Application of atormoxetine in the preparation of drugs that increase bone vascular H subtype endothelial cells

Abstract

This invention discloses the application of atormoxetine in the preparation of drugs that increase H-subtype endothelial cells in bone vessels. Specifically, it discloses the application of a combination of atormoxetine and deferoxamine mesylate in the preparation of drugs that increase H-subtype endothelial cells in bone vessels, drugs that increase bone mineral density, or drugs for treating osteoporosis. This invention discovers that the combined use of atormoxetine and deferoxamine mesylate can further promote the generation of H-subtype bone vascular endothelial cells. The generation of H-subtype bone vascular endothelial cells leads to an increase in the bone mineral density coupled with them, thus promoting bone formation. Using this combined medication, the treatment of senile osteoporosis can be achieved.

Description

Technical Field

[0001] This invention relates to bone and blood vessels, and to the use of combined drug applications to control the specificity of vascular endothelial cells in bone, specifically to the use of atormoxetine in the preparation of drugs that increase H subtype endothelial cells in bone blood vessels. Background Technology

[0002] Osteoporosis is a skeletal disease characterized by bone loss and deterioration of bone microstructure, leading to increased bone fragility and a higher risk of fractures. Currently, the two most widely accepted risk factors for osteoporosis are decreased estrogen levels and advanced age. Most existing medications for osteoporosis work by inhibiting osteoclasts from further breaking down bone and reducing bone density; however, these are not very helpful for elderly individuals who have already experienced significant bone loss.

[0003] Vascular endothelial cells are a single layer of cells distributed along the inner wall of blood vessels, exhibiting rich heterogeneity and organ specificity. Through dense capillary branches, the endothelium establishes connections with almost all cells in various organs. Vascular endothelium exhibits significant morphological specificity in different organs. Furthermore, endothelial cells in different organs possess different transcription factor clusters, expressing and secreting different vascular secretory factors to support organ physiological functions according to different organ needs. Vascular endothelium in bone has been found to possess rich heterogeneity. One subtype, the H subtype of bone vascular endothelium, promotes bone formation. The H subtype of bone vascular endothelium is mainly distributed in an arched pattern near the bone growth plate and endothelial lining. It is a highly metabolically active endothelial cell subtype that couples itself with bone metabolism through the Notch signaling pathway, promoting bone formation. With age, the expression of CD31 and EMCN in H subtype endothelial cells decreases, transforming into the L subtype endothelium, which no longer retains its active metabolic growth and bone-forming properties. In vivo levels of H subtype endothelial cells are associated with hypoxia-inducible factor, Notch signaling pathway, blood flow, platelet-derived growth factor secreted by osteoclast precursors, and the adaptor protein Schnurri311 secreted by osteoblasts.

[0004] Deferroamine mesylate for injection is a mature chemical drug with the following indications: 1. For treatment: Treatment of chronic iron overload, such as transfusion-induced hemosiderosis, including severe thalassemia, sideroblastic anemia, autoimmune hemolytic anemia, and other chronic anemias. Treatment of idiopathic (primary) hemochromatosis patients whose comorbidities (e.g., severe anemia, heart disease, hypoproteinemia) prevent venipuncture. Treatment of iron overload caused by delayed-onset cutaneous porphyria, preventing venipuncture. Treatment of acute iron poisoning. Treatment of chronic aluminum overload in patients with advanced renal failure (continuous dialysis) accompanied by aluminum-related osteopathy and / or dialysis encephalopathy and / or aluminum-related anemia. 2. For diagnostic purposes: Used to diagnose iron or aluminum overload. Studies have shown that deferroamine mesylate can promote the reverse conversion of L-type vascular endothelium to H-type and increase bone mineral density in aged C57BL / 6J male rats.

[0005] Atormoxetine is a medication used to treat attention deficit hyperactivity disorder (ADHD) and is classified as a non-centrally acting stimulant. Its main side effects include dry mouth and fatigue. This drug is a norepinephrine reuptake inhibitor. It is primarily used to treat the symptoms of ADHD. Norepinephrine is an important substance in the brain that regulates attention, pulsation, and activity levels. This drug works by blocking or slowing the reuptake of norepinephrine, thereby increasing its concentration. Summary of the Invention

[0006] To address the shortcomings of the prior art, the purpose of this invention is to provide the application of atormoxetine in the preparation of drugs that increase bone vascular H subtype endothelial cells.

