CN114588242B

CN114588242B - Pharmaceutical composition for treating rheumatoid arthritis

Info

Publication number: CN114588242B
Application number: CN202210399662.5A
Authority: CN
Inventors: 李延萍; 张莹; 尚存芸
Original assignee: Chongqing Traditional Chinese Medicine Hospital
Current assignee: Chongqing Traditional Chinese Medicine Hospital
Priority date: 2022-04-15
Filing date: 2022-04-15
Publication date: 2023-08-01
Anticipated expiration: 2042-04-15
Also published as: CN114588242A

Abstract

The invention relates to the technical field of traditional Chinese medicines, in particular to a pharmaceutical composition for treating rheumatoid arthritis, which comprises 10 parts of cassia twig, 10 parts of white paeony root, 30 parts of astragalus, 10 parts of bighead atractylodes rhizome, 15 parts of Chinese angelica, 6 parts of turmeric, 10 parts of stiff silkworm, 20 parts of coix seed, 30 parts of suberect spatholobus stem and 15 parts of prepared rehmannia root. In the pharmaceutical composition, cassia twig and white paeony root are used as monarch drugs, chinese angelica, astragalus and largehead atractylodes rhizome are used as ministerial drugs, suberect spatholobus stem is used as auxiliary drugs for strengthening the functions of nourishing blood and activating blood, coix seed, turmeric and stiff silkworm are used as auxiliary drugs, and prepared rehmannia root is added for preventing stiff silkworm and turmeric from being pungent and warm and excessively dry. The above medicinal herbs cooperate to regulate nutrient and defensive qi, and also to dispel dampness, tonify middle-jiao, and activate collaterals. The technical problem that a traditional Chinese medicine formula which is specially used for rheumatoid arthritis and can be matched with western medicines for use is lacking in the market is solved. The pharmaceutical composition can effectively relieve clinical symptoms of rheumatoid arthritis, improve immunity, alleviate toxic and side effects of western medicines, and has great application and popularization values.

Description

Pharmaceutical composition for treating rheumatoid arthritis

Technical Field

The invention relates to the technical field of traditional Chinese medicines, in particular to a pharmaceutical composition for treating rheumatoid arthritis.

Background

Rheumatoid arthritis (Rheumatoid arthritis, RA) is a common autoimmune disease, belonging to the category of "arthralgia syndrome" in traditional Chinese medicine. At present, RA still belongs to a disease with unknown etiology and difficult to control at home and abroad, so the search of an effective control method for RA is an important subject in the current RA research. Current treatment of RA is based on non-steroidal anti-inflammatory drugs (NSAIDs), slow acting antirheumatic drugs (DMARDs), which, although they can relieve symptoms, improve conditions, often require co-administration and the presence of toxic side effects severely affects patient compliance.

The traditional Chinese medicine has a plurality of different schemes, is useful for clinical application and experimental treatment research of single medicine, single traditional Chinese medicine components and prescription traditional Chinese medicines, has the unique advantages of definite curative effect and good tolerance in the aspect of treating RA, can play a role in reinforcing and supplementing short-term by being combined with western medicines, and also accords with the diagnosis psychology of patients. However, no sufficient clinical effectiveness study on a formula for treating RA has been performed in the prior art, so that a traditional Chinese medicine formula which is specially used for treating rheumatoid arthritis and can be matched with western medicines is lacking in the market.

Disclosure of Invention

The invention aims to provide a pharmaceutical composition for treating rheumatoid arthritis, which aims to solve the technical problem that a traditional Chinese medicine formula which is specially used for treating rheumatoid arthritis and can be matched with western medicines is lacking in the market.

In order to achieve the above purpose, the invention adopts the following technical scheme:

the medicine composition for treating the rheumatoid arthritis comprises, by weight, 10 parts of cassia twig, 10 parts of white peony root, 30 parts of astragalus, 10 parts of bighead atractylodes rhizome, 15 parts of Chinese angelica, 6 parts of turmeric, 10 parts of stiff silkworm, 20 parts of coix seed, 30 parts of suberect spatholobus stem and 15 parts of prepared rehmannia root.

The principle and the advantages of the scheme are as follows:

(1) Square solution

The cassia twig and the white paeony root are selected as monarch drugs, and the cassia twig has the functions of regulating yin and yang and can be used for activating yang to disperse arthralgia, warming channels to dispel cold and relieving pain; bai Shao is sour and cold, has the actions of replenishing blood, pacifying liver and relieving pain, and is combined with Gui Zhi, xin Ganhua yang, so it can regulate qi of the whole body. The two herbs are matched to be "Guizhi Tang" to regulate nutrient and defensive functions, so that the patient is slightly about to sweat and the wind-damp can go.

Angelica sinensis, astragalus mongholicus and bighead atractylodes rhizome are ministerial drugs, bighead atractylodes rhizome is bitter and sweet in taste, can dry dampness and invigorate spleen, is the warmest in nature, is the first key drug for invigorating spleen and qi, can remove phlegm and water, and can promote the circulation of turbid urine in joints; the angelica is sweet and warm in nature, enters liver, heart and spleen meridians, and has the effects of enriching blood and activating blood; astragalus mongholicus is sweet in taste and has the effects of tonifying middle-jiao, tonifying qi and strengthening exterior. The astragalus and the bighead atractylodes rhizome are combined to fill nutrient and defensive qi and blood, the principal drug efficacy is assisted, the astragalus and the angelica are combined to benefit the defensive qi and nourish the nutrient and blood, the bighead atractylodes rhizome and the angelica are matched to eliminate phlegm and turbid, and the blood stasis is removed by matching the three drugs.

