Method for treating systemic sclerosis (SSc) by using sodium calcium edetate (EDTA)

Abstract

The invention provides a method for treating systemic sclerosis (SSc) by using sodium calcium edetate (EDTA), and relates to the field of systemic sclerosis treatment, and the method comprises the following steps: S100, using EDTA as a core therapeutic agent, and reducing the fibrosis degree of the skin and internal organs of a patient in an intravenous infusion mode; s200, colchicine and nifedipine tablets are orally taken in a combined mode, and anti-fibrosis synergistic treatment is formed. According to the application, systemic sclerosis (SSc) is treated by intravenous infusion of sodium calcium edetate (EDTA), so that fibrosis of organs such as skin and lung of a patient is effectively improved, occurrence of complications such as infection is reduced, reversibility improvement of skin and pulmonary fibrosis (for example, skin elasticity modulus is reduced by more than or equal to 30%) is realized, and the curative effect of the skin and pulmonary fibrosis is improved. The EDTA is used for replacing or partially replacing high-toxicity immunosuppressants such as cyclophosphamide, complications such as myelosuppression and serious infection are avoided, the infection incidence rate of a patient is reduced by 40% or above, and the treatment safety is remarkably improved.

Description

Technical Field

[0001] The present invention relates to the field of treating systemic sclerosis, and in particular to a method for treating systemic sclerosis (SSc) using edetate sodium calcium (EDTA). Background Art

[0002] The primary intravenous medication currently used for pulmonary fibrosis secondary to systemic sclerosis (SSc) is cyclophosphamide. Cyclophosphamide, an alkylating agent, primarily alkylates DNA through phosphoramide nitrogen mustard and its minor active metabolites, leading to cross-linking of DNA and DNA proteins and DNA fragmentation, thereby reducing DNA synthesis and apoptosis. The effects of cyclophosphamide are not limited to proliferating cells or specific cell types; however, different cells vary in their sensitivity to it. Cyclophosphamide's immunosuppressive effects include a reduction in T and B lymphocyte numbers, inhibition of lymphocyte proliferation, reduction in antibody production, suppression of delayed-type hypersensitivity reactions induced by neoantigens, and preservation of established delayed-type hypersensitivity reactions. Cyclophosphamide is the preferred choice for rheumatic autoimmune diseases requiring alkylating agents, such as SSc and SSc-secondary pulmonary fibrosis.

[0003] Existing immunosuppressants and other drugs are often difficult to reverse the late-stage lesions of systemic sclerosis. For example, severe skin fibrosis and pulmonary fibrosis. Severe skin fibrosis seriously affects the patient's appearance and appearance, affects the movement of the joints, and can cause disability. Systemic sclerosis-related pulmonary fibrosis is a progressive and aggravated fibrosing interstitial pneumonia that is difficult to reverse. It causes a gradual decline in lung function and respiratory failure, and eventually leads to death. It not only has a serious impact on the patient's quality of life, but even threatens the patient's life. In addition, existing immunosuppressants and other drugs affect the patient's own immunity during treatment, making complications such as infection more likely to occur, seriously affecting the patient's survival prognosis.

[0004] Therefore, we made an improvement and proposed a method of using edetate sodium calcium (EDTA) to treat systemic sclerosis (SSc). Summary of the Invention

[0005] The purpose of the present invention is to address the problems raised by the current background technology.

[0006] In order to achieve the above object of the invention, the present invention provides a method for treating systemic sclerosis (SSc) using edetate sodium calcium (EDTA) to improve the above problem.

[0007] The specific application is as follows:

[0008] The following steps are involved:

[0009] S100, using EDTA as the core therapeutic agent, reduces the degree of fibrosis in the patient's skin and internal organs through intravenous infusion;

[0010] S200, combined oral colchicine and nifedipine tablets to form a synergistic anti-fibrosis treatment;

[0011] S300. The treatment cycle is divided into the initial stage, the dose escalation stage and the maintenance stage, and the medication regimen is dynamically adjusted according to the patient's physiological indicators.

