CN103690548A - Application of stibene glucoside in preparation of medicament for inhibiting pressure-overload ventricular remodeling - Google Patents
Application of stibene glucoside in preparation of medicament for inhibiting pressure-overload ventricular remodeling Download PDFInfo
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- CN103690548A CN103690548A CN201410017906.4A CN201410017906A CN103690548A CN 103690548 A CN103690548 A CN 103690548A CN 201410017906 A CN201410017906 A CN 201410017906A CN 103690548 A CN103690548 A CN 103690548A
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Abstract
The invention relates to the field of medicine, and provides application of stibene glucoside and pharmaceutically acceptable salts or esters thereof in preparation of a medicament for inhibiting pressure-overload ventricular remodeling. The invention opens up a novel application field of stibene glucoside, and provides a novel thought and theoretical basis for the development of novel medicaments.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to stilbene glucoside and pharmaceutically acceptable salt thereof or ester and there is in preparation the application suppressing in pressure load type remodeling ventricle medicine.
Background technology
Chinese medicine as black beard and hair, improving healthy complexion, benefiting essence-blood, invigorating the liver and kidney; Radix Polygoni Multiflori has quite long history in the field of Chinese Traditional Medicine; there is defying age, improve the effects such as immunity, neuro-protective, blood fat reducing, cardiovascular protection, be widely used in the treatment of cardiovascular and cerebrovascular vessel and hepatorenal disease.Chinese medicine Radix Polygoni Multiflori is Polygonaceae arsesmart, mainly containing three effective constituents: hexichol alkene glycosides compound, hydroxyanthraquinone compounds, phospholipid and contain multiple important trace element.2,3,4 ', 5-tetrahydroxystilbene-2-0-β-D glucoside (is called for short: stilbene glucoside) be the main water soluble ingredient of natural drug Radix Polygoni Multiflori, its content is the quality control index that < < Chinese Pharmacopoeia > > stipulates this medical material and preparation.
Modern pharmacological research shows, the main effective active effect composition that stilbene glucoside is Radix Polygoni Multiflori, has oxidation and removing free radicals; Antitumor; Reduce cholesterol; Suppress the sclerosis of tremulous pulse medicated porridge sample shape; The liver protecting; Control senile dementia; Improve the pharmacologically actives such as memory.About the base application research of Radix Polygoni Multiflori pharmaceutically-active ingredients stilbene glucoside has become the focus of researches on natural drugs and exploitation.And it is suppressing to have no bibliographical information aspect pressure load type remodeling ventricle.
Pressure load is overweight is common in hypertension, aortic stenosis, pulmonary hypertension, pulmonary stenosis etc., and the disease of Ventricular SD resistance increment.The increase of heart continuous pressure over loading easily causes remodeling ventricle, and its characteristic is changed into left ventricular hypertrophy and myocardial fibrosis, is to be independent of increase cardiovascular diseases sickness rate outside blood pressure and the risk factor of case fatality rate.Pressure load type remodeling ventricle medicine mainly comprises antihyperalgesic, matrix metallo-proteinase inhibitor, blockade of endothelin receptors agent, prolyl hydroxylase inhibitors, stem-cell therapy etc. at present, but curative effect is not good enough, the medicine of finding more effective control pressure load type remodeling ventricle is very important.
Summary of the invention
The object of this invention is to provide stilbene glucoside and there is in preparation the application suppressing in pressure load type remodeling ventricle medicine.
The concrete technical scheme of the present invention is as follows:
There is the stilbene glucoside of following structural and pharmaceutically acceptable salt thereof or ester and there is in preparation the application suppressing in pressure load type remodeling ventricle medicine.
Stilbene glucoside (2,3,4 ', 5-tetrahydroxystilbene-2-O-beta-D-glucoside) MW=406
Said medicine is containing stilbene glucoside and pharmaceutically acceptable salt thereof or ester and acceptable carrier pharmaceutically.
Application of the present invention, stilbene glucoside and pharmaceutically acceptable salt thereof or ester can with the form of single medicine by administration or can with other medicines administering drug combinations.
The pharmaceutically acceptable salt of compound of the present invention comprises various inorganic or acylate example hydrochloric acid salt, hydrobromate, phosphate, sulfate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalates; Various inorganic or organic alkali salts are as sodium hydroxide, Tris and N-methyl-glucamine.
