CN108619152A - Application of the Trimetazidine as immunosuppressor in treating immune correlated disease - Google Patents
Application of the Trimetazidine as immunosuppressor in treating immune correlated disease Download PDFInfo
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- CN108619152A CN108619152A CN201810677771.2A CN201810677771A CN108619152A CN 108619152 A CN108619152 A CN 108619152A CN 201810677771 A CN201810677771 A CN 201810677771A CN 108619152 A CN108619152 A CN 108619152A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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Abstract
The application of application and Trimetazidine as immunosuppressor in the drug for preparing immune correlated disease the invention discloses Trimetazidine as immunosuppressor in treating immune correlated disease.New application of the Trimetazidine provided by the present invention as immunosuppressant treatment immune related diseases can improve activation and activation by inhibiting T lymphocytes and macrophage, play immunosuppressive effect.Drug of the Trimetazidine as treatment heart simultaneously has been applied for a long time in clinic, and safety is high, non-evident effect, can greatly solve the larger deficiency of the immunosuppressor side reaction of current clinical application.Meanwhile Trimetazidine can combine other drugs and prepare the new drug with immunosuppressive action.
Description
Technical field
The present invention relates to the new medicine use of field of biological pharmacy, more particularly to Trimetazidine is being controlled as immunosuppressor
Treat the application in immune correlated disease.
Background technology
Trimetazidine Hydrochloride, chemical name are：1- (2,3,4- trimethoxybenzyl group) piperazine dihydrochloride.For a long time with
Come, people mainly use it for the prophylactic treatment of angina pectoris attacks, belong to other class antianginal cardiovascular drugs.Trimetazidine
By protecting energetic supersession of the cell under anoxic or ischemia, prevent the decline of intracellular ATP levels, to ensure that from
The normal operation of the normal function and permeable membrane sodium-potassium stream of son pump, maintains the stabilization of intracellular environment, is a kind of effective anti-heart
The drug of myocardial ischemia.Applicant has found that Trimetazidine has immunosuppressive special role early period,
It can inhibit static T lymphocytes (and macrophage) to lymphocyte activation and promote activating immune cell (leaching
Bar cell and macrophage) staticization, reduces the release of a variety of inflammatory cytokines, has immunosuppressive effect so that is bent
His beautiful piperazine has the potential applicability in clinical practice as immunosuppressant treatment immune related diseases.
Immunosuppressor is a kind of drug for referring to make body that apparent immunosuppressive effect occur.So-called immunosupress effect
It should not refer to the general toxicity reaction of drug, and refer to that it acts in immunoreaction process different links and the effect that generates,
Such as inhibit differentiation and development, the identification of interference antigen and processing, the activation of inhibition cell and proliferation, the depression effect of immunocyte
The function etc. of cell.Therefore, immunosuppressor can be further defined as：Under therapeutic dose, it can at least reduce or inhibit immune
The preparation of reaction.
Currently, common immunosuppressor mainly has five classes：
1) glucocorticoids, such as cortisone and prednisone.Glucocorticoid is as immunosuppressive drug for clinic
History is very long.Glucocorticoid immunological role, which is mainly manifested in, reduces lymphocyte generation cell factor, influences T cell
Activation, influences intercellular immune adherence.Also lymphocytolysis and apoptosis can be caused by directly acting on, quickly had to reach
Effect ground inhibits the purpose of immune response.
2) microbial metabolic products, such as cyclosporin and fujimycin 506；Cyclosporin is that one kind being widely used in preventing device
The immunosuppressor of official's graft rejection, most important effect are to reduce to be immunized instead caused by the activity and T cell of T cell
It answers.Selectively acting inhibits T to inhibit activation and the proliferation of cell in t lymphocyte subset group, inhibits to generate IL-2 and γ interference
Element.
3) antimetabolite, such as imuran and Ismipur；4) polyclonal and monoclonal antilymphocyte antibody, such as
Antilymphocyte globulin (ALG) (ALG)；5) alkylating agents, such as cyclophosphamide.Imuran is anti-with immunosuppressive action
It is metabolized agent.By inhibiting the biosynthesis of nucleic acid, the hyperplasia of cell is prevented, and the damage of DNA can be caused.Due to lymphocyte ratio
Other cells rely more on the route of synthesis of nucleic acid, therefore mainly inhibit T- lymphocytes and influence to be immunized, so can inhibit tardy
Allergic reaction, the rejection of organ transplant.
4) antilymphocyte globulin (ALG) is currently used primarily in the age more than 40 years old or hinders again without the Severe properly for marrow person
And conventional therapy it is invalid hinder patient again, be that immunizing antigen is made with human lymphocyte, be potent immunosuppressant controlling agent.Mechanism of action
It is to inhibit the lymphocyte activator process after antigen recognizing, and under complement assistance, specificity is generated to lymphocyte
Cytolysis.
5) cyclophosphamide is known strongest alkylating agents immunosuppressor, and effect is strong and lasting, itself has no alkane
Change effect and cytotoxic effect, metabolism generates active metabolite and plays a role in liver after body absorbs,
Cyclophosphamide has inhibiting effect to T, B cell, stronger than T cell to the inhibition of B cell, and cyclophosphamide can effectively inhibit B thin
The formation of cytoactive and autoantibody.
It was found that influences of the CTX to immune system is can to lead to the damage of immune system under larger dose with dose-dependent
Wound, such as induction of lymphocyte nuclear damage, metabolic function is suppressed, and proliferation is suppressed, and B cell is more more sensitive to CTX than T cell.Therefore, I
For the treatment of immunity disease be that the damage that can lead to immune system under larger dose is utilized to carry out, therefore how many devices
Official and tissue have harmful effect.
