Traditional Chinese medicine composition for treating scleroderma and application

Abstract

The invention discloses a traditional Chinese medicine composition for treating scleroderma, which is prepared from the following traditional Chinese medicines in parts by weight: 60-100 parts of agkistrodon halys, 60-100 parts of cobra and 30-50 parts of dragon's blood. In the formula, the agkistrodon halys and the cobra have the effects of dispelling wind, dredging collaterals and resisting rheumatism, the dragon's blood has the effects of removing blood stasis and relieving pain, the formula conforms to the treatment principle of scleroderma for promoting blood circulation, removing blood stasis, dispelling wind and dredging collaterals, and research in recent years shows that the snake medicine still has the effect of regulating the immune function. Clinical experiment research shows that the treatment effect of the Soukang capsule taken by a scleroderma patient is compared with the treatment effect of a patient taking penicillamine in the same period, and the effectiveness and the safety of the Soukang capsule in treating systemic scleroderma are proved, so that the medicine disclosed by the invention has a remarkable effect of treating the scleroderma and has a good application value.

Description

Technical Field

[0001] This invention relates to the field of medicine, specifically to a traditional Chinese medicine composition and its application for treating scleroderma. Background Technology

[0002] Systemic scleroderma (SSc) is an autoimmune disease characterized by widespread fibrosis of the skin and internal organs. Hyperactive autoimmune function and vascular lesions are two other distinctive features. Clinically, it is divided into three stages: sclerosis, sclerema, and active / atrophic stages. Treatment of SSC requires a comprehensive approach, considering four aspects: ① anti-fibrosis, ② suppression of autoimmune responses, ③ improvement of vascular lesions, and ④ correction of organ function. Since excessive collagen fiber proliferation in connective tissue is the most fundamental pathological change in SSC, inhibiting collagen fiber proliferation is the most crucial aspect of SSC treatment. Currently, Western medicine anti-fibrotic drugs include penicillamine, colchicine, and propafenone. c Interferon, relaxin, etc. However, these drugs either have significant side effects, are too expensive, or have uncertain clinical efficacy. In comparison, penicillamine's low-dose escalation therapy is more effective and practical, but this drug also has many side effects, such as allergic reactions, bone marrow suppression, liver and kidney damage, drug-induced myositis, etc., which affect its clinical application. When patients experience severe side effects, they may have to reduce the dosage of penicillamine or discontinue it, affecting their treatment.

[0003] Therefore, developing a drug with clear efficacy and low side effects is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0004] To overcome the shortcomings of existing technologies, this invention aims to provide a traditional Chinese medicine composition for treating scleroderma, its preparation method, and its application, specifically employing the following technical solutions: The first aspect of the present invention provides a traditional Chinese medicine composition for treating scleroderma, which is made from the following traditional Chinese medicines in parts by weight: 60-100 parts of viper, 60-100 parts of cobra, and 30-50 parts of dragon's blood. Furthermore, the traditional Chinese medicine composition for treating scleroderma is made from the following traditional Chinese medicines in parts by weight: 80 parts viper, 80 parts cobra, and 40 parts dragon's blood. A second aspect of the present invention provides a pharmaceutical composition for treating scleroderma, comprising any of the above-mentioned traditional Chinese medicine compositions for treating scleroderma and a pharmaceutically acceptable carrier; Furthermore, the pharmaceutical composition is an oral formulation; Furthermore, the oral preparation is a decoction, granules, capsules, tablets, oral liquid, pills, or powder; more preferably, the oral preparation is a capsule. A third aspect of the present invention provides a method for preparing any of the above-mentioned medicaments for treating scleroderma, comprising the following steps: Weigh out the medicines according to the above weight ratio. After the viper and cobra are dried and sterilized at 80-100℃ for 3-5 hours, add the blood dragon, grind into 80-120 mesh, add 90-95 parts of starch and 5-10 parts of talc, mix well, and package into capsules to obtain the product. The fourth aspect of the present invention provides the use of any of the above-mentioned traditional Chinese medicine compositions or pharmaceutical compositions for treating scleroderma in the preparation of medicaments for treating scleroderma; Furthermore, the therapeutic effects include treating skin hardening, improving joint function, improving vascular lesions, and / or enhancing immune function; Furthermore, the therapeutic effect is achieved in combination with penicillamine; The present invention has achieved the following beneficial effects: In Traditional Chinese Medicine (TCM), this disease falls under the category of "skin arthralgia." It arises from insufficient Qi and blood, and spleen and kidney Yang deficiency, allowing wind, cold, and dampness to invade and congeal in the skin and meridians, causing the disease. In the early stages, Qi and blood are imbalanced, and the Ying and Wei (nutritive and defensive Qi) are not in harmony, leading to malnourishment of the skin and meridians. Prolonged stagnation can transform into heat. In the later stages, Qi and blood deficiency further depletes the skin and muscles. Therefore, the corresponding TCM classifications are as follows: Early stage – cold congealing in the skin and meridians, spleen and kidney Yang deficiency syndrome. Treatment principle: warming the kidneys and strengthening the spleen, promoting blood circulation and removing blood stasis; Hardening stage – Qi stagnation and blood stasis, meridian obstruction syndrome. Treatment principle: tonifying Qi and promoting blood circulation, dispelling wind and unblocking meridians; Acute attack and induration stage – heat toxin, phlegm, dampness, and blood stasis syndrome. Treatment principle: clearing heat, cooling blood, promoting blood circulation and unblocking meridians; Atrophic stage – Qi and blood deficiency, blood stasis obstructing meridians syndrome. Treatment principle: tonifying Qi and blood, promoting blood circulation and unblocking meridians. The differentiation of syndromes emphasizes the signs of phlegm turbidity and blood stasis. Since phlegm and blood stasis often obstruct the meridians throughout the entire course of a disease, the treatment principle of promoting blood circulation, removing blood stasis, dispelling wind, and unblocking the meridians is also applied to the treatment of all stages of the disease.

[0005] The drug of this invention is named "Fukang Capsules". The formula of Fukang Capsules includes: viper, cobra, and dragon's blood. Viper and cobra have the effects of dispelling wind, clearing the meridians, and resisting rheumatism, while dragon's blood has the effect of promoting blood circulation and relieving pain. This aligns with the treatment principles of scleroderma—promoting blood circulation, clearing the meridians, and dispelling wind. Furthermore, recent studies have found that snake-based medicines also have the effect of regulating immune function. Clinical experimental studies have shown that comparing the treatment effects of Fukang Capsules on scleroderma patients with those on penicillamine during the same period demonstrates the effectiveness and safety of Fukang Capsules in treating systemic scleroderma. Therefore, the drug of this invention has significant efficacy in treating scleroderma and has good application value. Detailed Implementation

[0006] The invention will now be further described in conjunction with specific embodiments. It should be noted that, without conflict, the various embodiments or technical features described below can be arbitrarily combined to form new embodiments. Unless otherwise specified, the materials and equipment used in this embodiment are commercially available. The following embodiments are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0007] (I) Implementation Examples Example 1 A type of capsule for treating scleroderma, Fukang, is made from 60g of viper, 60g of cobra, and 30g of dragon's blood. After the viper and cobra are dried and sterilized at 80℃ for 3 hours, the dragon's blood is added and pulverized into 80 mesh. Then, 90g of starch and 10g of talcum powder are added, mixed well, and packaged into 1000 capsules.

[0008] Example 2 A type of capsule for treating scleroderma, Fukang, is made from 100g of viper, 100g of cobra, and 50g of dragon's blood. After the viper and cobra are dried and sterilized at 100℃ for 5 hours, the dragon's blood is added and the mixture is pulverized into 120 mesh. 95g of starch and 5g of talcum powder are added, mixed well, and packaged into 1000 capsules.

[0009] Example 3 A type of capsule for treating scleroderma, Fukang, is made from 80g of viper, 80g of cobra, and 40g of dragon's blood. The viper and cobra are dried and sterilized at 80-100℃ for 3-5 hours, then dragon's blood is added, pulverized, and passed through a No. 6 sieve to 100 mesh. 95g of starch and 5g of talc are added, mixed well, and packaged into 1000 capsules.

[0010] (II) Experimental Examples 2.1 Experimental Methods: 2.1.1 Objective: To compare the therapeutic effects of Fukang capsules on inpatients and outpatients with systemic scleroderma from January 2009 to December 2010 with the therapeutic effects on patients taking penicillamine during the same period, thereby demonstrating the efficacy and safety of Fukang capsules in treating systemic scleroderma.

[0011] 2.1.2 Grouping: Patients with systemic scleroderma who were treated in outpatient and inpatient departments between January 2009 and December 2010 were randomly divided into experimental group and control group by lottery.

[0012] Subject inclusion criteria: 1) Main criteria: (Both of the following criteria must be met simultaneously) A. Undergraduate inpatients or outpatients from January 2009 to December 2010.

[0013] B. Meets the diagnostic criteria for SSc proposed by the American College of Rheumatology in 1980.

[0014] Note: Systemic sclerosis classification diagnostic criteria (American College of Rheumatology, 1980) A: Primary criterion: Proximal scleroderma. Symmetrical thickening, tautness, and hardening of the skin above the finger and metacarpophalangeal joints. These changes can affect the entire limb, face, neck, and trunk (chest and abdomen). B: Secondary Standards ① Scleroderma of the fingers: The above skin changes are limited to the fingers. ② Pitting scars or loss of finger pad tissue: Pitting of the fingertips or loss of finger pad (finger pad) tissue due to ischemia. ③ Bilateral basal pulmonary fibrosis: Standard chest X-ray shows bilateral reticular linear or linear nodular shadows, prominent in the basal part of both lungs, which may present as diffuse spots or a "honeycomb" appearance. These changes cannot be explained by primary lung disease.

[0015] Diagnosis: A diagnosis of systemic sclerosis can be made if one major criterion or two or more minor criteria are met.

[0016] C: Exclusion criteria for participants: 1) Pregnant or lactating women. 2) Individuals with heart failure or pericardial effusion. 3) Individuals with contraindications to penicillamine use, such as: A. Severe liver or kidney dysfunction. B. Cholecytopenia that has not returned to normal levels after treatment. C. Myositis symptoms such as myalgia, muscle weakness, and elevated blood lactate dehydrogenase. D. Positive occult blood or protein in urinalysis. 4) Individuals unable to complete the course of treatment. 5) Individuals with a positive penicillin skin test. Individuals with any of the above conditions will be excluded from the study.

[0017] 2.1.3 Drug administration: Experimental group: Administered the test drug and oral Fukan capsules (prepared according to Example 3), two capsules three times daily. Basic treatment drugs were also administered concurrently. Control group: No test drug was administered; only the same basic treatment drugs as the experimental group were administered.

[0018] 2.1.4 Effectiveness evaluation indicators: (1) Clinical manifestations: skin hardness score, joint function score, Raynaud's phenomenon score, maximum tooth distance, maximum finger distance, and acral lesion score, see appendix for details.

