A traditional chinese medicine composition for regulating inflammation-oxidative stress-bone metabolism axis and application thereof

Abstract

The application discloses a traditional Chinese medicine composition for regulating inflammation-oxidative stress-bone metabolism axis and application thereof, and belongs to the field of kidney disease treatment. The traditional Chinese medicine composition is composed of Herba Epimedii, Rhizoma Drynariae, Radix Eucommiae, Radix Rehmanniae Preparata, Radix Angelicae Sinensis, Rhizoma Chuanxiong, Flos Carthami, Radix Salviae Miltiorrhizae, Olibanum, Poria, Rhizoma Atractylodis Macrocephalae, Radix Trichosanthis, Radix Clematidis, Caulis Spatholobi and Radix Glycyrrhizae. The composition can be prepared into pharmaceutically acceptable dosage forms such as granules, granules for oral taking, capsules, tablets, pills, oral liquid or ointments. The traditional Chinese medicine composition has the characteristics of sustained curative effect, good safety and comprehensive regulation of multiple targets, and can be used for preparing drugs for regulating inflammation-oxidative stress-bone metabolism axis, improving mineral and bone metabolism abnormalities of chronic kidney disease and treating chronic musculoskeletal pain of patients with maintenance hemodialysis.

Description

Technical Field

[0001] This invention belongs to the field of kidney disease treatment, specifically relating to a traditional Chinese medicine composition that regulates the inflammation-oxidative stress-bone metabolism axis and its application. Background Technology

[0002] Chronic kidney disease (CKD) has become a significant public health problem worldwide. As the disease progresses, some patients reach end-stage renal disease, requiring maintenance hemodialysis (MHD) to sustain life. With continuous improvements in dialysis technology and comprehensive management, the survival time of maintenance hemodialysis patients has significantly increased. However, various chronic complications arising during long-term dialysis are gradually becoming important factors affecting patients' quality of life and prognosis.

[0003] Chronic musculoskeletal pain (CMSP) is one of the most common and easily overlooked complications in maintenance hemodialysis patients. Studies have shown that the incidence of chronic musculoskeletal pain is high in maintenance hemodialysis patients. The pain can be persistent and manifests as recurrent pain in the lower back, limb joints, and muscles, severely affecting patients' mobility, sleep quality, emotional state, and social function. Long-term pain not only reduces patients' quality of life but may also lead to problems such as depression, anxiety, decreased dialysis adherence, and increased hospitalization risk.

[0004] The pathogenesis of chronic musculoskeletal pain in maintenance hemodialysis patients is currently considered complex, closely related to multiple factors including chronic kidney disease-related mineral and bone metabolism abnormalities (CKD-MBD), microinflammatory states, oxidative stress damage, and uremic toxin accumulation. Among these, CKD-MBD can lead to abnormal bone turnover, impaired bone mineralization, and decreased bone strength, serving as a crucial pathological basis for bone pain. Maintenance hemodialysis patients commonly exhibit a chronic microinflammatory state characterized by elevated levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity C-reactive protein (hs-CRP). These inflammatory factors can activate peripheral and central pain sensitization mechanisms, lowering the pain threshold. Oxidative stress damage can further exacerbate and maintain chronic pain through lipid peroxidation, mitochondrial dysfunction, and neuronal sensitization. These factors interact and promote each other, forming a pathological network involving inflammatory responses, oxidative stress, and abnormal bone metabolism.

[0005] Currently, clinical treatments for chronic musculoskeletal pain in maintenance hemodialysis patients mainly include nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antidepressants, and physical therapy. However, due to the prevalence of severely impaired renal function, multiple underlying diseases, and long-term combination therapy in maintenance hemodialysis patients, the practical application of these treatments is significantly limited. Long-term use of NSAIDs can increase gastrointestinal adverse reactions and cardiovascular events; opioids may cause constipation, nausea, drowsiness, and dependence; and some drugs also suffer from complex dosage adjustments and unstable long-term efficacy. Therefore, developing a novel treatment regimen that is safe, suitable for long-term use, and can simultaneously address the underlying pathological basis of pain is of great importance.