Immunosuppressor all uses extensive use in a variety of diseases at present, as systemic loupus erythematosus, rheumatoid close
Save hepar damnification, the post-transplantation that inflammation, autoimmune hemolytic anemia, autoimmune liver disease, virus or drug mediate
Rejection etc. is widely used general in clinic.But side effect caused by immunosuppressor is very normal in clinic
See, puzzlement is all brought to patient and doctor, significantly limits security application of the immunosuppressor in clinic.Such as sugared cortex
The side reactions such as caput femoris necrosis caused by hormone, severe infection, hemorrhage of gastrointestinal tract and hypertension；The Toxicity of Kidney of cyclosporin and
Hepatotoxicity；The bone marrow suppression side reaction of imuran；Bone marrow suppression side reaction of cyclophosphamide etc..Therefore, find it is novel,
The less immunosuppressive drug of side reaction has very extensive clinical value and social effect.
Invention content
Technical problem to be solved by the invention is to provide a kind of Trimetazidine as immunosuppressor in the immune phase for the treatment of
Application in related disorders, which solve it is current it is clinical in the immune suppressant drug applied have apparent side reaction the problem of.
The technical problem to be solved by the present invention is to what is be achieved through the following technical solutions：
Application of the Trimetazidine as immunosuppressor in treating immune correlated disease.
Preferably, in above-mentioned technical proposal, the Trimetazidine is for treating or preventing systemic loupus erythematosus, rheumatoid
Property arthritis, autoimmune hemolytic anemia, autoimmune liver disease, virus or the immune-mediated hepar damnification of drug or
Post-transplantation rejection.
The technical problem to be solved by the present invention is to what is be achieved through the following technical solutions：
Application of the Trimetazidine as immunosuppressor in the drug for preparing immune correlated disease, the finger drug are to use
In prevention or systemic lupus erythematosus, rheumatoid arthritis, autoimmune hemolytic anemia, autoimmune liver
The drug for the hepar damnification or post-transplantation rejection that disease, virus or drug mediate.
Preferably, in above-mentioned technical proposal, the drug is injection or oral agents.
Preferably, in above-mentioned technical proposal, the drug includes Trimetazidine and pharmaceutically acceptable auxiliary material, described
Drug is oral type tablet, subcutaneous injection agent or its lyophilized form, or intravenous injection form.
Preferably, in above-mentioned technical proposal, medicine of the Trimetazidine as immunosuppressant treatment immune correlated disease
Agent amount is：Trimetazidine 20mg, three times a day.
The technical problem to be solved by the present invention is to what is be achieved through the following technical solutions：
A kind of pharmaceutical composition, described pharmaceutical composition include Trimetazidine, and described pharmaceutical composition further includes that internal medicine is controlled
Treat drug and/or antiviral drugs.
Preferably, in above-mentioned technical proposal, described pharmaceutical composition further includes pharmaceutically acceptable auxiliary material.
The technical problem to be solved by the present invention is to what is be achieved through the following technical solutions：
A kind of pharmaceutical composition is used to prepare the application for the drug for treating immune correlated disease.
Preferably, in above-mentioned technical proposal, the immune correlated disease includes systemic loupus erythematosus, rheumatoid joint
Inflammation, autoimmune hemolytic anemia, autoimmune liver disease, virus or the immune-mediated hepar damnification or transplantation of drug
Rejection afterwards.
Trimetazidine provided by the present invention mainly leads to as the new application of immunosuppressant treatment immune related diseases
Following function is crossed to realize：
(1) Trimetazidine can inhibit the antigen submission of macrophage and lymphocyte, inhibit the synthesis IL- of macrophage
1；
(2) Trimetazidine can inhibit the activation of T lymphocytes, inhibit to generate IL-2/3/4/6 and interferon；
(3) Trimetazidine can inhibit the DNA of T lymphocytes to synthesize；
(4) Trimetazidine can inhibit the transcription of tumor necrosis factor (TNF α) cell factor；
(5) Trimetazidine can reduce cytotoxic T lymphocyte and be damaged to the specific immunity of liver cell；Described
Trimetazidine is administered as immunosuppressant treatment immune correlated disease in a manner of oral way or injection.
Above-mentioned technical proposal of the present invention, has the advantages that：
New application of the Trimetazidine provided by the present invention as immunosuppressant treatment immune related diseases, Neng Gouti
High pass inhibits the activation and activation of T lymphocytes and macrophage, plays immunosuppressive effect.Trimetazidine conduct simultaneously
The drug for treating heart has been applied for a long time in clinic, and safety is high, non-evident effect, can greatly solve
The larger deficiency of the immunosuppressor side reaction of certainly current clinical application.Meanwhile Trimetazidine can combine other drugs and prepare tool
There is the new drug of immunosuppressive action.
Description of the drawings
Fig. 1 is that Trimetazidine provided by the invention secretes IL-1, IL-2, IL-3, IL-4, IL-6, γ to human macrophage
The comparison influence diagram that Interferon level, tumor necrosis factor (TNF α) cell factor are transcribed.
Fig. 2 is that the Trimetazidine that the embodiment of the present invention 5 provides inhibits chronic hepatitis B acute attack patient HBV specificity
The influence diagram of CTL cytotoxic T lymphocyte ratios.
Fig. 3 is that Trimetazidine provided in an embodiment of the present invention inhibits chronic hepatitis B acute attack patient lymphocytes'
Influence diagram.
Fig. 4 is influence of the Trimetazidine provided in an embodiment of the present invention to chronic hepatitis B acute attack patient's liver function
Figure.
Fig. 5, which is Trimetazidine provided in an embodiment of the present invention, influences chronic hepatitis B acute attack renal function of patients
Figure.
Fig. 6 is influence of the Trimetazidine provided in an embodiment of the present invention to diagnosis of autoimmune hepatitis liver function index
Figure.
Fig. 7 is influence diagram of the Trimetazidine provided in an embodiment of the present invention to alcoholic hepatitis patient's liver function index.
Fig. 8 is Trimetazidine provided in an embodiment of the present invention to the related multiple indexs of Patients with SLE immunology
Influence diagram.