[0019] (2) Laboratory tests: Erythrocyte sedimentation rate (ESR), gamma globulin, IgG (3) Systemic examination: Esophageal examination: observe esophageal peristalsis and the width of the lower end of the esophagus; chest X-ray to observe lung markings. Holter monitoring and echocardiography.

[0020] 2.1.5 Evaluation of clinical efficacy: (1) The efficacy of the above treatment was assessed after one year of continuous treatment.

[0021] (2) Criteria for judging therapeutic efficacy: Clinical cure: After treatment, the skin hardened and softened, Raynaud's phenomenon and joint and muscle symptoms subsided, and visceral function and laboratory tests returned to normal.

[0022] Significant effect: After treatment, the skin sclerema score and joint function score decreased by more than 50%, Raynaud's phenomenon was significantly reduced, serous cavity effusion decreased by more than 50% (if there is an echocardiogram report from our hospital), and laboratory tests showed significant improvement.

[0023] Effective: After treatment, the skin sclerema score and joint function score are reduced by more than 30% (if there is an echocardiogram report from our hospital), Raynaud's phenomenon is alleviated, serous cavity effusion is reduced by more than 30%, and laboratory tests show improvement.

[0024] Ineffective: Those whose condition does not improve after 6 months of treatment, or those who die during the treatment period.

[0025] The obtained data were analyzed using SPSS software version 17.0, including chi-square analysis, t-test, rank-sum test, and analysis of variance.

[0026] 2.2 Treatment process: Test drug: Fukan capsules (Example 3), manufactured by Shanghai Liantang Pharmaceutical Factory on behalf of our hospital; Positive control drug: Penicillamine tablets, manufactured by Shanghai Pharmaceutical (Group) Co., Ltd. Xinyi Pharmaceutical Factory, approval number: National Drug Approval Number H31022286; Dosage form: tablets; Specification: 0.125g; Batch number: The batch numbers of Fukan capsules used from January 2009 to December 2010 are 20080901, 20090101, 20090701, 20091101, 20100201, 20100401, and 20101001.

[0027] Administration: Experimental group: The experimental drug was administered orally, two capsules of Fukan capsules three times a day, and continued to be taken without interruption during the 1-year observation period; the following basic treatment drugs were also administered during the 1-year observation period.

[0028] Control group: No experimental drug was given; during the 1-year observation period, only the same basic treatment regimen as the experimental group was given.

[0029] Basic treatment plan: A. Oral penicillamine, initial dose 0.0625g / day, gradually increased to 0.25-0.75g / day according to the condition. After the condition stabilizes, the dose can be gradually reduced to the maintenance dose of 0.125g / day according to changes in the condition. It should be taken continuously throughout the observation period.

[0030] B. Anti-fibrosis: Centella asiatica tablets 24 mg each time, three times a day; take continuously throughout the observation period.

[0031] C. Promote blood circulation and remove blood stasis: Add 20 ml of Danshen injection to 100 ml of 5% glucose solution or 0.9% saline (for diabetic patients) for intravenous drip, once a day, for 14 days as one course of treatment; use as needed.

[0032] D. To invigorate Qi and unblock collaterals: Add 20 ml of Shenmai injection to 250 ml of 5% glucose solution or 0.9% saline (for diabetic patients) for intravenous drip, once a day, for 14 days as one course of treatment; use as needed.

[0033] E: Immunomodulatory: Add 4 ml of Ganoderma lucidum peptide injection to 100 ml of 5% glucose solution or 0.9% saline (for diabetic patients) for intravenous drip, once a day, for 14 days as one course of treatment; use as needed.

[0034] F: Promote metabolism: Take 0.1g of vitamin E capsules orally once a day; continue taking them throughout the observation period.

[0035] G: External treatment: Apply Centella asiatica cream to the affected area 1-2 times daily; continue use throughout the entire observation period.

[0036] During the trial, both groups of subjects received the same basic treatment regimen.

[0037] Permissible treatment measures for co-existing diseases during the experiment: 1) Skin allergic reaction: After the appearance of skin allergic symptoms, reduce the dosage of penicillamine or discontinue its use. Administer loratadine 10 mg orally once in the morning and ketotifen 1 mg orally once before bedtime. Three months after the skin allergic reaction subsides, penicillamine can be tried again using desensitization therapy. The initial dose is 0.041 g / day (1 / 3 tablet). If no allergic reaction is observed after 2 weeks, the dose can be increased to the original dose of 0.0625 g / day. If the rash reappears, discontinue penicillamine.

[0038] 2) Abnormal urinalysis: Discontinue penicillamine and nephrotoxic drugs, avoid soy products, follow a low-sodium, low-protein diet, and repeat urinalysis.

[0039] 3) Elevated alanine aminotransferase: Reduce or discontinue penicillamine dosage, and administer Sedum sarmentosum granules orally, three times a day, one small packet each time, or administer polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day.

[0040] 4) Increased lactate dehydrogenase: Reduce or discontinue penicillamine dosage, and administer Sedum sarmentosum granules orally, three times a day, one small packet each time.

[0041] 5) Decreased blood cell count: Take 2 tablets of Leukogen orally three times a day; for decreased blood cell count, add 2 tablets of Shark Liver Oil orally three times a day; for decreased platelet count, add 2 tablets of Deoxyribonucleic Acid Sodium orally three times a day.

[0042] Treatment measures that may be used during the experiment and affect the experimental results: The following treatment measures may affect the final conclusions of the experiment. Therefore, if a subject adopts the following treatment measures as a treatment need, the subject will be withdrawn from the experiment.

[0043] 1) Hormones: Hormones are the treatment drugs for scleroderma. Taking hormones can affect the patient's skin hardening, joint function, and changes in the condition. Taking hormones can have a great impact on the final conclusion of the experimental results.

[0044] 2) Other traditional Chinese medicines: Other traditional Chinese medicines besides the basic treatment plan and Fukang capsules, including Huoxue Jianfu granules, Qingre Jianfu granules, Wenshen Jianfu granules and other traditional Chinese medicine preparations, will interfere with the evaluation of experimental results if taken during the experimental phase.

[0045] 3) Traditional Chinese medicine decoctions: interfered with the experimental results of Fukang capsules, which are traditional Chinese medicine preparations.

[0046] 4) Immunosuppressants: Taking immunosuppressants will interfere with the assessment of the patient's immune indicators.

[0047] 2.3 Evaluation Indicators and Methods for Therapeutic Effect This disease is rare, and there are currently no authoritative international treatment principles or guidelines. Our department, by referring to international evaluation indicators for the treatment efficacy of systemic scleroderma and our long-term medical practice, has developed the following indicators: 1) Key therapeutic indicators: A. Skin hardness score: Skin hardening is the main manifestation of systemic scleroderma, and the skin hardness score can provide a direct and numerical assessment of the degree of skin hardening in patients; this index is derived from foreign literature.

[0048] Note: The degree of skin hardening at 16 sites on the body of the subject was scored, with a minimum score of 0 and a maximum score of 4. The total score was then used as the patient's skin hardness score.

[0049] The 16 scoring areas are: fingers, back of hand, forearm, upper arm, shoulder, breast, thigh, calf, instep, and toes (these 10 areas are scored on both sides); neck, cheek, chest, abdomen, upper back, and lower back (these 6 areas are scored on one side only); a total of 26 areas, with a total score of 104 points.

[0050] The scoring criteria are as follows: 0 points - Normal skin, soft skin, skin can be pinched.

[0051] 1 point - Thickened skin, the skin feels similar to raw pigskin when touched, the epidermis can still be pinched, but there is a clear feeling of thickened epidermis.

[0052] 2 points - Grade I skin hardening: The skin feels similar to tanned leather (such as a leather jacket) when touched. A small amount of the epidermis can be pinched. The skin is hardened, but there may still be a slight feeling of softness.

[0053] 3 points - Grade II skin hardening: The skin feels like a hard leather shoe when touched; the epidermis cannot be pinched, and the skin is hardened and lacks softness.

[0054] 4 points - Grade III dermatitis, the skin feels like a wooden board when touched, and the epidermis is tightly attached to the subcutaneous tissue.

[0055] B. Joint Function Score: Although systemic scleroderma has not been found to cause organic damage to the joint structure in patients, the hardening of the skin at the joints has a direct impact on joint function. Therefore, the joint function score, which directly and numerically assesses joint function, can intuitively reflect the changes in the patient's condition. This index is derived from foreign literature.

[0056] Note: The subjects independently complete 12 test actions. The speed and fluency of the subjects' actions are observed and scored. The total score is used as the patient's joint function score to assess the patient's joint function. The lowest score is 0 points, the highest score is 4 points, and the total score is 48 points.

[0057] The 12 test actions are as follows: (1) Open a bottle cap with your hand. (2) Turn a doorknob to open a door. (3) Open a drawer. (4) Cut food. (5) Wind a watch. (6) Write. (7) Use chopsticks freely. (8) Place your palm flat on a table. (9) Make a fist. (10) Comb your hair. (11) Touch the opposite ear from behind your neck. (12) Bending over freely (to pick up an object).

[0058] Scoring criteria: 0 points - The test action was completed normally without any obstruction, the movement was smooth, and there was no restriction on joint movement.

[0059] 1 point - Able to complete the test movements well, the movements are slow and relatively smooth, with an occasional failure in multiple attempts, and slight limitation of joint movement.

[0060] 2 points - Able to barely complete the test movements, the movements are mechanically difficult, and the movements are often impossible to complete after repeated attempts, with obvious limitations in joint mobility.

[0061] 3 points - Occasionally able to complete the test, only succeeding once out of multiple attempts, the movement is difficult, joint mobility is limited, and some interphalangeal joints can only make slight movements.

[0062] 4 points - Unable to complete the test action, failed at least three times, claw hand, only a few interphalangeal joints can move slightly.

[0063] C. Raynaud's Phenomenon Score: The typical manifestation of Raynaud's phenomenon is that the fingers and toes turn white when exposed to cold or emotional excitement (due to vasospasm causing local ischemia), accompanied by tingling and numbness, turning purple after being warmed (the arteries open, but the veins are still spasming), followed by redness (arterial and venous dilation), and finally returning to normal color. The probability of Raynaud's phenomenon occurring in patients with systemic scleroderma is over 90%, and recent studies have shown that ischemic manifestations can also occur in internal organs (heart, brain, kidneys, etc.), which is called visceral Raynaud's phenomenon. The Raynaud's phenomenon score is designed by our department and can quantify the frequency of Raynaud's phenomenon attacks, thereby reflecting the patient's recent peripheral blood circulation status; this index is derived from our department's own development.

[0064] Note: The occurrence of Raynaud's phenomenon in spring, summer, autumn, and winter, as well as in external finger positions, was assessed separately, and the total score was obtained as the patient's Raynaud's phenomenon score to assess the severity of the patient's Raynaud's phenomenon; the minimum score was 0 points, the maximum score was 3 points, and the total score was 15 points.