The auxiliary action of the spatholobus stem is to strengthen the effects of nourishing blood and activating blood. Coix seed, turmeric and stiff silkworm are auxiliary medicines, and the coix seed records that ' principal muscle spasm and spasm can not be bent and stretched, chronic rheumatism, qi descending, long-term taking, body weight reducing and qi supplementing ' can dry muscle dampness and infiltrate striae and interstitial dampness ' in ' Bencaojing Jie '; curcuma rhizome has pungent and warm nature and can promote blood circulation to remove blood stasis, is the same plant as Yu jin, has the actions of promoting qi circulation to relieve pain, and is pungent and salty in flavor, enters liver meridian, can activate collaterals and clear meridians, and can dissipate nodulation and reduce swelling. The prepared rhizome of rehmannia can prevent stiff silkworm, turmeric has the effects of nourishing yin and blood when being used for pungent and warm over-dryness. The whole formula is first to harmonize nutrient and defensive qi, is good at resolving dampness, penetrates through spleen and treats phlegm and blood stasis simultaneously, and is matched with the worm medicine to dredge collaterals, so that all evils are removed, and healthy qi is not damaged.

(2) Mechanism analysis

The pathogenesis of RA is mainly wind, cold and damp evil, and the disease is mainly caused by deficiency of qi and blood, disharmony of nutrient and defensive qi, internal injury of viscera with unsmooth channels and collaterals, long-term phlegm and blood stasis generation, or feeling, or the occurrence of the feeling of the disease, finally forming the Wang Bi. The long-term cold and dampness in Chongqing, the deficiency of the intrinsic factors, tiredness injury and the like cause viscera weakness, the external evil is easy to attack the human body, and the viscera and joints are left in the body, so that the channels and collaterals are blocked, the qi and blood are not smooth, and the arthralgia syndrome is frequent.

The inventors found through a great deal of research that: whether the qi of ying and wei is smooth or not is closely related to the occurrence of Wang Bi, so that ying and wei are harmonized for the first time in the treatment; because it is not complicated with arthralgia due to dampness, it is often easy to treat damp-evil from cold and heat, it is often combined with yang-warming and spleen-invigorating methods; the RA patients can use antirheumatic drugs and analgesic drugs for a long time, the spleen and the stomach are vulnerable, and the spleen and the stomach can be fixed and protected, so that qi and blood of the RA patients can be full of energy to nourish joints, the drug injury is reduced, and the compliance of the patients is improved; the damp evil can cause phlegm and blood stasis to grow for a long time, and three evil is stuck and can not attack urgently, attack violently and attack singly, so that the damp evil needs to be slowly attacked and dispersed, and the qi-moving product is used as an auxiliary material; the worm medicine is used at proper time, and the body yin uses yang to penetrate into the marrow collaterals by the nature and dynamic jump of the blood and meat, and the meridian evil is searched out to deep penetrate the disease root, attack and eliminate evil accumulation; in the later stage, attention is paid to tonifying liver and kidney, liver governs tendons and bones, and deficiency of liver and kidney not only can cause the occurrence of Wang arthralgia, but also can cause lingering pathogenic factors due to deficiency of vital qi, repeated pathogenic factors, frequent and unhealed diseases, and influences the prognosis. According to years of clinical experience and experimental research, the inventor researches and forms the formula of the scheme, which is based on harmonizing nutrient and defensive qi, and has the functions of resolving dampness, tonifying middle-jiao and activating collaterals.

The failure of nutrient and blood to circulate and the failure of defensive qi to circulate and the failure of the triple energizer to keep the viscera qi and blood circulating can lead to injuries of tendons and bones and collaterals. The joint muscle and joint soreness and weakness due to qi failure, the treatment is to benefit qi; malnutrition of the body can lead to numbness of the extremities, muscle and tendon, , muscular atrophy, and the like. The prescription can tonify qi, nourish blood, and dredge collaterals, and realize qi-blood coherence to remove arthralgia and relieve pain. The cassia twig and the white paeony root are selected as monarch drugs, and the cassia twig has the functions of regulating yin and yang and can be used for activating yang to disperse arthralgia, warming channels to dispel cold and relieving pain; bai Shao is sour and cold, has the actions of replenishing blood, pacifying liver and relieving pain, and is combined with Gui Zhi, xin Ganhua yang, so it can regulate qi of the whole body. The two herbs are matched to be "Guizhi Tang" to regulate nutrient and defensive functions, so that the patient is slightly about to sweat and the wind-damp can go. Angelica sinensis, astragalus mongholicus and bighead atractylodes rhizome are ministerial drugs, bighead atractylodes rhizome is bitter and sweet in taste, can dry dampness and invigorate spleen, is the warmest in nature, is the first key drug for invigorating spleen and qi, can remove phlegm and water, and can promote the circulation of turbid urine in joints; the angelica is sweet and warm in nature, enters liver, heart and spleen meridians, and has the effects of enriching blood and activating blood; astragalus mongholicus is sweet in taste and has the effects of tonifying middle-jiao, tonifying qi and strengthening exterior. The astragalus and the bighead atractylodes rhizome are combined to fill nutrient and defensive qi and blood, the principal drug efficacy is assisted, the astragalus and the angelica are combined to benefit the defensive qi and nourish the nutrient and blood, the bighead atractylodes rhizome and the angelica are matched to eliminate phlegm and turbid, and the blood stasis is removed by matching the three drugs. The auxiliary actions of the spatholobus stem are reinforcing the functions of nourishing blood and activating blood, and can be supplemented without stagnation. Coix seed, turmeric and stiff silkworm are used as adjuvant drugs, and the Coix seed can dry the dampness of muscle and infiltrate the dampness of skin and muscle space; curcuma rhizome has pungent and warm nature and can promote blood circulation to remove blood stasis, is the same plant as Yu jin, has the actions of promoting qi circulation to relieve pain, and is pungent and salty in flavor, enters liver meridian, can activate collaterals and clear meridians, and can dissipate nodulation and reduce swelling. The three medicines of coix seed, turmeric and stiff silkworm are added into the prepared rhizome of rehmannia to nourish yin and blood, so as to prevent the stiff silkworm and the turmeric from being pungent and warm and excessively dry. The whole formula is first to harmonize nutrient and defensive qi, is good at resolving dampness, penetrates through spleen and treats phlegm and blood stasis simultaneously, and is matched with the worm medicine to dredge collaterals, so that all evils are removed, and healthy qi is not damaged.