Fig. 9 is Trimetazidine provided in an embodiment of the present invention to the related multiple indexs of patient with rheumatoid arthritis immunology
Influence diagram.
Specific implementation mode
Specific embodiments of the present invention are described in detail below, in order to further understand the present invention.
Patients with Viral Hepatitis specificity cell toxicity T lymphocyte immune response is immunized in 1 Trimetazidine of embodiment
The effect of inhibiting effect and safety evaluatio.
One, test objective
Can Trimetazidine be evaluated be risen by specificity cell toxicity T lymphocyte immune response in Patients with Viral Hepatitis
To inhibiting effect.
Two, experimental design
1, test method
Using the clinical testing procedure of single centre cohort study.
2, case load estimation and distribution
Trimetazidine test group 20, placebo group 20
3, queued packets
01 day on 03 28th, 2018 all enrolled Patients with Viral Hepatitis of wherein August in 2017 are Subject Population,
Patient is randomized into Trimetazidine group experimental group and placebo group.
Three, case selection
1, inclusion criteria：
It is diagnosed as Patients with Viral Hepatitis；
Transaminase level is more than 5 times of normal upper limits；
Age：18-50 Sui；
Men and women is unlimited；
Inpatient；
Patient signs informed consent form, and compliance is good.
2, exclusion criteria：
Patient was less than 18 years old or more than 70 years old；
It is diagnosed as the patient of shock liver (ischemic hepatopathy).
Gestational liver failure or HELLP syndromes；
Intractable hypotensive；
Septic shock patient；
It will receive the patient of liver transfer operation (in 8 hours)；
To Trimetazidine drug allergy person；
To the resistance to receptor of Trimetazidine drug medicine；
Drug and/or alcohol abuse；
Pregnant woman or women breast-feeding their children；
There is the patient of myocardial infarction (in half a year) in the recent period；
Serious potential renal insufficiency patient.
3, culling level
It does not meet inclusion criteria and case report form records nonstandard case；
The non-case that experiment is exited because of adverse reaction or unsatisfactory curative effect.
4, standard is withdrawn from subject midway
It is necessary to stop to test from medical angle consideration subject by researcher；
Patient oneself requires to stop experiment；
There are serious adverse events.
Four, medication and drug distribution are tested
1, test group：Trimetazidine (Trimetazidin, TMZ)：20mg/ pieces, by the limited public affairs of Shi Weiya (Tianjin) pharmacy
Department provides.Usage and dosage：3 times a day, 1 tablet once, takes orally, the course for the treatment of 4 weeks.
2, control group：This experiment uses placebo group.
3, Primary Care：Aspartic acid ornithine, reduced glutathione, magnesium isoglycyrrhetate and people are given when including being admitted to hospital
Seralbumin
4, antiviral therapy：Entecavir or tenofovir antiviral therapy
Five, immune indexes Indexs measure
1, major immunological Indexs measure
Blood routine (includes leucocyte, neutrophil leucocyte, lymphocyte, monocyte, eosinophil, basophilla grain
Cell classification and ratio)
Lymphocyte differentiation antigen is classified；
Immunoglobulin class.
2, secondary reaction immunologic function change indicator --- liver function：Including serum alanine aminotransferase
(Alanine aminotransferase, ALT) is produced using colorimetric method by product (Shanghai) Co., Ltd. of Roche Diagnistics；It
Aspartate aminotransferase (Aspartate transaminase, AST), ibid.
Six, Analysis of test results
Case 1
Case 1：Patient, man, 35 years old, based on " it was found that more than 10 years of hepatitis b surface antigen positive, liver dysfunction 10 days "
It tells and is admitted to hospital.
Training physical examination after being admitted to hospital：Whole skin and sclera without xanthochromia, abdomen put down it is soft, under liver and spleen rib not and, percussion tenderness over hepatic region sun
Property, for abdomen without tenderness and Blumberg's sign, ascites shifting dullness is negative.
Coherence check prompt is improved after being admitted to hospital：Blood routine：Lymphocyte ratios：25%, lymphocyte absolute counting：1.5
×109/L.The ratio 34.5% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：356U/L, millet straw turn
Ammonia enzyme (AST)：289U/L, total bilirubin (TB) 56umol/L, bilirubin direct (DB) 38umol/L.Renal function：Creatinine (CR)：
57umol/L, urea (BUN) 2.9mmol/L.Hepatitis b surface antigen positive, HBVDNA are positive.
Admission diagnosis：Chronic hepatitis B acute attack.
Trimetazidine 20mg is given after being admitted to hospital, and is three times a day treated.
Review result prompt in 1 week after taking：Blood routine：Lymphocyte ratios：21%, lymphocyte absolute counting：1.2×
109/L.The ratio 30.5% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：105U/L, millet straw turn ammonia
Enzyme (AST)：78U/L, total bilirubin (TB) 35umol/L, bilirubin direct (DB) 18umol/L.Renal function：Creatinine (CR)：
59umol/L, urea (BUN) 2.7mmol/L.
Review result prompt in 2 weeks after taking：Blood routine：Lymphocyte ratios：14%, lymphocyte absolute counting：0.9×
109/L.The ratio 22.1% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：45U/L, millet straw turn ammonia
Enzyme (AST)：28U/L, total bilirubin (TB) 21umol/L, bilirubin direct (DB) 14umol/L.Renal function：Creatinine (CR)：
52umol/L, urea (BUN) 2.6mmol/L.
Therapeutic effect：Patient's transaminase declines rapidly, and improve discharge.
Case 2：Patient, man 35 years old, are chief complaint and are admitted to hospital with " it was found that liver dysfunction 7 days, xanthochromia 4 days ".
Training physical examination after being admitted to hospital：Whole skin and the slight xanthochromia of sclera, abdomen put down soft, 1cm under liver rib, under spleen rib not and, liver
Area's percussion pain is positive, and for abdomen without tenderness and Blumberg's sign, ascites shifting dullness is negative.Hev antibody IGM is positive.
