CN113332423A - Application of PCSK9 inhibitor in anti-rejection reaction after heart transplantation - Google Patents
Application of PCSK9 inhibitor in anti-rejection reaction after heart transplantation Download PDFInfo
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Abstract
The invention discloses an application of a PCSK9 inhibitor in rejection reaction after a heart transplantation operation, wherein the PCSK9 inhibitor Alirocumab (alirocumab) is subcutaneously injected, and the using dose is 10 mg/kg/week. Compared with the prior method for treating rejection after heart transplantation by simply using an immunosuppressant, the application of the PCSK9 inhibitor in the anti-rejection after heart transplantation is more favorable for relieving the immune rejection after heart transplantation and prolonging the survival time of heart transplant after the PCSK9 inhibitor is jointly used. And the PCSK9 inhibitor alone may also be effective in prolonging the survival cycle of the graft.
Description
Technical Field
The invention relates to the technical field of medical treatment, in particular to application of a PCSK9 inhibitor in rejection resistance after heart transplantation.
Background
Heart transplantation surgery is the process of replacing a heart with a failing end-stage heart disease patient by a healthy donor heart of a brain-dead donor through surgical techniques. The most difficult complication to treat after transplantation is rejection of transplanted heart, and its clinical symptoms include cardiac insufficiency, palpitation, asthma, low fever, arrhythmia, edema of both lower limbs, swollen face, pericardial effusion, pleural effusion, cough and shock, etc., and serious patients are life threatening, and the long-term survival rate of patients after transplantation is seriously affected. Therefore, establishing a practical and effective treatment plan for postoperative rejection is particularly important for improving the long-term survival rate of patients after transplantation.
The aleurocusumab is a compound for inhibiting PCSK9 (the 9 th member of Kexin-like pre-invertase subtilisin family), the inhibitor is a new lipid-lowering drug at present, and Chinese invention CN201480066894.2 provides the application of the PCSK9 inhibitor in treating hyperlipidemia, and the inhibitor can effectively treat hyperlipidemia.
However, the drug is not used for anti-rejection therapy after heart transplantation. Meanwhile, the immunosuppressive agent treatment scheme adopted clinically and conventionally at the present stage has limited effect on inhibiting rejection reaction after heart transplantation, and has numerous side effects such as infection, tumor, neurotoxicity and the like.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides the application of a PCSK9 inhibitor in the anti-rejection reaction after heart transplantation, aiming at reducing the rejection reaction after heart transplantation to the maximum extent and prolonging the survival time of heart transplants on the basis of the prior immunosuppressive treatment.
(II) technical scheme
In order to achieve the purpose, the invention provides the following technical scheme: an application of a PCSK9 inhibitor in anti-rejection reaction after heart transplantation.
Preferably, the PCSK9 inhibitor and the immunosuppressant are combined for use in anti-rejection after heart transplantation.
Preferably, the PCSK9 inhibitor is aleurozumab.
Preferably, the combined immunosuppressant is FK 506.
Preferably, the PCSK9 inhibitor is administered by subcutaneous injection at a dose of 10 mg/kg/week.
Preferably, the immunosuppressant is administered by intraperitoneal injection at a dose of 1 mg/kg/day.
(III) advantageous effects
Compared with the prior art, the invention has the following beneficial effects:
the application of the PCSK9 inhibitor in the anti-rejection reaction after the heart transplantation can effectively prolong the survival period of the transplant when being used alone;
the PCSK9 inhibitor is combined with the existing immunosuppressant (FK506), compared with the single use of the immunosuppressant, the combination is more beneficial to reducing graft rejection after heart transplantation and prolonging the survival time of heart transplant.
Drawings
FIG. 1 is a graph of PCSK9 expression in hearts and spleens following mouse heart transplantation, as detected by immunohistochemistry (immunohistochemistry), Polymerase Chain Reaction (PCR) and Western blotting (Western Blot);
FIG. 2 is a graph showing survival rate of transplanted heart of mouse after PCSK9 inhibitor blocks PCSK9 in receptor and pathological section of transplanted heart of receptor mouse (hematoxylin and eosin staining);
FIG. 3 is a graph showing the survival rate of transplanted hearts of recipient mice for the use of a PCSK9 inhibitor in combination with an immunosuppressant for anti-rejection after heart transplantation;
FIG. 4 is a pathological section of transplanted heart of recipient mouse (hematoxylin and eosin staining) of the application of PCSK9 inhibitor combined with immunosuppressant in anti-rejection reaction after heart transplantation operation;
FIG. 5 is a graph of CD8 and CD4 cell infiltration of transplanted hearts of recipient mice (immunohistochemical staining) using a PCSK9 inhibitor in combination with an immunosuppressant in anti-rejection after heart transplantation.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and the described embodiments are only a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
An application of a PCSK9 inhibitor in anti-rejection reaction after heart transplantation.