[0065] Scoring criteria: 0 points - No signs of attack at all.

[0066] 1 point - Occasional, with an average frequency of less than once per week.

[0067] 2 points - moderate, with an average frequency of more than once a week but less than once a day.

[0068] 3 points - Frequent, with an average number of attacks equal to or greater than once a day.

[0069] 2) Secondary efficacy endpoints: A. Maximum tooth distance: This measures the maximum distance between the teeth when the patient opens their mouth, reflecting the degree of skin hardening on the face, especially the cheeks; this indicator is derived from our own formulation.

[0070] B. Maximum finger distance: The maximum value is taken as the difference between the thumb and middle or ring finger when the patient's palm is open. This reflects the degree of hardening of the palm and fingers, as well as the involvement of the metacarpophalangeal joints and interphalangeal joints. This indicator is derived from our own formulation.

[0071] C. Acral Lesion Score: The acral lesion score is designed by our department. It can quantify the manifestations of acral lesions in patients and reflect the long-term peripheral blood circulation status of patients from another perspective. This indicator is derived from our department's own formulation.

[0072] Note: Scores are assigned based on the severity of four symptoms in the extremities (flattening of the finger pads, fingertip indentation, fingertip ulceration, and phalangeal bone resorption) and the number of fingers affected. The total score is the patient's extremity lesion score to assess the severity of the lesions. The minimum score is 0 points, the maximum score is 3 points, and the total score is 12 points.

[0073] Scoring criteria; 0 points - Normal, no symptoms.

[0074] 1 point - Mild, symptoms appear in 1-3 fingers, no symptoms appear in toes.

[0075] 2 points - moderate, 4-6 fingers have corresponding symptoms, more than 1 toe has corresponding symptoms.

[0076] 3 points - Severe, symptoms are present in 7-10 fingers, and more than 3 toes may also show symptoms.

[0077] D. Erythrocyte sedimentation rate (ESR), gamma globulin (γ-globulin), CIC, and IgG: These reflect the activity of the patient's immune system.

[0078] Erythrocyte sedimentation rate (ESR): 1.6 ml of 3.8% sodium citrate anticoagulated whole blood, dynamic method, measured by LENA ESR analyzer; normal range is 0-20 mm / h.

[0079] γ-globulin: 1 ml serum, cellulose acetate membrane method. Home-prepared formulation; normal range is 0-23%.

[0080] CIC: 1 ml of serum, turbidity by polyethylene glycol precipitation. Self-prepared formulation; normal range is 0.023–0.065 OD.

[0081] IgG: 1 mL of serum, turbidimetric assay; IgG kit, manufactured by Siemens HeaItycare Diagnostics Products GmbH; normal range is 7.0–16.0 g / L.

[0082] E. Barium swallow, chest X-ray, echocardiography, 24-hour Holter monitoring: These reflect the extent of involvement of the patient's esophagus, lungs, heart, and other organs.

[0083] Clinical efficacy evaluation: The efficacy was assessed after one year of the above treatment. Each observation item was scored before and one year after treatment. Two senior physicians scored each observation item before and one year after treatment, and the average score was taken to obtain the score before and after treatment. Based on the changes in the patient's score, the patient was divided into cured, significantly effective, effective, and ineffective.

[0084] Clinical cure: After treatment, the skin hardened and softened, Raynaud's phenomenon and joint and muscle symptoms subsided, and visceral function and laboratory tests returned to normal.

[0085] Significant effect: After treatment, the skin sclerema score and joint function score decreased by more than 50%, Raynaud's phenomenon and muscle and joint pain were significantly reduced, serous cavity effusion decreased by more than 50% (if there is echocardiography result from our hospital), and laboratory tests showed significant improvement.

[0086] Effective: After treatment, the skin sclerema score and joint function score are reduced by more than 30%, Raynaud's phenomenon and muscle and joint pain are alleviated, serous cavity effusion is reduced by more than 30% (if there is an echocardiogram result from our hospital), and laboratory tests show improvement.

[0087] Ineffective: Those whose condition does not improve after 6 months of treatment, or those who die during the treatment period.

[0088] The effectiveness of Fukang capsules was analyzed by comparing the number of effective cases (cured + significantly effective) after treatment in the experimental group and the control group.

[0089] 2.4 Safety Evaluation Indicators and Methods 1) Safety indicators: Observe for rash and myalgia. Laboratory tests include complete blood count, alanine aminotransferase, serum creatinine, urinalysis, and lactate dehydrogenase. Follow-up is required once a month before the start of the 1-year observation period and during the observation period. If some subjects cannot do this, they should come to the hospital for a follow-up examination at least once every 3 months during the observation period.

[0090] Skin allergic reaction: Normal result is negative; abnormal result is systemic skin allergic reaction (skin itching, maculopapular rash, erythema multiforme, or large-area skin peeling). Skin allergic reaction is one of the adverse reactions listed in the penicillamine package insert.

[0091] After the onset of skin allergy symptoms, reduce or discontinue penicillamine and administer loratadine 10 mg orally once in the morning and ketotifen 1 mg orally once before bedtime. Three months after the skin allergy reaction subsides, penicillamine can be tried again using desensitization therapy. The initial dose is 0.041 g / day (1 / 3 tablet). If no allergic reaction is observed after 2 weeks, the dose can be increased to the original dose of 0.0625 g / day. If the rash reappears, discontinue penicillamine.

[0092] Blood cell reduction: 2 ml of whole blood, EDTA-K2 anticoagulation, and flow cytometry and radiofrequency resistance method were used.

[0093] Red blood cells: The normal range is 3.5–5.5 × 10^12 / L, and <3.5 × 10^12 / L is considered abnormal.

[0094] White blood cell count: The normal range is 4.0–10.0 × 10^9 / L, and <4.0 × 10^9 / L is considered abnormal.

[0095] Platelets: The normal range is 100-300×10^9 / L, and <100×10^9 / L is considered abnormal.

[0096] Decreased blood cell count is one of the adverse reactions listed in the penicillamine package insert.

[0097] For decreased blood cell count, take Lixusheng orally, 2 tablets three times a day; for decreased blood leukocyte count, add shark liver oil orally, 2 tablets three times a day; for decreased platelet count, add deoxyribonucleic acid sodium orally, 2 tablets three times a day.

[0098] Serum alanine aminotransferase (ALT): 1 ml serum, rate assay; Roche ALT kit; normal range is 10-50 units / L, >50 units / L is considered abnormal. Elevated ALT is one of the adverse reactions listed in the penicillamine package insert.

[0099] If elevated alanine aminotransferase (ALT) is observed, reduce or discontinue penicillamine. Administer *Sedum sarmentosum* granules orally, three times a day, one small packet each time, or polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. Repeat liver function tests until normal levels are achieved.

[0100] Urinalysis: 10 ml urine sample, URIT dry chemical method, URIT-500 urine analyzer. Urine protein: Normal is negative, abnormal is positive.

[0101] Occult blood in urine: Normal is negative, abnormal is positive. Abnormal urinalysis is one of the adverse reactions listed in the penicillamine package insert.

[0102] If abnormalities are found in the urinalysis, discontinue penicillamine and nephrotoxic drugs, avoid soy products, follow a low-sodium, low-protein diet, and repeat the urinalysis until it returns to normal.

[0103] Serum creatinine: 1 mL serum, enzyme colorimetric method; Roche creatinine kit; normal range is 59–104 μmol / L for men, >104 μmol / L is abnormal; for women, 45–84 μmol / L, >84 μmol / L is abnormal. Abnormally elevated creatinine is one of the adverse reactions listed in the penicillamine package insert.

[0104] If abnormal creatinine levels are detected, discontinue penicillamine and nephrotoxic drugs, avoid soy products, follow a low-sodium, low-protein diet, and repeatedly check creatinine levels until they return to normal.

[0105] Blood lactate dehydrogenase: 1 ml serum, UV detection method; Changzheng lactate dehydrogenase kit; normal range is 114-240 units / L, >240 units / L is considered abnormal. Elevated lactate dehydrogenase is one of the adverse reactions listed in the penicillamine package insert.

[0106] If lactate dehydrogenase is elevated, reduce or discontinue penicillamine dosage and administer *Sedum sarmentosum* granules orally, three times a day, one small packet each time. B. Adverse reactions when taking Fukan capsules: allergic reactions, gastrointestinal reactions, etc.

[0107] 2) Compare the number of cases of penicillamine side effects in the experimental group and the control group during the treatment process, and compare the dosage of penicillamine before treatment, 3 months, 6 months, 9 months and 12 months after treatment to analyze the safety of Fukang capsules.

[0108] 2.5 Quality Control and Assurance 1) All cases participating in the trial met the diagnostic criteria established by the American College of Rheumatology in 1980.

[0109] 2) Subjects were randomly assigned to the experimental group and the control group. The variances between the two groups were homogeneous according to the Levene test. There were no statistically significant differences in gender, age, disease duration, and disease severity between the two groups according to the t-test (P>0.05).

[0110] 3) Based on statistical principles, calculate the number of cases required to achieve the intended purpose of the experiment.

[0111] 4) The use, delivery and storage of investigational drugs, including placebos and control drugs, shall comply with the provisions of the drug instructions, be administered according to the prescribed dosage, route and dosing interval, and patients' clinical symptoms and auxiliary examination results shall be observed.

[0112] 5) If adverse reactions to medication are found during treatment, discontinue the medication immediately, take appropriate measures based on the patient's clinical symptoms and auxiliary examination results, and record the adverse drug reactions.

[0113] 6) The prescribed efficacy evaluation criteria, including the methods for evaluating parameters, observation time, recording and analysis.

[0114] 7) If a patient is unable to complete treatment or data collection for any reason, they will be considered to have withdrawn from observation.

[0115] 2.6 Data Management 1) When evaluating the efficacy of treatment for patients, two senior physicians will conduct the assessment and score, and the average score will be used to obtain the pre- and post-treatment score, so as to minimize the influence of the subjective factors of the assessors on the assessment results.

[0116] 2) If two senior physicians have a dispute over the data collected from the subjects, a senior physician will be asked to re-evaluate and verify the data.

[0117] 3) The patient's attending physician does not participate in the patient's treatment efficacy evaluation, and the physicians who participate in the treatment efficacy evaluation do not participate in data collection, entry, review, locking, and statistical analysis.

[0118] 2.7 Statistical Analysis Using SPSS version 17.0 software, chi-square analysis, t-test, rank-sum test (Wilcoxon, Mann-Whitney test), and analysis of variance were performed on the data of the experimental group and the control group to determine whether there were statistical differences.

