CN112791116A - Application of musk heart-through dropping pill in preparing antiplatelet medicine for treating gene mutation clopidogrel resistance - Google Patents
Application of musk heart-through dropping pill in preparing antiplatelet medicine for treating gene mutation clopidogrel resistance Download PDFInfo
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Abstract
The invention provides an application of a musk heart-through dropping pill in the preparation of an antiplatelet medicament for treating gene mutation clopidogrel resistance. The invention solves the problem of clopidogrel resistance in clinical antiplatelet therapy, particularly aims at the antiplatelet therapy of clopidogrel slow reaction type patients caused by gene mutation, the PCI preoperative loading application is favorable for reducing myocardial damage in perioperative period, and the use of the musk tongxuan dropping pill for medium and long periods is favorable for changing the epigenetics of clopidogrel metabolic mutation genes, thereby improving the adenosine diphosphate inhibition rate and improving clopidogrel resistance.
Description
Technical Field
The invention relates to the field of antiplatelet drug therapy, in particular to application of musk heart-through dropping pills in preparation of antiplatelet drugs for treating gene mutation clopidogrel resistance.
Background
Aspirin and clopidogrel are the most commonly used antiplatelet therapeutics in patients with coronary heart disease (CAD), and they can exert antiplatelet efficacy by inhibiting thromboxane a2(TXA2) and Adenosine Diphosphate (ADP) -induced platelet activation, respectively. Double-resistant therapy (aspirin in combination with clopidogrel) is required for at least one year after stenting in CAD patients. Whereas ischemic events still reoccur in approximately 10% of patients after receiving conventional, apparently adequate antiplatelet therapy, clinical studies have shown that there is heterogeneity in the response of different patients to antiplatelet therapy, and the phenomenon of "resistance" or "hyporesponsiveness" to antiplatelet therapy is closely associated with an increased risk of thrombosis and adverse cardiac events within the stent. The results of the systematic review and meta-analysis show that the incidence of aspirin hyporesponsiveness is 0.4% -65% in patients with cardiovascular disease, while the incidence of clopidogrel hyporesponsiveness is 4% -30%, with some patients presenting dual aspirin and clopidogrel resistance. The clinical attention degree to the clopidogrel resistance phenomenon is higher. Researches find that various factors play important roles, including medication compliance, bioavailability, gene polymorphism, drug interaction and the like; our earlier studies found that the gene carrying CYP2C19 slow metabolism is an independent risk factor for clopidogrel resistance.
Clopidogrel (brivudine) is the most widely used thiophene pyridine antiplatelet drug at present, the clinical treatment reaction of clopidogrel has obvious individual difference, and some patients have clopidogrel resistance to influence the treatment effect. In the CYP2C subfamily, the CYP2C19 subtype plays a critical role in drug response. In 2010, the FDA in the united states issued a warning that clopidogrel could be sold by attaching a "black box label" to the clopidogrel package, suggesting that clopidogrel dosage could be directed by detecting the genotype of CYP2C19.
Different treatment measures are respectively taken for patients with different clopidogrel reactivity clinically, such as avoiding drug influence, replacement or combined medication to achieve the aim of individual treatment so as to further improve the prognosis of the patients. Ticagrelor is a novel reversible P2Y12 receptor inhibitor, has faster effect and more obvious platelet inhibition effect than clopidogrel, and is recommended to be used for ACS treatment by a plurality of international guidelines. The PLATO research shows that ticagrelor further reduces the incidence rate of death, myocardial infarction or stroke of patients with Acute Coronary Syndrome (ACS) than clopidogrel, and the reason is related to that ticagrelor is adenosine receptor activation dependent and has stronger anti-inflammatory effect than clopidogrel. However, use is limited in clinical practice due to the high risk of small bleeding, high incidence of breathlessness, etc. of ticagrelor.
Therefore, combining the current medical conditions, clopidogrel and aspirin are still the most commonly used antiplatelet drugs for ACS patients, and if one drug can be used in combination on the basis, the antiplatelet and anti-inflammatory effects of clopidogrel and aspirin can be enhanced, the bleeding risk is not increased, the medical insurance and the personal economic burden are not excessively increased, and a great promoting effect is generated on the treatment of the coronary heart disease.