(3) Clinical observations

The inventor finds that a series of problems exist in the traditional DMARDs for treating RA in long-term clinical practice, such as (1) the traditional DMARDs have slow effect in treating RA, and the illness state of a patient can not be controlled in time; (2) the long-term use of DMARDs and NSAIDs can cause weakness of spleen and stomach functions of RA patients, and even can cause damage such as gastric ulcer, erosion and the like; (3) the DMARDs are used for treating liver dysfunction and hypoimmunity of patients. Therefore, the method is repeatedly fuelled and practiced in long-term clinical practice, and is summarized and clinically verified, and the method is found to be capable of effectively relieving clinical symptoms of patients with RA, improving immunity of the patients and relieving toxic and side effects of western medicines.

Further, the traditional Chinese medicine raw materials of the pharmaceutical composition are prepared by the following method: decocting the Chinese medicinal materials in water to obtain medicinal liquid.

By decocting, the effective components in the Chinese medicinal materials are leached out, the bioavailability of the effective components is improved, and the Chinese medicinal materials are convenient for patients to take.

Further, the ratio of the traditional Chinese medicine raw materials to the liquid medicine is 156g:450mL.

The traditional Chinese medicine raw materials with the total mass of 156g are decocted into 450mL of liquid medicine, and the liquid medicine is taken by patients three times a day respectively, and the concentration of the effective components in the liquid medicine is moderate, and the liquid medicine is convenient to take and has high compliance.

Further, the pharmaceutical composition further comprises methotrexate and leflunomide.

Methotrexate and leflunomide are traditional western medicines for treating rheumatoid arthritis, and the traditional Chinese medicines and the western medicines are combined to help to increase the curative effect, and the traditional Chinese medicine components of the scheme also have certain relieving effect on the side effects of the western medicines. The traditional western medicines can cause damage such as gastric ulcer, erosion and the like, abnormal liver function and low immunity of patients, and the traditional Chinese medicine composition can greatly relieve the above phenomena.

Further, the weekly dose ratio of the traditional Chinese medicine raw materials, methotrexate and leflunomide is 1092g:7.5mg:70mg. Under the condition of the dosage ratio, western medicine components and traditional Chinese medicine components can exert the most ideal synergistic effect.

Further, loxoprofen sodium is also included. If joint tenderness or swelling integral is more than or equal to 6 minutes, loxoprofen sodium is added to relieve the symptoms.

Further, the daily dosage ratio of the traditional Chinese medicine raw materials to loxoprofen sodium is 156g:180mg. The dosage ratio can effectively relieve joint tenderness or swelling and improve the treatment effect of rheumatoid arthritis.

The scheme also provides application of the pharmaceutical composition in preparing a medicament for treating the qi-blood deficiency type rheumatoid arthritis.

The medicine composition of the scheme takes the principle of tonifying qi and activating, nourishing and regulating blood, and the method of regulating nutrient and defensive qi for the first time promotes the qi and blood in nutrient and activating pulse to nourish the striae and striae outside the defensive pulse, regulates the inside and outside and smoothens the channels and collaterals, so that the arthralgia can be healed. The composition balances the attack and the supplement, flexibly uses methods of strengthening spleen, regulating liver and tonifying kidney, and is suitable for matching with worm medicines to search and remove collateral evil so as to deep penetrate the root of disease. The pharmaceutical composition has remarkable treatment effect on the rheumatoid arthritis with qi and blood deficiency syndrome, can effectively improve traditional Chinese medicine syndrome and clinical symptoms of a rheumatoid arthritis patient by combining with slow-acting antirheumatic treatment, reduces ESR (equivalent series resistance) and CRP (common-point-reactive protein) inflammatory indexes, down regulates the levels of TNF-alpha and IL-6 pro-inflammatory factors, has better treatment effect compared with the pure use of the slow-acting antirheumatic treatment, and has good drug safety.

Drawings

Fig. 1 is a diagram showing a clinical laboratory technique route in experimental example 1.

Detailed Description

The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. Unless otherwise indicated, the technical means used in the following examples and experimental examples are conventional means well known to those skilled in the art, and the materials, reagents and the like used are all commercially available.

Examples

The pharmaceutical composition for treating rheumatoid arthritis of the scheme is specifically prepared as follows: 10g of cassia twig, 10g of stiff silkworm, 10g of white paeony root, 6g of turmeric, 30g of astragalus, 10g of bighead atractylodes rhizome, 20g of coix seed, 15g of Chinese angelica, 15g of prepared rehmannia root and 30g of suberect spatholobus stem. 1 dose per day, 3 times per day, 150ml each time orally. The preparation method comprises the following steps: the Chinese medicine preparation room of the XXXXXXXXXXXXHospital is decocted into 3 bags, and each bag is 150mL.

Experimental example

The clinical experimental technique route diagram of this experimental example is shown in fig. 1, and the study design adopts a simple random, control and non-blind study method. SPSS15.0 statistical software was used to derive random numbers, and selected subjects were randomly assigned to control and experimental groups using a simple random method. The experimental scheme is as follows:

1. case selection principle

(1) Diagnostic criteria:

(1.1) Western diagnostic criteria

RA diagnostic criteria promulgated by the 2009 ACR/EULAR union were used:

(1) number of cumulative joints (0-5):

1 middle and large joint (0 min); 2-10 middle and large joints (1 minute);

1-3 facet joints (2 minutes); 4-10 facet joints (3 minutes); > 10 facet joints (5 min).

(2) Serological antibody detection (0-3 points): both RF and anti-CCP anti-negative (0 points); at least one low titer positive (2 points) for RF or anti-CCP; at least one high titer positive score (3 score) for RF or anti-CCP.

(3) Synovitis duration (0-1 score): < 6 weeks (0 minutes); > 6 weeks (1 min).

(4) Acute phase reactant (0-1 min): CRP and ESR were both normal (0 points); CRP or ESR increased (1 minute).

Note that: in each section, the highest score is selected. If a patient has 5 facet joints and 4 facet joints affected, a score of 3 is obtained. The sum of the fractions obtained from the four parts is more than or equal to 6, and is determined to be RA. Number of affected joints: excluding distal interphalangeal joints, first carpometacarpal joints, and first toe joints; middle and large joints: shoulder joints, elbow joints, hip joints, knee joints and mania joints; facet joints: except for the middle and large joints, and excluding the distal interphalangeal joint, the first carpometacarpal joint and the remaining joints of the first site joint. Low titers are defined as exceeding the upper normal limit, but not exceeding the upper 3-fold normal limit. High titre is defined as exceeding the upper normal limit by a factor of 3.

