquid, it was unexpectedly found that for individual patients with pemphigus, Renshen Guben Oral Liquid could, to a certain extent, improve the clinical symptoms of the patients.

[0029] Based on the above clinical use feedback of Renshen Guben Oral Liquid, the inventor has carried out a series of developments on the use of Renshen Guben Oral Liquid in the treatment of herpes dermatoses. To verify the efficacy of Renshen Guben Oral Liquid in the treatment of herpes dermatoses, especially in the treatment of herpes zoster and pemphigus, the inventor has conducted animal experimental studies. Only some experimental models are taken as examples for illustration below. For other types of herpes dermatoses described in the specification, the inventor has also conducted pharmacological experimental studies. The composition of the present invention has good therapeutic effects. For example, Renshen Guben Oral Liquid can significantly reduce the degree of acantholysis in the experimental model of pemphigus vulgaris mice, etc. However, due to space limitations, they will not be described one by one here.

[0030] The inventor wishes to state that the following experimental studies are all carried out on the basis of the proof of drug safety in acute toxicity tests and long-term toxicity tests, and the dosing doses in the experimental studies are all within the safe dose range.

[0031] (1) Therapeutic effect of the traditional Chinese medicine composition of the present invention on rabbits with herpes zoster

[0032] 1. Materials

[0033] 1.1 Animals:

[0034] Rabbits, weighing about 2 kg, experimental animal license number: SYXK (Lu) 2018 0008, provided by Lunan Pharmaceutical Group Co., Ltd., and adaptively fed for one week before the experiment.

[0035] 1.2 Drugs, reagents

[0036] 1.2.1 Drugs

[0037] Commercially available Renshen Guben Oral Liquid (produced by Lunan Houpu Pharmaceutical Co., Ltd., national drug approval number: Z10940013).

[0038] Commercially available acyclovir tablets (national drug approval number: H20045859).

[0039] 1.2.3 Dosage of drugs for rabbits

[0040] Renshen Guben Oral Liquid: 1.86 mL / kg (high dose), 0.93 mL / kg (medium dose), 0.46 mL / kg (low dose);

[0041] Acyclovir tablets: 0.19 g / kg.

[0042] 2. Methods

[0043] 2.1 Virus Collection

[0044] Within 7 days of the onset of the rash in patients with herpes zoster, the contents of the herpes zoster lesions were directly collected, stored in 50% glycerol buffer solution, and kept at low temperature for later use (the herpes zoster contents were provided by a hospital in Linyi).

[0045] 2.2 Virus inoculation

[0046] Male rabbits were observed for two days after hair loss, and were then inoculated separately after confirming no problems; anterior chamber inoculation was used.

[0047] Anterior chamber inoculation: After inserting a 1.0ml syringe with a fine needle into the anterior chamber, remove the syringe and allow a small amount of anterior chamber fluid to flow out from the needle. Once the injection site is confirmed to be the anterior chamber, reconnect the syringe and inject the inoculum at a dose of 0.05–1ml. After injection, wash the eye with 3% boric acid.

[0048] 2.3 Grouping, inoculation, and administration

[0049] Rabbits were randomly divided into 6 groups of 8 each: a blank control group, a model group, an acyclovir tablet group, and three dosage groups of ginseng tonic oral liquid (high, medium, and low).

[0050] After the experiment began, except for the control group, the mice in the other groups were inoculated with the virus according to the method described in "2.2 Virus Inoculation". The control group was given an equal amount of physiological saline.

[0051] After inoculation, rabbits in each drug treatment group were given the corresponding drugs by gavage, while the blank control group and the model group were given the same amount of distilled water.

[0052] 3. Observation Indicators

[0053] 3.1 Observation of the rabbit model

[0054] The appearance of herpes and the general condition of the rabbit (sensitivity, appetite, respiration, body temperature, excretion and activity).

[0055] 3.2 Observation of therapeutic effect

[0056] Observe the time for pain relief, the time for herpes to subside, the time for scab formation, and the time for complete recovery.