The pharmaceutically acceptable ester of compound of the present invention includes, but are not limited to have C1-C6 Arrcostab, C3-C6 straight chained alkyl ester or benzyl ester.
Stilbene glucoside of the present invention and pharmaceutically acceptable salt thereof or ester can be used separately or use with the form of pharmaceutical composition.Pharmaceutical composition comprises as the stilbene glucoside of active component and pharmaceutically acceptable salt or ester and pharmaceutically suitable carrier.Preferably, pharmaceutical composition of the present invention has the stilbene glucoside as active component and pharmaceutically acceptable salt or the ester of 0.1-99.9% percentage by weight." pharmaceutically suitable carrier " can not destroy the pharmaceutical active of compound or pharmaceutically acceptable salt thereof of the present invention, its effective dose simultaneously, and the consumption that can play pharmaceutical carrier and as the used time be is nontoxic to human body.
" pharmaceutically suitable carrier " includes but not limited to: ion exchange material, aluminium oxide, aluminium stearate, lecithin, self-emulsifying drug delivery system (SEDDS) is as d-TPGS 1000, the surfactant that the pharmaceutical preparatioies such as tween or other similar polymerisation mediums are used, serum albumin is as human serum albumin, buffer substance is as phosphate, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glyceride mixes, water, salt, electrolyte is as sulfate protamine, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium silicate etc.Polyvidon, cellulosic material, polyvinyl alcohol, sodium carboxymethyl cellulose, polyacrylate, ethylene-polyoxyethylene-block polymer and lanoline, cyclodextrin as α-, β-, gamma-cyclodextrin or its derivant through chemical modification all can be used for promoting the drug delivery of compound of the present invention, its pharmaceutical salts or prodrug as the hydroxyalkyl cyclodextrin such as 2-and 3-HP-β-CD or other soluble derivatives etc.
Other pharmaceutically acceptable auxiliaries also can add in pharmaceutical composition of the present invention as filler (as Lactis Anhydrous, starch, lactose beadlet and glucose), binding agent (as microcrystalline Cellulose), disintegrating agent (as crosslinked carboxymethyl fecula sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and cross-linked pvp), lubricant (as magnesium stearate), absorption enhancer, flavouring agent, sweeting agent, diluent, excipient, wetting agent, solvent, solubilizing agent and coloring agent etc.
The stilbene glucoside of the invention described above and pharmaceutically acceptable salt thereof or ester and pharmaceutical composition can pass through intestinal or parenteral route administration.Non-intestinal drug delivery agent comprises injection, cream, ointment, patch, spray etc.That route of administration comprises is subcutaneous, in Intradermal, intra-arterial, intravenous, intramuscular, intraarticular, synovial fluid, in breastbone, in sheath, intralesional, intracranial injection or infusion, or, oral, local, rectum, per nasal, through cheek, vagina, Sublingual, Intradermal, mucosa, trachea, urethra administration, or by sucking aerosol or implantation is accumulated or the administration of acupuncture mode.
The treatment effective dose of the stilbene glucoside of the invention described above and pharmaceutically acceptable salt thereof or ester and pharmaceutical composition is between 0.001-100mg/kg/d, can be used for the single drug of relevant disease or drug combination treatment, the scope that can understand for those skilled in the art.
Stilbene glucoside of the present invention can adopt prior art to prepare, if application number is 201310045725, name is called disclosed method in the Chinese patent literature of " a kind of method of extracting stilbene glucoside from Radix Polygoni Multiflori ", or as application number be 99119853.0, name is called disclosed method in the Chinese patent literature of " a kind of Tetrahydroxydiphenylglycosides glycosides compounds of preventing and treating cardiovascular and cerebrovascular disease ", obtains stilbene glucoside.
Accompanying drawing explanation
Fig. 1 is pressure load type remodeling ventricle rat model myocardial cell HE coloration result.
Fig. 2 is pressure load type remodeling ventricle rat model myocardial cell cross-sectional area (CSA) statistical result.
Fig. 3 is pressure load type remodeling ventricle rat model cardiac muscle interstitial collagen sirius red coloration result.