(1.2) diagnostic criteria for TCM

The diagnosis standard of the RA traditional Chinese medicine is formulated by referring to the diagnosis and treatment standard of the rheumatoid arthritis in the Chinese medical industry standard of the people's republic of China, namely the diagnosis and treatment standard of the traditional Chinese medical science, and is specifically as follows:

pain and swelling of the facet joints usually occur at the beginning, usually in the joints or the back, and the movement is unfavorable and morning stiffness occurs;

slow onset, repeated lasting, gradual loss of body, repeated attack due to pathogenic wind-cold-dampness;

the affected joints are in fusiform swelling, pain during movement, and tenderness are refused to press. Later stage joint deformity, smooth surface, peripheral muscular atrophy, few visible subcutaneous nodules;

rheumatoid factor positive and blood sedimentation in the onset stage can be increased. The X-ray film can be used for treating osteoporosis, or joint bone surface candles, such as subluxation or dislocation, bone rigidity, joint surface fusion, etc.

(1.3) criteria for diagnosis of the waiting for Chinese medical symptoms

The "common symptoms of rheumatism" and "dialectical treatment of rheumatoid arthritis" in reference to "practical traditional Chinese medicine rheumatology" version 2 are divided into the following types 8:

(1) wind-damp arthralgia: symptoms are pain, heavy pain or swelling of the joints, irregular movement of the pain parts, unfavorable flexion and extension of the joints, pale red tongue with white and greasy coating, soft or slippery pulse.

(2) Cold-dampness arthralgia syndrome: symptoms are cold pain in limbs, severe local swelling, joint spasm, difficulty in flexing and extending, local aversion to cold, severe cold pain, pain due to heat, reddened skin, fat tongue, pale and dark tongue with white greasy or slippery coating, and wiry, slow or deep pulse.

(3) Syndrome of damp-heat blockage: symptoms are that the joint is locally painful and heavy, burning or has heat sensation, thirst, no desire to drink, vexation and restlessness, or fever, red tongue with yellow and greasy coating, and soft and rapid pulse or slippery and rapid pulse.

(4) Syndrome of phlegm stagnation and obstruction: swelling of joint pain, morning stiffness, difficulty in flexing and extending, nodule around joints or subcutaneous, dark and purple tongue, white, thick or greasy coating, deep, thready, astringent or deep and slippery pulse.

(5) Deficiency of both Qi and Yin: the joint is enlarged, the mouth and eyes are dry, the lips are dry, the lassitude and weakness are caused, or the muscle is lean, the tongue is red and little fluid is cracked, or the tongue is fat and large, the teeth mark is formed, the tongue coating is thin and white, and the pulse is deep, thin, weak or deep and thin.

(6) Deficiency of liver and kidney: pain in joint and muscle, difficulty in flexing and extending, swelling or stiff joint, soreness and weakness of waist and knees, cold or local fever of joint, red tongue, thin and white coating, and deep and weak pulse.

(7) The symptoms of blood exhaustion and obstruction of collaterals: pain in joints, night pain, stinging pain, dry and lusterless skin, or even a wrong nail, dark tongue, tongue edge and tip with blood stasis, thin and white coating, and thready and astringent pulse.

(8) Deficiency of both Qi and blood: the joint muscles are ache and weakness, aggravated after movement, shortness of breath and weakness, palpitation, dizziness, pale complexion, muscular atrophy, joint deformation, pale tongue, thin and white coating and weak pulse.

(1.4) criteria for active rheumatoid arthritis

By adopting an evaluation standard established by ACR, DAS28 is more than 5.1, DAS28 is more than 3.2 and less than 5.1, DAS28 is more than 2.6 and less than 3.2, DAS28 is less than 2.6, and DAS28 is less than 2.6.

(2) Case inclusion criteria, exclusion criteria, abort or exit criteria, reject or drop criteria

(2.1) case inclusion criteria:

meets the diagnosis standard of RA diseases; age above 18 years old, unlimited in sex; the complete clinical data includes general conditions, differentiation and classification, treatment and prescription medication; the patients are treated by taking the traditional Chinese medicine decoction.

(2.2) exclusion criteria:

female patients under 18 years of age, gestation and lactation; patients with serious primary diseases and mental diseases such as cardiovascular, cerebrovascular, liver, kidney and hematopoietic system; those with severe gastric or duodenal ulcer or erosion; patients with severe joint deformity and loss of function; patients with other rheumatic diseases; a history of joint trauma; intolerant to the medicine.

(2.3) abort or exit criteria: "exit case" refers to a case that does not complete the entire treatment or follow-up procedure. For all cases of clinical observations taken in, there should be a clear record. The reason for the discontinuation should be faithfully recorded. The reasons for this may include any one or more of the following: serious adverse events (including worsening disease, death, teratogenesis, disability, etc.); researchers require discontinuation of the trial based on the protection of the patient's greatest benefit; violating the treatment scheme; patient non-compliance with study procedure; the patient is pregnant; patient loss; the administrative department requires suspension; the researcher requests termination.

(2.4) reject and drop criteria:

and (3) removing: cases that should not be counted and cannot be counted should be eliminated. Such as misdiagnosis, misna (patients who did not meet inclusion criteria, and who entered the group with exclusion criteria), application of other medications without physician consent during the trial, no stem cell treatment, lack of record or no record. The removed cases should account for reasons, and their records should be kept for review, not included in the efficacy statistical analysis.

And (3) falling off: cases that did not complete the clinical trial regimen should be considered sloughed off. Including the patient withdrawing by himself (e.g. unwilling to continue to receive stem cell therapy, etc.) and the physician withdrawing (the patient seriously needs to add other medicines to affect the curative effect judgment or serious adverse events need to stop the therapy). The abscission case should explain the reason and take the last main curative effect detection result as the final result for statistical analysis. All records of stem cell treatment are subjected to safety analysis, and all abscission case data are reserved for examination.

