CN104800194A - Medicine composition for treating hypertrophic cardiomyopathy and application of medicine composition - Google Patents
Medicine composition for treating hypertrophic cardiomyopathy and application of medicine composition Download PDFInfo
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Abstract
The invention discloses medicine composition for treating hypertrophic cardiomyopathy and an application of the medicine composition. The medicine composition is prepared from an active component and auxiliary materials, wherein the active component comprises 1,2,3,4-tetrahydro-1,2,4-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthranone. The biological activity of the compound is further researched with the method adopting a model suffering from cardiac hypertrophy caused by isoproterenol, and a result shows that the medicine composition can relieve cardiac hypertrophy remarkably and fibrosis in tissue is reduced remarkably.
Description
Technical field
The invention belongs to medical art, specifically, particularly relate to a kind of pharmaceutical composition and application thereof for the treatment of hypertrophic neuropathy.
Background technology
Along with economic development and growth in the living standard, the ratio of heart failure shared by the incidence rate and case fatality rate of cardiovascular event is more and more higher, it is the modal complication of myocardial hypertrophy, be that a kind of heart systolic and diastolic function is complete and cannot meet the syndrome of the complexity of organism metabolism needs, it is one of mankind nowadays underlying cause of death.The left ventricular hypertrophy reconstruct focusing on heart of current research is current generally acknowledged cardiovascular disease risk of mortality factor.Myocardial hypertrophy is heart to many external irritants as a kind of adaptation response of hypertension, valvular heart disease, myocardial infarction and cardiomyopathy etc., is a kind of adaptive change of cardiac load left ventricle aneurysm normalization when to increase.Although this process is compensatory to the one of heart increase work done, so heart failure, arrhythmia and sudden death can be caused for a long time.The feature of myocardial hypertrophy is that myocardial cell volume increases, protein synthesis increases and muscle fiber increases.Study on Molecular Mechanism at present about myocardial hypertrophy generation is numerous, mainly contains: l, neurocalcin-NFAT signal path.2, P13K/AKT/GSK-3 relies on signal path.3, MEF2/HPAC is to the transcriptional control of myocardial hypertrophy.4, the loose signal path of G-protein coreceptor.5, small G-protein and sarcostyle signal path.6, MAPK signal path.7, PKC signal path.8, GPl30/STAT3 signal path.9, lipidosis mechanism.10, MMP/TNF mechanism etc.But existing research can not annotate the mechanism of myocardial hypertrophy completely.Therefore need to find survival rate and the quality of life that new Therapeutic Method, particularly drug treatment improves Patients with Cardiac Failure, explain that the mechanism of myocardial hypertrophy is the key factor of leading to this target better.
Naphthoquinone compound is the micromolecular compound that a class is extensively present in occurring in nature, has multiple biological activity.CN104262130A discloses a kind of naphthoquinone compound of ocean microorganism, this system of compounds called after 1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthrone, it can for the preparation of antitumor drug, and the environmental friendliness of preparation, application cost is low.By retrieval domestic and foreign literature, still do not find that 1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthrone has the bibliographical information for the treatment of hypertrophic neuropathy or myocardial fibrosis.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical composition and application thereof for the treatment of hypertrophic neuropathy.
In order to realize object of the present invention, the present inventor is studied and persistent exploration by lot of experiments, finally obtains following technical scheme:
Treat pharmaceutical composition and the application thereof of hypertrophic neuropathy, be prepared from by active component and adjuvant, wherein said active component comprises 1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthrone.This compound is identified through structural analysis, and its Spectral data is as follows: molecular formula C
17h
18o
7, HR-ESI-MS:357.0947 ([M+Na]+, calcd.forC17H18O7Na) .1H-NMR (DMSO-D6, 500MHz): 4.44 (d, J=5.0, H-1), 3.34 (m, H-2), 1.73 (td, J=8.1, 4.8, H-3), 2.66 (dd, J=5.0, 18.0, H-4a), 2.12 (dd, J=9.0, 18.0, H-4b), 7.14 (s, H-8), 1.03 (d, J=6.4, 3-CH3), 3.80 (s, 6-OCH3), 3.95 (s, 7-OCH3), 11.96 (s, 5-OH) .13C-NMR (DMSO-D6, 126MHz): 68.9 (C-1), 75.7 (C-2), 32.0 (C-3), 26.2 (C-4), 154.4 (C-5), 140.1 (C-6), 157.6 (C-7), 103.2 (C-8), 182.7 (C-9), 188.6 (C-10), 110.3 (C-11), 127.8 (C-12), 143.4 (C-13), 143.8 (C-14), 17.4 (CH3-3), 60.2 (OCH3-6), 56.2 (OCH3-7).