The Chinese medicinal compound preparation is combined according to the compatibility rule of monarch, minister, assistant and guide under the guidance of the theory of traditional Chinese medicine, has the characteristics of multiple components, multiple targets, multiple ways and overall action, and has obvious advantages in treating complex diseases compared with western medicines. A dripping pill, SHEXIANGTONGXIN dripping pill, is prepared from artificial Moschus, total saponin of caulis Et folium Ginseng, venenum Bufonis, radix Salviae Miltiorrhizae, artificial calculus bovis, fel Ursi, and Borneolum Syntheticum. Recent research proves that the musk heart-dredging dropping pill has the effects of stabilizing vascular endothelium, stabilizing atheromatous plaque, improving coronary blood flow and the like. Analyzing the components of the musk heart-freeing dropping pill: the venenum bufonis and the artificial musk can be used as monarch drugs for detoxifying, relieving pain and inducing resuscitation, and the combination of the venenum bufonis and the artificial musk can relieve vasospasm and improve hemodynamics; the ginseng stem and leaf total saponin and the salvia miltiorrhiza are used as ministerial drugs and can tonify heart qi, activate blood and remove stasis; the artificial bezoar and the bear gall are used as adjuvant drugs for clearing away heart-fire and toxic materials, reducing phlegm and inducing resuscitation, are cold medicines, and have good therapeutic effect on dredging blood vessels; borneol is used as a guiding drug for inducing resuscitation and inducing the flow of the medicine upwards. Therefore, the musk heart-dredging dropping pill has the functions of clearing away heat, removing blood stasis and promoting blood circulation in traditional Chinese medicine, and corresponds to the functions of anti-inflammation, lipid regulation and anti-platelet in western medicine. However, the advantages of the antiplatelet therapy of the musk heart-freeing dropping pill are not clarified, so that the musk heart-freeing dropping pill is not used in a targeted manner.
Disclosure of Invention
The invention aims to solve the problem of clopidogrel resistance in clinical antiplatelet treatment, and provides application of a musk heart-through dropping pill in preparing an antiplatelet medicament for treating gene mutation clopidogrel resistance.
In order to achieve the purpose, the invention provides application of a musk heart-through dropping pill in preparing an antiplatelet medicament for treating gene mutation clopidogrel resistance, which is characterized in that the gene mutation clopidogrel resistance refers to the gene mutation clopidogrel resistance of an acute coronary syndrome patient subjected to percutaneous coronary intervention treatment.
As a preferred scheme, the musk heart-dredging dropping pill is combined with clopidogrel.
As a preferred scheme, the musk heart-dredging dropping pill is combined with clopidogrel and aspirin.
As a preferred embodiment, the gene mutation clopidogrel resistance refers to gene mutation caused by CYP2C19 x 2, CYP2C19 x 3, ABCB1 and CES1, and upstream and downstream regulatory signals of four mutant genes.
As a further preferred scheme, the musk heart-dredging dripping pill with loading dose is used before Percutaneous Coronary Intervention (PCI), and the using time is more than or equal to 3 months.
As a further preferred embodiment, the loading dose is 4 initial doses plus 2 Tid.
Acute Coronary Syndrome (ACS) is a group of clinical syndromes caused by acute myocardial ischemia, mainly including Unstable Angina (UA), non-ST elevation myocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI). Rupture or erosion of atherosclerotic unstable plaques leading to acute thrombosis in the coronary arteries is considered to be the major pathological basis for the onset of most ACS. Platelet activation plays a very important role in its pathogenesis.
A dripping pill, SHEXIANGTONGXIN dripping pill (SANGLONGXIAN of inner Mongolian Connbei pharmaceutical industry Co., Ltd., Chinese medicine Standard Z20080018, specification: 35mg, 2 grains of tid oral administration), is mainly prepared from artificial Moschus, Ginseng radix stem and leaf total saponin, Bufonis venenum, Saviae Miltiorrhizae radix, artificial bezoar, fel Ursi, Borneolum, etc.
The load dose of the musk tongxin dropping pill is that 4 granules of the first dose are taken immediately, and 2 granules of the subsequent dose are taken orally.