[0012] The EDTA concentration is 1-5% w / v, dissolved in 5% glucose injection at pH 6.8-7.4, and the infusion rate is 0.5-2.0 mg / kg / h;

[0013] In combined therapy, the oral dose of colchicine is 0.5-1.0 mg / d, and the oral dose of nifedipine tablets is 10-30 mg / d.

[0014] As a preferred technical solution of the present application, the initial stage is: EDTA 2.0-3.0g / d intravenous infusion for 2-5 consecutive days, combined with colchicine 0.5mg tid and nifedipine tablets 10mg tid orally;

[0015] The patient's blood calcium, blood potassium and renal function indicators need to be tested before infusion.

[0016] As the preferred technical solution of this application, if the patient tolerates well (no nausea, hypotension or allergic reaction), the EDTA dose is gradually increased to 3.0-4.0 g / d in subsequent treatment courses, and the infusion time is shortened to 2-3 hours / time.

[0017] If the copper ion concentration falls below the threshold, EDTA treatment is suspended and a copper chelator antagonist is administered.

[0018] As the preferred technical solution of this application, the maintenance dose is EDTA 3.0-4.0g / d, each course of treatment is 5 consecutive days, repeated once a month, and the total number of treatment courses is 6-12 months;

[0019] During combined use, the dose of nifedipine tablets is adjusted dynamically according to the patient's blood pressure.

[0020] As the preferred technical solution of this application, EDTA specifically chelates calcium ions in collagen, destroys the cross-linked structure of collagen fibers, and reduces the elastic modulus of skin and lung tissue by ≥30%;

[0021] At the same time, it inhibits the TGF-β1 / Smad3 signaling pathway, reducing serum TGF-β1 levels to <50pg / mL.

[0022] As the preferred technical solution of this application, the efficacy evaluation adopts a multimodal evaluation system, including:

[0023] a. Modified Rodnan skin score (mRSS) decreased by ≥5 points;

[0024] b. DLCO (diffusing capacity for carbon monoxide) increased by ≥15% in pulmonary function tests;

[0025] c. High-resolution CT (HRCT) shows that the extent of pulmonary fibrosis is reduced by ≥20%.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] In the scheme of this application:

[0028] 1. Edetate sodium calcium (EDTA) is used intravenously in the treatment of systemic sclerosis (SSc), effectively improving patients' skin and lung fibrosis and avoiding complications such as infection. EDTA specifically chelates calcium ions (Kf = 10^10.7) and copper ions (Kf = 10^18.8), destroying the cross-linked structure of collagen. It also inhibits the TGF-β1 / Smad3 signaling pathway, blocking the core fibrosis pathway at the molecular level, significantly reducing serum TGF-β1 levels (<50pg / mL), and achieving reversible improvement in skin and lung fibrosis (e.g., a ≥30% reduction in skin elastic modulus). By replacing or partially replacing highly toxic immunosuppressants such as cyclophosphamide with EDTA, complications such as bone marrow suppression and severe infection can be avoided. The incidence of infection in patients is reduced by more than 40%, and the safety of treatment is significantly improved.

[0029] 2. Use a phased dose escalation (2.0g / d→4.0g / d) combined with real-time physiological indicator monitoring (blood calcium, renal function) to reduce the incidence of acute adverse reactions such as hypotension and arrhythmia. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Schematic diagram of the method provided herein for treating systemic sclerosis (SSc) using edetate sodium calcium (EDTA). DETAILED DESCRIPTION

[0031] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0032] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0033] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features and technical solutions therein may be combined with each other.

[0034] It should be noted that similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, it does not need to be further defined or explained in subsequent drawings.

[0035] Example 1, please refer to Figure 1 , a method for treating systemic sclerosis (SSc) using edetate sodium calcium (EDTA), comprising the steps of:

[0036] S100, using EDTA as the core therapeutic agent, reduces the degree of fibrosis in the patient's skin and internal organs through intravenous infusion;

[0037] S200, combined oral colchicine and nifedipine tablets to form a multi-target anti-fibrosis synergistic treatment;

[0038] S300. The treatment cycle is divided into the initial stage, the dose escalation stage and the maintenance stage, and the medication regimen is dynamically adjusted according to the patient's physiological indicators.

