Combination therapy for treating rheumatoid arthritis by statins and glucocorticoids

Abstract

The invention relates to the field of medicines, and particularly discloses a method for treating rheumatoid arthritis (RA) by combining statins and glucocorticoids. According to the method, statins (such as atorvastatin, rosuvastatin, simvastatin and the like) and glucocorticoids (such as prednisone, methylprednisolone, dexamethasone and the like) are jointly applied to RA patients, so that the anti-inflammatory and immunoregulation effects are enhanced, and meanwhile, the adverse reaction of the glucocorticoids is reduced. Animal experiments and clinical research show that the pharmaceutical composition can effectively inhibit an NF-kappa B signal channel, reduce the level of inflammatory factors (such as CRP and ESR), improve synovitis, reduce joint injury and reduce RA-related cardiovascular risks. In addition, the combined treatment can reduce the dosage of glucocorticoid, so that side effects (such as osteoporosis, hypertension, hyperglycemia and the like) caused by long-term use of the glucocorticoid are reduced. The invention provides a safe and effective RA combined treatment strategy which can be used for clinical treatment of RA and has important application value.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and specifically, to a pharmaceutical composition and its application of a combination of statins and glucocorticoids for the treatment of rheumatoid arthritis (RA). Background Art

[0002] Rheumatoid Arthritis (RA) is a chronic autoimmune disease, mainly manifested as joint inflammation, synovial hyperplasia and joint damage. Currently, glucocorticoids (such as prednisone, dexamethasone, etc.) are widely used in the treatment of RA, with strong anti-inflammatory effects, but long-term use can cause adverse reactions such as steroid-induced osteonecrosis of the femoral head, osteoporosis, hypertension, diabetes, obesity, etc.

[0003] Statins such as atorvastatin, simvastatin, rosuvastatin, etc. are mainly used to regulate blood lipids, but studies have found that they have anti-inflammatory and immunomodulatory effects and may contribute to the treatment of RA. However, there is currently no systematic study on the combined treatment of RA with statins and glucocorticoids. Summary of the Invention

[0004] The present invention provides a method for the combined use of statins and glucocorticoids for the treatment of RA, in order to enhance the treatment effect and reduce the adverse reactions of glucocorticoids. Brief Description of the Drawings

[0005] Figure 1 It is a schematic diagram of the molecular docking of atorvastatin and NF-κB in this invention patent.

[0006] Figure 2 It is a schematic diagram of the molecular docking of glucocorticoid and NF-κB in this invention patent.

[0007] Figure 3 It is a schematic diagram of the action of statins and the NF-κB signaling pathway in this invention patent.

[0008] Figure 4 It is a schematic diagram of the action of glucocorticoid and the NF-κB signaling pathway in this invention patent.

[0009] Figure 5 It is the statistical result of the reduction of CRP in rheumatoid arthritis patients by the combination of statins and glucocorticoids in this invention patent.

[0010] Figure 6 It is the statistical result of the reduction of ESR in rheumatoid arthritis patients by the combination of statins and glucocorticoids in this invention patent. Technical Solution

[0011] The present invention provides the following pharmaceutical composition: Statins: selected from atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin or pharmaceutically acceptable salts thereof.

[0012] Glucocorticoids: selected from prednisone, methylprednisolone, dexamethasone, betamethasone or pharmaceutically acceptable salts thereof.

[0013] The pharmaceutical composition of the present invention can be applied in the following ways: Combined administration method: Administered by oral or injection; Combined drug use regimen with fixed dose or gradually adjusted dose; Administered simultaneously or sequentially.

[0014] Dosage recommendation: Statins: 5 - 40 mg per day, and the specific dosage is adjusted according to the patient's condition; Glucocorticoids: 5 - 20 mg per day, and gradually reduced to reduce side effects.

[0015] Pharmacodynamic study Animal experiments and pre - clinical study results show that statins can enhance the therapeutic effect of glucocorticoids through the following mechanisms: Inhibit the NF - κB signaling pathway and reduce the release of inflammatory factors; Improve endothelial function and reduce cardiovascular complications related to RA; Reduce synovial inflammation through immunomodulatory effects. Specific implementation mode

[0016] Example 1: Study on RA animal model Experimental design: Experimental animals: albino rats were selected, and the RA model was induced by Freund's adjuvant.

[0017] Grouping: Group 1: Normal control group Group 2: 0.1 mL Freund's adjuvant Group 3: Atorvastatin: 10 mg / kg / day Group 4: Prednisolone: 10 mg / kg / day Group 5: Atorvastatin: 10 mg / kg / day + Prednisolone: 10 mg / kg / day Results: The combined treatment group was significantly superior to the single - drug treatment group in inhibiting joint inflammation and reducing the level of inflammatory factors (CRP).

[0018] Histological analysis showed that the combined treatment group had significantly increased bone volume and bone density and reduced joint destruction.

[0019] Example 2: Clinical Observation Study Research Subjects: 69 patients with moderate to severe RA were included and randomly divided into two groups: Control Group: Received glucocorticoid (prednisone 10 mg / day).

[0020] Experimental Group: Received glucocorticoid (prednisone 10 mg / day) + atorvastatin (20 mg / day).

[0021] Results: After 12 weeks, the ACR20 response rate (the improvement standard of RA by the American College of Rheumatology) in the experimental group reached 75%, while that in the control group was 55%.

[0022] In the experimental group, the decreases in CRP and ESR were more significant, and the improvement in joint pain score was more obvious.

[0023] The incidence of glucocorticoid-related adverse reactions (such as hyperglycemia and hypertension) in the experimental group decreased.

[0024] Conclusion The proposed regimen of combined treatment of statins and glucocorticoids for RA in the present invention can enhance the anti-inflammatory effect, improve clinical symptoms, and reduce the adverse reactions of glucocorticoids, providing a new strategy for the treatment of RA.

Claims

1. A pharmaceutical composition for treating rheumatoid arthritis, characterized in that: The composition comprises: (1) at least one statin; (2) at least one glucocorticoid; and (3) an optional pharmaceutically acceptable carrier or excipient.

2. The pharmaceutical composition according to claim 1, characterized in that The statin is selected from one or more of the following groups: atorvastatin, simvastatin, rosuvastatin, pitavastatin, pravastatin or fluvastatin.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The glucocorticoid is selected from one or more of the following groups: prednisone, prednisolone, dexamethasone, betamethasone or methylprednisolone.

4. The pharmaceutical composition according to claims 1-3, characterized in that: The mass ratio of statins to glucocorticoids is 1:10-10:

1.

5. A method for treating rheumatoid arthritis, characterized in that: The method comprises administering an effective dose of the pharmaceutical composition according to any one of claims 1 to 4 to a patient in need of treatment.

6. The method according to claim 5, characterized in that: This method is used to relieve inflammation, pain and joint destruction in patients with rheumatoid arthritis and reduce side effects such as steroid-induced femoral head necrosis.

7. The method according to claim 5 or 6, characterized in that: The method further includes combining with other DMARDs, such as methotrexate, leflunomide, or sulfasalazine.

8. A method for preparing a drug for treating rheumatoid arthritis, characterized in that: The medicine comprises the pharmaceutical composition according to any one of claims 1 to 4.

9. The use according to claim 8, characterized in that The drug is administered orally, by injection or intravenous drip.

10. The use according to claim 8 or 9, characterized in that: The drug is used to reduce joint inflammation and destruction in patients with rheumatoid arthritis and to improve joint function with fewer side effects.

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