CYP2C19 x 2, CYP2C19 x 3 were used for in vitro diagnostic genotyping according to us FDA approval, but the homozygous mutant fund for polivitamin resistance to which the present invention relates also included ABCB1 and CES1, as well as upstream and downstream regulatory signals for the four mutant genes.
Percutaneous Coronary Intervention (PCI) refers to a treatment method for improving the perfusion of the blood flow of the cardiac muscle by opening the narrow or even occluded coronary artery lumen through the cardiac catheter technique.
The invention has the advantages that the invention solves the problem of the porcine vitamin resistance in clinical anti-platelet treatment, in particular to the anti-platelet treatment of a porcine vitamin slow reaction type patient caused by gene mutation, the PCI preoperative load application is favorable for reducing the myocardial damage in the perioperative period, and the musk tongxin dripping pill used for a medium-term and long-term period is favorable for changing the epigenetics of a clopidogrel metabolic mutation gene, thereby improving the ADP (adenosine diphosphate) inhibition rate and improving the porcine vitamin resistance.
Drawings
FIG. 1 shows that the pre-operative loading dose musk heart-dredging dripping pill reduces the CK-MB level of ACS patients 24 hours after PCI operation, and has the effect of protecting the myocardial damage in the perioperative period.
FIG. 2 shows that the Moschus heart-relaxing drop pill can significantly reduce the peripheral blood inflammation index of ACS patients in 3 months after PCI operation.
FIG. 3A is a dripping pill of Moschus with heart dredging effect for reducing platelet number in peripheral blood of ACS patient 3 months after PCI operation without changing platelet number and average platelet volume.
Figure 4 shows that the loaded musk heart-through dropping pill before PCI operation can obviously improve ADP inhibition rate of slow metabolism type organisms by combining clopidogrel and aspirin.
FIG. 5 is a correlation analysis of how musk tongxin dripping pills improve the resistance to boli.
Figure 6 musk tongxin drop pills improve MVO level of IR myocardium thereby improving microcirculation perfusion.
FIG. 7 left ventricular slice row MVO detection (302nm UV condition).
Detailed Description
Hereinafter, the technique of the present invention will be described in detail with reference to specific embodiments. It should be understood that the following detailed description is only for the purpose of assisting those skilled in the art in understanding the present invention, and is not intended to limit the present invention.
Example 1.
Clinical studies were conducted using single-blind, randomized, positive control principles to collect 120 routine phase-selective Percutaneous Coronary Intervention (PCI) patients with Acute Coronary Syndrome (ACS), including unstable angina and myocardial infarction. Dividing into two groups, and subjecting control group (n ═ 60) to standard treatment (taking clopidogrel 300mg and aspirin 300mg before PCI operation, clopidogrel 75 mg/day after PCI operation, aspirin 100 mg/day); the treatment group (n ═ 60) is added with a load dose of musk tongxin dripping pills (STDP, 4 first doses and 2 tins, oral administration, PCI treatment is carried out after at least 2 days, till 3 months after PCI operation) on the basis of standard treatment. The patient's general condition (including sex, age, presence or absence of coronary heart disease predisposition, etc.) was recorded and the patient's coronary stenosis was estimated using the SYNTAX score. CYP2C19 enzyme gene polymorphism detection is carried out before the operation. The detection of hypersensitive troponin (hs-TnI) and CK-MB is carried out by chemiluminescence method 24 hours before and after operation. Platelet count and Mean Platelet Volume (MPV) were measured by conventional methods for 3 months before and after surgery, and Total Cholesterol (TC), oxidized low-density lipoprotein (ox-LDL), Triglyceride (TG), and high-density lipoprotein C (HDL-C) were measured by enzymatic method. The method comprises the steps of detecting Fasting Plasma Glucose (FPG) by a hexokinase method, detecting hypersensitive C-reactive protein (hs-CRP) by an immunoassay method, detecting proBNP by a chemiluminescence method, and detecting glutamic-oxaloacetic transaminase (AST), glutamic-pyruvic transaminase (ALT), urea nitrogen (BUN) and creatinine (Cr) by a biochemical method. All patients underwent thromboelastography at baseline levels and 3 months post-PCI surgery to measure ADP inhibition rate (ADP%). Peripheral blood of the patients before and after one week and 3 months is collected, and ICAM-1, VCAM-1, Galectin-3, MCP-1 and P-selectin expression is detected by ELISA. The peripheral blood flow test before and after 3 months