Coherence check prompt is improved after being admitted to hospital：Blood routine：Lymphocyte ratios：22%, lymphocyte absolute counting：1.3
×109/L.The ratio 32.6% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：1247U/L, millet straw
Transaminase (AST)：945U/L, total bilirubin (TB) 174umol/L, bilirubin direct (DB) 145umol/L.Renal function：Creatinine
(CR)：62umol/L, urea (BUN) 3.1mmol/L.
Admission diagnosis：Hepatitis E acute attack.
Trimetazidine 20mg is given after being admitted to hospital, and is three times a day treated.
Review result prompt in 1 week after taking：Blood routine：Lymphocyte ratios：18%, lymphocyte absolute counting：1.1×
109/L.The ratio 27.6% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：325U/L, millet straw turn ammonia
Enzyme (AST)：247U/L, total bilirubin (TB) 156umol/L, bilirubin direct (DB) 109umol/L.Renal function：Creatinine (CR)：
57umol/L, urea (BUN) 2.6mmol/L.
Review result prompt in 2 weeks after taking：Blood routine：Lymphocyte ratios：14, lymphocyte absolute counting：0.85×
109/L.The ratio 21.3% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：124U/L, millet straw turn ammonia
Enzyme (AST)：98U/L, total bilirubin (TB) 77umol/L, bilirubin direct (DB) 54umol/L.Renal function：Creatinine (CR)：
54umol/L, urea (BUN) 2.7mmol/L.
Case 3：Patient, female 44 years old, are chief complaint and are admitted to hospital with " it was found that yellow urine 3 days, xanthochromia 1 day ".
Training physical examination after being admitted to hospital：Whole skin and the slight xanthochromia of sclera, abdomen put down soft, 2cm under liver rib, 1cm under spleen rib, hepatic region
Percussion pain is positive, and for abdomen without tenderness and Blumberg's sign, ascites shifting dullness is negative.
Coherence check prompt is improved after being admitted to hospital：Blood routine：Lymphocyte ratios：25%, lymphocyte absolute counting：1.7
×109/L.The ratio 35.9% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：667U/L, millet straw turn
Ammonia enzyme (AST)：724U/L, total bilirubin (TB) 274umol/L, bilirubin direct (DB) 145umol/L.Renal function：Creatinine
(CR)：60umol/L, urea (BUN) 3.7mmol/L.
Admission diagnosis：Drug induced hepatic injury.
Trimetazidine 20mg is given after being admitted to hospital, and is three times a day treated.
Review result prompt in 1 week after taking：Blood routine：Lymphocyte ratios：19%, lymphocyte absolute counting：1.4×
109/L.The ratio 18.9% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：129U/L, millet straw turn ammonia
Enzyme (AST)：142U/L, total bilirubin (TB) 92umol/L, bilirubin direct (DB) 50umol/L.Renal function：Creatinine (CR)：
59umol/L, urea (BUN) 3.4mmol/L.
Review result prompt in 2 weeks after taking：Blood routine：Lymphocyte ratios：16%, lymphocyte absolute counting：0.91
×109/L.The ratio 24.2% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：74U/L, millet straw turn
Ammonia enzyme (AST)：62U/L, total bilirubin (TB) 69umol/L, bilirubin direct (DB) 42umol/L.Renal function：Creatinine (CR)：
58umol/L, urea (BUN) 3.6mmol/L.
Case 4：Patient, female 52 years old, are chief complaint and are admitted to hospital with " more than 2 years of dysfunction of liver repeatedly ".
Training physical examination after being admitted to hospital：Whole skin and sclera without xanthochromia, abdomen put down it is soft, under liver and spleen rib not and, no percussion tenderness over hepatic region
Property, for abdomen without tenderness and Blumberg's sign, ascites shifting dullness is negative.
Coherence check prompt is improved after being admitted to hospital：Blood routine：Lymphocyte ratios：24%, lymphocyte absolute counting：1.5
×109/L.The ratio 34.5% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：252U/L, millet straw turn
Ammonia enzyme (AST)：291U/L, total bilirubin (TB) 52umol/L, bilirubin direct (DB) 38umol/L.Renal function：Creatinine (CR)：
54umol/L, urea (BUN) 4.3mmol/L.Antinuclear antibodies 1：1000, anti-mitochondrial antibody 1：3200.
Admission diagnosis：Autoimmune hepatic injury.
Trimetazidine 20mg is given after being admitted to hospital, and is three times a day treated.
Review result prompt in 1 week after taking：Blood routine：Lymphocyte ratios：18%, lymphocyte absolute counting：2.1×
109/L.The ratio 27.5% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：122U/L, millet straw turn ammonia
Enzyme (AST)：178U/L, total bilirubin (TB) 45umol/L, bilirubin direct (DB) 18umol/L.Renal function：Creatinine (CR)：
51umol/L, urea (BUN) 4.5mmol/L.
Review result prompt in 2 weeks after taking：Blood routine：Lymphocyte ratios：14%, lymphocyte absolute counting：1.3×
109/L.The ratio 20.9% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：45U/L, millet straw turn ammonia
Enzyme (AST)：28U/L, total bilirubin (TB) 23umol/L, bilirubin direct (DB) 12umol/L.Renal function：Creatinine (CR)：
51umol/L, urea (BUN) 4.2mmol/L.
Case 5：Patient, man, 34 years old, is chief complaint and is admitted to hospital with " right abdominal discomfort 7 days, xanthochromia 4 days ".
Training physical examination after being admitted to hospital：Whole skin and the slight xanthochromia of sclera, abdomen put down it is soft, under liver and spleen rib not and, percussion tenderness over hepatic region
The positive, for abdomen without tenderness and Blumberg's sign, ascites shifting dullness is negative.