[0119] 2.8 Test Results 1. Analysis of the Subject Population A total of 140 patients were observed, all of whom were outpatients and inpatients of the Scleroderma Department at Shanghai Municipal Hospital of Integrated Traditional and Western Medicine. All cases met the diagnostic criteria for SSc proposed by the American College of Rheumatology in 1980. During the study, 6 patients in the control group withdrew from the observation due to discontinuation of penicillamine, and 17 patients in both groups were lost to follow-up, resulting in a total of 23 patients withdrawing from the observation, leaving 117 patients. Among them, there were 25 males and 92 females, with a male:female ratio of 1:3.68. Patients were randomly divided into two groups by lottery. The control group consisted of 47 patients (14 lost), including 10 males and 37 females, aged 20-62 years, with a disease duration of 7-96 months. The experimental group consisted of 70 patients (9 lost), including 15 males and 55 females, aged 17-65 years, with a disease duration of 4-90 months. Statistical analysis showed no significant differences in gender, age, or disease duration between the two groups. (See Table 1).

[0120] Table 1. Subject Grouping

[0121] At enrollment, the main symptoms and signs of the two groups of subjects were compared. The scores of skin hardness, joint function, Raynaud's phenomenon, maximum tooth distance, maximum finger distance, skin pigmentation change, acral lesion, erythrocyte sedimentation rate, gamma globulin, and IgG showed no statistically significant differences after the two-sample mean t-test. However, the symptoms of patients in the CIC control group were more severe than those in the experimental group. Since this experiment compared the differences between the two groups before and after treatment, it was considered that the difference in CIC symptoms between the experimental and control groups had no significant impact on the results of this experiment (see Table 2).

[0122] Table 2. Comparison of main symptoms and signs between the control group and the experimental group before treatment (Mean±SD)

[0123] Since the skin hardness integral, Reynolds phenomenon integral, skin pigmentation change integral, and acral lesion integral are integral indicators, it cannot be determined whether their data are normally distributed. Therefore, a nonparametric two-sample rank-sum test (Wilcoxon, Mann-Whitney test) was performed again, and the results are shown in Table 3.

[0124] Table 3. Comparison of main scores before treatment between the control group and the experimental group (Nonparametric two-sample rank-sum test - Wilcoxon, Mann-Whitney test)

[0125] Both groups of subjects received intravenous infusions of Danshen, Shenmai, and Bozhi for different durations, and the comparison is shown in Table 4.

[0126] Table 4. Comparison of treatment duration between the control group and the experimental group (Mean±SD)

[0127] Comparison of the number of days of treatment received between the control group and the experimental group (Nonparametric two-sample rank-sum test - Wilcoxon, Mann-Whitney test)

[0128] There was no statistically significant difference in the number of days that the two groups of subjects received intravenous injections of Danshen, Shenmai, and Bozhi, which had no impact on the experimental results.

[0129] In the control group, 4 cases experienced skin allergic reactions, 7 cases had decreased blood cell counts, 8 cases had elevated serum alanine aminotransferase, 11 cases had abnormal urinalysis results (positive urine protein or occult blood), and 3 cases had elevated serum lactate dehydrogenase. A total of 25 cases experienced side effects. After penicillamine dosage reduction and corresponding treatment, 19 cases recovered and continued to be observed. The remaining 6 cases discontinued penicillamine and withdrew from the observation. 8 cases were lost to follow-up and withdrew from the observation, for a total of 14 cases withdrawing from the observation.

[0130] In the experimental group, 3 patients experienced skin allergic reactions, 5 patients had decreased blood cell counts, 3 patients had elevated serum alanine aminotransferase (ALT), 6 patients had abnormal urinalysis results (positive urine protein or occult blood), 1 patient had elevated serum lactate dehydrogenase (LDH), 15 patients experienced upper abdominal fullness and poor appetite, and a total of 15 patients experienced side effects. After penicillamine dosage reduction and appropriate treatment, 15 patients recovered and continued to be observed. 9 patients were lost to follow-up and withdrew from the observation.

[0131] 2.5 Evaluation of therapeutic effect 1) Efficacy Analysis After treatment, the control group patients had the following scores: skin hardness score, joint function score, maximum tooth distance, maximum finger distance, skin pigmentation change score, acral lesion score, and erythrocyte sedimentation rate. r All observed parameters, including globulin levels, showed significant improvement compared to pre-treatment levels, as confirmed by a two-sample t-test. However, while Raynaud's phenomenon score, CIC, and IgG levels improved compared to pre-treatment levels, these improvements were not statistically significant by a two-sample t-test. Erythrocyte sedimentation rate (ESR) and... r - The average globulin levels recovered from above the normal range to within the normal range after treatment. Although CIC and IgG levels did not recover to the normal range, they were close to the upper limit of the normal range. Since the skin hardness score, Raynaud's phenomenon score, skin pigmentation change score, and acral lesion score are integral indicators, it cannot be determined whether their data are normally distributed. Therefore, a nonparametric two-sample rank-sum test (Wilcoxon, Mann-Whitney test) was performed again. The results were the same as those of the two-sample t test, as shown in Tables 5 and 6.

[0132] Table 5. Comparison of main symptoms and signs before and after treatment in the control group (Mean±SD)

[0133] Table 6: Comparison of main symptom and sign scores before and after treatment in the control group (Nonparametric two-sample rank-sum test - Wilcoxon, Mann-Whitney test)

[0134] After treatment, the experimental group patients had the following scores: skin stiffness score, joint function score, Raynaud's phenomenon score, maximum tooth distance, maximum finger distance, skin pigmentation change score, acral lesion score, and erythrocyte sedimentation rate. r The levels of gamma globulin, CIC, and IgG all showed significant improvement compared to before treatment, which was statistically significant according to the two-sample t-test. Among them, the average detection indicators of erythrocyte sedimentation rate, CIC, and IgG returned to within the normal range after treatment, while the gamma globulin index, although not returned to the normal range, also showed a significant improvement compared to the pre-treatment test results, approaching the upper limit of the normal range. Since the skin hardness score, Raynaud's phenomenon score, skin pigmentation change score, and acral lesion score are integral indicators, it cannot be determined whether their data are normally distributed. Therefore, a nonparametric two-sample rank-sum test (Wilcoxon, Mann-Whitney test) was performed again, and the results were the same as those of the two-sample t-test, as shown in Tables 7 and 8.

[0135] Table 7. Comparison of main symptoms and signs before and after treatment in the experimental group (Mean±SD)

[0136] Table 8. Comparison of main symptom and sign scores before and after treatment in the experimental group (Nonparametric two-sample rank-sum test - Wilcoxon, Mann-Whitney test)

[0137] Comparing the differences before and after treatment, the experimental group showed better treatment results than the control group in the observed items such as skin hardness score, joint function score, Raynaud's phenomenon score, maximum tooth distance, maximum finger distance, CIC, and IgG, which were statistically significant according to the two-sample t-test; while the two groups showed differences in acral lesion score, erythrocyte sedimentation rate, and eosinophil count. r The differences in pre- and post-treatment values ​​for observation items such as globulin levels showed no statistically significant differences according to the two-sample t-test. Furthermore, since the skin hardness score, Raynaud's phenomenon score, skin pigmentation change score, and acral lesion score are integral indicators, it cannot be determined whether their data are normally distributed. Therefore, a nonparametric two-sample rank-sum test (Wilcoxon, Mann-Whitney test) was performed again, and the results were the same as those of the two-sample t-test, as shown in Tables 9 and 10.

[0138] Table 9. Comparison of numerical changes in main symptoms and signs before and after treatment in the control group and experimental group. (Mean±SD)

[0139] Table 10: Comparison of changes in the scores of main symptoms and signs before and after treatment in the control group and the experimental group. (Nonparametric two-sample rank-sum test - Wilcoxon, Mann-Whitney test)

[0140] Statistical differences in skin hardness score, maximum tooth distance, and maximum finger distance indicate that oral administration of Fukan capsules can accelerate the softening of hardened skin in SSc patients; statistical differences in joint function score indicate that oral administration of Fukan capsules can promote the improvement of joint function in SSc patients; statistical differences in Raynaud's phenomenon score indicate that oral administration of Fukan capsules can reduce the occurrence of Raynaud's phenomenon in SSc patients; and statistical differences in CIC and IgG indicate that oral administration of Fukan capsules has a significant therapeutic effect on patients with hyperactive immune response.

[0141] 2) Effects of Fukang capsules on visceral lesions in SSc patients: Barium swallow examinations were performed on patients with dysphagia and choking on dry food. In the control group (n=33), 28 cases showed lesions; in the experimental group (n=59), 46 cases showed lesions. The main manifestations were decreased esophageal motility, esophageal wall rigidity, widening of the lower esophagus, and thickening of the mucosal striations. After treatment, 20 patients in the control group reported symptom relief, and 13 showed improvement on barium swallow examination. In the experimental group, 40 patients experienced symptom relief or disappearance, with 32 showing improvement on barium swallow examination. Statistical analysis using chi-square test showed no significant difference in the improvement rate between the two groups (χ²=3.90, p<0.001, see Table 11).

[0142] Table 11. Comparison of esophageal lesion improvement rates before and after treatment in the two groups of patients.

[0143] Chest X-rays were performed on 114 patients, including a control group of 46 (41 cases with abnormalities) and an experimental group of 68 (62 cases with abnormalities). The main findings were increased and disordered lung markings in a reticular pattern, ground-glass opacities, subpleural lines, thickening of the interlobular septa, and honeycomb-like opacities in the lower lobes. After treatment, 14 patients in the control group and 43 patients in the experimental group showed improvement. Statistical analysis using the chi-square test showed that the improvement rate in the experimental group was significantly higher than that in the control group (χ²=12.38, P<0.001). See Table 12.

[0144] Table 12. Comparison of lung lesion improvement rates before and after treatment in the two groups of patients.

[0145] Eighty-seven patients underwent Holter monitoring, including a control group of 35 (27 cases with abnormalities) and an experimental group of 52 (39 cases with abnormalities). The main manifestations included atrial premature beats, ventricular premature beats, right bundle branch block, myocardial ischemia, abnormal Q waves, supraventricular tachycardia, and right ventricular hypertrophy. After treatment, 9 patients in the control group and 17 patients in the experimental group showed improvement. Statistical analysis using the chi-square test showed no significant difference in improvement rates between the two groups (χ²=0.70, P>0.05). See Table 13.

[0146] Table 13. Comparison of cardiac (Holter) improvement rates before and after treatment in the two groups of patients.

[0147] 101 patients underwent echocardiography, including a control group of 46 (38 cases with abnormalities) and an experimental group of 68 (49 cases with abnormalities). The main findings included valvular insufficiency, decreased myocardial compliance, right ventricular hypertrophy, right atrial enlargement, pericardial effusion, and pulmonary hypertension. After treatment, 11 patients in the control group and 18 patients in the experimental group improved. Statistical analysis using the chi-square test showed no significant difference in the improvement rate between the two groups (χ²=0.58, P>0.05). See Table 14.

[0148] Table 14. Comparison of cardiac (echocardiogram) improvement rates before and after treatment in the two groups of patients.