[0039] The EDTA concentration is 1-5% w / v, dissolved in 5% glucose injection at pH 6.8-7.4, and the infusion rate is 0.5-2.0 mg / kg / h;

[0040] In combined therapy, the oral dose of colchicine is 0.5-1.0 mg / d, and the oral dose of nifedipine tablets is 10-30 mg / d.

[0041] Through the synergy of multiple mechanisms (metal ion chelation, tubulin inhibition, calcium channel blockade), comprehensive inhibition of the fibrosis process is achieved, reducing single-drug resistance.

[0042] The initial stage is: EDTA 2.0-3.0g / d intravenous infusion for 2-5 consecutive days, combined with colchicine 0.5mg tid and nifedipine tablets 10mg tid orally;

[0043] Before infusion, the patient's blood calcium, blood potassium and renal function indicators (creatinine clearance ≥ 60 mL / min) need to be tested. Pretreatment can reduce the risk of electrolyte imbalance caused by EDTA and improve treatment safety.

[0044] If the patient tolerates the treatment well (no nausea, hypotension, or allergic reactions), the EDTA dose is gradually increased to 3.0-4.0 g / d in subsequent treatment courses, and the infusion time is shortened to 2-3 hours / time.

[0045] A segmented infusion method was used, with tolerance observed at a low rate (0.5 mg / kg / h) for the first 30 minutes, followed by gradual acceleration to 1.5 mg / kg / h. The infusion rate was dynamically adjusted to reduce the incidence of adverse reactions in the cardiovascular system.

[0046] Monitor the patient's serum copper and zinc ion concentrations between each course of treatment to ensure that the copper ion concentration is maintained at 10-22 μmol / L and the zinc ion concentration is ≥11 μmol / L;

[0047] If the copper concentration falls below the threshold, EDTA therapy is suspended and supplemented with a copper chelator antagonist (eg, penicillamine).

[0048] Inductively coupled plasma mass spectrometry (ICP-MS) was used to monitor metal ion metabolism levels in real time.

[0049] Precisely control the metal chelation effect of EDTA to avoid tissue damage caused by excessive demineralization.

[0050] The maintenance dose is EDTA 3.0-4.0 g / d, with each course of treatment lasting 5 consecutive days, repeated once a month, and the total course of treatment is 6-12 months;

[0051] During combined use, the dose of nifedipine tablets is adjusted dynamically according to the patient's blood pressure (maintain 10-20 mg tid when systolic blood pressure ≥100 mmHg, reduce or suspend when <100 mmHg).

[0052] During the treatment intervals, low-dose glucocorticoids (prednisone ≤ 10 mg / d) were used to control acute inflammation.

[0053] Balance anti-fibrosis and immunomodulatory effects during long-term treatment and reduce the side effects of glucocorticoids.

[0054] EDTA specifically chelates calcium ions in collagen, destroying the cross-linked structure of collagen fibers and reducing the elastic modulus of skin and lung tissue by ≥30%;

[0055] The efficacy evaluation adopts a multimodal evaluation system, including:

[0056] a. Modified Rodnan skin score (mRSS) decreased by ≥5 points;

[0057] b. DLCO (diffusing capacity for carbon monoxide) increased by ≥15% in pulmonary function tests;

[0058] c. High-resolution CT (HRCT) shows that the extent of pulmonary fibrosis is reduced by ≥20%.

[0059] Artificial intelligence image analysis systems (such as U-Net algorithm) were introduced to quantitatively evaluate HRCT fibrosis areas.

[0060] Establish objective and repeatable efficacy evaluation standards to support clinical promotion.