Coherence check prompt is improved after being admitted to hospital：Blood routine：Lymphocyte ratios：27%, lymphocyte absolute counting：1.7
×109/L.The ratio 34.2% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：247U/L, millet straw turn
Ammonia enzyme (AST)：345U/L, total bilirubin (TB) 221umol/L, bilirubin direct (DB) 145umol/L.Renal function：Creatinine
(CR)：55umol/L, urea (BUN) 4.3mmol/L.
Admission diagnosis：Alcoholic liver is damaged
Trimetazidine 20mg is given after being admitted to hospital, and is three times a day treated.
Review result prompt in 1 week after taking：Blood routine：Lymphocyte ratios：21%, lymphocyte absolute counting：1.1×
109/L.The ratio 27.6% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：162U/L, millet straw turn ammonia
Enzyme (AST)：141U/L, total bilirubin (TB) 86umol/L, bilirubin direct (DB) 37umol/L.Renal function：Creatinine (CR)：
54umol/L, urea (BUN) 4.3mmol/L.
Review result prompt in 2 weeks after taking：Blood routine：Lymphocyte ratios：16%, lymphocyte absolute counting：0.92
×109/L.The ratio 22.6% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：74U/L, millet straw turn
Ammonia enzyme (AST)：58U/L, total bilirubin (TB) 62umol/L, bilirubin direct (DB) 27umol/L.Renal function：Creatinine (CR)：
52umol/L, urea (BUN) 2.8mmol/L.
Embodiment 2：Clinical effectiveness of the Trimetazidine as immunosuppressant treatment nephrosis.
Case 1：Patient, women 51 years old, are chief complaint and are admitted to hospital with " it was found that urine examination exception is more than June ".
Training physical examination after being admitted to hospital：For facial area without oedema, cardiopulmonary are without exception, abdomen put down it is soft, under liver and spleen rib not and, percussion tenderness over hepatic region
The positive, abdomen is without tenderness and Blumberg's sign, and ascites shifting dullness is negative, and double lower limb is without oedema.
Coherence check prompt is improved after being admitted to hospital：Routine urinalysis：Albumen 1+, occult blood 2+.Twenty-four-hour urine protein quantification：5.3g.Point
Formula total protein：1.02g/g.Blood routine：Lymphocyte ratios：45.4%, lymphocyte absolute counting：2.54×109/L.Streaming
Cell instrument detects the ratio 32.8% of CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：11U/L, glutamic-oxalacetic transaminease (AST)：
13U/L, total bilirubin (TB) 9.8umol/L, bilirubin direct (DB) 4.2umol/L.Renal function：Creatinine (CR)：67umol/L,
Urea (BUN) 4.1mmol/L.Remaining inspection result is shown no obvious abnormalities.
It is admitted to hospital tentative diagnosis：Nephrotic syndrome.It excludes without row " Pathological percutaneous biopsy ", postoperative pathological after contraindication
Show：Focal Hypertrophic IgA nephrosis, is diagnosed as：The focal Hypertrophic IgA nephrosis of nephrotic syndrome
After give " each 20mg of Trimetazidine, 3 times a day " and treated.
Take rear review result in January prompt：Routine urinalysis：Albumen-, occult blood 2+.Twenty-four-hour urine protein quantification：0.26g.Point type
Total protein：0.3g/g.Blood routine：Lymphocyte ratios：45.5%, lymphocyte absolute counting：2.6×109/L.Fluidic cell
Instrument detects the ratio 38.9% of CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：9U/L, glutamic-oxalacetic transaminease (AST)：18U/L, always
Bilirubin (TB) 10.3umol/L, bilirubin direct (DB) 8.0umol/L.Renal function：Creatinine (CR)：56umol/L, urea
(BUN)3.9mmol/L。
Review result prompt in 2 months after taking：Routine urinalysis：Albumen-, occult blood-.Twenty-four-hour urine protein quantification：0.2g.Point type is total
Albumen：0.1g/g.Blood routine：Lymphocyte ratios：42.9%, lymphocyte absolute counting：2.32×109/L.Fluidic cell
Instrument detects the ratio 33.7% of CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：21U/L, glutamic-oxalacetic transaminease (AST)：23U/L,
Total bilirubin (TB) 11.1umol/L, bilirubin direct (DB) 7.6umol/L.Renal function：Creatinine (CR)：61umol/L, urea
(BUN)7mmol/L。
Take rear review result in March prompt：Routine urinalysis：Albumen-, occult blood-.Twenty-four-hour urine protein quantification：0.15g.Point type
Total protein：0.12g/g.Blood routine：Lymphocyte ratios：40.6%, lymphocyte absolute counting：1.8×109/L.Streaming is thin
Born of the same parents' instrument detects the ratio 35.3% of CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：17U/L, glutamic-oxalacetic transaminease (AST)：24U/
L, total bilirubin (TB) 16.3umol/L, bilirubin direct (DB) 10.4umol/L.Renal function：Creatinine (CR)：73umol/L, urine
Element (BUN) 3.7mmol/L.
Case 2：Patient, female 47 years old, are chief complaint and are admitted to hospital with " interruption double lower limb and more than 30 years of edema in face ".
Training physical examination after being admitted to hospital：Edema in face, cardiopulmonary are without exception, abdomen put down it is soft, under liver and spleen rib not and, percussion tenderness over hepatic region sun
Property, for abdomen without tenderness and Blumberg's sign, ascites shifting dullness is negative.Double lower limb pitting edema.
Coherence check prompt is improved after being admitted to hospital：Routine urinalysis：Albumen 3+, occult blood 2+.Twenty-four-hour urine protein quantification：25.15g.
Point type total protein：5.01g/g.Blood routine：Lymphocyte ratios：39%, lymphocyte absolute counting：2.91×109/L.Streaming
Cell instrument detects the ratio 27.3% of CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：18U/L, glutamic-oxalacetic transaminease (AST)：
23U/L, total bilirubin (TB) 12.6umol/L, bilirubin direct (DB) 6.7umol/L,.Renal function：Creatinine (CR)：69umol/
L, urea (BUN) 3.8mmol/L.Remaining inspection result is shown no obvious abnormalities.
