Application of a formula of effective ingredients of Radix Angelicae Pubescentis in treating rest pain caused by diabetes

Abstract

The present invention relates to the application field of traditional Chinese medicine technology, and discloses an application of a formula of effective ingredients of Guizhi tangnausea in treating rest pain caused by diabetes. The present invention includes the composition and corresponding proportion of the formula of effective ingredients of Guizhi tangnausea, the optimal ratio and preparation type of each ingredient of the formula of effective ingredients of Guizhi tangnausea, and the application type of the formula of effective ingredients of Guizhi tangnausea in treating rest pain caused by diabetes. Combined with the behavioral pain test of rats and the clinical trial of lower limb arteriosclerosis, it is illustrated that the formula of effective ingredients of Guizhi tangnausea has a good analgesic effect and an effect of relieving lower limb arteriosclerosis in treating rest pain caused by diabetes.

Description

Technical Field

[0001] The invention relates to the application field of traditional Chinese medicine technology, and in particular to the application of a formula of effective ingredients of Radix Angelicae Dahuricae in treating rest pain caused by diabetes. Background Art

[0002] Rest pain is pain in the limbs when they are at rest. It is a mid-term manifestation of vascular lesions. When the lesions develop, ischemia of the lower limbs worsens, and pain occurs even when not walking, which is called rest pain. The pain persists and cannot be relieved by rest. It may be more obvious at night. The occurrence of rest pain often indicates that the degree of lesions and ischemia has worsened. Both arterial and venous lesions can cause rest pain, and the former is more painful than the latter. Rest pain is mainly caused by insufficient arterial blood supply, venous hypertension and congestion, and is common in arterial embolism, thromboangiitis obliterans, and lower limb arteriosclerosis obliterans. Lower limb arteriosclerosis obliterans is one of the common complications of diabetic patients. Clinical treatment measures include functional exercise, risk factor control, drug therapy, surgical treatment, intravascular interventional therapy, gene therapy and bone marrow stem cell transplantation. In clinical practice, the main treatment for rest pain caused by ASO is still symptomatic treatment with non-steroidal anti-inflammatory drugs, but the efficacy is poor. Therefore, new and effective treatment methods are urgently needed in this field to relieve the pain of ASO patients.

[0003] The effective ingredient formula of Guizhi Tanghu is a traditional Chinese medicine compound preparation made from angelica sinensis, rhizoma anemarrhenae, vine of honeysuckle, honeysuckle, coptis chinensis, rehmannia root, figwort, liquorice and safflower seed, which is mainly used to promote blood circulation, dissipate blood stasis, and relieve wind and dredge collaterals. However, there is no relevant research on the application of the effective ingredient formula of Guizhi Tanghu in the preparation of treatment of rest pain caused by diabetes. Summary of the invention

[0004] In order to make up for the deficiencies of the prior art, the present invention provides an application of a formula of effective ingredients of Radix Angelicae Sinensis in treating rest pain caused by diabetes.

[0005] The present invention is achieved through the following technical solutions:

[0006] An application of a formula of effective ingredients of guizhi sugar carbuncle in treating rest pain caused by diabetes, wherein the formula of effective ingredients of guizhi sugar carbuncle consists of the following ingredients: ligustilide, timosaponin E, tangerine glycoside, verbascoside, trilobate caryophyllein, and bamipine hydrochloride;

[0007] The mass ratios of the various components of the effective ingredient formula of the Guizhi sugar cane are as follows: ligustilide: anemarrhena saponin E: dactyloside: verbascoside: trilobate caryophyllein: bamipine hydrochloride: (4.2-5.7): (2.8-4.4): (1.9-2.5): (3.2-5.6): (1.3-2.1): (1.7-2.7).

[0008] Preferably, the mass ratio of each component of the effective ingredient formula of Gastrodia elata is 4.7:3.2:2.1:4.5:1.6:2.3 for ligustilide:timosaponin E:dangyao glycoside:verbascoside:salvinia quinata:bamazepine hydrochloride.