[0006] Traditional Chinese medicine categorizes chronic musculoskeletal pain in maintenance hemodialysis patients under the categories of "bone pain," "lower back pain," and "arthralgia." Long-term clinical observation and syndrome differentiation analysis have revealed that these patients often exhibit pathological characteristics such as kidney deficiency and blood stasis, and internal dampness and turbidity. Kidney deficiency leads to malnourishment of the tendons and bones, blood stasis obstructs the meridians, and dampness and turbidity hinder the smooth flow of qi and blood. These three factors interact and permeate the entire course of the disease. Therefore, comprehensive intervention focusing on tonifying the kidneys and replenishing essence, promoting blood circulation and removing blood stasis, and eliminating dampness and unblocking the meridians holds promise for simultaneously improving both the pain symptoms and their underlying pathology.

[0007] However, there is currently a lack of a traditional Chinese medicine composition that can simultaneously regulate inflammatory responses, alleviate oxidative stress damage, and improve abnormal bone metabolism, thereby achieving a comprehensive intervention for chronic musculoskeletal pain in maintenance hemodialysis patients. Therefore, developing a traditional Chinese medicine composition that regulates the inflammation-oxidative stress-bone metabolism axis and its application has significant clinical value and application prospects. Summary of the Invention

[0008] The purpose of this invention is to address the problems in existing technologies regarding the high incidence, prolonged course, limited long-term treatment efficacy, and lack of interventions that address both analgesia and the underlying pathological basis of chronic musculoskeletal pain in maintenance hemodialysis patients. This invention provides a traditional Chinese medicine composition that regulates the inflammation-oxidative stress-bone metabolism axis and its application. This composition can improve the symptoms of chronic musculoskeletal pain in maintenance hemodialysis patients while simultaneously regulating inflammatory responses, oxidative stress, and abnormal bone metabolism, thereby achieving comprehensive intervention on the pathological links related to the development and progression of the disease.

[0009] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0010] This invention provides a traditional Chinese medicine composition for regulating the inflammation-oxidative stress-bone metabolism axis. The traditional Chinese medicine composition is composed of Epimedium, Drynaria fortunei, Eucommia ulmoides, Rehmannia glutinosa, Angelica sinensis, Ligusticum chuanxiong, Carthamus tinctorius, Salvia miltiorrhiza, Boswellia carterii, Poria cocos, Atractylodes macrocephala, Coix lacryma-jobi, Clematis chinensis, Spatholobus suberectus, and Glycyrrhiza uralensis.

[0011] Preferably, the weight parts of each component in the traditional Chinese medicine composition are as follows: Epimedium 10-30 parts, Drynaria fortunei 10-30 parts, Eucommia ulmoides 8-20 parts, Rehmannia glutinosa 10-30 parts, Angelica sinensis 8-20 parts, Ligusticum chuanxiong 5-15 parts, Carthamus tinctorius 5-15 parts, Salvia miltiorrhiza 10-30 parts, Boswellia carterii 3-10 parts, Poria cocos 10-30 parts, Atractylodes macrocephala 8-20 parts, Coix lacryma-jobi 15-50 parts, Clematis chinensis 5-20 parts, Spatholobus suberectus 10-30 parts, and Glycyrrhiza uralensis 3-10 parts.

[0012] More preferably, the weight parts of each component are: 15 parts of Epimedium, 15 parts of Drynaria fortunei, 12 parts of Eucommia ulmoides, 15 parts of Rehmannia glutinosa, 12 parts of Angelica sinensis, 10 parts of Ligusticum chuanxiong, 10 parts of Carthamus tinctorius, 15 parts of Salvia miltiorrhiza, 6 parts of Boswellia carterii, 15 parts of Poria cocos, 12 parts of Atractylodes macrocephala, 30 parts of Coix lacryma-jobi, 10 parts of Clematis chinensis, 15 parts of Spatholobus suberectus, and 6 parts of Glycyrrhiza uralensis.

[0013] The traditional Chinese medicine composition of the present invention can be prepared into pharmaceutically acceptable dosage forms such as granules, powders, capsules, tablets, pills, oral liquids or ointments, with granules being the preferred form.

[0014] The traditional Chinese medicine composition can be used to prepare drugs that regulate the inflammation-oxidative stress-bone metabolism axis, drugs that improve symptoms related to mineral and bone metabolism abnormalities in chronic kidney disease, and drugs that treat chronic musculoskeletal pain in maintenance hemodialysis patients.

[0015] The composition can reduce the levels of inflammatory factors such as IL-6, TNF-α and hs-CRP, increase SOD activity and reduce MDA levels, while improving bone metabolism indicators such as PTH, serum phosphorus and β-CTX, thereby exerting a comprehensive intervention effect.