2. Patient enrollment

(1) Doctor-patient communication: the physician is designated to communicate with the patient in detail and signs the doctor-patient communication record and informed consent. Clinical researchers must indicate to patients that participation in the clinical trial of the project is voluntary, and have the right to withdraw from the trial at any stage of the trial without complaining, and that their medical treatments and rights are not affected at all, and still continue to receive other effective treatments. The patient must be kept secret from the personal data involved in the test. The patient is also informed of the nature of the clinical trial, the purpose of the trial, the expected potential benefits and the risks and inconveniences that may occur.

(2) Medical history collection: demographic data, basic conditions, past history, complications/diseases, allergic history, etc. of the patient are collected and recorded.

(3) Baseline screening: baseline screening period refers to screening prior to enrollment, requiring completion of the following: signing an informed consent form; demographic data and medical history collection (including immunosuppressant usage and treatment time); vital signs (body temperature, respiration, pulse and blood pressure); clinical symptoms and signs; blood, urine is normal, and feces is hidden; biochemistry of blood (including liver function, kidney function); chest X-ray film; disease activity score (DAS 28 score); autoantibody detection: rheumatoid factor, etc.

(4) Patients were enrolled: patient entries were selected based on whether the patient signed informed consent, and inclusion and exclusion criteria, and the patients were divided into two groups, a control group and a treatment group. Each group of treatment course is 1 month, and the curative effect and the safety are evaluated after the treatment course is over.

(5) Grouping and treatment scheme

(5.1) control group

(1) Methotrexate 3 tablets (2.5 mg/tablet), orally taken 1 time a week;

(2) leflunomide 1 tablet (10 mg/tablet) for oral administration 1 time a day;

(3) loxoprofen sodium 1 tablet (60 mg/tablet) is orally taken 3 times a day (if joint tenderness or swelling integral is more than or equal to 6 minutes, loxoprofen sodium is added).

(5.2) Experimental group

The decoction for regulating arthralgia is added on the basis of the control group, and the specific prescription is as follows: 10g of cassia twig, 10g of stiff silkworm, 10g of white paeony root, 6g of turmeric, 30g of astragalus, 10g of bighead atractylodes rhizome, 20g of coix seed, 15g of Chinese angelica, 15g of prepared rehmannia root and 30g of suberect spatholobus stem. 1 dose per day, 3 times per day, 150ml each time orally. The preparation method comprises the following steps: the Chinese medicine preparation room of the XXXXXXXXXXXXHospital is decocted into 3 bags, and each bag is 150ml.

Both treatment courses are 1 month, and the curative effect and safety evaluation are carried out after 1 month.

3. Observation index

(1) General items: name, gender, age, past medical history, medication, etc.

(2) Clinical observation index

(2.1) principal symptoms: the number of joint tenderness and swelling.

(2.2) applying a visual analog scoring (Visual analogue scale VAS) score (0-100 mm)

Patient pain was assessed: the VAS is widely used for pain assessment in clinic in China, a swimming scale with the length of about 10cm is used, 10 scales are marked on the first scale, the two ends of the VAS are respectively divided into a 0-part end and a 10-part end, the 0-part end represents no pain, the 10-part end represents the most severe pain which is unbearable, the scale is opposite to a patient in clinic, the patient marks a corresponding position which can represent the pain degree of the patient on the ruler, a doctor marks the score according to the marked position of the patient, the clinical assessment is divided into ' excellent ' by 0-2 ', the ' excellent ' by 3-5 ', the ' acceptable ' by 6-8 ', and the ' poor ' by ' 8 '. The same method can make a more objective score before and after clinical treatment, and can evaluate the pain treatment effect more objectively. The method is simple and easy to implement, relatively objective and sensitive. The ruler commonly used in clinic at present has a free mark between the 0 end and the 10 end and has scales on the back, and is practical and convenient.

(2.2) use of Health Assessment Questionnaires (HAQ)

The HAQ disability index calculation method is an evaluation of the following activities that were undertaken during the last 2 months: can (1) self dress (including tying shoelace and button) (2) go up and down bed (3) by oneself from the end water and send to mouth (4) level ground walk (5) oneself wash the operation, and dry health (6) switch tap or bottle plug (7), comb (8) cut the dish (9) squat down and pick up clothes (10) on the ground go up and down vehicles (11) such as car from the chair do not support oneself with the hand and stand (12) shop etc.. Each score was as follows: 0 min = without any difficulty; score 1 = somewhat difficult, can be done; score 2 = difficult, barely maintained; score 3 = incomplete. And adding the components to obtain a total score.

The HAQ discomfort index calculation method is whether there is the following feeling in the past 2 months: (1) you like you do not work (2) tension or anxiety (3) dysphoria, difficulty calm 94, hurt or low mood, difficulty excitation. Each score was as follows: 0 = never; 1 = sometimes; 2 = often; 3=always.

The study summed together the disability index and discomfort index into a total score.

(2.3) index of inflammatory Activity

Blood sedimentation: normal values of the wei-shi method: less than or equal to 20mm/h;

c-reactive protein: rate nephelometry, normal values: less than or equal to 8mg/L;

rheumatoid factor: combined adsorption method, normal values: not more than 20IU/ml;

three values were recorded for each group of patients for comparison prior to treatment and month 1.

4. Clinical efficacy assessment

(1) DAS28 efficacy assessment

(1.1) DAS28 scoring

The patient was examined for 28 joints, bilateral proximal interphalangeal, metacarpophalangeal, wrist, elbow, shoulder and knee joints, to determine the number of Swollen Joints (SJC), the number of Tender Joints (TJC), and the DAS28 was calculated.

DAS28: including total joint tenderness, total joint swelling, blood sedimentation, and evaluation of overall health status

DAS28＝0.56×√TJC+0.28×√SJC+0.7×lnESR+0.14×GH

Wherein, TJC: pain-relieving joint number; SJC: number of swollen joints; ESR: erythrocyte sedimentation rate (in mm/h); GH: the overall health status (General Health Status) exhibited by the visual simulation scale method (VAS method, 0-100 mm).

(1.2) DAS28 efficacy determination

The effect is shown: after receiving treatment, DAS28 of the patient is reduced by more than or equal to 1.2;

the method is effective: DAS28 is reduced to 0.6-1.2;

invalidation: DAS28 decrease < 0.6 or DAS28 is greater than 5.1.