[0009] Preferably, the formula of the effective ingredient of Gastrocnemius sutchuenensis can increase the latency of the hind paw withdrawal reaction of rats with neuralgia induced by thermal stimulation at 30 minutes, and is still effective within 60 minutes.

[0010] Preferably, the formula of the effective ingredient of Gastrocnemius sutchuenensis can increase the latency of the hind paw withdrawal reaction of rats with neuralgia induced by mechanical stimulation at 30 minutes, and is still effective within 60 minutes.

[0011] Preferably, the types of rest pain caused by diabetes include rest pain caused by lower limb arteriosclerosis obliterans and rest pain of neuralgia.

[0012] A medicine for treating rest pain caused by diabetes, the medicine comprises an effective ingredient formula of Anemarrhena asphodeloides, and the effective ingredient formula consists of the following ingredients: ligustilide: anemarrhena saponin E: dactyloside: verbascoside: trilobate caryophyllein: bamipine hydrochloride (4.2-5.7): (2.8-4.4): (1.9-2.5): (3.2-5.6): (1.3-2.1): (1.7-2.7).

[0013] Preferably, the mass ratio of each component of the effective ingredient formula of Gastrodia elata is 4.7:3.2:2.1:4.5:1.6:2.3 for ligustilide:timosaponin E:dangyao glycoside:verbascoside:salvinia quinata:bamazepine hydrochloride.

[0014] Preferably, the drug preparation types include but are not limited to granules, capsules, and tablets.

[0015] Compared with the prior art, the present invention is beneficial in that: the present invention provides a formula of effective ingredients of Gastrocnemius sphaerocephalus and a medicine prepared by using the formula, and the medicine has an excellent therapeutic effect on rest pain caused by diabetes mellitus. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The present invention will be further described below in conjunction with the accompanying drawings.

[0017] Figure 1 is the change rate of the latency period of the hind paw withdrawal reaction to heat stimulation (left) of the present invention (%);

[0018] Figure 2 is the change rate of the latency period of the hind paw withdrawal reaction to heat stimulation (right) of the present invention (%);

[0019] Figure 3The percentage change of the latency period of the hind paw withdrawal reaction to mechanical stimulation (left) of the present invention;

[0020] Figure 4 is the change rate of the latency period of the hind paw withdrawal reaction to mechanical stimulation (right) of the present invention, where Figure 1-4 The data of each experimental group were P < 0.001, with significant statistical differences. DETAILED DESCRIPTION

[0021] The present invention is further described in detail below. The pharmaceutical preparation type adopted in the present invention is granules.

[0022] Example 1: Formulation of the active ingredient of Gyuzhi saccharomyces

[0023] The formula of the effective ingredients of Guizhi Tangnacles is composed of the following ingredients: Ligusticum chuanxiong lactone: Anemarrhena saponin E: Dangyao glycoside: Verbascoside: Salvinia quinata glycoside: Bamipine hydrochloride is (4.2-5.7): (2.8-4.4): (1.9-2.5): (3.2-5.6): (1.3-2.1): (1.7-2.7).

[0024] Specifically, the mass ratio of the effective ingredient formula of Anemarrhena asphodeloides adopted in this embodiment is 4.7:3.2:2.1:4.5:1.6:2.3 for ligustilide:anemarrhena saponin E:dangyao glycoside:verbascoside:caryophyllein:bamazine hydrochloride.

[0025] Example 2: Experiment on the treatment of resting pain in rats with Guizhi Tangu Granules

[0026] 1 Materials and methods

[0027] 1.1 Experimental animals

[0028] Thirty adult male rats, weighing between 180 and 220 g, were provided by Liaoning Changsheng Biotechnology Co., Ltd.

[0029] 1.2 Drugs and main reagents

[0030] Guizhi Tangu Granules (prepared into granules according to the mass ratio of Example 1); Tramadol Tablets: 6 tablets*1 plate / box, purchased from Hongjitang Pharmacy, produced by Shaanxi Jiuzhou Pharmaceutical Co., Ltd. Physiological saline: Qidu Pharmaceutical; Chloral hydrate: Sinopharm Chemical Reagent Co., Ltd.; Anhydrous ethanol: Yantai Shuangshuang Chemical Reagent Co., Ltd.; Penicillin: North China Pharmaceutical Co., Ltd.