[0007] The specific technical solution of the present invention is as follows:

[0008] The first aspect of the present invention provides the use of atormoxetine in the preparation of any one of (1)-(3) of the medicament:

[0009] (1) Drugs that increase bone vascular H subtype endothelial cells;

[0010] (2) Medications that increase bone density;

[0011] (3) Medications for treating osteoporosis.

[0012] A second aspect of the present invention provides the use of a composition of atormoxetine and deferoxamine mesylate in the preparation of any one of the medicaments described in (1)-(3):

[0013] (1) Drugs that increase bone vascular H subtype endothelial cells;

[0014] (2) Medications that increase bone density;

[0015] (3) Medications for treating osteoporosis.

[0016] Furthermore, in the above application, the osteoporosis mentioned is senile osteoporosis.

[0017] A third aspect of the present invention provides a pharmaceutical composition for increasing H subtype endothelial cells of bone vessels, the pharmaceutical composition comprising atormoxetine and deferoxamine mesylate.

[0018] A fourth aspect of the present invention provides a pharmaceutical composition for increasing bone density, the pharmaceutical composition comprising atormoxetine and deferoxamine mesylate.

[0019] A fifth aspect of the present invention provides a pharmaceutical composition for treating osteoporosis, the pharmaceutical composition comprising atormoxetine and deferoxamine mesylate.

[0020] Furthermore, the osteoporosis mentioned is senile osteoporosis.

[0021] Furthermore, the above-mentioned pharmaceutical composition also contains a pharmaceutically acceptable carrier.

[0022] Furthermore, the administration method of the above-mentioned pharmaceutical composition is as follows: intraperitoneal injection of deferoxamine mesylate, followed by oral administration of atormoxetine;

[0023] Preferably, the administration method of the pharmaceutical composition is as follows: first, intraperitoneal injection of deferoxamine mesylate for a certain period of time every other day, and then intraperitoneal injection of deferoxamine mesylate and oral administration of atormoxetine every other day.

[0024] Furthermore, when the above-mentioned drug composition is administered to mice, the dosage of deferoxamine mesylate by intraperitoneal injection is 300 mg / kg, and the dosage of atormoxetine by gavage is 10 mg / kg.

[0025] The beneficial effects of this invention are as follows:

[0026] This invention discovers that the combined use of atormoxetine and deferoxamine mesylate can further promote the generation of H subtype bone vascular endothelial cells. The generation of H subtype bone vascular endothelial cells leads to an increase in bone density coupled with them, thereby promoting bone formation.

[0027] In response to the problem of significant bone loss in the elderly, this invention utilizes a combination of medications to promote bone formation by stimulating the generation of H subtype bone vascular endothelial cells, thereby achieving the treatment of senile osteoporosis. Attached Figure Description

[0028] Figure 1 shows fluorescence imaging of vascular endothelium in the long bones of mice and microCT imaging of the bones. Control: control group; DFM: deferroamyl mesylate injection group; DFM+ATX: combination of intraperitoneal injection of deferroamyl mesylate and oral administration of atomoxetine. Figure 1AFluorescence imaging of vascular endothelium, characterizing heterogeneous changes in endothelial cells. Figure 1B , bone microCT imaging image. Figure 1C Bone parameters change, n=3. Detailed Implementation

[0029] To better understand the present invention, it is now further described with reference to the following embodiments and accompanying drawings. The embodiments are for illustrative purposes only and do not limit the invention in any way. In the embodiments, all original reagents and materials are commercially available, and experimental methods not specifically specified are conventional methods and conditions well known in the art, or according to the conditions recommended by the instrument manufacturer.

[0030] Example 1

[0031] This embodiment included a control group, a deferoxamine mesylate alone group (DFM), and a combination group receiving deferoxamine mesylate and atormoxetine via gavage (DFM+ATX). Each group contained 3-4 60-week-old aged C57 mice. The treatments for each group were as follows:

[0032] Control group: injected with normal saline.