[0016] Compared with the prior art, the main advantages of the present invention are as follows:

[0017] This invention, based on the pathological characteristics of the interaction between "persistent activation of inflammation—oxidative stress damage—abnormal bone metabolism" in chronic musculoskeletal pain in maintenance hemodialysis patients, constructs a traditional Chinese medicine compound system composed of kidney-tonifying drugs, blood-activating drugs, dampness-removing drugs, and meridian-clearing and pain-relieving drugs. Clinical research results show that the composition of this invention can significantly reduce patients' pain scores, improve their quality of life, and alleviate TCM syndrome manifestations, with its efficacy lasting until the follow-up stage after drug discontinuation. Simultaneously, the composition of this invention can significantly reduce the levels of inflammatory markers such as IL-6, TNF-α, and hs-CRP, alleviating the body's chronic micro-inflammatory state; reduce MDA levels and increase SOD activity, improving oxidative stress damage; reduce PTH, serum phosphorus, and β-CTX levels, improving chronic kidney disease-related mineral and bone metabolism abnormalities. Furthermore, no serious adverse reactions were observed during continuous use of the composition of this invention, demonstrating good safety and tolerability, making it suitable for widespread application as a long-term intervention for chronic musculoskeletal pain in maintenance hemodialysis patients. Attached Figure Description

[0018] Figure 1 Flowchart for subject screening and research Detailed Implementation

[0019] The technical solution of the present invention will be further described below with reference to specific embodiments. However, those skilled in the art should understand that the following embodiments are only for illustrating the present invention and should not be regarded as limiting the present invention. Specific conditions not specified in the embodiments are performed according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the reagents or instruments used are all conventional products obtained through commercial channels.

[0020] Example 1: Preparation of a traditional Chinese medicine composition granule for regulating the inflammation-oxidative stress-bone metabolism axis

[0021] In order to obtain a traditional Chinese medicine composition granule that can be used for the intervention of chronic musculoskeletal pain in maintenance hemodialysis patients, this embodiment uses the traditional Chinese medicine formula granulation process to prepare a kidney-tonifying, blood-activating, and pain-relieving formula, and obtain a granule formulation for subsequent efficacy evaluation and clinical research.

[0022] The traditional Chinese medicine composition described in this embodiment consists of the following raw materials in parts by weight: Epimedium 15 parts, Drynaria fortunei 15 parts, Eucommia ulmoides 12 parts, Rehmannia glutinosa 15 parts, Angelica sinensis 12 parts, Ligusticum chuanxiong 10 parts, Carthamus tinctorius 10 parts, Salvia miltiorrhiza 15 parts, Boswellia carterii 6 parts, Poria cocos 15 parts, Atractylodes macrocephala 12 parts, Coix lacryma-jobi 30 parts, Clematis chinensis 10 parts, Spatholobus suberectus 15 parts, and Glycyrrhiza uralensis 6 parts.

[0023] The above-mentioned medicinal materials were identified and inspected for quality according to the current version of the Chinese Pharmacopoeia. After removing impurities, the materials underwent a cleaning process. Epimedium was used from the leaves; Drynaria fortunei from the dried rhizome; Eucommia ulmoides from the dried bark; Rehmannia glutinosa from the wine-processed form; Angelica sinensis from the root; Ligusticum chuanxiong from the rhizome; Carthamus tinctorius from the inflorescence; Salvia miltiorrhiza from the root and rhizome; Boswellia carterii from the resin; Poria cocos from the sclerotium; Atractylodes macrocephala from the rhizome; Coix lacryma-jobi from the mature seed; Clematis chinensis from the root and rhizome; Spatholobus suberectus from the stem; and Glycyrrhiza uralensis from the root and rhizome. The moisture content of each medicinal material was controlled between 8% and 14%.

[0024] Each medicinal material was pulverized to a particle size of 10-20 mesh and then extracted separately. Epimedium, Drynaria fortunei, Eucommia ulmoides, Rehmannia glutinosa, Angelica sinensis, Ligusticum chuanxiong, Carthamus tinctorius, Salvia miltiorrhiza, Boswellia carterii, and Spatholobus suberectus were extracted by decoction with water, using 10 times the total weight of the herbs, at a temperature controlled at 98-100℃, twice, 1.5 hours each time. Poria cocos, Atractylodes macrocephala, Coix lacryma-jobi, and Clematis chinensis were extracted by decoction with water, using 8 times the total weight of the herbs, at a temperature controlled at 98-100℃, twice, 1 hour each time. Licorice was extracted separately, using 10 times the weight of the herbs, twice, 1 hour each time. All extracts were filtered through a 100-mesh sieve and then combined.