[0149] 3) Summary of effectiveness Based on the overall scores of patients before and after treatment, in the control group, 13 cases showed significant improvement and 27 cases showed improvement, with a significant improvement rate of 27.66% and an effective rate of 85.11%; in the experimental group, 33 cases showed significant improvement and 28 cases showed improvement, with a significant improvement rate of 20.8% and an effective rate of 91.3%. Statistical analysis using the chi-square test showed that the significant improvement rate of the experimental group was significantly better than that of the control group (X2=4.47, p<0.001, see Table 15).

[0150] Table 15. Overall efficacy evaluation of the two groups of patients

[0151] In conclusion, Fukang capsules have therapeutic effects on skin hardening, joint function, vascular lesions, and immune function in patients with SSc, and the experimental group showed better efficacy than the control group.

[0152] 3. Safety Evaluation 1) Side effects: Note: Apart from the cases reported as adverse events, the laboratory test results of the other subjects were within the normal range during the observation period and before and after treatment.

[0153] Control group: 25 cases in total.

[0154] In the control group, 4 cases experienced skin allergic reactions, 7 cases had decreased blood cell counts, 8 cases had elevated serum alanine aminotransferase, 11 cases had abnormal urinalysis results (positive urine protein or occult blood), and 3 cases had elevated serum lactate dehydrogenase. A total of 25 cases experienced side effects. After penicillamine dosage reduction and corresponding treatment, 19 cases recovered and continued to be observed. The remaining 6 cases discontinued penicillamine and withdrew from the observation. 8 cases were lost to follow-up and withdrew from the observation, for a total of 14 cases withdrawing from the observation.

[0155] A. Allergic reaction: 4 cases. Allergic reaction is one of the adverse reactions listed in the penicillamine package insert.

[0156] I. A 24-year-old female developed generalized skin rashes and itching one week after taking penicillamine 0.0625g / day. Penicillamine was discontinued at that time, and loratadine 10mg orally once in the morning and ketotifen 1mg orally once before bedtime were given. The rash subsided completely after one week. Three months after the skin allergy subsided, penicillamine was tried again with desensitization therapy. The first dose was 0.041g / day (1 / 3 tablet). After one week, small patches of rash appeared on the trunk again, so penicillamine was discontinued and she was withdrawn from observation.

[0157] II. A 76-year-old male developed generalized skin irritation and itching after taking penicillamine 0.0625g / day for 5 days. Penicillamine was discontinued at that time, and loratadine 10mg was administered orally once in the morning, and ketotifen 1mg was administered orally once before bedtime. The rash subsided completely after one week. Three months after the skin allergy subsided, penicillamine was tried again using desensitization therapy. The initial dose was 0.041g / day (1 / 3 tablet). After one week, the rash did not reappear. The penicillamine dose was increased to 0.125g / day. During this period, the medication was discontinued for 2 months due to elevated alanine aminotransferase. No recurrence was observed until the end of the observation period.

[0158] III. A 15-year-old female developed generalized skin rashes and itching after taking penicillamine 0.0625g / day for 10 days. Penicillamine was discontinued at that time, and loratadine 10mg was administered orally once in the morning, and ketotifen 1mg was administered orally once before bedtime. The rash subsided completely after one week. Three months after the skin allergy subsided, penicillamine was tried again using desensitization therapy. The first dose was 0.041g / day (1 / 3 tablet). If small patches of rash appeared on the trunk again after one week, penicillamine was discontinued and the patient was withdrawn from observation.

[0159] IV. A 50-year-old female developed generalized skin irritation and itching after taking penicillamine 0.0625g / day for 8 days. Penicillamine was discontinued at that time, and loratadine 10mg was administered orally once in the morning, and ketotifen 1mg was administered orally once before bedtime. The rash subsided completely after one week. Three months after the skin allergy subsided, penicillamine was reintroduced using desensitization therapy. The initial dose was 0.041g / day (1 / 3 tablet). After one week, no rash recurred. The penicillamine dosage was increased to 0.125g / day. No recurrence was observed until the end of the observation period.

[0160] B. Cholecytopenia: 7 cases. Cholecytopenia is one of the adverse reactions listed in the penicillamine package insert.

[0161] I. A 54-year-old female patient had a white blood cell count of 3.3 × 10^9 / L after taking penicillamine for 7 months. At that time, she was taking penicillamine 0.5g / day, which was then reduced to 0.125g / day. She was also given 2 tablets of leukogenol orally three times a day and 2 tablets of squalene orally three times a day. One month later, her white blood cell count was 5.6 × 10^9 / L. The penicillamine dosage was increased to 0.25g / day and continued until the end of the observation period. No recurrence of white blood cell count was observed during the follow-up examination.

[0162] II. A 62-year-old male was found to have a white blood cell count of 3.8 × 10^9 / L after taking penicillamine for 4 months. At that time, he was taking 0.375g / day of penicillamine. He then stopped taking penicillamine and was given 2 tablets of leucogen orally three times a day and 2 tablets of shark liver oil orally three times a day. One month later, his white blood cell count was 4.9 × 10^9 / L. The dosage of penicillamine was gradually increased to 0.125g / day until the end of the observation period. During this period, he stopped taking the medication for 1 month due to proteinuria. The white blood cell count did not recur during the follow-up examination.

[0163] III. A 62-year-old female patient was found to have a platelet count of 55 × 10⁻⁶ after taking penicillamine for 3 months. 9 The patient was initially taking penicillamine 0.375g / day, but discontinued it immediately. She was then given leucogen orally, two tablets three times a day, and sodium deoxyribonucleotide orally, two tablets three times a day. One month later, a follow-up platelet count was 88×10⁹ / L. 9 / L, a follow-up platelet count 3 months later was 92×10 9 / L, discontinue penicillamine until the end of the observation period, and repeat platelet count is 135×10. 9 / L, and exit observation.

[0164] IV. Zhou Yuanfeng, a 47-year-old female outpatient, had a white blood cell count of 3.3 × 10⁻⁶ after taking penicillamine for 6 months. 9 / L, at that time, penicillamine 0.5g / day was taken, then penicillamine was discontinued, and leucogen was given orally 2 tablets three times a day, and squalene orally 2 tablets three times a day. One month later, a follow-up blood test showed a white blood cell count of 5.4×10. 9 / L, oral penicillamine was gradually increased to 0.125g / day and taken until the end of the observation period. Follow-up blood tests showed no recurrence of white blood cell count.

[0165] V. Female, 59 years old, a platelet count of 87 × 10⁸ was found during a check-up after taking penicillamine for 9 months. 9 The patient was initially taking penicillamine 0.375g / day, but discontinued it immediately. She was then given leucogen orally, two tablets three times a day, and sodium deoxyribonucleotide orally, two tablets three times a day. One month later, a follow-up platelet count was 169 × 10⁹ / L. 9 / L, oral penicillamine was gradually increased to 0.125g / day and continued until the end of the observation period. No recurrence was found in the platelet count during the follow-up examination.

[0166] VI. A 62-year-old male patient who had been taking penicillamine for 9 months (during which he stopped taking the medication for 1 month due to proteinuria and the dosage was reduced to 0.25g / day) had a platelet count of 75×10⁻⁶ during a subsequent examination. 9 The patient was initially taking 0.25g / day of penicillamine, but discontinued the medication. She was then given two tablets of leucogen orally three times a day and two tablets of sodium deoxyribonucleotide orally three times a day. One month later, a follow-up platelet count was 148×10^9 / L. The oral penicillamine dosage was gradually increased to 0.125g / day until the end of the observation period. A follow-up platelet count showed no recurrence.

[0167] VII. A 72-year-old female patient had a white blood cell count of 3.1 × 10^9 / L after taking penicillamine for 6 months. At that time, she was taking 0.5g of penicillamine per day. She then stopped taking penicillamine and was given 2 tablets of leucogen orally three times a day and 2 tablets of shark liver oil orally three times a day. One month later, her white blood cell count was 6.7 × 10^9 / L. The dosage of penicillamine was gradually increased to 0.125g / day until the end of the observation period. No recurrence of white blood cell count was observed during the follow-up examination.

[0168] C. Elevated ALT: 8 cases. Elevated ALT is one of the adverse reactions listed in the penicillamine package insert.

[0169] I. Female, 49 years old, took penicillamine for 9 months (during which she stopped taking the medication for 1 month due to proteinuria). During the examination, her serum alanine aminotransferase (ALT) was found to be elevated to 78 units / L. At that time, she was taking penicillamine 0.375g / day. After that, she stopped taking penicillamine and was given Sedum sarmentosum granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. One month later, her ALT was 33 units / L. Two months after stopping the medication, she tried the penicillamine small dose gradual increase method again, gradually increasing the oral penicillamine to 0.125g / day until the end of the observation period. Follow-up examination showed no increase in ALT level.

[0170] II. A 51-year-old female patient took penicillamine for 8 months (during which she stopped taking the medication for 1 month due to proteinuria). During the subsequent examination, her serum alanine aminotransferase (ALT) was found to be elevated to 66 units / L. At that time, she was given penicillamine 0.3125g / day. She then discontinued penicillamine and was given *Sedum sarmentosum* granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. One month later, her ALT was retested at 36 units / L. Two months after stopping the medication, she tried a small-dose incremental approach with penicillamine, gradually increasing the oral dose to 0.125g / day until the end of the observation period. Follow-up examinations showed no increase in ALT levels.

[0171] III. A 54-year-old female patient was found to have elevated alanine aminotransferase (ALT) to 101 units / L after taking penicillamine for 4 months. At that time, she was taking penicillamine 0.4375g / day. She then discontinued penicillamine and was given Sedum sarmentosum granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. One month later, her ALT was 77 units / L. Five months after stopping the medication, her ALT was 56 units / L. At the end of the observation period, her ALT was 49 units / L. She did not resume taking penicillamine and was withdrawn from the observation.

[0172] IV. A 51-year-old female patient was found to have elevated alanine aminotransferase (ALT) to 79 U / L after taking penicillamine for 6 months. At that time, she was taking penicillamine 0.4375 g / day. She then discontinued penicillamine and was given Sedum sarmentosum granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. Two months later, her ALT was 28 U / L. Four months after stopping the medication, she tried penicillamine again using a small-dose incremental method, gradually increasing the oral penicillamine to 0.125 g / day. She continued this treatment until the 11-month observation period, when occult blood in urine was found and the medication was discontinued. She did not resume taking penicillamine and was withdrawn from the observation period. At the end of the observation period, her ALT level was not elevated.

[0173] V. Male, 76 years old. After taking penicillamine for 8 months, a check-up revealed that his serum alanine aminotransferase (ALT) level had increased to 52 units / L. At that time, he was taking penicillamine 0.125g / day. He then stopped taking penicillamine and was given Sedum sarmentosum granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. One month later, a follow-up test showed that his ALT level was 38 units / L. Two months after stopping the medication, he tried penicillamine again using a small-dose incremental method, gradually increasing the oral penicillamine dosage to 0.0625g / day until the end of the observation period. Follow-up tests showed no increase in ALT level.