[0033] Deferroamine mesylate injection group (DFM): Deferroamine mesylate was administered intraperitoneally every other day for four weeks at a dose of 300 mg / kg.

[0034] The combined intraperitoneal injection of deferoxamine mesylate and oral administration of atormoxetine (DFM+ATX) group: For the first two weeks, deferoxamine mesylate was administered intraperitoneally at a dose of 300 mg / kg every other day. Starting from the third week, atormoxetine was administered intraperitoneally every other day concurrently with deferoxamine mesylate, at a dose of 300 mg / kg, and atormoxetine at a dose of 10 mg / kg, for a total of four weeks.

[0035] After each group of drug administration was completed, mouse leg bones were sampled to observe the heterogeneity of vascular endothelial cells in long bones. The specific procedures were as follows: mouse leg bones were fixed, decalcified, dehydrated, embedded, and sectioned. Immunofluorescence staining was performed using two endothelial cell-specific markers (CD31 and EMCN), and CD31 in long bones was observed using a laser confocal microscope. + Blood vessels (green), EMCN + Blood vessels (red), CD31 + EMCN + Blood vessels (H subtype), yellow blood vessels represent CD31. + EMCN + Colocalized H subtype vessels.

[0036] After each group of mice completed drug administration, bone mineral density of long bones was measured by sampling mouse leg bones. The specific procedure was as follows: bone specimens were fixed with 4% PFA and subjected to MicroCT scans under the same conditions. Bone parameters were then statistically analyzed.

[0037] The results are shown in Figure 1. Compared to the control group, the group receiving intraperitoneal injection of deferoxamine mesylate alone showed an increase in H-subtype bone vascular endothelial cells and bone mineral density. The group receiving the combined intraperitoneal injection of deferoxamine mesylate and intragastric administration of atormoxetine further increased the number of H-subtype bone vascular endothelial cells and bone mineral density. This invention alters bone vascular endothelial cell heterogeneity and affects bone mineral density through the combined use of intraperitoneal injection of deferoxamine mesylate and intragastric administration of atormoxetine.

[0038] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. The application of atormoxetine in the preparation of drugs for treating osteoporosis.

2. According to claim 1, the atormoxetine has the effect of increasing H subtype endothelial cells of bone vessels; the atormoxetine has the effect of increasing bone mineral density.

3. The use of the combination of atormoxetine and deferoxamine mesylate in the preparation of a drug for treating osteoporosis.

4. In the application according to claim 3, the atormoxetine has the effect of increasing H subtype endothelial cells of bone vessels; the atormoxetine has the effect of increasing bone mineral density.

5. The application according to any one of claims 1-4, characterized in that, The osteoporosis mentioned is senile osteoporosis.

6. A pharmaceutical composition for increasing bone vascular H subtype endothelial cells, characterized in that, The pharmaceutical composition consists of atormoxetine and deferoxamine mesylate.

7. A pharmaceutical composition for increasing bone density, characterized in that, The pharmaceutical composition consists of atormoxetine and deferoxamine mesylate.

8. A pharmaceutical composition for treating osteoporosis, characterized in that, The pharmaceutical composition consists of atormoxetine and deferoxamine mesylate.

9. The pharmaceutical composition according to claim 8, characterized in that, The osteoporosis mentioned is senile osteoporosis.

10. The pharmaceutical composition according to any one of claims 6-9, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to any one of claims 6-9, characterized in that, The administration method of the pharmaceutical composition is as follows: intraperitoneal injection of deferoxamine mesylate and oral administration of atormoxetine.

12. The pharmaceutical composition according to claim 11, characterized in that, The administration method of the pharmaceutical composition is as follows: first, intraperitoneal injection of deferoxamine mesylate for a certain period of time every other day, and then intraperitoneal injection of deferoxamine mesylate and oral administration of atomoxetine every other day.

13. The pharmaceutical composition according to claim 12, characterized in that, When the drug composition is administered to mice, the dosage of deferoxamine mesylate by intraperitoneal injection is 300 mg / kg, and the dosage of atormoxetine by gavage is 10 mg / kg.

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