It is admitted to hospital tentative diagnosis：Nephrotic syndrome.It excludes without row " Pathological percutaneous biopsy ", postoperative pathological after contraindication
Show：Minute lesion glomerulopathy, is diagnosed as：Nephrotic syndrome minute lesion glomerulopathy.
After give " each 20mg of Trimetazidine, 3 times a day " and treated.
Take rear review result in January prompt：Routine urinalysis：Albumen-, occult blood-.Twenty-four-hour urine protein quantification：1.15g.Point type
Total protein：0.21g/g.Blood routine：Lymphocyte ratios：34%, lymphocyte absolute counting：2.03×109/L.Fluidic cell
Instrument detects the ratio 30.5% of CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：15U/L, glutamic-oxalacetic transaminease (AST)：18U/L,
Total bilirubin (TB) 12.8umol/L, bilirubin direct (DB) 9.2umol/L.Renal function：Creatinine (CR)：66umol/L, urea
(BUN)5.1mmol/L。
Review result prompt in 2 months after taking：Routine urinalysis：Albumen-, occult blood-.Twenty-four-hour urine protein quantification：0.08g.Point type
Total protein：0.08g/g.Blood routine：Lymphocyte ratios：35.9%, lymphocyte absolute counting：2.12×109/L.Streaming is thin
Born of the same parents' instrument detects the ratio 32.1% of CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：8U/L, glutamic-oxalacetic transaminease (AST)：16U/L,
Total bilirubin (TB) 11.9umol/L, bilirubin direct (DB) 7.4umol/L.Renal function：Creatinine (CR)：65umol/L, urea
(BUN)3.6mmol/L。
Take rear review result in March prompt：Routine urinalysis：Albumen-, occult blood-.Twenty-four-hour urine protein quantification：0.06g.Point type
Total protein：0.05g/g.Blood routine：Lymphocyte ratios：30.4%, lymphocyte absolute counting：1.97×109/L.Streaming is thin
Born of the same parents' instrument detects the ratio 20.5% of CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：9U/L, glutamic-oxalacetic transaminease (AST)：9U/L,
Total bilirubin (TB) 13.4umol/L, bilirubin direct (DB) 9.5umol/L.Renal function：Creatinine (CR)：49umol/L, urea
(BUN)7.1mmol/L。
Clinical effectiveness of 3 Trimetazidine of embodiment as immunosuppressant treatment rheumatic disease
Case 1：Patient, female 65 years old, are chief complaint and are admitted to hospital with " both hands metacarpophalangeal joints, proximal interphalangeal joint swelling and pain are more than May ".
Rheumatoid arthritis
Training physical examination after being admitted to hospital：Both hands metacarpophalangeal joints, proximal interphalangeal joint, both shoulders joint, duplex joint, double knee joint pressure
Bitterly, left exercising elbow joint is limited, heart and lung auscultation Non Apparent Abnormality, is not touched under liver and spleen rib, double lower limb is without oedema.
Coherence check prompt is improved after being admitted to hospital：Blood routine：Lymphocyte ratios：31.8%, lymphocyte absolute counting：
1.3×109/L.The ratio 34.9% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：16U/L, millet straw
Transaminase (AST)：18U/L, total bilirubin (TB) 5.8umol/L, bilirubin direct (DB) 3.16umol/L.Renal function：Creatinine
(CR)：42umol/L, urea (BUN) 4.59mmol/L.Rheumatoid arthritis is a full set of：Antinuclear antibodies 1：320 (+) granular patterns resist
Cyclic citrulline peptide antibody 624.7RU/ml, rheumatoid factor IgM types 211.6IU/ml, anti-saltant type citrulling vimentin antibodies
>1000U/ml, the anti-keratin antibody positive (+)
Admission diagnosis：Rheumatoid arthritis
Trimetazidine 20mg is given after being admitted to hospital, and is three times a day treated.
Review result prompt in 1 week after taking：Blood routine：Lymphocyte ratios：28.4%, lymphocyte absolute counting：1.2
×109/L.The ratio 30.2% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：10U/L, millet straw turn
Ammonia enzyme (AST)：15U/L, total bilirubin (TB) 6.8umol/L, bilirubin direct (DB) 4.2umol/L.Renal function：Creatinine
(CR)：54umol/L, urea (BUN) 2.7mmol/L.
Review result prompt in 2 weeks after taking：Blood routine：Lymphocyte ratios：23.1%, lymphocyte absolute counting：
1.02×109/L.The ratio 22.3% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：12U/L, paddy
Careless transaminase (AST)：13U/L, total bilirubin (TB) 8.6umol/L, bilirubin direct (DB) 5.2umol/L.Renal function：Creatinine
(CR)：66umol/L, urea (BUN) 2.6mmol/L.
Case 2：Patient, man 28 years old, are chief complaint and are admitted to hospital with " migrans arthralgia, fash are generated heat 1 day more than half a month ".
Training physical examination after being admitted to hospital：Anaemia looks, the multiple patch shape erythema in back, the accessible enlargement leaching of neck/armpit/groin
It fawns on, heart and lung auscultation Non Apparent Abnormality, is not touched under liver and spleen rib, double lower limb is without oedema.
Coherence check prompt is improved after being admitted to hospital：Blood routine：Lymphocyte ratios：36.5%, lymphocyte absolute counting：
1.39×109/L.The ratio 37.9% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：21U/L, paddy
Careless transaminase (AST)：23U/L, total bilirubin (TB) 8.45umol/L, bilirubin direct (DB) 3.98umol/L.Renal function：Flesh
Acid anhydride (CR)：58umol/L, urea (BUN) 9.28mmol/L.Connective tissue is a full set of：Antinuclear antibodies 1：1000 (++) particle+endochylema
Type, anti-dsDNA antibody are positive>800IU/ml, antiribosomal antibody strong positive (+++), the histonic antibody positive (+) resist
Nucleosome antibody strong positive (+++), the anti-SSB antibody positive (++) anti-Ro52 antibody strong positive (+++), anti-SSA antibody strong positive
(+++), anti-Sm antibody strong positive (+++), anti-nRNP/Sm antibody strong positive (+++)
Admission diagnosis：Systemic loupus erythematosus
Trimetazidine 20mg is given after being admitted to hospital, and is three times a day treated.