The use of a combination of a PCSK9 inhibitor and an immunosuppressant for anti-rejection after heart transplantation.
The PCSK9 inhibitor is aleurozumab (alirocumab).
The combined immunosuppressant is tacrolimus (FK 506).
The PCSK9 inhibitor was administered by subcutaneous injection at a dose of 10 mg/kg/week.
The immunosuppressant is administered by intraperitoneal injection at a dose of 1 mg/kg/day.
The following specific experimental examples are combined to illustrate the application of the PCSK9 inhibitor in the anti-rejection reaction after heart transplantation:
the first experimental example:
step one, selecting forty sample mice. Twenty donor mice (BALB/C) and twenty recipient mice (C57BL/6) among them;
selecting ten receptor mice to establish a heart transplantation animal model, and detecting the expression of PCSK9 in the transplanted heart and spleen seven days after transplantation;
establishing a heart transplantation model for the other ten receptor mice, receiving the aleuropodium monoclonal antibody injection treatment by the receptor mice 24 hours before operation, and observing the beating state of the transplanted heart of the mice after transplantation;
and step four, starting the first day after transplantation, continuing to perform aleurocusumab injection treatment on the mouse, and observing the beating state of the transplanted heart of the mouse every day. The complete stop of the heart transplantation is the end of the experiment, and the survival time of the graft is recorded;
wherein:
the injection dosage of the aleurozumab is 10 mg/kg/week, the mass of the injected body is 25-30mg, and the injection mode of the aleurozumab is subcutaneous injection;
step five, pathological section analysis is carried out on the transplanted heart on the 7 th day of the experiment;
referring to fig. 1, PCSK9 expression was increased in both transplanted hearts and spleens during the period of acute rejection after heart transplantation, indicating that PCSK9 was positively correlated with acute rejection, and therefore, theoretically, by inhibiting PCSK9, it was possible to reduce rejection after heart transplantation. With reference to figure 2, PCSK9 was blocked with PCSK9 antibody starting before transplantation and heart transplantation was performed 24 hours later. Experimental results show that blocking PCSK9 can alleviate acute rejection of transplanted hearts and prolong graft survival time. It is concluded that after heart transplantation, the use of the auriroc library can effectively alleviate rejection of the transplanted heart.
Experiment example two:
use of an immunosuppressant alone in anti-rejection reactions following heart transplantation:
step one, selecting an immunosuppressant, preferably FK 506;
and step two, selecting sample mice, wherein the number of the sample mice is twenty. Ten donor mice (BALB/C) and ten recipient mice (C57BL/6) among them;
establishing a heart transplantation model for ten receptor mice, and observing the beating state of the transplanted heart of the transplanted mice;
and step four, starting to perform intraperitoneal injection of FK506 treatment on the first day after transplantation, and observing the beating state of the transplanted heart of the mouse every day. The complete stop of the heart transplantation is the end of the experiment, and the survival time of the graft is recorded;
wherein:
FK506 is used in a dosage of 1 mg/kg/day, the mass of an injected body is 25-30mg, and the FK506 is injected in an intraperitoneal injection mode;
step five, pathological section analysis is carried out on the transplanted heart on the 7 th day and the 14 th day of the experiment;
step six, detecting the infiltration condition of CD8 cells and CD4 cells in the transplanted heart on the 7 th day and the 14 th day of the experiment.
Experiment example three:
use of a PCSK9 inhibitor in combination with FK506 for anti-rejection after heart transplantation:
step one, selecting a PCSK9 inhibitor, preferably aleurocusumab, and selecting an immunosuppressant, preferably FK 506;
and step two, selecting sample mice, wherein the number of the sample mice is twenty. Ten donor mice (BALB/C) and ten recipient mice (C57BL/6) among them;
establishing a heart transplantation model for ten receptor mice, receiving injection of the aleuropodium monoclonal antibody by the 24 preoperative receptor mice, and observing the beating state of the transplanted heart of the mice after transplantation;
and step four, starting from the first day after transplantation, carrying out combined injection treatment on the Arirokumab and the FK506 on the mice, and observing the beating state of the transplanted hearts of the mice every day. The complete stop of the heart transplantation is the end of the experiment, and the survival time of the graft is recorded;
wherein:
the injection dosage of the aleurozumab is 10 mg/kg/week, the mass of the injected body is 25-30mg, and the injection mode of the aleurozumab is subcutaneous injection;
the dose of FK506 injection is 1 mg/kg/day, the mass of the injected body is 25-30mg, and the FK506 injection mode is intraperitoneal injection;
step five, pathological section analysis is carried out on the transplanted heart on the 7 th day and the 14 th day of the experiment;
step six, detecting the infiltration condition of CD8 cells and CD4 cells in the transplanted heart on the 7 th day and the 14 th day of the experiment.