(2) ACR efficacy assessment

ACR20 standard: the number of swollen and tender joints is reduced by more than or equal to 20 percent; and 3 of the following 5 indexes improve pain scores of more than or equal to 20 percent (1) of subjects; (2) scoring the overall disease condition of the subject; (3) a researcher disease overall status VAS score; (4) health status questionnaire (HAQ) (5) esr or CRP.

ACR50 standard: the number of joints with swelling and tenderness is reduced by more than or equal to 50% and 3 of the following 5 indexes are improved by more than or equal to 50% (5 indexes are the same as above).

ACR70 standard: the number of joints with swelling and tenderness is reduced by more than or equal to 70% and 3 of the following 5 indexes are improved by more than or equal to 70% (the same 5 indexes are used).

5. Evaluation of therapeutic effects of traditional Chinese medicine

The nimodipine method is adopted to calculate the integral of the symptoms of the traditional Chinese medicine, evaluate the curative effect of the symptoms of the traditional Chinese medicine, refer to the guidelines of the clinical research of new traditional Chinese medicine (2002 edition), and the standard is as follows:

clinical recovery: the clinical symptoms and signs disappear or disappear basically, and the integral of symptoms is reduced by more than or equal to 95 percent.

The effect is shown: the clinical symptoms and signs are obviously improved, and the integral of symptoms is reduced by more than or equal to 70 percent.

The method is effective: the clinical symptoms and signs are all improved, and the integral of symptoms is reduced by more than or equal to 30 percent.

Invalidation: the clinical symptoms and signs are not obviously improved or even aggravated, and the integral of symptoms is reduced by less than 30 percent.

6. Inflammatory cytokine detection

The content of TNF-alpha, IL-6 and IL-10 in the peripheral serum is detected by adopting an enzyme-linked adsorption method according to the specification of the kit. The values of the content of each group of patients at the base line and at the 1 month time point were recorded separately for comparison.

7. Visit flow

Visit flow: the patients in the control group and the treatment group are respectively subjected to corresponding visit examination 1 month after the first treatment, and the examination contents comprise blood urine routine; liver and kidney function; a rheumatoid factor; peripheral serum cytokines, and the like.

8. Provision for treatment of complications

Not allow: treatment that the researcher deems to interfere with the trial efficacy decision is not allowed; other drug treatments outside of the protocol specifications are not allowed; other clinical trial drugs are not allowed.

Allowing: allowing the combined use of supportive and symptomatic treatments. During the test, the immunosuppressant for treating the disease should be accurately recorded in the case report table, wherein the recording content comprises the date of start and stop, the treatment mode, the dosage and the like.

9. Adverse event, safety measure and emergency plan

Adverse events: any adverse events that occurred during the clinical study were carefully observed for all patients, and their clinical manifestations, severity, time of occurrence, duration, treatment method, and prognosis were recorded in time. All adverse events were followed until satisfactory results were obtained.

Safety measures and emergency plans:

(1) and (3) body mounting measures: patients were evaluated thoroughly prior to treatment, rigorous observations were made during treatment, and appropriate symptomatic and adjuvant measures were made after treatment.

(2) Emergency plan: once adverse events occur, such as any adverse medical manifestations, all abnormal findings, subjective and objective disease symptoms, concurrent conditions and accidents, in the patient during treatment, whether or not those events are associated with the present treatment, positive and appropriate treatments should be administered.

10. Inspection of

The commission specialist is responsible for the inspection of clinical research so as to ensure that the clinical research scheme is strictly adhered to and executed, and the data record table and the original data are checked so as to ensure that the data on the table are consistent with the original data, and the data are error-free and tamper-free.

11. Independent Ethics Committee (IEC)

Prior to starting the study, the study protocol, informed consent, and related information and/or advertising to the patient must be approved by the subject scientific review Board (Institutional Review Board, IRB). The clinical test protocol can be modified appropriately in the following cases: to reduce immediate damage to the study patient, deviate from or change the study protocol; any action that increases patient risk and/or can significantly affect the performance of the study; all serious and unexpected adverse reactions; new conditions that may adversely affect patient safety or the performance of the study.

12. Statistical analysis

Data analysis Using SPSS17.0 softwareThe measurement data are expressed by mean ± standard deviation. The counting data adopts X ² The test, the measurement data adopts t test, and the difference of P < 0.05 is statistically significant.

13. Experimental results

(1) Clinical efficacy index comparison

There were no statistical differences between the two groups of pre-treatment comparative TJC, SJC, morning stiffness time, VAS, HAQ scores (P >0.05, see tables 1 and 2), baseline was comparable. After 1 month of treatment, the TJC, SJC, morning stiffness time, VAS and HAQ scores were significantly improved compared with those before treatment for both groups of patients (P < 0.05, see Table 1 and Table 2). The treatment effect of TJC, SJC, morning stiffness time, VAS and HAQ scores of the experimental group is superior to that of the control group after 1 month of treatment, and the statistical difference is found (P < 0.05, see Table 1 and Table 2).

Table 1: comparison of two groups of TJC, SJC and morning stiffness time

Note that: the comparison between groups adopts independent sample rank sum test; in-group comparison using paired sample rank sum test, in-control group comparison ^* P < 0.05, comparison in experimental group ^△ P＜0.05。

Table 2: comparison of two sets of VAS and HAQ

Note that: the comparison between groups adopts independent sample rank sum test; intra-group comparisons employ independent sample rank sum tests,

comparison in control group ^* P < 0.05, comparison in experimental group ^△ P＜0.05。

(2) Traditional Chinese medicine syndrome integration, main syndrome differentiation factors and curative effect comparison

The comparison of the traditional Chinese medicine symptoms before treatment shows that the two groups of main syndrome differentiation factors have no statistical difference (P is more than 0.05, see table 3 and table 4), and the baselines are comparable. After 1 month of treatment, the two groups of patients have obvious improvement on the integral of the traditional Chinese medicine symptoms, the main differentiation factors (arthralgia, joint swelling, morning stiffness, spontaneous perspiration, shortness of breath, debilitation and numbness, and incoordination) compared with the prior treatment, and the treatment effect of the experimental group is superior to that of the control group, and the experimental group has statistical difference (P is less than 0.05, see table 3 and table 4), wherein the shortness of breath and the debilitation have obvious difference (P is less than 0.01, see table 4). The integral effective rate of the traditional Chinese medicine symptoms in the experimental group after 1 month of treatment is 86.67%, which is higher than that in the control group by 57.14%, and the statistical difference is found (P is less than 0.05, see Table 5).