[0025] The obtained extract was concentrated under reduced pressure at 60℃, controlling the relative density to 1.20–1.30. The concentrated extract was then spray-dried to prepare an extract powder. The inlet air temperature for spray drying was controlled at 160–180℃, and the outlet air temperature was controlled at 80–95℃. The obtained extract powder was granulated after granulation with the addition of appropriate excipients. The excipients included maltodextrin and soluble starch, with the amount of excipients accounting for 15%–30% of the total weight of the granules. Fluidized bed granulation was used for granulation, controlling the particle size to 20–40 mesh.

[0026] The resulting granules were dried to a moisture content of less than 5% and then packaged in aluminum-plastic composite bags. Each bag of granules contained the equivalent of 7.3 g of crude drug extract. After packaging, the formulation was stored in a cool, dry place.

[0027] The prescription comprises a combination of herbs including Epimedium, Drynaria fortunei, Eucommia ulmoides, and Rehmannia glutinosa to tonify the kidneys and replenish essence; Angelica sinensis, Ligusticum chuanxiong, Carthamus tinctorius, Salvia miltiorrhiza, and Boswellia carterii to invigorate blood and remove blood stasis; Poria cocos, Atractylodes macrocephala, and Coix lacryma-jobi to strengthen the spleen and promote diuresis; Clematis chinensis and Spatholobus suberectus to unblock the meridians and relieve pain; and Glycyrrhiza uralensis to harmonize the effects of the other herbs. This combination of herbs forms a synergistic system of tonifying the kidneys, invigorating blood, promoting diuresis, and unblocking the meridians, providing a material basis for subsequent improvement of chronic inflammation, oxidative stress damage, and abnormal bone metabolism.

[0028] This embodiment rationally combines kidney-tonifying drugs, blood-activating drugs, dampness-removing drugs, and meridian-clearing and pain-relieving drugs to form a compound system targeting the pathological characteristics of "kidney deficiency and blood stasis, and internal accumulation of dampness and turbidity" in maintenance hemodialysis patients. This composition not only has a foundation in traditional Chinese medicine theory, but also demonstrated comprehensive effects in subsequent clinical studies, including regulating inflammatory factor levels, improving oxidative stress, and modulating bone metabolism indicators. This provides an experimental basis for its use as a traditional Chinese medicine composition regulating the inflammation-oxidative stress-bone metabolism axis.

[0029] Example 2: A randomized controlled clinical study of a traditional Chinese medicine composition regulating the inflammation-oxidative stress-bone metabolism axis for the treatment of chronic musculoskeletal pain in maintenance hemodialysis patients.

[0030] To verify the clinical efficacy, safety, and regulatory effect of the traditional Chinese medicine composition of this invention on chronic musculoskeletal pain in maintenance hemodialysis patients, as well as its effect on the inflammation-oxidative stress-bone metabolism axis, this embodiment adopts a randomized, parallel-controlled, single-blind clinical trial design to conduct a 12-week intervention and a 4-week follow-up observation on chronic musculoskeletal pain patients receiving regular hemodialysis treatment.

[0031] The study included patients undergoing maintenance hemodialysis between June 2024 and May 2026. Inclusion criteria included: age 18–75 years, regardless of gender; regular hemodialysis duration for at least 3 months; dialysis 3 times per week, 4 hours each time; Kt / V ratio not less than 1.2; chronic musculoskeletal pain lasting at least 3 months; most severe pain score in the most recent week not less than 4; and TCM diagnosis conforming to kidney deficiency and blood stasis syndrome: primary symptoms were soreness and weakness in the lower back and knees, secondary symptoms included numbness in the limbs, sallow complexion, rough and dry skin, dark tongue or ecchymosis, and deep, thready, and hesitant pulse.

[0032] Patients with severe cardiovascular, cerebrovascular, or hepatic diseases, malignant tumors, severe infections, recent surgeries, rheumatic or immune diseases, or who are pregnant or lactating should be excluded.