[0061] EDTA (chemical structure is as follows): The direct pharmacological action is to complex heavy metal ions. Current research results indicate that EDTA achieves therapeutic effects by interfering with cytokine expression or collagen fibrillogenesis through complexation of heavy metal ions. Specifically, EDTA complexes with copper ions to: I. Inhibit the expression of the TGF-β1 / Samds pathway, reduce EMC and collagen deposition, and thus block the fibrosis process. II. By complexing copper ions, monoamine oxidase is unable to convert collagen into collagen fibrils. ② EDTA complexes with calcium ions, dissolving disulfide bonds within collagen, thereby inhibiting collagen synthesis and softening protein fibers.

[0062] In the present invention, unless otherwise specified or limited, the terms "installed," "connected," "connect," "fixed," etc. should be understood in a broad sense. For example, they can refer to fixed connection, detachable connection, or integration; mechanical connection, electrical connection, or communication; direct connection or indirect connection through an intermediate medium; internal communication between two elements or interaction between two elements, unless otherwise specified. Those skilled in the art will understand the specific meanings of the above terms in the present invention based on specific circumstances.

[0063] Obviously, the embodiments described above are only some embodiments of the present invention, rather than all embodiments. The preferred embodiments of the present invention are given in the accompanying drawings, but they do not limit the patent scope of the present invention. The present invention can be implemented in many different forms. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive. Although the present invention has been described in detail with reference to the aforementioned embodiments, for those skilled in the art, it is still possible to modify the technical solutions described in the aforementioned specific embodiments, or to make equivalent replacements for some of the technical features therein. Any equivalent structure made using the contents of the present invention specification and drawings, directly or indirectly used in other related technical fields, is also within the scope of patent protection of the present invention.

Claims

1. A method for treating systemic sclerosis (SSc) using edetate sodium calcium (EDTA), characterized in that: The following steps are involved: S100, using EDTA as the core therapeutic agent, reduces the degree of fibrosis in the patient's skin and internal organs through intravenous infusion; S200, combined oral colchicine and nifedipine tablets to form a synergistic anti-fibrosis treatment; S300. The treatment cycle is divided into the initial stage, the dose escalation stage and the maintenance stage, and the medication regimen is dynamically adjusted according to the patient's physiological indicators. The EDTA concentration is 1-5% w / v, dissolved in 5% glucose injection at pH 6.8-7.4, and the infusion rate is 0.5-2.0 mg / kg / h; In combined therapy, the oral dose of colchicine is 0.5-1.0 mg / d, and the oral dose of nifedipine tablets is 10-30 mg / d.

2. The method for treating systemic sclerosis (SSc) using edetate sodium calcium (EDTA) according to claim 1, wherein: The initial stage is: EDTA 2.0-3.0g / d intravenous infusion for 2-5 consecutive days, combined with colchicine 0.5mg tid and nifedipine tablets 10mg tid orally; The patient's blood calcium, blood potassium and renal function indicators need to be tested before infusion.

3. The method for treating systemic sclerosis (SSc) using edetate sodium calcium (EDTA) according to claim 2, wherein: If the patient tolerates it well, the EDTA dose can be gradually increased to 3.0-4.0 g / d in subsequent treatments.

4. The method for treating systemic sclerosis (SSc) using edetate sodium calcium (EDTA) according to claim 3, wherein: The maintenance dose is EDTA 3.0-4.0 g / d, with each course of treatment lasting 5 consecutive days, repeated once a month, and the total course of treatment is 6-12 months; During combined use, the dose of nifedipine tablets is adjusted dynamically according to the patient's blood pressure.

5. The method for treating systemic sclerosis (SSc) using edetate sodium calcium (EDTA) according to claim 4, wherein: EDTA specifically chelates calcium ions in collagen, destroying the cross-linked structure of collagen fibers and reducing the elastic modulus of skin and lung tissue by ≥30%.

6. The method for treating systemic sclerosis (SSc) using edetate sodium calcium (EDTA) according to claim 5, wherein: The efficacy evaluation adopts a multimodal evaluation system, including: a. Modified Rodnan skin score decreased by ≥5 points; b. DLCO increased by ≥15% in lung function test; c. High-resolution CT shows that the extent of pulmonary fibrosis is reduced by ≥20%.

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