Preferably, the pharmaceutical composition for the treatment of hypertrophic neuropathy as mentioned above, wherein said active component is made up of as sole component 1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthrone.
Further preferably, the pharmaceutical composition for the treatment of hypertrophic neuropathy as mentioned above, wherein said pharmaceutical composition is injection, and described injection comprises injection and freeze-dried powder injection.
The present inventor causes obesity and high triglyceride type animal model after adopting high lipid food Long-term Feeding, and adopt 1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthrone carries out therapeutic intervention, found that Herba corydalis edulis diketone can substantial reduction in triglycerides level, show the effect of weight reducing to obesity mice simultaneously.
Heart is by left and right coronary artery blood supply, and its subbranch often penetrates in cardiac muscle with right angle, and is branched off into net at subendocardial layer, and arteria coronaria is easily suffered oppression when myocardial contraction.Therefore, coronary blood flow to reduce and relaxing period increases at systole, therefore the blood supply amount that cardiac muscular tissue obtains at relaxing period is more than systole.Isoproterenol has increase heart rate, brings out the effect of arrhythmia and the circulation of reduction body and Pulmonary Vascular Resistance.The present inventor is to after rat skin lower injection isoproterenol, and causing ventricular diastole to shorten due to increased heart rate can make deficiency myocardial blood supply; In addition, isoproterenol can bring out arrhythmia, can cause consuming excessively of cardiac energy when there is tachycardia and ventricular fibrillation; Isoproterenol also can with skeletal muscle, mesentery, intestinal, pulmonary vascular B2 receptors bind and Peripheral resistance is reduced, thus auterial diastole is pressed decline further.Each factor all can make blood supply of cardiac muscle reduce and cause cardiac energy deficient above, and metabolism disorder, causes myocardial hypertrophy.In test, plump group heart hypertrophy in rats index obviously increases, cardiac structure there occurs significant change, show as under light microscopic: cardiac muscle fiber Shu Biankuan is large, loosen edema in muscle fiber gap, gap is broadening, between part muscle bundle, fibrous tissue increases, the ratio of cardiac muscular tissue/interstitial connective tissues is less, and diameter of myocytes and cardiomyocytes cross-sectional area obviously increase, and illustrates that myocardial hypertrophy model is successfully established.Inventor adopts 1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6, after 7-dimethoxy-3-methyl-9,10-anthrone therapeutic intervention, compared with myocardial hypertrophy model control group, rat whole-heartedly plump index, the plump index of myocardium of left ventricle, diameter of myocytes, cardiomyocytes cross-sectional area reduces, and this imply that this compound serves the effect of control myocardial hypertrophy generation to a certain extent.Therefore, present invention also offers following pharmaceutical applications, the application of 1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthrone in the medicine of preparation treatment hypertrophic neuropathy; Preferably, described hypertrophic neuropathy comprises left ventricular hypertrophy, right ventricular hypertrophy and myocardial fibrosis.
Detailed description of the invention
The present invention adopts isoproterenol to cause the method for myocardial hypertrophy model, observes the impact of 1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthrone (CWL-168) on the plump index of model great master cardiac myocytes.Found that, this compound serves the effect that control myocardial hypertrophy occurs to a certain extent.Be below concrete process of the test, technical scheme of the present invention is done to describing further, but protection scope of the present invention be not limited to this test example.
Embodiment 1
SD rat 30, male and female half and half, weight 160 ~ 220g.Rat is divided at random Normal group, model control group and CWL-168 treatment group, often organizes 10.It is 6.5mg/ (kgd) lumbar injection that treatment group gives CWL-168 dosage, continuous 10d; Normal group and model control group normal saline lumbar injection isopyknic with CWL-168 treatment group, continuous 10d.Afterwards, model control group give isoproterenol 0.5mg/ (kgd) subcutaneous injection and with normal saline lumbar injection, continuous 10d, to cause myocardial hypertrophy model; And treatment group is giving also to give while CWL-168 dosage is 13.0mg/ (kgd) lumbar injection isoproterenol 0.5mg/ (kgd) subcutaneous injection, continuous 10d; Normal group subcutaneous injection and the isopyknic normal saline of isoproterenol and lumbar injection and the isopyknic normal saline of CWL-168, continuous 10d.