[0033] A total of 112 subjects were screened, of whom 22 did not meet the inclusion criteria, and 90 were ultimately included. Random sequences were generated using SAS 9.4 software, and subjects were randomly assigned to the treatment group and the control group in a 1:1 ratio, with 45 subjects in each group. The treatment group received the granules of the traditional Chinese medicine composition prepared in Example 1, twice daily, one sachet each time; the control group received placebo granules with the same appearance, color, specifications, and packaging. Both groups received routine hemodialysis and basic Western medicine treatment, including recombinant human erythropoietin for anemia, lanthanum carbonate and calcitriol for calcium and phosphorus metabolism regulation, and blood pressure and blood glucose control. The treatment period was 12 weeks, followed by a 4-week follow-up period. The subject screening and research flowchart is shown below. Figure 1 As shown.

[0034] Pain intensity was assessed using the NRS score at baseline, weeks 4, 8, 12, and 16. Pain functional status was assessed using the BPI scale. Quality of life was assessed using the SF-36 Physical Health Scale. Traditional Chinese medicine syndromes were assessed using the Kidney Deficiency and Blood Stasis Syndrome Score Scale. Inflammatory markers included IL-6, TNF-α, and hs-CRP levels; oxidative stress markers included MDA and SOD levels; and bone metabolism markers included PTH, serum calcium, serum phosphorus, and β-CTX levels.

[0035] Table 1 Comparison of baseline data between the two groups of patients

[0036]

[0037] As shown in Table 1, the mean age of the treatment group was 58.22 ± 8.50 years, and the mean age of the control group was 59.02 ± 9.12 years. The baseline NRS score of the treatment group was 6.79 ± 1.16, and that of the control group was 6.85 ± 1.15. The baseline BPI score of the treatment group was 6.52 ± 1.02, and that of the control group was 6.62 ± 0.92. The baseline SF-36 PCS score of the treatment group was 33.22 ± 4.82, and that of the control group was 32.82 ± 5.02. There were no statistically significant differences in any of the indicators.

[0038] Table 2 Comparison of primary and secondary clinical outcome indicators between the two groups (x̄±s)

[0039]

[0040] The results are shown in Table 2. After 12 weeks of treatment, the NRS score in the treatment group decreased to 3.07±0.89, while that in the control group was 5.55±1.21. The decrease in NRS score in the treatment group was 3.72±1.28, while that in the control group was 1.30±1.42. The pain relief rate in the treatment group reached 73.3%, significantly higher than the 31.1% in the control group. At the 16-week follow-up, the NRS score in the treatment group was 3.59±0.89, while that in the control group was 5.63±1.09, indicating that the efficacy was maintained after drug discontinuation.

[0041] Regarding BPI scores, the treatment group's score decreased from 6.52±1.02 to 3.18±0.82, while the control group's score decreased from 6.62±0.92 to 5.28±0.92. Regarding SF-36 PCS scores, the treatment group's score increased from 33.22±4.82 to 43.52±5.22, while the control group's score increased from 32.82±5.02 to 36.82±4.82.

[0042] Regarding the TCM syndrome score, the score in the treatment group decreased from 22.18±3.63 to 10.22±2.73, while the score in the control group decreased from 23.80±3.07 to 19.85±3.01. The treatment group's score decreased by 11.96±3.82 points, and the control group's decreased by 3.95±3.52 points. The cure rate in the treatment group reached 51.1%, and the total effective rate reached 86.7%. The breakdown of the TCM syndrome score is shown in Table 3.

[0043] Table 3. Comparison of TCM syndrome scores between the two groups (x̄±s)

[0044]

[0045] In summary, the traditional Chinese medicine composition of the present invention can significantly improve the symptoms of chronic musculoskeletal pain in patients undergoing maintenance hemodialysis and maintain a sustained therapeutic effect after discontinuation of the drug.

[0046] Example 3: Verification of the regulatory effect of a traditional Chinese medicine composition regulating the inflammation-oxidative stress-bone metabolism axis on inflammation and oxidative stress indicators.

[0047] To verify the regulatory effect of the traditional Chinese medicine composition of the present invention on the inflammatory response and oxidative stress damage related to chronic musculoskeletal pain in maintenance hemodialysis patients, this embodiment evaluates the effect of the composition of the present invention on intervening in the inflammation-oxidative stress pathway by detecting changes in serum inflammatory factors and oxidative stress indicators.