[0031] 1.3 Main instruments

[0032] Randall-Selitto pain tester: from UGO, Italy; YLS-6B intelligent hot plate instrument: from Shandong Jinan Yiyan Technology Development Co., Ltd.; YP1201N electronic balance: from Shanghai Jingke Industrial Group; gavage needle: from Shenzhen Ruiwode Company; in addition, syringes, large and small beakers, etc. are also needed.

[0033] 1.4 Test preparation and process

[0034] 1.4.1 Training

[0035] Before the start of the experiment, the rats need to undergo at least 7 days of behavioral training, specifically hot plate and pressure test training, 3 rounds per day, 3 times per round. The formal experiment can only begin when the change rate of the rat's hind paw withdrawal reaction latency is less than 10%.

[0036] 1.4.2 Behavioral pain test

[0037] Before the drug was injected, the latency of the rat's hind paw withdrawal reaction was tested once as the baseline value, so as to compare the changes after the drug injection and calculate the effect. The withdrawal time of the rat's hind paw on the hot plate and the pressure plate was recorded at 5, 10, 15, 20, 30, 45, and 60 minutes after the drug was injected orally, and each measurement time did not exceed 15 seconds.

[0038] 1.4.3 Hot plate test

[0039] Heat the hot plate to maintain its temperature at 52°C (51.7-52.3°C), hold the rat tightly with your left hand and try to make it comfortable, hold its hind paw to be tested with your right hand and place it close to the hot plate, record the time when its hind paw actively retracts and leaves the hot plate due to pain, and make sure to place it in the same position each time.

[0040] 1.4.4 Stress Testing

[0041] Use a pressure analgesic to perform a pressure test on rats. Hold the rat tightly with your left hand to make it as comfortable as possible, and hold its hind paw to be tested with your right hand. During the test, press the switch with one foot and record the time when the small wedge-shaped plexiglass on the analgesic is pressed on the tarsophalangeal joint of the rat's hind paw until the hind paw actively retracts due to pain. Try to ensure that the joint is the same each time you test it.

[0042] 1.4.5 Preparation of neuropathic pain model

[0043] The rats were anesthetized with chloral hydrate and then placed in lateral position. The skin was incised near the knee joint and hip joint on the upper lateral side of the thigh. The sciatic nerve was picked out and ligated. Finally, the rats were disinfected and sutured, and powdered anti-inflammatory drugs were applied to the wounds.

[0044] 1.4.6 Method of administration

[0045] The Chinese medicine group was given Guizhi Tangju Granules aqueous solution (concentration 10 mg / ml) by intragastric administration.

[0046] Western medicine group: Tramadol tablets were added to distilled water to make a 10ug / ml suspension and administered by gavage.

[0047] The model group and the normal group were intragastrically administered with an equal volume of saline.

[0048] Gavage cycle: 8 consecutive weeks, once a day.

[0049] 2. Test results

[0050] The experiment of the present invention was statistically analyzed by data software, such as Figure 1-Figure 4 By comparing the rats with resting pain who were gavaged with 0.9% saline, the latency of the hind paw withdrawal reaction on the hot plate and the pressure plate in the Chinese medicine group and the Western medicine group were both higher, and the effect was best when the gavage lasted for 30 minutes, indicating that the effective ingredient formula of the present invention has a very good analgesic effect on resting pain such as neuralgia.

[0051] pass Figure 1-Figure 4 The analysis shows that in terms of drugs, the analgesic effect of the Chinese medicine group is more obvious; in terms of time, the analgesic effect is best 30 minutes after intragastric administration, and there is still an analgesic effect at 60 minutes, indicating that the analgesic effect will last for a period of time after intragastric administration. The specific variance analysis is:

[0052] Table 1 Analysis of variance of the hot plate on the left side of the rat

[0053] sum of squares Degrees of Freedom Mean Square F Significance Between groups 2865.361 3 955.120 8.716 0.001 Within group 2630.123 24 109.588 - - total 5495.484 27 - - -