[0057] Pain relief time: from the start of treatment until the rabbit's neurological symptoms (based on the rabbit's activity level and human-like condition) are significantly relieved;

[0058] Swelling reduction time: From the start of treatment until the redness and swelling disappear;

[0059] Scabbing time: from the start of treatment until all blisters and blood blisters have dried up and scabbed over;

[0060] Recovery time: from the start of treatment until all experimental symptoms disappear and the patient returns to the pre-vaccination state.

[0061] 3.3 Statistical analysis

[0062] The data were statistically analyzed using SPSS 22.0 software. The data of each experimental group were expressed as mean ± standard deviation and significant tests were performed using the T-test method.

[0063] 4. Results and conclusions

[0064] 4.1 Herpes observation

[0065] After virus inoculation, the rabbits in the model group and each drug administration group showed lesions within 24 - 48 hours. The characteristics of the lesions were the appearance of herpes, which swelled and became round. The walls of the blisters were tense and shiny, and the contents were clear, and then gradually became turbid. New groups of blisters gradually appeared, and the skin between each group of blisters was normal.

[0066] 4.2 General conditions

[0067] The rabbits infected with the virus had reduced appetite, slowed breathing, elevated body temperature, reduced activity, and reduced feces, etc.

[0068] 4.3 Therapeutic effects

[0069] Compared with the model group, the pain relief time, swelling reduction time, crusting time, and recovery time of the rabbits in each drug administration group were significantly shortened (P < 0.01); compared with the acyclovir tablet group, the pain relief time, swelling reduction time, crusting time, and recovery time of the high and medium dose groups of Renshen Guben were significantly shortened (P < 0.05, P < 0.01).

[0070] Table 1 Observation of the treatment of rabbits in each group( n = 8)

[0071]

[0072] Note: Compared with the model group,

[0075] , P < 0.01;

[0073] Compared with the acyclovir tablet group, & P < 0.05, @ P < 0.01.

[0074] II. Therapeutic effect of the traditional Chinese medicine composition of the present invention on rats with postherpetic neuralgia

[0075] 1 Materials

[0076] 1.1 Animals: <​​

[0078] 1.2 Drugs and reagents

[0079] 1.2.1 Drugs

[0080] Commercially available Ginseng Strengthening Oral Liquid (produced by Lunan Houpu Pharmaceutical Co., Ltd., National Drug Approval Number Z10940013).

[0081] Commercially available pregabalin capsules (National Drug Approval Number H20130064).

[0082] 1.2.3 Dosage in rats

[0083] Ginseng Strengthening Oral Liquid: 3.6 mL / kg (high dose), 1.8 mL / kg (medium dose), 0.9 mL / kg (low dose);

[0084] Pregabalin capsules: 27 mg / kg.

[0085] 2. Methods

[0086] 2.1 Model Establishment

[0087] A rat model of postherpetic neuralgia was established using rats chronically infected with varicella-zoster virus. The specific procedures are as follows:

[0088] First, CV-1 cells (African green monkey kidney fibroblasts) were added to complete culture medium (DMEM / F12) to prepare a cell suspension. After cell counting, the cells were then grown at a ratio of 5 × 10⁻⁶ cells / mL. 4 / cm 2 The cells were inoculated into culture flasks at a concentration of [specific concentration not specified], and then CV-1 cells were infected with VZV (varicella-zoster virus). When approximately 80% of the cells were infected, the infected cells were collected in PBS to prepare a virus-inoculated cell suspension, with a final concentration of approximately 12 × 10⁻⁶. 6 50 μl of the virus inoculation solution per rat was injected into the left toe of each SD rat. The rats were considered successfully modeled when they began to show abnormal mechanical pain thresholds 3–4 days after VZV infection. Successfully modeled rats were then selected for grouping.

[0089] 2.2 Grouping and Administration

[0090] Fifty rats that successfully developed the model were randomly divided into five groups of ten each: the model group, the pregabalin capsule group, and three dosage groups of ginseng tonic oral liquid (high, medium, and low). Ten normal rats were also used as the blank group (the left toe of each rat was injected with an equal volume of physiological saline).

[0091] After grouping, rabbits in each treatment group were administered the corresponding drug via gavage, while the control group and model group were given an equal volume of physiological saline. The administration was continued for 14 consecutive days.