[0048] The subjects were derived from those who completed treatment and follow-up under Example 2. The treatment group received oral administration of the herbal composition granules of this invention twice daily, one sachet each time, while the control group received placebo granules. The treatment period was 12 weeks. Venous blood samples were collected from subjects at baseline and at week 12. Blood collection was uniformly scheduled for the morning before dialysis in a fasting state, with 5 mL of blood collected from the cubital vein. The blood samples were centrifuged at 3000 rpm for 10 min to separate serum, and the serum samples were stored at -80℃ for later use.

[0049] Inflammatory markers included interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity C-reactive protein (hs-CRP). IL-6 and TNF-α were measured using enzyme-linked immunosorbent assay (ELISA) according to the kit instructions. hs-CRP was measured using immunoturbidimetric assay. Oxidative stress markers included malondialdehyde (MDA) and superoxide dismutase (SOD). MDA was measured using the thiobarbituric acid method; SOD was measured using the WST-1 method. All markers were measured in duplicate wells, and the average values ​​were used for statistical analysis.

[0050] Table 4 Comparison of inflammatory factors and oxidative stress indicators between the two groups (x̄±s)

[0051]

[0052] The experimental results are shown in Table 4. In the treatment group, the IL-6 level decreased from 19.22±3.98 pg / mL before treatment to 10.52±2.28 pg / mL, with a mean decrease of 8.70±4.32 pg / mL; in the control group, it decreased from 19.52±3.82 pg / mL to 17.22±3.22 pg / mL, with a mean decrease of 2.30±4.12 pg / mL. In the treatment group, the TNF-α level decreased from 29.52±5.18 pg / mL to 17.22±3.82 pg / mL, with a mean decrease of 12.30±6.52 pg / mL; in the control group, it decreased from 30.12±4.82 pg / mL to 26.52±4.22 pg / mL, with a mean decrease of 3.60±5.72 pg / mL. In the treatment group, hs-CRP decreased from 13.52±3.18 mg / L to 6.82±1.82 mg / L, with an average decrease of 6.70±3.72 mg / L; in the control group, hs-CRP decreased from 13.82±3.02 mg / L to 11.52±2.52 mg / L, with an average decrease of 2.30±3.42 mg / L.

[0053] Results of oxidative stress marker tests showed that in the treatment group, MDA decreased from 8.82±1.62 nmol / mL to 5.52±1.12 nmol / mL, with a mean decrease of 3.30±1.82 nmol / mL; in the control group, it decreased from 8.62±1.52 nmol / mL to 7.82±1.32 nmol / mL, with a mean decrease of 0.80±1.52 nmol / mL. In the treatment group, SOD increased from 67.52±9.82 U / mL to 89.52±10.22 U / mL, with a mean increase of 22.00±12.52 U / mL; in the control group, it increased from 68.22±9.22 U / mL to 73.82±9.52 U / mL, with a mean increase of 5.60±10.22 U / mL. All inter-group differences were statistically significant.

[0054] IL-6 and TNF-α are key mediators in the chronic pain-related inflammatory network; their sustained elevation can lead to peripheral and central sensitization, lowering the pain threshold. Elevated hs-CRP reflects systemic inflammatory activation. Decreased MDA levels and increased SOD activity indicate reduced oxygen free radical damage and enhanced antioxidant defense. Inflammatory response and oxidative stress have a mutually reinforcing relationship, both participating in the maintenance of chronic pain. The composition of this invention simultaneously improves inflammatory and oxidative stress markers, demonstrating its therapeutic effect through regulation of the inflammation-oxidative stress network, providing experimental evidence for its regulation of the inflammation-oxidative stress-bone metabolism axis.

[0055] Example 4: Verification of the regulatory effect of a traditional Chinese medicine composition that regulates the inflammation-oxidative stress-bone metabolism axis on abnormal bone metabolism.

[0056] To verify the regulatory effect of the traditional Chinese medicine composition of the present invention on the abnormal state of bone metabolism in maintenance hemodialysis patients, this embodiment evaluates the bone metabolism function of the composition of the present invention by detecting changes in parathyroid hormone, serum calcium, serum phosphorus and bone turnover markers.

[0057] The subjects, randomization method, dosing regimen, and treatment period were consistent with those in Example 2. Fasting venous blood samples were collected from all subjects at baseline and at 12 weeks of treatment. The blood samples were centrifuged and used for the detection of bone metabolism parameters.