Rat used is all raised with Conventional solid feedstuff and tap water, in drug withdrawal 12h overnight fasting, carry out the mensuration of myocardial hypertrophy index, method is as follows: rat claims quality (BW), after the chloral hydrate intraperitoneal injection of anesthesia of 10%, the normal saline that taking-up heart is placed in 4 DEG C of pre-coolings is rinsed well, use double-layer filter paper suck dry moisture, by electronic balance precise wet quality (HW) whole-heartedly, left ventricle (comprising interventricular septum) and right ventricle wet quality, calculate wet quality/body mass ratio (HW/BW) whole-heartedly, wet quality/body mass ratio (LVW/BW) and right ventricle of left ventricle wets quality/body mass ratio (RVW/BW), respectively as plump index whole-heartedly, the plump index of the plump exponential sum myocardium of right ventricle of myocardium of left ventricle.
The statistical result of each group of heart hypertrophy in rats index is in table 1.Can be found out by the result of the test of table 1, model control group is compared with Normal group, and plump group rat whole-heartedly plump index, the plump index of myocardium of left ventricle, the plump index of myocardium of right ventricle obviously increases (P < 0.01); Compared with model control group, CWL-168 treatment group rat whole-heartedly plump index, the plump index of the plump exponential sum myocardium of right ventricle of myocardium of left ventricle obviously reduces (P < 0.01 or P < 0.05).
Table 1 respectively group heart hypertrophy in rats index compares (mg/g)
Compare with Normal group,
*p < 0.0; Compare with model group,
#p < 0.01,
##p < 0.01.
In addition, core tip cardiac muscular tissue, and be placed in 4% paraformaldehyde immediately and fix, Gradient elution using ethanol, routine paraffin wax embeds, and paraffin section does HE dyeing, then carries out PATHOMORPHOLOGICAL OBSERVATION OF PULLORUM.Under light microscopic, visible Normal group cellular morphology is normal, and cardiac muscle fiber marshalling, has no cardiac muscular tissue's fibrosis; Compared with Normal group, model control group rat heart muscle fibre bundle is more roomy, and loosen edema in muscle fiber gap, gap is broadening, fibrosiss a large amount of as seen in tissue, diameter of myocytes and cell cross section is long-pending obviously increases; Compared with myocardial hypertrophy group, CWL-168 treatment group heart hypertrophy in rats degree obviously alleviates, and in tissue, fibrosis obviously reduces.
Claims (5)
1. treat a pharmaceutical composition for hypertrophic neuropathy, said composition is prepared from by active component and adjuvant, it is characterized in that: described active component comprises 1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthrone.
2. treat the pharmaceutical composition of hypertrophic neuropathy according to claim 1, it is characterized in that: described active component is made up of as sole component 1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthrone.
3. according to claim 1 or 2, treat the pharmaceutical composition of hypertrophic neuropathy, it is characterized in that: described pharmaceutical composition is injection, and described injection comprises injection and freeze-dried powder injection.
The application of 4.1,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6,7-dimethoxy-3-methyl-9,10-anthrone in the medicine of preparation treatment hypertrophic neuropathy.
5. according to claim 41,2,3,4-tetrahydrochysene-1,2,5-trihydroxy-6, the application of 7-dimethoxy-3-methyl-9,10-anthrone in the medicine of preparation treatment hypertrophic neuropathy, is characterized in that: described hypertrophic neuropathy comprises left ventricular hypertrophy, right ventricular hypertrophy, myocardial fibrosis.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108913655A (en) * | 2018-07-16 | 2018-11-30 | 浙江大学 | The method for establishing " humanized " myocardial hypertrophy model based on multipotential stem cell technology |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101917988A (en) * | 2007-12-31 | 2010-12-15 | 麦仁斯有限公司 | Pharmaceutical composition for treating and preventing heart disease |
| CN104262130A (en) * | 2014-09-05 | 2015-01-07 | 大丰海洋生物医药研究所 | Naphthaquinone compound derived from marine microbes, and preparation method and application thereof |
-
2015
- 2015-04-16 CN CN201510178603.5A patent/CN104800194A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101917988A (en) * | 2007-12-31 | 2010-12-15 | 麦仁斯有限公司 | Pharmaceutical composition for treating and preventing heart disease |
| CN104262130A (en) * | 2014-09-05 | 2015-01-07 | 大丰海洋生物医药研究所 | Naphthaquinone compound derived from marine microbes, and preparation method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108913655A (en) * | 2018-07-16 | 2018-11-30 | 浙江大学 | The method for establishing " humanized " myocardial hypertrophy model based on multipotential stem cell technology |
| CN108913655B (en) * | 2018-07-16 | 2022-07-15 | 浙江大学 | A method for establishing a "human-derived" cardiac hypertrophy model based on pluripotent stem cell technology |
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Application publication date: 20150729 |