[0054] Table 2 Analysis of variance of the hot plate on the right side of the rat

[0055]

[0056]

[0057] Table 3 Analysis of variance of the left side of the rat's pressure plate

[0058] sum of squares Degrees of Freedom Mean Square F Significance Between groups 2314.113 3 771.371 7.355 0.001 Within group 2516.901 24 104.871 - - total 4831.014 27 - - -

[0059] Table 4 Analysis of variance of the right side of the rat's pressure plate

[0060] sum of squares Degrees of Freedom Mean Square F Significance Between groups 2004.160 3 668.053 8.087 0.001 Within group 1982.668 24 82.611 - - total 3986.828 27 - - -

[0061] Example 3: Comparison of clinical efficacy of Guizhi Tangru Granules in treating diabetic lower extremity vascular disease

[0062] 1. General

[0063] The pathological basis of diabetic lower limb vascular disease is atherosclerosis. Compared with non-diabetic people, diabetic lower limb vascular pathological changes are more severe, the onset age is younger, and the progression is faster. Patients experience numbness and coldness in their limbs, and even pain at rest. Severe lower limb arteriosclerosis may cause intermittent claudication, disappearance of dorsalis pedis artery pulsation, and even gangrene.

[0064] According to the WHO diabetes diagnostic criteria and classification criteria, 60 patients with type 2 diabetes and lower limb vascular disease were randomly selected (0.6<ABI<0.9). Inclusion criteria: ① Age 40-80 years old; ② Clear consciousness. Exclusion criteria: ① Severe heart, liver, and kidney dysfunction; ② Patients who need to rely on a wheelchair for daily activities, with severe lower limb ulcers, gangrene, and lower limb amputations; ③ Patients with complications that limit walking ability: such as Parkinson's syndrome, hip fracture, heart failure, COPD, spinal stenosis, and intervertebral disc herniation; ④ Angina pectoris or myocardial infarction in the past month; ⑤ Resting heart rate >120 beats

[0065] / min; ⑥ Systolic blood pressure>180mmHg, diastolic blood pressure>100mmHg; ⑦ Anticoagulants and / or vasodilators were used one month before admission.

[0066] 60 patients were randomly divided into lipoic acid group, Guizhi Tanghu group and lipoic acid + Guizhi Tanghu group, 20 in each group. There were 9 males and 11 females in the lipoic acid group (lipoic acid 600 mg / d, 21 days in total); there were 10 males and 10 females in the Guizhi Tanghu group (Guizhi Tanghu granules 4 g / d, 21 days in total); there were 13 males and 7 females in the lipoic acid + Guizhi Tanghu group (lipoic acid 600 mg / d, Guizhi Tanghu granules 4 g / d, 21 days in total).

[0067] After admission, all patients were given insulin to regulate blood sugar and treat complications, including the use of antiplatelet drugs, antihypertensive drugs, lipid-lowering drugs, anti-infective drugs, etc. There was no significant difference in age, duration of diabetes, body mass index (BMI), fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), and blood lipids (TG, TC) among the three groups (P>0.05), and they were comparable (Table 5).

[0068] Table 5 Comparison of general conditions among the three groups (n=60, )

[0069]

[0070] 2. Test methods

[0071] Each patient was scored according to clinical symptoms before and after treatment, and the score changes before and after medication in the three groups were compared. Clinical symptom scoring: ① Numbness: 0 to 3 points from mild to severe. 0 points: no numbness; 1 point: occasional numbness; 2 points: frequent numbness; 3 points: frequent numbness and other abnormal sensations. ② Cold sensation: 0 to 3 points from mild to severe. 0 points: no cold sensation; 1 point: general; 2 points: obvious, but sometimes it can be alleviated; 3 points: obvious, completely unable to alleviate. ③ Resting pain: 0 to 4 points from mild to severe. 0 points: no pain; 1 point: occasional pain; 2 points: frequent pain, but can be tolerated, occasionally use general analgesics; 3 points: frequent pain, need general analgesics; 4 points: continuous pain, affecting sleep and appetite, general analgesics are difficult to relieve continuous numbness, unbearable.