[0058] Whole-segment parathyroid hormone (PTH) was measured using chemiluminescence immunoassay; serum calcium was measured using the azoarsine III method; serum phosphorus was measured using the phosphomolybdic acid method; and type I collagen cross-linked C-terminal peptide (β-CTX) was measured using electrochemiluminescence immunoassay. All tests were performed according to the instrument's standard operating procedures for quality control.

[0059] Table 5 Comparison of bone metabolism indicators between the two groups (x̄±s)

[0060]

[0061] The experimental results are shown in Table 5. In the treatment group, PTH levels decreased from 395±115 pg / mL to 258±92 pg / mL, with an average decrease of 137±118 pg / mL; in the control group, PTH levels decreased from 402±110 pg / mL to 368±105 pg / mL, with an average decrease of 34±115 pg / mL. In the treatment group, serum phosphorus levels decreased from 2.08±0.32 mmol / L to 1.75±0.25 mmol / L, with an average decrease of 0.33±0.38 mmol / L; in the control group, serum phosphorus levels decreased from 2.10±0.30 mmol / L to 1.98±0.28 mmol / L, with an average decrease of 0.12±0.36 mmol / L. In the treatment group, β-CTX decreased from 1.88±0.42 ng / mL to 1.28±0.32 ng / mL, with an average decrease of 0.60±0.48 ng / mL; in the control group, it decreased from 1.95±0.40 ng / mL to 1.75±0.35 ng / mL, with an average decrease of 0.20±0.46 ng / mL.

[0062] Blood calcium levels changed from 2.14±0.22 mmol / L to 2.24±0.18 mmol / L in the treatment group and from 2.16±0.20 mmol / L to 2.11±0.21 mmol / L in the control group. Both groups remained within a relatively stable range.

[0063] Sustained elevation of PTH is a key characteristic of mineral and bone metabolism abnormalities in chronic kidney disease, leading to increased bone resorption, abnormal bone turnover, and bone pain. A decrease in PTH indicates improvement in secondary hyperparathyroidism. β-CTX is a sensitive indicator of bone resorption activity; a decrease in its level suggests reduced osteoclast activity and inhibition of bone resorption. Decreased serum phosphorus levels indicate improved mineral metabolism. The consistent trend between improved bone metabolism and decreased pain scores suggests that the composition of this invention not only exerts analgesic effects but also intervenes in the pathological basis leading to pain. Therefore, the composition of this invention has application value in regulating abnormal bone metabolism and in the preparation of a drug for treating chronic musculoskeletal pain in maintenance hemodialysis patients.

[0064] Example 5: Safety evaluation of a traditional Chinese medicine composition regulating the inflammation-oxidative stress-bone metabolism axis

[0065] To evaluate the safety and tolerability of the traditional Chinese medicine composition of the present invention in maintenance hemodialysis patients, this embodiment statistically analyzes the adverse events and laboratory safety indicators that occurred during the study in Example 2.

[0066] The subjects were all enrolled in Example 2. The treatment group received the granules of the herbal composition of this invention for 12 weeks, while the control group received placebo granules for 12 weeks. Adverse event monitoring files were established during the treatment period, and all clinical symptoms, signs, and laboratory abnormalities were recorded. Safety follow-ups and laboratory tests were conducted every 4 weeks.

[0067] Safety monitoring indicators include the incidence of adverse events, the incidence of serious adverse events, liver function indicators, and general laboratory test indicators. Liver function tests include alanine aminotransferase (ALT) and aspartate aminotransferase (AST). General laboratory tests include complete blood count and electrocardiogram (ECG).

[0068] Table 6 Comparison of adverse event occurrences between the two groups [examples (%)]

[0069]

[0070] The experimental results are shown in Table 6. In the treatment group, a total of 7 adverse events occurred, with an overall incidence rate of 15.6%. Among these, 3 cases (6.7%) experienced gastrointestinal discomfort, 2 cases (4.4%) experienced mild dizziness, and 2 cases (4.4%) experienced rash. In the control group, a total of 5 adverse events occurred, with an overall incidence rate of 11.1%. Among these, 2 cases (4.4%) experienced gastrointestinal discomfort, 2 cases (4.4%) experienced dizziness, and 1 case (2.2%) experienced rash. There was no statistically significant difference in the incidence of adverse events between the two groups.