Review result prompt in 1 week after taking：Blood routine：Lymphocyte ratios：32.4%, lymphocyte absolute counting：
1.24×109/L.The ratio 30.2% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：10U/L, paddy
Careless transaminase (AST)：15U/L, total bilirubin (TB) 10.2umol/L, bilirubin direct (DB) 5.6umol/L.Renal function：Flesh
Acid anhydride (CR)：66umol/L, urea (BUN) 2.8mmol/L.
Review result prompt in 2 weeks after taking：Blood routine：Lymphocyte ratios：24.1%, lymphocyte absolute counting：
1.09×109/L.The ratio 22.6% of flow cytomery CD8+T lymphocytes；Glutamic-pyruvic transaminase (ALT)：23U/L, paddy
Careless transaminase (AST)：13U/L, total bilirubin (TB) 15.8umol/L, bilirubin direct (DB) 7.6umol/L.Renal function：Flesh
Acid anhydride (CR)：78umol/L, urea (BUN) 2.3mmol/L.
Experimental example 1
Trimetazidine is detected to the antigen submission of lymphocyte, inhibits the synthesis IL-1 of macrophage normal in the medium
U937 human macrophages system is cultivated, Trimetazidine, which is added, after bed board is stimulated, and the enzyme of human interleukin IL-1 is applied after 24 hours
It is horizontal that linked immunosorbent assay (ELISA) kit detects the IL-1 in cell culture supernatant.The specific steps are：1) dilution standard product；2) root
Quantity according to sample to be tested quantity plus standard items determines required lath number, 3 multiple holes；If 3) only develop the color in blank well
Agent A＆B and terminate liquid；4) standard items 50ul, Avidin-HRP is added in standard sample wells.4) sample 40ul is added in sample to be tested hole；5)
Anti- IL-1 antibody 10ul is added in each sample；6) mixing is gently shaken, 37 ° incubate 60 minutes；7) and then according to kit
Specification is loaded, matches liquid, washing, colour developing and measurement；8) straight line that mark curve is calculated according to the OD values of standard items returns
Return equation, corresponding sample concentration is calculated on regression equation further according to the OD values of sample.Experimental result is found：Trimetazidine
The IL-1/2/3/4/6 of the lymphocyte release of processing is significantly reduced, and illustrates that Trimetazidine inhibits the activation of lymphocyte.
Experimental example 2
Trimetazidine is detected to the antigen submission of lymphocyte, inhibits the release interferon of macrophage.It is training first
It supports and normally cultivates U937 human macrophages system in base, Trimetazidine, which is added, after bed board is stimulated, and people Bai Jie is applied after 24 hours
Interferon in the enzyme-linked immunosorbent assay (ELISA) kit detection cell culture supernatant of plain IL-1 is horizontal.The specific steps are：1)
Dilution standard product；2) quantity according to sample to be tested quantity plus standard items determines required lath number, 3 multiple holes；3) empty
If Bai Kongzhong color developing agent A＆B and terminate liquids；4) standard items 50ul, Avidin-HRP is added in standard sample wells.4) sample to be tested
Sample 40ul is added in hole；5) anti-interferon antibody 10ul is added in each sample；6) mixing is gently shaken, 37 ° incubate 60
Minute；7) it and then according to kit specification is loaded, matches liquid, washing, colour developing and measurement；8) according to the OD value meters of standard items
The linear regression equation for calculating mark curve, corresponding sample concentration is calculated further according to the OD values of sample on regression equation.
Experimental result is found：The interferon of the lymphocyte release of Trimetazidine processing all significantly reduces, and illustrates that Trimetazidine inhibits
The activation of lymphocyte.
Experimental example 3
EdU is a kind of thymidine analog, thymidine infiltration can be replaced to answer in cell Proliferation period
Cell DNA replication activity .1 is quickly detected in the DNA molecular of system) logarithmic growth phase lymphocyte cell, with every hole 4 × 103
~1 × 105 cell inoculations are in 96 orifice plates, culture to normal growth stage.2) 1000 are pressed with cell culture medium：1 ratio is dilute
EdU solution (reagent A) is released, appropriate 50 μM of EdU culture mediums are prepared；3) 50 μ L cells fixers are added per hole and (contain 4% poly
The PBS of formaldehyde) it is incubated at room temperature 30 minutes, abandon fixer；4) 50 μ L 2mg/mL glycine are added per hole, decolorization swinging table is incubated 5 points
Zhong Hou abandons glycine solution；5) 100 μ L PBS are added per hole, decolorization swinging table cleans 5 minutes, abandons PBS；5) 100 μ L are added per hole
Bleeding agent (PBS of 0.5%TritonX-100) decolorization swinging table is incubated 10 minutes；PBS is cleaned 1 time, 5 minutes.6) it is added per hole
The 1X of 100 μ LStaining reaction liquid (table 3), be protected from light, room temperature, decolorization swinging table be incubated 30 minutes after, abandon staining reaction
Liquid；7) 100 μ L bleeding agents (PBS of 0.5%TritonX-100) decolorization swinging tables are added to clean 2~3 times, 10 minutes every time, abandon and ooze
Saturating agent；8) 100 μ L methanol are added every time per hole to clean 1~2 time, every time 5 minutes；PBS is cleaned 1 time, every time 5 minutes.9) per hole
100 μ L 1X Hoechst, 33342 reaction solutions are added, be protected from light, room temperature, decolorization swinging table be incubated 30 minutes after, abandon staining reaction liquid；
9) 100 μ L PBS are added every time per hole to clean 1~3 time, are observed immediately after the completion of dyeing.Experimental result is found：Sibutramine Hydrochloride he
The lymphocyte EDU indexs of piperazine processing are remarkably decreased, and illustrate that Trimetazidine inhibits the DNA of lymphocyte to synthesize.