[0072] 3. Statistical methods

[0073] SPSS13.0 software was used to process all data and perform statistical analysis. The experimental data were quantitative and rank data. Quantitative data were expressed as (x±s), and rank data were expressed as average rank. ANOVA was used to compare the means among the three groups, and the LSD method was used for multiple comparisons. Nonparametric test (H test) was used for rank data, and Nemenyi test was used for multiple comparisons. The test level α=0.05.

[0074] 4. Test results

[0075] There was no significant difference in symptom scores among the three groups before treatment (P>0.05). After treatment, the changes in numbness, coldness, and rest pain scores of patients in the lipoic acid + Guizhi carbuncle group were greater than those in the lipoic acid group and Guizhi carbuncle group (P<0.05) (Table 6).

[0076] Table 6 Comparison of symptom scores before and after treatment in the three groups (n=60, average rank)

[0077]

[0078] Note: H test was used to compare the three groups. *P<0.05 compared with lipoic acid group and saccharomyces cerevisiae group.

[0079] The results showed that oral administration of 4g of Guizhi Tangru Granules, intravenous infusion of 600mg of lipoic acid, and intravenous infusion of 600mg of lipoic acid plus oral administration of 4g of Guizhi Tangru Granules for 3 consecutive weeks significantly improved the symptoms of limb pain, numbness, and coldness in patients with mild to moderate diabetic lower extremity vascular disease. The above symptoms basically disappeared in some patients, which significantly improved the quality of life of patients. In addition, it was found that the clinical symptoms of diabetic lower extremity vascular disease in the lipoic acid + Guizhi Tangru group were significantly improved after treatment compared with the Guizhi Tangru group and the lipoic acid group. Therefore, compared with the Guizhi Tangru group and the lipoic acid group, lipoic acid combined with Guizhi Tangru Granules is more conducive to the improvement of clinical symptoms in patients with diabetic lower extremity vascular disease.

Claims

1. Use of a formula of effective ingredients of Gastrodia elata in the preparation of a drug for treating rest pain caused by diabetes, characterized in that: The effective ingredient formula of the radix sutchuenensis is composed of the following ingredients: ligustilide, timosaponin E, tangerine, verbascoside, trilobate caryophyllein, and palmatine hydrochloride; The mass ratios of the various components of the effective ingredient formula of the Guizhi sugar cane are as follows: ligustilide: anemarrhena saponin E: dactyloside: verbascoside: trilobate caryophyllein: bamipine hydrochloride: (4.2-5.7): (2.8-4.4): (1.9-2.5): (3.2-5.6): (1.3-2.1): (1.7-2.7).

2. The use according to claim 1, characterized in that: The mass ratio of each component of the effective ingredient formula of the Guizhi sugar cane is 4.7:3.2:2.1:4.5:1.6:2.3 for ligustilide:timosaponin E:dangyao glycoside:verbascoside:trilobate:bamazine hydrochloride.

3. The use according to claim 1, characterized in that: The types of rest pain caused by diabetes are rest pain caused by lower limb arteriosclerosis obliterans and neuralgia-type rest pain.

4. A drug for treating rest pain caused by diabetes, characterized in that: The medicine includes a formula of effective ingredients for tangerine peel, which is composed of the following ingredients: ligustilide, timosaponin E, tangerine glycoside, verbascoside, trilobate caryophyllein, and bamipine hydrochloride; the mass ratios of the various ingredients in the formula of effective ingredients for tangerine peel are ligustilide: timosaponin E: tangerine glycoside: verbascoside: trilobate caryophyllein: bamipine hydrochloride (4.2-5.7): (2.8-4.4): (1.9-2.5): (3.2-5.6): (1.3-2.1): (1.7-2.7).

5. The drug according to claim 4, characterized in that The mass ratio of each component of the effective ingredient formula of the Guizhi sugar cane is 4.7:3.2:2.1:4.5:1.6:2.3 for ligustilide:timosaponin E:dangyao glycoside:verbascoside:trilobate:bamazine hydrochloride.

6. The drug according to claim 4, characterized in that The drug is in the form of granules, capsules, or tablets.

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