[0071] All adverse events were mild. Gastrointestinal discomfort mainly manifested as mild abdominal distension and stomach upset; dizziness manifested as transient headache; and rash manifested as localized itchy skin and scattered erythema. All symptoms subsided with continued observation or symptomatic treatment and did not lead to permanent discontinuation of the drug.

[0072] No serious adverse events were observed during treatment. No life-threatening events, deaths, or drug-related adverse reactions requiring hospitalization occurred. Laboratory tests showed no significant abnormal fluctuations in ALT and AST levels before and after treatment. Complete blood counts showed no clinically significant abnormalities in white blood cell, red blood cell, or platelet counts. Electrocardiogram results did not reveal any new serious arrhythmias or myocardial ischemia.

[0073] This indicates that the composition of the present invention exhibits good safety and tolerability under continuous application for 12 weeks. The adverse event spectrum in the treatment group was essentially consistent with that in the control group, suggesting that the aforementioned adverse events may be related to underlying disease states and dialysis treatment, rather than being directly caused by the composition of the present invention. Stable liver function indicators indicate that the composition of the present invention did not produce significant hepatotoxicity. Normal blood routine and electrocardiogram results suggest that it did not produce significant hematologic or cardiotoxicity.

[0074] Patients undergoing maintenance hemodialysis are at high risk of adverse drug reactions. The composition of this invention maintained a low incidence of adverse reactions and did not cause serious safety issues even after 12 weeks of continuous use in this group of patients, indicating a good foundation for clinical application. It can be used to prepare drugs that regulate the inflammation-oxidative stress-bone metabolism axis and treat chronic musculoskeletal pain in maintenance hemodialysis patients.

[0075] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. The basic principles and main features of the present invention have been described above with specific implementation schemes. Based on the present invention, some modifications or substitutions can be made, but these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of protection claimed by the present invention.

Claims

1. A traditional Chinese medicine composition for regulating the inflammation-oxidative stress-bone metabolism axis, characterized in that, The traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: Epimedium 10-30 parts, Drynaria fortunei 10-30 parts, Eucommia ulmoides 8-20 parts, Rehmannia glutinosa 10-30 parts, Angelica sinensis 8-20 parts, Ligusticum chuanxiong 5-15 parts, Carthamus tinctorius 5-15 parts, Salvia miltiorrhiza 10-30 parts, Boswellia carterii 3-10 parts, Poria cocos 10-30 parts, Atractylodes macrocephala 8-20 parts, Coix lacryma-jobi 15-50 parts, Clematis chinensis 5-20 parts, Spatholobus suberectus 10-30 parts, and Glycyrrhiza uralensis 3-10 parts.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: Epimedium 15 parts, Drynaria fortunei 15 parts, Eucommia ulmoides 12 parts, Rehmannia glutinosa 15 parts, Angelica sinensis 12 parts, Ligusticum chuanxiong 10 parts, Carthamus tinctorius 10 parts, Salvia miltiorrhiza 15 parts, Boswellia carterii 6 parts, Poria cocos 15 parts, Atractylodes macrocephala 12 parts, Coix lacryma-jobi 30 parts, Clematis chinensis 10 parts, Spatholobus suberectus 15 parts, and Glycyrrhiza uralensis 6 parts.

3. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition has the effects of reducing the level of inflammatory factors, alleviating oxidative stress damage, and improving abnormal bone metabolism indicators.

4. The traditional Chinese medicine composition according to claim 3, characterized in that, The inflammatory factors include one or more of IL-6, TNF-α, and hs-CRP.

5. The traditional Chinese medicine composition according to claim 3, characterized in that, The reduction of oxidative stress damage includes reducing one or more of MDA and SOD.

6. The traditional Chinese medicine composition according to claim 3, characterized in that, The bone metabolism indicators include one or more of parathyroid hormone (PTH), serum phosphorus, serum calcium, and β-CTX.

7. The use of the traditional Chinese medicine composition according to any one of claims 1 to 6 in the preparation of a drug for regulating the inflammation-oxidative stress-bone metabolism axis.

8. The use of the traditional Chinese medicine composition according to any one of claims 1 to 6 in the preparation of a medicament for improving symptoms related to mineral and bone metabolism disorders in chronic kidney disease.

9. The use of the traditional Chinese medicine composition according to any one of claims 1 to 6 in the preparation of a medicament for treating chronic musculoskeletal pain in patients undergoing maintenance hemodialysis.

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