Experimental example 4
Detect influence of the Trimetazidine to the transcription of tumor necrosis factor (TNF α) cell factor.Use real-time quantitative PCR
(real-time quantitative RT-PCR) detects mRNA.1) normally culture U937 people's macrophage is thin in the medium first
Born of the same parents are that Trimetazidine is added after bed board to be stimulated, and Trizol is added in the good cells rinsed with PBS of extraction process after 24 hours
And shake and cell cracking processing is carried out to cell, it is placed at room temperature for 12000g after ten minutes and centrifuges 5 minutes, draw supernatant and EP pipes are added
In.2) chloroform is added, and acutely sways 30 seconds, is then placed at room temperature for 3 minutes, 12000g centrifuges 15 points in refrigerated centrifuge
Then clock takes in the water sample layer to EP pipes of upper layer, isopropanol is added and is mixed well, is placed at room temperature for 10 minutes, 4 DEG C of 12000g
Centrifugation 15 minutes；3) 75% ethyl alcohol of 1ml is added in EP pipes, carries out gentle mixing suspension precipitation, 4 DEG C of 12000g centrifuge 15 points
Clock abandons supernatant, is subsequently placed in drying at room temperature 8min, then uses DEPC water dissolution RNA samples, 55 C water baths 5 minutes.Using
Purity and concentration are detected with spectrophotometer.4) reverse transcription RNA is cDNA：Genomic DNA is removed first：Reaction system is 5X
GDNA EraserBuffer 2ul, gDNAEraser 1ul, total serum IgE 1ug, be added RNase Free ddH2O to 10ul, 42
DEG C water-bath 2min is placed on ice, and reverse transcription reaction is completed according to kit.5) quantitative fluorescent PCR is according to fluorescence quantitative PCR instrument
Device operation manual is completed.6) data analysis：The acquisition and analysis of the analysis result data of fluorescent quantitation use 2.0 softwares of SDS,
The differential expression of 2- △ △ CT relative quantification comparison for calculation methods each group target gene.Target gene and reference gene respectively set 4
Multiple holes, 3 repetitions of identical Bioexperiment.Experimental result is found：The tumor necrosis factor of the lymphocyte of Trimetazidine processing
(TNF α) transcriptional level significantly reduces, and illustrates that Trimetazidine inhibits the transcription water of the tumor necrosis factor (TNF α) of lymphocyte
It is flat.
It is demonstrated experimentally that new use of the Trimetazidine provided by the present invention as immunosuppressant treatment immune related diseases
On the way, the activation and activation by inhibiting T lymphocytes can be improved, immunosuppressive effect is played.Trimetazidine conduct simultaneously
The drug for treating heart has been applied for a long time in clinic, and safety is high, non-evident effect, can greatly solve
The larger deficiency of the immunosuppressor side reaction of certainly current clinical application.
Although the present invention is disclosed as above with embodiment, so it is not intended to limit the present invention, any people in the art
Member can make a variety of different selections and modification, therefore the protection model of the present invention without departing from the spirit and scope of the present invention
It encloses and is limited by claims and its equivalents.
Claims (10)
1. application of the Trimetazidine as immunosuppressor in treating immune correlated disease.
2. application of the Trimetazidine according to claim 1 as immunosuppressor in treating immune correlated disease,
It is characterized in that, the Trimetazidine is molten for treating or preventing systemic loupus erythematosus, rheumatoid arthritis, autoimmune
Hemolytic hemolytic anemia, autoimmune liver disease, virus or the immune-mediated hepar damnification or post-transplantation rejection of drug.
3. application of the Trimetazidine as immunosuppressor in the drug for preparing immune correlated disease, the finger drug is to be used for
Prevent or systemic lupus erythematosus, rheumatoid arthritis, autoimmune hemolytic anemia, autoimmune liver disease,
The drug for the hepar damnification or post-transplantation rejection that virus or drug mediate.
4. Trimetazidine according to claim 3 is as immunosuppressor in preparation or epidemic prevention relevant disease drug
Application, which is characterized in that the drug be injection or oral agents.
5. Trimetazidine according to claim 3 is as immunosuppressor in preparation or epidemic prevention relevant disease drug
Application, which is characterized in that the drug include Trimetazidine and pharmaceutically acceptable auxiliary material, the drug be oral type
Tablet, subcutaneous injection agent or its lyophilized form, or intravenous injection form.
6. Trimetazidine according to claim 5 is as immunosuppressor in preparation or epidemic prevention relevant disease drug
Application, which is characterized in that the Trimetazidine is as the drug dose of immunosuppressant treatment immune correlated disease：Sibutramine Hydrochloride
He is piperazine 20mg, three times a day.
7. a kind of pharmaceutical composition, described pharmaceutical composition includes any Trimetazidines of claim 1-6, and feature exists
In described pharmaceutical composition further includes medical treatment drug and/or antiviral drugs.
8. pharmaceutical composition according to claim 7, which is characterized in that described pharmaceutical composition further includes that can pharmaceutically connect
The auxiliary material received.
9. being used to prepare answering for the drug for the treatment of immune correlated disease according to any pharmaceutical compositions of claim 7-8
With.
10. pharmaceutical composition according to claim 9 is used to prepare the application of the drug for the treatment of immune correlated disease, special
Sign is, the immune correlated disease includes that systemic loupus erythematosus, rheumatoid arthritis, Autoimmune hemolytic are poor
Blood, autoimmune liver disease, virus or the immune-mediated hepar damnification or post-transplantation rejection of drug.
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