Table 3: integral comparison of two groups of Chinese traditional medicine syndromes

Note that: the comparison between groups adopts independent sample t test; the intra-group comparisons employed paired sample t-test.

Table 4: comparison of two main syndrome differentiation factors

Table 5: the integral curative effect comparison of two groups of traditional Chinese medicine syndromes

Note that: rank sum checking is adopted for the rank data; the counting data is checked by X2.

(3) Laboratory index comparison

There were no statistical differences (P >0.05, see tables 6 and 7) between the two groups, CRP (C-reactive protein), NLR (neutrophil lymphocyte ratio), RF (rheumatoid factor), ESR (erythrocyte sedimentation rate), and baseline was comparable. After 1 month of treatment, both patients had improved ESR and CRP compared to the pre-treatment, and the experimental group had better efficacy than the control group with statistical differences (P < 0.05, see table 6), while RF and NLR were not significantly changed and were not statistically different (P >0.05, see table 7).

Table 6: laboratory index comparison between two groups

Note that: the comparison between groups adopts independent sample rank sum test; in-group comparison using paired sample t-test and paired sample rank sum test, in-control group comparison ^* P < 0.05, comparison in experimental group ^△ P＜0.05。

Table 7: laboratory index comparison between two groups

Note that: the comparison between groups adopts independent sample rank sum test; in-group comparison using paired sample t-test and paired sample rank sum test, in-control group comparison ^* P < 0.05, comparison in experimental group ^△ P < 0.05, comparison in experimental group ^▲ P＞0.05。

(4) Disease activity comparison and efficacy comparison

The DAS28 groups were compared prior to treatment for no statistical difference (P >0.05, see table 8), baseline was comparable. Both groups of DAS28 improved after 1 month of treatment, and the efficacy of the experimental group was better than the control group with statistical differences (P < 0.05, see table 8). The DAS28 efficiency was 83.33% after 1 month of treatment, which was higher than 67.86% of the control group, with no statistical differences (P >0.05, see Table 9).

Table 8: two sets of DAS28 score comparisons

Note that: the comparison between groups adopts independent sample t test, and the comparison between groups adopts paired sample t test.

Table 9: comparison of efficacy of two groups of DAS28 scores

Note that: rank sum checking is adopted for the rank data; the count data is verified using a continuous calibration χ2.

(5) Inflammatory cytokine comparison

There was no statistical difference (P >0.05, see Table 10 and Table 11) between the two groups TNF- α, IL-6, IL-10 prior to treatment, and baseline was comparable. Both groups TNF-alpha, IL-6 improved after 1 month of treatment, and the efficacy of the experimental group was better than that of the control group with statistical differences (P < 0.05, see Table 10), while IL-10 was not significantly altered with statistical differences (P >0.05, see Table 11).

Table 10: comparison of two groups of proinflammatory cytokines/>

Note that: the comparison between groups adopts independent sample rank sum test, the comparison between groups adopts paired sample rank sum test, and the comparison between control groups ^* P < 0.05, comparison in experimental group ^△ P＜0.05。

Table 11: comparison of two groups of anti-inflammatory cytokines

Note that: the comparison between groups adopts independent sample rank sum test, the comparison between groups adopts paired sample rank sum test, and the comparison between control groups ^# P >0.05, comparison in experimental group ^▲ P＞0.05。

(5) Safety evaluation

After treatment, the two groups of hematuria are normal, obvious abnormality and clinically significant change of liver and kidney function indexes are not seen (see tables 12-14), adverse reaction is not generated, and safety is ensured.

Table 12: two sets of security comparisons

Table 13: routine comparison of urine before and after treatment of two groups/>

Note that: positive/negative: normal before treatment and abnormal after treatment; abnormal before treatment and normal after treatment; abnormal/abnormal pre-treatment and abnormal post-treatment. The normal and abnormal judgment of the index is based on clinical significance.

Table 14: description of two sets of positive/negative ratio conditions

14. Analysis of results

All cases of rheumatoid arthritis (deficiency of both qi and blood) in the group are from the clinic and ward of rheumatism in the hospitals in Chongqing city from 02 month 2021 to 02 month 2022, 60 cases are divided into an experimental group and a control group at random, 2 cases of patients falling off from the two groups after 1 month treatment are the control group, 1 case of patients is required to exit by oneself, and 1 case of patients is lost. Control 28, 1 male and 27 female, average age (55.36 + -10.76) years, course (1.88+ -2.63) years; 30 experimental groups, 1 male and 27 female, with average age (54.50 + -12.92) years and course (1.99+ -4.58) years. The RA disease of two groups of patients is in moderate activity period (3.2 < DAS28 is less than or equal to 5.1), the comparison difference of two groups of general data has no statistical significance, and the baseline is comparable (P is more than 0.05). The study design meets the requirements of the declaration of helsinki, and patients and family members sign informed consent. All cases met inclusion exclusion criteria.

The control group adopts simple western medicine treatment, and makes a treatment scheme with reference to domestic diagnosis and treatment guidelines; the experimental group is treated by the composition according to the scheme based on western medicine treatment; both groups of treatment courses are one month. After 1 month of treatment, the VAS score, HAQ score, DAS28 score and ESR, CRP, PLT, NLR of the two groups of patients are obviously improved compared with those before treatment, and the differences are statistically significant (P is less than 0.05); the improvement of VAS score, HAQ score and DAS28 score of the experimental group is better than that of the control group after 1 month of treatment, and the difference is statistically significant (P < 0.05). The medicine composition of the scheme can improve the treatment effect of western medicines on rheumatoid arthritis and reduce the side effects caused by western medicine treatment.