[0174] VI. A 45-year-old female patient was found to have elevated alanine aminotransferase (ALT) to 61 units / L after taking penicillamine for 3 months. At that time, she was taking penicillamine 0.5g / day. After taking penicillamine, she stopped taking it and was given Sedum sarmentosum granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. One month later, her ALT was 38 units / L. After stopping the medication for 3 months, she tried penicillamine again using a small dose gradual increase method, gradually increasing the oral penicillamine to 0.125g / day until the end of the observation period. During this period, she stopped taking the medication for 1 month due to proteinuria (±) and reduced the dose to 0.0625g / day. Follow-up examinations showed no increase in ALT levels.

[0175] VII. A 32-year-old female patient was found to have elevated alanine aminotransferase (ALT) to 95 U / L after taking penicillamine for 6 months. At that time, she was taking penicillamine 0.5g / day. She then discontinued penicillamine and was given Sedum sarmentosum granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. One month later, her ALT was 71 U / L. Three months after stopping the medication, her ALT was 52 U / L. At the end of the observation period, her ALT was 41 U / L. She did not resume taking penicillamine and was withdrawn from the observation.

[0176] VIII. A 53-year-old female patient took penicillamine for 9 months (during which she stopped taking the medication for 1 month due to proteinuria). During the subsequent examination, her serum alanine aminotransferase (ALT) was found to be elevated to 74 units / L. At that time, she was given penicillamine 0.125g / day. She then discontinued penicillamine and was given *Sedum sarmentosum* granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. One month later, her ALT was retested at 26 units / L. Two months after stopping the medication, she tried a small-dose incremental approach with penicillamine, gradually increasing the oral dose to 0.0625g / day until the end of the observation period. Follow-up examinations showed no increase in ALT levels.

[0177] D. Abnormal urinalysis: 11 cases. Abnormal urinalysis is one of the adverse reactions listed in the penicillamine package insert.

[0178] I. Female, 51 years old, took penicillamine for 11 months (during which she stopped taking the medication for 4 months due to elevated alanine aminotransferase). During the subsequent examination, occult blood in urine was found to be positive. She was then taking penicillamine 0.125g / day. After stopping penicillamine, occult blood in urine was positive after 2 weeks. She did not resume taking penicillamine until the end of the observation period and withdrew from the observation. No abnormalities were found in routine urine tests at the end of the observation period. No abnormalities were found in serum creatinine during the observation period.

[0179] II. A 51-year-old female patient was found to have proteinuria after taking penicillamine for 6 months. She was initially taking penicillamine 0.5g / day, which was then reduced to 0.125g / day. Two weeks later, a follow-up urine test showed proteinuria, and penicillamine was discontinued. Two weeks later, a follow-up urine test showed negative proteinuria. After one month of discontinuation, she tried penicillamine again using a small-dose incremental method, gradually increasing the oral penicillamine dosage to 0.3125g / day. She continued this treatment until the 8-month observation period, when she stopped taking the medication for 2 months due to elevated alanine aminotransferase (ALT). Subsequently, she gradually increased the oral penicillamine dosage to 0.0625g / day until the end of the observation period. Follow-up urine tests showed no abnormalities, and serum creatinine tests during the observation period were also normal.

[0180] III. A 53-year-old female patient was found to have proteinuria after taking penicillamine for 3 months. She was initially taking penicillamine 0.5g / day, which was then reduced to 0.125g / day. Two weeks later, a follow-up urine test showed proteinuria ±, and penicillamine was discontinued. Two weeks later, a follow-up urine test showed negative proteinuria. After one month of discontinuation, she tried penicillamine again using a small-dose incremental method, gradually increasing the oral penicillamine dosage to 0.125g / day. She continued this treatment until the 9-month observation period, when she stopped taking the medication for 2 months due to elevated alanine aminotransferase (ALT). Subsequently, she gradually increased the oral penicillamine dosage to 0.0625g / day until the end of the observation period. Follow-up urine tests showed no abnormalities, and serum creatinine tests during the observation period were also normal.

[0181] IV. A 44-year-old female patient was found to have proteinuria after taking penicillamine for 9 months. She was initially taking penicillamine 0.5g / day, which was then reduced to 0.125g / day. Two weeks later, a follow-up urine test showed proteinuria, and penicillamine was discontinued. Two weeks later, a follow-up urine test showed negative proteinuria. After one month of discontinuation, a small-dose incremental method of penicillamine was tried again, with the oral penicillamine gradually increased to 0.3125g / day until the end of the observation period. Follow-up urine routine tests showed no abnormalities, and serum creatinine tests during the observation period showed no abnormalities.

[0182] V. Female, 64 years old. After taking penicillamine for 6 months, a urine test showed proteinuria. She was initially taking penicillamine 0.375g / day, which was then reduced to 0.125g / day. Two weeks later, a follow-up urine test showed negative proteinuria. She stopped taking the medication for 1 month and tried the penicillamine small-dose incremental method again, gradually increasing the oral penicillamine to 0.25g / day until the end of the observation period. Follow-up urine routine tests showed no abnormalities, and serum creatinine tests during the observation period showed no abnormalities.

[0183] VI. A 62-year-old male patient took penicillamine for 9 months (during which he stopped taking the medication for 1 month due to a decrease in blood cell count, and the dosage was reduced to 0.125g / day). During the subsequent examination, proteinuria was found to be positive. He then took penicillamine 0.125g / day. After stopping penicillamine, a follow-up urine protein test was negative. After stopping the medication for 1 month, he tried the penicillamine small-dose incremental method again, gradually increasing the oral penicillamine dosage to 0.0625g / day until the end of the observation period. Follow-up urine routine tests showed no abnormalities, and serum creatinine tests during the observation period showed no abnormalities.

[0184] VII. A 49-year-old female patient was found to have proteinuria after taking penicillamine for 3 months. She was initially taking penicillamine 0.5g / day, which was then reduced to 0.125g / day. Two weeks later, a follow-up urine protein test was negative, and she discontinued penicillamine. Another follow-up urine protein test was negative. After one month of discontinuation, she tried a small-dose incremental method with penicillamine, gradually increasing the oral penicillamine dosage to 0.375g / day. She continued this treatment until the 9-month observation period, when she discontinued the treatment for 2 months due to elevated alanine aminotransferase (ALT). She then gradually increased the oral penicillamine dosage to 0.125g / day until the end of the observation period. Follow-up urine tests showed no abnormalities, and serum creatinine tests during the observation period were also normal.

[0185] VIII. A 45-year-old female patient took penicillamine for 9 months (during which she stopped taking the medication for 3 months due to alanine aminotransferase (ALT) and reduced the dosage to 0.125g / day). During the examination, proteinuria was found to be positive. She then took penicillamine 0.125g / day. After stopping penicillamine, a follow-up urine protein test was negative. After stopping the medication for 1 month, she tried the penicillamine small-dose incremental method again, gradually increasing the oral penicillamine dosage to 0.0625g / day until the end of the observation period. Follow-up urine routine tests showed no abnormalities, and serum creatinine tests during the observation period showed no abnormalities.

[0186] IX. Female, 55 years old. After taking penicillamine for 3 months, a urine protein test showed ±. She was initially taking penicillamine 0.5g / day, which was then reduced to 0.125g / day. Two weeks later, a urine protein test was negative, and penicillamine was discontinued. Two weeks later, another urine protein test was negative. After one month of discontinuation, a small-dose incremental method of penicillamine was tried again, with the oral penicillamine gradually increased to 0.25g / day until the end of the observation period. Follow-up urine routine tests showed no abnormalities, and serum creatinine tests during the observation period showed no abnormalities.

[0187] Male X, 62 years old, was found to have proteinuria after taking penicillamine for 3 months. He was then taking penicillamine 0.375g / day. After discontinuing penicillamine, a repeat urine protein test was negative. After one month of discontinuation, he tried penicillamine again using a small-dose incremental method, gradually increasing the oral penicillamine dosage to 0.25g / day until the end of the observation period. During this period, he stopped taking the medication for one month due to a decrease in blood cells, and the dosage was reduced to 0.125g / day. Follow-up urine routine tests showed no abnormalities, and serum creatinine tests during the observation period were normal.

[0188] XI. Female, 38 years old. After taking penicillamine for 7 months, a urine test showed ± protein. At that time, she was taking penicillamine 0.3125g / day, which was reduced to penicillamine 0.125g / day. Two weeks later, a follow-up urine test showed ± protein, and penicillamine was discontinued. Two weeks later, a follow-up urine test showed negative protein. After discontinuing the medication for 1 month, she tried the penicillamine small-dose incremental method again, gradually increasing the oral penicillamine to 0.3125g / day until the end of the observation period. Follow-up urine routine examination showed no abnormalities, and serum creatinine was normal during the observation period.

[0189] E. Blood lactate dehydrogenase: 3 cases. Elevated blood lactate dehydrogenase is one of the adverse reactions listed in the penicillamine package insert.

[0190] I. A 47-year-old female patient was found to have elevated blood lactate dehydrogenase (LDH) to 365 IU / L after taking penicillamine for 9 months. At that time, she was taking penicillamine 0.25g / day. After that, she stopped taking penicillamine and was given Sedum sarmentosum granules orally, three times a day, one small packet each time. One month later, her LDH level was 119 IU / L. Six weeks after stopping the medication, she tried penicillamine again using a small dose gradual increase method, gradually increasing the oral penicillamine to 0.125g / day until the end of the observation period. Follow-up examinations showed no increase in LDH level.

[0191] II. A 61-year-old female patient was found to have elevated blood lactate dehydrogenase (LDH) to 287 U / L after taking penicillamine for 6 months. She was initially prescribed penicillamine 0.375 g / day, which was reduced to 0.125 g / day. She was also given *Sedum sarmentosum* granules orally, three times a day, one small packet each time. Two weeks later, her LDH level increased to 273 U / L, at which point penicillamine was discontinued. Six weeks later, her LDH level was 195 U / L. Two months after discontinuation, a small-dose incremental approach to penicillamine was tried again, gradually increasing the oral dose to 0.125 g / day until the end of the observation period. Follow-up examinations showed no increase in LDH levels.

[0192] III. A 56-year-old female patient was found to have elevated blood lactate dehydrogenase (LDH) to 294 IU / L after taking penicillamine for 9 months. At that time, she was taking penicillamine 0.25g / day. After that, she stopped taking penicillamine and was given Sedum sarmentosum granules orally, three times a day, one small packet each time. One month later, her LDH level was 152 IU / L. Six weeks after stopping the medication, she tried penicillamine again using a small dose gradual increase method, gradually increasing the oral penicillamine to 0.125g / day until the end of the observation period. Follow-up examinations showed no increase in LDH level.