As can be seen from the second and third experimental examples,
the PCSK9 inhibitor is combined with the existing immunosuppressant (FK506), compared with the single use of the immunosuppressant, the combination is more beneficial to reducing graft rejection after heart transplantation and prolonging the survival time of heart transplant.
In conclusion, the application of the PCSK9 inhibitor in anti-rejection after heart transplantation is provided, and the PCSK9 inhibitor and the existing immunosuppressant (FK506) are used together, so that compared with the single use of the immunosuppressant, the combination is more beneficial to reducing the immune rejection after heart transplantation and prolonging the survival time of heart transplant. And the PCSK9 inhibitor alone may also be effective in prolonging the survival cycle of the graft.
It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising an … …" does not exclude the presence of other identical elements in a process, method, article, or apparatus that comprises the element.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. An application of a PCSK9 inhibitor in anti-rejection reaction after heart transplantation.
2. The use of the PCSK9 inhibitor for anti-rejection after heart transplantation according to claim 1, wherein the PCSK9 inhibitor and the immunosuppressant are used in combination for anti-rejection after heart transplantation.
3. The use of the PCSK9 inhibitor for anti-rejection after heart transplant surgery according to claim 1 or 2, wherein the PCSK9 inhibitor is aurirocumab.
4. Use of an immunosuppressant according to claim 2 for anti-rejection after heart transplant surgery, wherein the combined immunosuppressant is FK 506.
5. The PCSK9 inhibitor for use in anti-rejection after heart transplant surgery according to claim 1 or 2, wherein the PCSK9 inhibitor is administered subcutaneously at a dose of 10 mg/kg/week.
6. Use of an immunosuppressive agent according to claim 2 in anti-rejection after heart transplantation, wherein said immunosuppressive agent is administered by intraperitoneal injection at a dose of 1 mg/kg/day.
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| CN202110576518.XA CN113332423A (en) | 2021-05-26 | 2021-05-26 | Application of PCSK9 inhibitor in anti-rejection reaction after heart transplantation |
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| CN202110576518.XA CN113332423A (en) | 2021-05-26 | 2021-05-26 | Application of PCSK9 inhibitor in anti-rejection reaction after heart transplantation |
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Citations (5)
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| CN106488987A (en) * | 2014-05-02 | 2017-03-08 | 塞勒尼斯医疗控股公司 | HDL therapy mark |
| WO2019197477A1 (en) * | 2018-04-12 | 2019-10-17 | Bayer Aktiengesellschaft | C-type natriuretic peptide engrafted antibodies |
| WO2019197475A1 (en) * | 2018-04-12 | 2019-10-17 | Bayer Aktiengesellschaft | Brain natriuretic peptide engrafted antibodies |
| CN112236196A (en) * | 2018-04-12 | 2021-01-15 | 拜耳公司 | Atrial natriuretic peptide grafted antibody |
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-
2021
- 2021-05-26 CN CN202110576518.XA patent/CN113332423A/en active Pending
Patent Citations (8)
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| CN106488987A (en) * | 2014-05-02 | 2017-03-08 | 塞勒尼斯医疗控股公司 | HDL therapy mark |
| WO2019197477A1 (en) * | 2018-04-12 | 2019-10-17 | Bayer Aktiengesellschaft | C-type natriuretic peptide engrafted antibodies |
| WO2019197475A1 (en) * | 2018-04-12 | 2019-10-17 | Bayer Aktiengesellschaft | Brain natriuretic peptide engrafted antibodies |
| CN112236196A (en) * | 2018-04-12 | 2021-01-15 | 拜耳公司 | Atrial natriuretic peptide grafted antibody |
| CN112236197A (en) * | 2018-04-12 | 2021-01-15 | 拜耳公司 | Brain natriuretic peptide grafted antibody |
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| US20210139555A1 (en) * | 2018-04-12 | 2021-05-13 | Bayer Aktiengesellschaft | Atrial natriuretic peptide engrafted antibodies |
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| BRUCE A等: "Management of dyslipidemia in adult solid Q1 organ transplant recipients", 《JOURNAL OF CLINICAL LIPIDOLOGY》 * |
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