of operation of the patients is collected, and the peripheral blood of two groups of patients has the number of platelet microparticles (CD31+ CD41a + PMPs). Two groups of patients were statistically analyzed for basal, blood biochemistry, ADP%, inflammation index, and PMPs counts. The clinical characteristics of the two groups of patients were not different; 36 cases (28 cases of intermediate metabolic types and 8 cases of slow metabolic types) of the control group CYP2C19 enzyme gene polymorphism detection metabolic abnormalities and 36 cases (20 cases of intermediate metabolic types and 12 cases of slow metabolic types) of the treatment group metabolic abnormalities have no obvious difference between the two groups; CK-MB levels were significantly down-regulated (P < 0.05) in the treatment group after 24 hours, while hsTnI levels were not significantly different (adjustment of the test time points or further expansion of the sample size was required); detecting the inflammation level of peripheral blood of a patient one week after operation, wherein the two groups have no obvious difference; after three months, no obvious difference in blood biochemical level of two groups of patients is detected respectively; peripheral blood ICAM-1, VCAM-1, Gal-3, MCP-1 levels were significantly down-regulated (P < 0.05), PMPs were significantly reduced (P < 0.05), and ADP% in CYP2C19 slow metabotropic patients was significantly increased (P < 0.05), but had little effect on ADP% in fast-reacting and intermediate metabotropic patients (P > 0.05). In addition, the musk heart-dredging dropping pills are found to be related to the improvement of the boli resistance and the reduction of PMPs (PMPs) level and the reduction of inflammation, which means the expression of Galectin-3.
FIG. 1 shows that the pre-operative loading dose musk heart-dredging dripping pill reduces the CK-MB level of ACS patients 24 hours after PCI operation, and has the effect of protecting the myocardial damage in the perioperative period. Control is Control group; STDP: moschus heart-dredging dripping pill; data in the figure are mean ± sd
To indicate. # indicates P < 0.05, # indicates P < 0.01, and is compared to pre-operative control baseline; p < 0.05, P < 0.01, compared to baseline of pre-operative treatment group;&p < 0.05, compared to control post-surgery. .
FIG. 2 shows that the Moschus heart-relaxing drop pill can significantly reduce the peripheral blood inflammation index of ACS patients in 3 months after PCI operation. Control is Control group; STDP: moschus heart-dredging dripping pill; data in the figure are mean ± sd
To indicate. Row t test compared to Control group, P < 0.05; denotes P < 0.01.
FIG. 3A is a dripping pill of Moschus with heart dredging effect for reducing platelet number in peripheral blood of ACS patient 3 months after PCI operation without changing platelet number and average platelet volume. Control is Control group; STDP: moschus heart-dredging dripping pill; MVP: platelet volume. Data in the figure are mean ± sd
To indicate. Row t test compared to Control group, P < 0.05; denotes P < 0.01.
Figure 4 shows that the loaded musk heart-through dropping pill before PCI operation can obviously improve ADP inhibition rate of slow metabolism type organisms by combining clopidogrel and aspirin. Control is Control group; STDP: moschus heart-dredging dripping pill; data in the figure are mean ± sd
To indicate. Row t test was compared to Control group, which indicates P < 0.05.
FIG. 5 is a correlation analysis of how musk tongxin dripping pills improve the resistance to boli.
Animal Studies an ischemia-reperfusion (IR) model (door XM, Liu Y, White D, Su Y, drive BG, Bruce CR, Kiriazis H, Xu Q, Jennings N, Bobik A et al: Deletion of secretion inhibition mechanisms of J Mol Cell Cardiol, 50(6): 991. sup. 999. g. 991. sup. XM. 2011ng, Woodcoc. E, Du XJ: Expression of Expression alpha (1B) -Expression of Expression receptor of Cell Heart kinase (32. sup. J.9. sup. g. J.sup. 9. mu. g. J.sup. 9. J.sup. g. J.M.. STDP was dissolved in saline as described in the literature and injected subcutaneously at 70mg/kg, the first time administered prior to reperfusion, and the second and third times were injected after 4 hours intervals (Xiong MQ HC, Cui JG, Ning BB, Zhu YL, Wang WJ, Chen Y, Zhang T: Anti-atherosclerotic effects of Shexing Tongxin drying pill: a mechanistic study. Chinese Journal of Integrated Medicine 2015,35(9): 1083) 1089.). Mice were sacrificed at 24 hours and 48 hours, respectively, and the hearts were subjected to immunohistochemical examination, which was indicated by small vessel leakage (MVL) and small vessel occlusion (MVO). The study finds that the musk heart-dredging dropping pill improves the far-end blood flow perfusion of small blood vessels by reducing the MVO level of cardiac muscle of IR animals.