[0193] Experimental group: 15 cases in total In the experimental group, 3 patients experienced skin allergic reactions, 5 experienced cytopenia, 3 experienced elevated serum alanine aminotransferase (ALT), 6 experienced abnormal urinalysis results (positive urine protein or occult blood), and 1 experienced elevated serum lactate dehydrogenase. A total of 15 patients experienced side effects. After penicillamine dosage reduction and appropriate treatment, 15 patients recovered and continued to be observed. 9 patients were lost to follow-up and withdrew from the observation. A. Allergic reaction: 3 cases. Allergic reaction is one of the adverse reactions listed in the penicillamine package insert.

[0194] I. A 48-year-old male developed a full-body skin rash with itching after taking penicillamine 0.0625 mg / day for 6 days. Penicillamine was discontinued at that time, and loratadine 10 mg orally once in the morning and ketotifen 1 mg orally once at bedtime were administered. The rash subsided completely after one week. Three months after the skin allergy subsided, penicillamine was reintroduced using desensitization therapy. The initial dose was 0.041 g / day (1 / 3 capsule). After one week, no rash reappeared. The penicillamine dosage was increased to 0.125 mg / day. No recurrence was observed until the end of the observation period. Fukang capsules were not discontinued during this period. It is considered that the patient's allergic reaction to penicillamine was unrelated to the use of Fukang capsules.

[0195] II. A 56-year-old female patient took penicillamine 0.0625 mg / day. After 9 days, she developed a full-body skin rash accompanied by itching. At that time, penicillamine was discontinued, and she was given loratadine 10 mg orally once in the morning and ketotifen 1 mg orally once before bedtime. The rash subsided completely after one week. Three months after the skin allergy subsided, penicillamine was tried again using desensitization therapy. The initial dose was 0.041 g / day (1 / 3 capsule). After one week, the rash did not reappear. The penicillamine dose was increased to 0.1875 mg / day. No recurrence was observed until the end of the observation period. During this period, she did not stop taking Fukang capsules. It is considered that the patient's allergic reaction to penicillamine was unrelated to the use of Fukang capsules.

[0196] III. A 47-year-old female patient took penicillamine 0.0625 mg / day. After 5 days, she developed a full-body skin rash accompanied by itching. Penicillamine was discontinued at that time, and she was given loratadine 10 mg orally once in the morning and ketotifen 1 mg orally once before bedtime. The rash subsided completely after one week. Three months after the skin allergy subsided, penicillamine was tried again using desensitization therapy. The initial dose was 0.041 g / day (1 / 3 capsule). After one week, the rash did not reappear. The penicillamine dose was increased to 0.125 mg / day. No recurrence was observed until the end of the observation period. During this period, she did not stop taking Fukang capsules. It is considered that the patient's allergic reaction to penicillamine was unrelated to the use of Fukang capsules.

[0197] B. Cholecytopenia: 5 cases. Cholecytopenia is one of the adverse reactions listed in the penicillamine package insert.

[0198] I. A 56-year-old female patient had a white blood cell count of 3.6 × 10^9 / L after taking penicillamine for 5 months. At that time, she was taking penicillamine 0.5g / day, which was then reduced to 0.125g / day. She was also given 2 tablets of leukogenol orally three times a day and 2 tablets of squalene orally three times a day. One month later, her white blood cell count was 5.2 × 10^9 / L. The oral penicillamine was gradually increased to 0.25g / day until the end of the observation period. No recurrence of white blood cell count was observed during the observation period. She did not stop taking Fukang capsules during this period. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0199] II. A 57-year-old male patient had a white blood cell count of 3.8 × 10^9 / L after taking penicillamine for 6 months. At that time, he was taking penicillamine 0.5g / day, which was then reduced to 0.125g / day. He was also given 2 tablets of leucogen orally three times a day and 2 tablets of squalene orally three times a day. One month later, a follow-up white blood cell count was 6.1 × 10^9 / L. The oral penicillamine dosage was gradually increased to 0.125g / day. During this period, he stopped taking the medication for one month due to proteinuria and the dosage was reduced to 0.0625g / day. Follow-up white blood cell counts showed no recurrence. He did not stop taking Fukang capsules during this period. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0200] III. A 50-year-old female patient had a platelet count of 85 × 10^9 / L after taking penicillamine for 9 months. At that time, she was taking penicillamine 0.25g / day. She discontinued penicillamine and was given 2 tablets of leucogen orally three times a day and 2 tablets of deoxyribonucleic acid sodium orally three times a day. One month later, her platelet count was 148 × 10^9 / L. The oral penicillamine dosage was gradually increased to 0.125g / day until the end of the observation period. No recurrence of platelet count was observed during the observation period. She did not stop taking Fukang capsules during this period. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0201] IV. A 58-year-old male patient had a platelet count of 92 × 10^9 / L after taking penicillamine for 6 months. At that time, he was taking penicillamine 0.375g / day. He stopped taking penicillamine and was given 2 tablets of leukogen orally three times a day and 2 tablets of deoxyribonucleic acid sodium orally three times a day. One month later, his platelet count was 157 × 10^9 / L. The oral penicillamine dosage was gradually increased to 0.125g / day until the end of the observation period. No recurrence of platelet count was observed during the observation period. He did not stop taking Fukang capsules during this period. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0202] V. Female, 57 years old. After taking penicillamine for 9 months (during which she stopped taking the medication for 1 month due to proteinuria and the dosage was reduced to 0.25g / day), a blood test showed a white blood cell count of 3.4×10^9 / L. At that time, she was taking penicillamine 0.25g / day, which was then reduced to 0.125g / day. She was also given 2 tablets of leucogen orally three times a day and 2 tablets of squalene orally three times a day. One month later, a follow-up blood test showed a white blood cell count of 4.2×10^9 / L. The oral penicillamine dosage was gradually increased to 0.125g / day until the end of the observation period. Follow-up blood tests showed no recurrence of white blood cell count. She did not stop taking Fukang capsules during this period. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0203] C. Elevated alanine aminotransferase (ALT): 3 cases. Elevated ALT is one of the adverse reactions listed in the penicillamine package insert.

[0204] I. A female, 18 years old, was found to have elevated alanine aminotransferase (ALT) to 67 U / L after taking penicillamine for 6 months. At that time, she was taking penicillamine 0.25g / day. She stopped taking penicillamine and was given Sedum sarmentosum granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. One month later, her ALT was 38 U / L. Two months after stopping the medication, she tried penicillamine again using a small dose gradual increase method, gradually increasing the oral penicillamine to 0.125g / day until the end of the observation period. Follow-up examination showed no increase in ALT level. During this period, she did not stop taking Fukang capsules. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0205] II. A 41-year-old female patient took penicillamine for 9 months (during which she stopped taking the medication for 1 month due to proteinuria, and the dosage was reduced to penicillamine 0.25g / day). During the subsequent examination, her serum alanine aminotransferase (ALT) level was found to be elevated to 58 units / L. She then resumed taking penicillamine 0.25g / day, but discontinued it. She was given *Sedum sarmentosum* granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. One month later, her ALT level was 32 units / L. Two months after stopping the medication, she tried a small-dose incremental approach with penicillamine, gradually increasing the oral dosage to 0.125g / day until the end of the observation period. Follow-up examinations showed no increase in ALT levels. She did not discontinue Fukang capsules during this period. It is considered that the patient's condition was a side effect of penicillamine and unrelated to the use of Fukang capsules.

[0206] III. A 56-year-old male patient was found to have elevated alanine aminotransferase (ALT) to 72 U / L after taking penicillamine for 6 months. At that time, he was taking penicillamine 0.375 g / day. He then discontinued penicillamine and was given Sedum sarmentosum granules orally, three times a day, one small packet each time, and polyene phosphatidylcholine capsules orally, 456 mg / time, twice a day. One month later, his ALT level was 22 U / L. Two months after discontinuing the medication, he tried penicillamine again using a small-dose incremental method, gradually increasing the oral penicillamine dose to 0.125 g / day until the end of the observation period. Follow-up examinations showed no increase in ALT level. He did not discontinue Fukang capsules during this period. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0207] D. Abnormal urinalysis: 6 cases. Proteinuria is one of the adverse reactions listed in the penicillamine package insert.

[0208] I. A 57-year-old female patient was found to have proteinuria after taking penicillamine for 7 months. She was initially taking penicillamine 0.5g / day, which was then reduced to 0.125g / day. Two weeks later, a follow-up urine protein test was negative, and she discontinued penicillamine. Another follow-up urine protein test was negative. After one month of discontinuation, she tried a small-dose incremental approach with penicillamine, gradually increasing the oral dose to 0.25g / day until the end of the observation period. Follow-up urinalysis showed no abnormalities, and serum creatinine was normal during the observation period. She did not discontinue Fukang capsules during this period. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0209] II. A 57-year-old female patient was found to have proteinuria after taking penicillamine for 3 months. She was initially taking penicillamine 0.5g / day, which was then reduced to 0.125g / day. Two weeks later, a follow-up urine protein test was negative, and penicillamine was discontinued. Another follow-up urine protein test was negative. After a one-month break, she tried a gradual increase in penicillamine dosage, increasing the oral dosage to 0.25g / day. During the nine-month observation period, she discontinued the medication for one month due to a decrease in white blood cell count. The dosage was then gradually increased to 0.125g / day until the end of the observation period. Follow-up urine tests showed no abnormalities, and serum creatinine tests during the observation period were normal. She did not discontinue Fukang capsules during this period. It is considered that the patient's condition was a side effect of penicillamine and unrelated to the use of Fukang capsules.

[0210] III. A 43-year-old female patient was found to have proteinuria after taking penicillamine for 7 months. At that time, she was taking penicillamine 0.375g / day, which was reduced to 0.125g / day. Two weeks later, a follow-up urine protein test was negative, and penicillamine was discontinued. Another follow-up urine protein test was negative. After one month of discontinuation, a small-dose incremental method of penicillamine was tried again, with the oral penicillamine gradually increased to 0.125g / day until the end of the observation period. Follow-up urine routine tests showed no abnormalities, and serum creatinine tests during the observation period were normal. She did not stop taking Fukang capsules during this period. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0211] IV. A 76-year-old male patient was found to have proteinuria after taking penicillamine for 9 months. He was initially taking penicillamine 0.375g / day, which was then reduced to 0.125g / day. Two weeks later, a follow-up urine protein test was negative, and penicillamine was discontinued. Another follow-up urine protein test was negative. After one month of discontinuation, a small-dose incremental approach to penicillamine was tried again, gradually increasing the oral penicillamine dosage to 0.125g / day until the end of the observation period. Follow-up urinalysis showed no abnormalities, and serum creatinine tests during the observation period were normal. He did not discontinue Fukang capsules during this period. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0212] V. Male, 57 years old. After taking penicillamine for 9 months (during which he stopped taking the medication for 1 month due to decreased blood cell count and the dosage was reduced to 0.125g / day), a test revealed proteinuria. He then took penicillamine 0.125g / day. After stopping penicillamine, a repeat urine protein test was negative. After stopping the medication for 1 month, he tried the penicillamine small-dose incremental method again, gradually increasing the oral penicillamine dosage to 0.0625g / day until the end of the observation period. Follow-up urinalysis showed no abnormalities. Serum creatinine was normal during the observation period. He did not stop taking Fukang capsules during this period. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0213] VI. A 41-year-old female patient was found to have proteinuria after taking penicillamine for 3 months. She was initially taking penicillamine 0.5g / day, which was reduced to 0.125g / day. Two weeks later, a follow-up urine test showed proteinuria, and penicillamine was discontinued. Two weeks later, a follow-up urine test showed negative proteinuria. After one month of discontinuation, she tried a small-dose incremental approach with penicillamine, gradually increasing the dose to 0.25g / day. During the 9-month observation period, she discontinued the medication for 2 months due to elevated alanine aminotransferase (ALT). She then gradually increased the dose to 0.0625g / day until the end of the observation period. Follow-up urine tests showed no abnormalities, and serum creatinine tests during the observation period were normal. She did not discontinue Fukang capsules during this period. It is considered that the patient's condition was a side effect of penicillamine and unrelated to the use of Fukang capsules.