The inventor considers that whether nutrient qi and defensive qi are smooth or not has causal connection with the pathogenesis of rheumatoid arthritis, and the main pathogenesis is that nutrient qi and blood are not smooth, defensive qi is not moving, triple energizer is stopped, viscera qi and blood are not circulating, and tendons and bones and channels are injured. If the qi is lost, the joints and muscles are ache and powerless; malnutrition of the body will lead to movement of the body and numbness of the limbs and muscular wilting. On the basis, rheumatoid arthritis patients are susceptible to external pathogenic factors and develop internal pathogenic factors, and pathogenic factors such as wind, dampness, cold, heat, blood stasis, phlegm and the like are mixed to cause diseases. According to the pathogenesis, the inventor proposes a method for treating rheumatoid arthritis by taking the principles of tonifying qi and nourishing nutrient and blood as the principle, and regulating nutrient and defensive qi for the first time, so as to promote nutrient circulation and qi and blood to nourish, and the striae and striae outside the defensive circulation are dense, and the arthralgia can be healed by regulating the inside and outside and dredging the channels and collaterals. Meanwhile, the cold and heat are separated, deficiency and excess are distinguished, the balance is needed during the medication, the methods of strengthening spleen, regulating liver and tonifying kidney are flexibly used, and the medicine is suitable for being matched with worm medicines to search and remove collateral evil so as to deep penetrate the root of the disease.

In the prior art, the medicinal materials such as cassia twig, angelica, white paeony root, astragalus root, bighead atractylodes rhizome and the like have higher frequency of use in the practical operation of treating the rheumatoid arthritis. However, the effect of improving the therapeutic effect of western medicines cannot be satisfied by using the medicines, the inventor screens hundreds of medicines, discovers that the medicines (cassia twig, angelica, white paeony root, astragalus and bighead atractylodes rhizome) used at high frequency are matched with core medicine combinations (turmeric, stiff silkworm and coix seed), and the functions of reinforcing blood and activating blood by assisting the spatholobus stem and removing collateral evil by using the insect medicines are matched, so that the combined use of the medicines can obtain the synergistic effect, has the effects of tonifying qi and blood, dispelling wind and removing dampness and activating blood and dredging collaterals, and realizes the clinical treatment of the rheumatoid arthritis by combining western medicines. The decoction prepared by the pharmaceutical composition can effectively improve the traditional Chinese medicine symptoms and clinical symptoms of rheumatoid arthritis patients by combining slow-acting antirheumatic treatment, reduce ESR and CRP inflammatory indexes, lower the levels of TNF-alpha and IL-6 pro-inflammatory factors, and has better curative effect and good pharmaceutical safety compared with the treatment effect of simply using the slow-acting antirheumatic.

In addition to core drug combinations of turmeric, stiff silkworm and coix seed, the inventors have studied core drug combinations of other compositions, such as: the composition comprises a combination of cortex mori, radix scutellariae and cortex lycii radicis, a combination of radix scutellariae, ramulus cinnamomi and radix bupleuri, a combination of radix gentianae macrophyllae, radix angelicae pubescentis and frankincense, a combination of almond, fructus forsythiae and erythrina radicis, a combination of rhizoma anemarrhenae, caulis lonicerae and earthworm, a combination of red bean, silkworm excrement and cortex acanthopanacis, and a combination of red bean, silkworm excrement and erythrina radicis. The candidate core medicine combination is combined with medicinal materials such as cassia twig, angelica, white paeony root, astragalus root, largehead atractylodes rhizome and the like with higher frequency of medication, and suberect spatholobus stem, and has a treatment effect which is inferior to that of the core medicine combination consisting of turmeric, stiff silkworm and coix seed. The main expression is that the candidate core composition replaces the core medicine combination composed of turmeric, stiff silkworm and coix seed, and when the slow-acting antirheumatic drug combined with the scheme treats the rheumatoid arthritis, the candidate core composition has obvious differences with the core medicine combination composed of turmeric, stiff silkworm and coix seed in the aspects of reducing ESR, CRP inflammatory indexes, down regulating TNF-alpha and IL-6 pro-inflammatory factor levels, improving traditional Chinese medicine symptoms and clinical symptoms of rheumatoid arthritis patients and the like, and the core medicine combination composed of turmeric, stiff silkworm and coix seed has better effect.

The foregoing is merely exemplary of the present invention, and specific technical solutions and/or features that are well known in the art have not been described in detail herein. It should be noted that, for those skilled in the art, several variations and modifications can be made without departing from the technical solution of the present invention, and these should also be regarded as the protection scope of the present invention, which does not affect the effect of the implementation of the present invention and the practical applicability of the patent. The protection scope of the present application shall be subject to the content of the claims, and the description of the specific embodiments and the like in the specification can be used for explaining the content of the claims.

Claims

1. A pharmaceutical composition for the treatment of rheumatoid arthritis, characterized in that: the traditional Chinese medicine comprises, by weight, 10 parts of cassia twig, 10 parts of white peony root, 30 parts of astragalus, 10 parts of bighead atractylodes rhizome, 15 parts of angelica, 6 parts of turmeric, 10 parts of stiff silkworm, 20 parts of coix seed, 30 parts of suberect spatholobus stem and 15 parts of prepared rehmannia root;

it also includes methotrexate and leflunomide; the weekly dose ratio of the traditional Chinese medicine raw materials, the methotrexate and the leflunomide is 1092g:7.5mg:70mg;

if the joint tenderness or swelling integral of the patient is more than or equal to 6 minutes, the patient also comprises loxoprofen sodium; the daily dosage ratio of the traditional Chinese medicine raw materials to loxoprofen sodium is 156g:180mg.

2. A pharmaceutical composition for the treatment of rheumatoid arthritis according to claim 1, characterized in that: the traditional Chinese medicine raw materials are prepared by the following method: decocting the Chinese medicinal materials in water to obtain medicinal liquid.

3. The pharmaceutical composition for treating rheumatoid arthritis according to claim 2, wherein the ratio of the raw materials of the traditional Chinese medicine to the liquid medicine is 156g:450mL.

4. Use of a pharmaceutical composition according to any one of claims 1-3 for the preparation of a medicament for the treatment of rheumatoid arthritis of deficiency of both qi and blood.