Figure 6 musk tongxin drop pills improve MVO level of IR myocardium thereby improving microcirculation perfusion. Left ventricular sections were digitally photographed by exposure to 302nm uv light and MVO levels were evaluated using relevant imaging software. Left compartment percentage was used as data (mean ± variance), T-test.
FIG. 7 left ventricular slice row MVO detection (302nm UV condition). Left ventricular sections were digitally photographed by exposure to 302nm uv light and the areas of thioflavin-S fluorescence without evan blue staining were called the areas of risk (AAR), and the areas of reduced or absent fluorescence from the AAR areas were MVOs (i.e., low or no reflow areas).
CYP2C19 x 2, CYP2C19 x 3 were used for in vitro diagnostic genotyping according to FDA approval in the United states (Yang Y, Lewis JP, Hulot JS, et al, the pharmacological control of antisense response: candidate genes and CYP2C19.expert Opinion Drug protein toxin.2015; 11: 1599. epsilon. 1617.), but the homozygous mutant substrates for Potentional resistance involved in the present invention also include ABCB1 and CES1 (Riseria, Marpelagi, Ciperon. clopidogrel pharmacogenomics and non-genetic factor research progress. Chinese Pharmacology. 2019; 35: 1816. 1819.), as well as upstream and downstream regulatory signals of the four mutant genes.
The musk heart-through dropping pill (4 initial doses and 2 Tid which are orally taken) is combined with double resistance (Boravine and aspirin) before PCI operation, the musk heart-through dropping pill is suitable for anti-platelet treatment of clopidogrel slow reaction type patients caused by gene mutation, the using time is more than or equal to 3 months, and the patients (not suitable for replacement of ticagrelor) after stent operation are recommended to be orally taken for 1 year.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (6)
1. The application of the musk heart-through dropping pill in preparing antiplatelet drugs for treating gene mutation clopidogrel resistance is characterized in that the gene mutation clopidogrel resistance refers to the gene mutation clopidogrel resistance of patients suffering from acute coronary syndrome through percutaneous coronary artery interventional therapy.
2. The use of the musk cardiovascular dropping pill according to claim 1 for preparing an antiplatelet medicament for treating gene mutation clopidogrel resistance, wherein the musk cardiovascular dropping pill is used in combination with clopidogrel.
3. The use of the musk cardiovascular dropping pill according to claim 1 for preparing an antiplatelet medicament for treating gene mutation clopidogrel resistance, wherein the musk cardiovascular dropping pill is administered in combination with clopidogrel and aspirin.
4. The use of the dripping pill as claimed in any one of claims 1 to 3, wherein the gene mutation clopidogrel resistance is the gene mutation caused by CYP2C19 x 2, CYP2C19 x 3, ABCB1 and CES1, and the upstream and downstream regulatory signals of four mutated genes.
5. The use of the musk heart-through dripping pill according to claims 1-3 in the preparation of antiplatelet drugs for treating gene mutation clopidogrel resistance, characterized in that the musk heart-through dripping pill with a load dose is used before percutaneous coronary intervention treatment, and the use time is more than or equal to 3 months.
6. The use of the musk cardiovascular dropping pill according to claim 5 in the preparation of an antiplatelet medicament for treating gene mutation clopidogrel resistance, wherein the loading dose is 4 initial doses plus 2 tids.
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| CN113274504A (en) * | 2021-06-30 | 2021-08-20 | 南京市第一医院 | Application of compound acting on choline or TMAO related target in preparation of drugs for preventing and/or reversing clopidogrel resistance |
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