[0092] 3. Observation Indicators

[0093] 3.1 Determination of Mechanical Foot Withdrawal Threshold (PWT)

[0094] PWT of the right hind limb of rats was measured using a tactile analgesia meter at 1, 7, and 14 days after drug administration. The intensity of the stimulus was recorded when the rats exhibited behaviors such as lifting, licking, or avoiding the paw. Five measurements were taken for each rat, and the average of the three measurements after removing the maximum and minimum values ​​was taken as the PWT.

[0095] 3.2 Measurement of serum IL-2, IL-6, and TNF-α

[0096] After the last administration and PWT measurement, rats were decapitated and blood was collected. The blood was centrifuged and serum was collected. The levels of IL-2, IL-6, and TNF-α in the serum were measured by enzyme-linked immunosorbent assay (ELISA).

[0097] 3.3 Statistical Processing

[0098] Data were statistically processed using SPSS 22.0 software, and data for each experimental group were expressed as mean ± standard deviation. This indicates that a T-test is used to test the significance.

[0099] 4. Results and Conclusions

[0100] 4.1 Comparison of PWT in different groups of rats

[0101] Compared with the control group, the PWT values ​​of the model group and each drug-treated group were significantly lower at 1, 7 and 14 days after administration (P < 0.01). Compared with the model group, there was no significant difference in PWT values ​​at 1 day after administration, but the PWT values ​​at 7 and 14 days after administration were significantly higher (P < 0.01). Compared with the pregabalin capsule group, there was no significant difference in PWT values ​​at 1 day after administration, but the PWT values ​​of the high-dose ginseng tonic group were significantly higher at 7 and 14 days after administration (P < 0.05).

[0102] Table 2 Comparison of PWT in rats of different groups ( n=10)

[0103]

[0104] Note: Compared with the blank group, * P < 0.05 △ P < 0.01;

[0105] Compared with the model group, # P < 0.01;

[0106] Compared with the pregabalin capsule group, & P < 0.05.

[0107] 4.2 Comparison of serum IL-2, IL-6, and TNF-α levels in different rat groups

[0108] Compared with the blank group, the serum levels of IL-6 and TNF-α in the model group and each drug-treated group were significantly increased, while the IL-2 level was significantly decreased (P < 0.05, P < 0.01). Compared with the model group, the serum levels of IL-2, IL-6, and TNF-α in each drug-treated group were significantly improved (P < 0.05, P < 0.01). Compared with the pregabalin capsule group, there was basically no difference in the serum levels of IL-2, IL-6, and TNF-α in the three ginseng-based drug-treated groups (P > 0.05).

[0109] Table 3 Comparison of serum IL-2, IL-6, and TNF-α levels in rats from different groups ( n=10)

[0110]

[0111]

[0112] Note: Compared with the blank group, * P < 0.05 △ P < 0.01;

[0113] Compared with the model group, @ P < 0.05 # P < 0.01;

[0114] Compared with the pregabalin capsule group, & P < 0.05.

[0115] Clinical studies have shown that patients with herpes zoster neuralgia have lower serum IL-2 levels than healthy individuals, while IL-6 and TNF-α levels are significantly elevated. The decrease in IL-2 weakens the body's immunity and antiviral ability, accelerating viral replication in the dorsal root ganglia of the spinal cord, thus leading to postherpetic neuralgia. High levels of IL-6 and TNF-α may cause damage to the nervous system and stimulate inflammatory cells to produce inflammatory mediators, causing pain.

[0116] The above pharmacological experiments show that Ginseng Guben Oral Liquid can reduce the serum IL-6 and TNF-α levels and increase the IL-2 level in rats with postherpetic neuralgia, and can be used to treat postherpetic neuralgia.

Claims

1. The use of a ginseng-strengthening oral liquid prepared from ginseng, rehmannia root, prepared rehmannia root, cornus officinalis, yam, peony bark, alisma rhizome, poria cocos, asparagus root, and ophiopogon root in the preparation of a drug for treating herpetic skin diseases, wherein the herpetic skin disease is herpes zoster.

2. The use of the ginseng tonic oral liquid as described in claim 1 in the preparation of a drug for treating complications of herpes zoster, wherein the complications of herpes zoster refer to postherpetic neuralgia.

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