[0214] E. Blood lactate dehydrogenase: 1 case. Elevated blood lactate dehydrogenase is one of the adverse reactions listed in the penicillamine package insert.

[0215] I. A 47-year-old female patient was found to have elevated blood lactate dehydrogenase (LDH) to 280 IU / L after taking penicillamine for 9 months. At that time, she was taking penicillamine 0.25g / day. After discontinuing penicillamine, she was given Sedum sarmentosum granules orally, three times a day, one small packet each time. One month later, her LDH level was 185 IU / L. Six weeks after stopping the medication, she tried penicillamine again using a small-dose incremental method, gradually increasing the oral penicillamine to 0.125g / day until the end of the observation period. Follow-up examinations showed no increase in LDH level. During this period, she did not stop taking Fukang capsules. It is considered that the patient's condition was a side effect of taking penicillamine and was unrelated to taking Fukang capsules.

[0216] The number of adverse reactions in the two groups of patients is shown in Table 16.

[0217] Table 16. Number of adverse reactions in the two groups of patients

[0218] Note: Some patients experience two or more side effects.

[0219] The incidence of penicillamine side effects was lower in the experimental group than in the control group (χ²=9.10, p<0.001, see Table 17). This indicates that the combined use of Fukang capsules and penicillamine can reduce the side effects of penicillamine.

[0220] Table 17. Comparison of the incidence of side effects between the two groups of patients

[0221] 2) Comparison of penicillamine dosage Observing the penicillamine dosage before and after treatment in the control and experimental groups (Note: the unit of measurement for penicillamine dosage below is capsule / day, and the dosage is 0.125 g / capsule), it can be found that before taking Fukan capsules, the penicillamine dosage in the experimental and control groups was similar. As the treatment progressed, the penicillamine dosage in both groups gradually increased. The dosage in the control group reached its peak after 9 months of treatment. Subsequently, as some patients reduced their penicillamine dosage to a maintenance dose, the dosage gradually decreased. However, the increase in penicillamine dosage in the experimental group using Fukan capsules was significantly slower than that in the control group, reaching its peak after 6 months of treatment. Subsequently, during the experimental period, some patients reduced their penicillamine dosage to a maintenance dose, and the dosage also gradually decreased. Comparison showed that at the beginning of 9 months of treatment and at the end of the observation period, the penicillamine dosage in the experimental group was lower than that in the observation group. This was confirmed by t-test and nonparametric rank-sum test (Wilcoxon, Mann-Whitney). The difference was statistically significant, indicating that taking Fukang capsules can accelerate the treatment process and allow patients to start taking maintenance doses of penicillamine earlier, which can significantly reduce the amount of penicillamine used in the treatment of SSC patients (see Tables 18 and 19).

[0222] Note: Penicillamine is a capsule formulation. The drug instructions state that each capsule contains 0.125 grams of penicillamine.

[0223] Table 18. Comparison of penicillamine dosage (unit: tablets / day) before and after treatment in the two groups of patients (Mean±SD)

[0224] Table 19. Comparison of penicillamine dosage (unit: tablets / day) before and after treatment in the two groups of patients. (Nonparametric rank-sum test - Wilcoxon, Mann-Whitney test)

[0225] 3) Safety Summary: In conclusion, taking Fukang capsules can accelerate the treatment process, allowing patients to start taking maintenance doses of penicillamine earlier, which can significantly reduce the amount of penicillamine used during the treatment of SSC patients; and compared with the control group, the incidence of penicillamine side effects in the experimental group was significantly lower than that in the control group.

[0226] analyze A comparison of the clinical manifestations and laboratory test results of the experimental group and the control group before and after treatment reveals the following: 1. Oral administration of Fukang capsules can accelerate the softening of hardened skin in patients with SSc.

[0227] A. Skin hardness scores in both groups decreased significantly before and after treatment compared to before treatment. Further analysis of the difference in scores before and after treatment using a two-sample t-test and a two-sample rank-sum test (Wilcoxon, Mann-Whitney test) revealed that the experimental group had a significantly higher score than the control group.

[0228] B. By performing a t-test on the changes in maximum finger distance and maximum tooth distance before and after treatment in both groups of patients, it was found that the maximum finger distance and maximum tooth distance in the control group increased significantly after treatment compared to before treatment, while the increase was more significant in the experimental group. The difference in scores before and after treatment was greater in the experimental group than in the control group, and the difference was statistically significant.

[0229] 2. Oral administration of Fukan capsules can accelerate the improvement of joint function in patients with SSc. The joint function scores of both groups were significantly reduced before and after treatment compared to before treatment. Further analysis of the difference in scores before and after treatment in the two groups using a two-sample t-test and a two-sample rank-sum test (Wilcoxon, Mann-Whitney test) revealed that the experimental group had a significantly higher score than the control group.

[0230] 3. Oral administration of Fukan capsules can reduce the frequency of Raynaud's phenomenon attacks. After treatment, the Raynaud's phenomenon scores in the experimental group were significantly reduced compared with those before treatment. The control group showed some improvement after treatment compared with those before treatment, but the difference was not statistically significant, indicating that hormones alone have no significant effect on improving Raynaud's phenomenon in SSC patients. The difference in scores before and after treatment in the two groups was further analyzed by two-sample t-test and two-sample rank-sum test (Wilcoxon, Mann-Whitney test). The difference in scores before and after treatment in the experimental group was greater than that in the control group, and the difference was statistically significant.

[0231] 4. Oral administration of Fukang capsules can enhance the inhibitory effect on the hyperactive immune response of SSc.

[0232] A. A mean t-test was performed on the changes in CIC before and after treatment in both groups of patients. It was found that the serum CIC concentration in the experimental group was significantly reduced after treatment compared with that before treatment, while the control group showed some improvement after treatment compared with that before treatment, but the difference was not statistically significant. The difference in CIC level between the two groups before and after treatment was significantly reduced in the experimental group compared with that in the control group, and the t-test showed a significant statistical significance. This indicates that Fukang capsules are effective in treating the increase in CIC in patients with SSc and have a significant effect on the hyperactive immune response, especially the excessive complement response. B. The mean t-test was used to analyze the changes in IgG levels before and after treatment in both groups of patients. It was found that the serum IgG concentration in the experimental group was significantly lower after treatment than before treatment, while the control group showed some improvement after treatment, but the difference was not statistically significant. The difference between the two groups before and after treatment showed that the IgG level in the experimental group was significantly lower than that in the control group, which was statistically significant according to the t-test. This indicates that Fukang capsules are effective in reducing the IgG level in SSc patients and have a significant effect on the hyperactive immune response in patients.

[0233] 5. Oral administration of Fukang capsules can significantly improve the function of affected organs in patients with SSc.

[0234] A. Barium swallow examination was performed on patients with dysphagia and choking on dry food. After treatment, the improvement rate of the experimental group was better than that of the control group by chi-square test, X2=3.90, p<0.001.

[0235] B. Chest X-ray findings mainly showed increased and disordered lung markings in both lungs, appearing as a reticular pattern, ground-glass opacities, subpleural lines, thickening of the interlobular septa, and honeycomb-like shadows in both lower lungs. After treatment, statistical chi-square test analysis showed that the improvement rate in the experimental group was superior to that in the control group (X2=12.38, P<0.001).

[0236] 6. Oral administration of Fukang capsules can reduce the dosage of penicillamine and lower the probability of penicillamine side effects.

[0237] Taking Fukang capsules can accelerate the treatment process, allowing patients to start taking maintenance doses of penicillamine earlier, which can significantly reduce the amount of penicillamine used during the treatment of SSC patients; and compared with the control group, the incidence of penicillamine side effects in the experimental group was significantly lower than that in the control group.

[0238] In conclusion, the experimental group showed higher efficacy and safety than the control group, demonstrating that Fukang capsules are safe and effective in treating systemic scleroderma and have broad application prospects.

[0239] The above embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-substantial changes and substitutions made by those skilled in the art based on the present invention shall fall within the scope of protection claimed by the present invention.

Claims

1. A traditional Chinese medicine composition for treating scleroderma, characterized in that, It is made from the following Chinese medicinal herbs in parts by weight: 60-100 parts viper, 60-100 parts cobra, and 30-50 parts dragon's blood.

2. The traditional Chinese medicine composition for treating scleroderma according to claim 1, characterized in that, The herbal composition is made from the following parts by weight of herbs: 80 parts of viper, 80 parts of cobra, and 40 parts of dragon's blood.

3. A pharmaceutical composition for treating scleroderma, characterized in that, It is made from the traditional Chinese medicine composition for treating scleroderma as described in any one of claims 1 to 2 and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition for treating scleroderma according to claim 3, characterized in that, The drug is an oral preparation.

5. The pharmaceutical composition for treating scleroderma according to claim 4, characterized in that, The oral preparation is a decoction, granules, capsules, tablets, oral liquid, pills, or powder; more preferably, the oral preparation is a capsule.

6. A method for preparing a pharmaceutical composition for treating scleroderma according to any one of claims 3 to 5, characterized in that, Includes the following steps: Weigh out the medicines according to the above weight ratio. After drying and sterilizing the viper and cobra at 80-100℃ for 3-5 hours, add the blood dragon, pulverize into 80-120 mesh, add 90-95 parts of starch and 5-10 parts of talc, mix well, and package into capsules to obtain the final product.

7. The use of a traditional Chinese medicine composition for treating scleroderma according to any one of claims 1 to 2 or the use of a pharmaceutical composition according to any one of claims 3 to 5 in the preparation of a medicament for treating scleroderma.

8. The use according to claim 7, characterized in that, The therapeutic effects include treating skin hardening, improving joint function, improving vascular lesions, and / or enhancing immune function.

9. The use according to claim 7, characterized in that, The therapeutic effect is achieved when used in combination with penicillamine.

Images