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Application of platelet-related inhibitors in the preparation of drugs for treating thrombocytopenia

A technology for thrombocytopenia and inhibitors, applied in the field of application in the preparation of drugs for treating thrombocytopenia

Active Publication Date: 2022-06-07
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, about 15-25% of patients are not effective for IVIG or even splenectomy, and about 61% of patients still cannot maintain the platelet count at 30×10 after splenectomy. 9 / L or more, eventually progressing to refractory ITP

Method used

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  • Application of platelet-related inhibitors in the preparation of drugs for treating thrombocytopenia
  • Application of platelet-related inhibitors in the preparation of drugs for treating thrombocytopenia
  • Application of platelet-related inhibitors in the preparation of drugs for treating thrombocytopenia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The plasma of ITP patients is classified according to the different antibodies it contains and then incubated with normal human platelets for detection. figure 1 for the result. The results showed that, compared with the control, the plasma of anti-GPIbα antibody-positive ITP patients could reduce the mitochondrial membrane potential of normal human platelets ( figure 1 A), increased expression of P-selectin on the platelet membrane surface ( figure 1 E), with increased platelet membrane phosphatidylserine eversion ( figure 1B), and in the corresponding activation and apoptosis indicators, ITP patient plasma containing anti-GPIIbIIIa antibody did not lead to a decrease in platelet mitochondrial membrane potential ( figure 1 A), increased P-selectin expression ( figure 1 E), PS eversion ( figure 1 b); figure 1 C. figure 1 D can also see the difference.

[0028] Human washed platelets were incubated with 10ug / ml antibody IgG, anti-GPIbα antibody AN51, anti-GPIbα an...

Embodiment 2

[0031] Human washed platelets were pre-incubated with GPIbα cluster inhibitor GlcNAc (100mM) and GM3 (100uM) for 15 minutes at room temperature, activation inhibitor BAPTA (10uM) at 37°C for 15 minutes, apoptosis inhibitor Q-VD-Oph (100uM)37 After 30 minutes at ℃, AN51 10ug / ml was added to all groups, and PS valgus was detected after incubating at 37 ℃ for 8 hours. Similarly, mouse PRP was incubated with GPIbα cluster inhibitor GlcNAc (100mM) and GM3 (100uM) in advance at room temperature. After 15 minutes, activation inhibitor BAPTA (20uM) at 37°C for 15 minutes, apoptosis inhibitor Q-VD-Oph (100uM) at 37°C for 30 minutes, add R300 5ug / ml, and incubate at 37°C for 6 hours to detect PS eversion, mitochondrial membrane potential, P-selectin expression, see Figure 4 , the results showed that GlcNAc, GM3, BAPTA, Q-VD-Oph can inhibit the AN51-induced platelet activation and apoptosis common pathway PS eversion ( Figure 4 A); the mouse results are the same as the human results, ...

Embodiment 3

[0033] Fluorescent secondary antibody and control antibody, R300, R300F(ab) 2 After mixing, the mice were injected intraperitoneally, and the tissues and organs were taken out after 4 hours for observation by in vivo imaging of small animals; control antibody, R300, F(ab) were injected intraperitoneally, respectively. 2 After 4 hours, the liver was taken for frozen section, and the nuclei were stained with F4 / 80 (green) labeled macrophages, GPIbα (red) labeled platelets, and DAPI (blue), and the results were as follows Figure 5 shown.

[0034] Figure 5 A can see R300 and R300 F(ab) 2 The bound platelets are mainly accumulated in the liver; Figure 5 The results of B showed that platelets mainly co-localized with macrophages; Figure 5 C shows that the removal of macrophages with clodronate disodium liposome can rescue the thrombocytopenia caused by intraperitoneal injection of R300; Figure 5 D shows that the removal of macrophages can significantly reduce the removal o...

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Abstract

The invention discloses the application of platelet-related inhibitors in the preparation of medicines for treating thrombocytopenia, including platelet activation, apoptosis inhibitors and platelet phagocytosis inhibitors. Platelet-related inhibitors include anti-GPIb-IX and GPIIb / IIIa antibody binding inhibitors, GPIbα cluster inhibitors, intracellular calcium ion chelators, Caspase inhibitors, and phosphatidylserine receptor-ligand binding inhibitors. The invention solves the problem that the existing treatment plan has no therapeutic effect on some patients with thrombocytopenia; thus, it can provide a new therapeutic target for clinically refractory thrombocytopenia, and provide molecular theoretical basis and clinical treatment guidance.

Description

technical field [0001] The invention belongs to the technical field of medicines, and particularly relates to the application of platelet activation inhibitors, platelet apoptosis inhibitors or platelet phagocytosis inhibitors in the preparation of drugs for treating thrombocytopenia. Background technique [0002] Immune thrombocytopenia (ITP) is an autoimmune disease characterized by a decrease in the number of platelets and manifests as severe bleeding symptoms. When the platelet count is less than 10×10 9 / L, the risk of intracranial hemorrhage in patients will be greatly increased, which is life-threatening. First-line treatments for ITP include glucocorticoids, intravenous immunoglobulin (IVIG) and other immunosuppressive therapies. [0003] The pathogenesis of ITP is diverse and has not yet been fully elucidated. About 80% of ITP patients have anti-platelet autoantibodies in the serum, which are mainly divided into anti-GPIIbIIIa and anti-GPIb-IX antibodies; the prio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61K39/395A61K38/07A61K38/06A61P7/04A61P37/02
CPCA61K38/06A61K38/07A61K39/395A61K45/00
Inventor 戴克胜
Owner SUZHOU UNIV
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