Fig. 4 is the statistical result of pressure load type remodeling ventricle rat model cardiac muscle interstitial collagen fraction by volume.
Fig. 5 is pressure load type remodeling ventricle rat model myocardial vascular collagen sirius red coloration result around.
Fig. 6 is the collagen volume fraction statistical result around of pressure load type remodeling ventricle rat model myocardial vascular.
The specific embodiment
Concrete steps of the present invention are described by the following examples, but not limited by embodiment.
The term that used in the present invention, except as otherwise noted, generally has the implication that those of ordinary skills understand conventionally.
Below in conjunction with specific embodiment comparable data, the present invention is described in further detail.Should be understood that these embodiment just in order to demonstrate the invention, but not limit the scope of the invention by any way.
In following examples, various processes and the method do not described in detail are conventional methods as known in the art.
The rat pressure load type remodeling ventricle model of rat aorta ligation induction.Concrete scheme: rat random packet, 6 every group: Sham-operated control group, model group, stilbene glucoside low (30mg/kg/day), in (60mg/kg/day), high (120mg/kg/day) three dosage groups.With 4% pentobarbital sodium solution, with 1mlKg
-1dosage intraperitoneal injection of anesthesia rat, rat lateral position, xiphoid-process median incision of lower abdomen, the above separated ventral aorta of renal artery branch, No. 7 parallel being placed on ventral aorta of syringe needle, No. 4 silk thread ligation, extract syringe needle out, close abdomen, sew up.Make rat aorta diameter constriction to 0.7mm.Sham operated rats will be performed the operation silk thread through ventral aorta after opening abdomen, and except not ligation, other operations are identical with operation group.Postoperative penicillin 200,000 U/ only, lumbar injection once, prevention infection.In postoperative 3 days, start administration, administration 30 days.
The impact of table 1 stilbene glucoside on the heavy index of cardiac ultrasonic parameter, blood pressure and the heart
LVIDs, left ventricular end-systolic dimension; LVIDd, left ventricular end diastolic dimension; ESV, last volume is shunk in left chamber; EDV, LVEDV (left ventricular end-diastolic volume); LVPWT, Left ventricular posterior wall thickness; IVST, interventricular septal thickness; SBP, systolic pressure; DBP, diastolic pressure; MAP, mean arterial pressure; HR, heart rate; The heavy index of the HWI(heart)=heart Chong Liang ∕ body weight, the left cardiac index of LVWI()=Zuo Xin chamber Chong Liang ∕ body weight.* with sham operated rats than P<0.05, * * compares P<0.01 with sham operated rats; ## compares P<0.01 with model group.There were significant differences, P<0.01 has highly significant difference for P<0.05.
Adopt echocardiography result as shown in table 1, the middle and high dosage group of stilbene glucoside all can significantly suppress Left ventricular posterior wall thickness and interventricular septal thickness, significantly reduces systolic pressure, diastolic pressure and mean arterial pressure.Compare with model group, have significantly or highly significant difference.Compare with model group, the left cardiac index of the heavy exponential sum of the heart of TSG high dose group all significantly declines.
Pressure load type remodeling ventricle rat model myocardial cell is carried out to HE dyeing, (1 is Sham-operated control group to result as shown in Figure 1,2 is model group, 3 is stilbene glucoside 30mg/kg/day dosage group, 4 is stilbene glucoside 60mg/kg/day dosage group, 5 be stilbene glucoside 120mg/kg/day dosage group .* with sham operated rats than P<0.05, * * compares P<0.01 with sham operated rats; ## compares P<0.01 with model group.There were significant differences for P<0.05, P<0.01 have highly significant difference).Myocardial cell cross-sectional area (CSA) to HE dyeing is added up, and result as shown in Figure 2.Result shows that the middle and high dosage group of stilbene glucoside all can significantly reduce myocardial cell cross-sectional area.Compare with model group, have significantly or highly significant difference.
Collagen around pressure load type remodeling ventricle rat model cardiac muscle interstitial collagen and myocardial vascular is carried out to sirius red dyeing, (1 is Sham-operated control group to result as shown in Figure 3 and Figure 5 respectively, 2 is model group, 3 is stilbene glucoside 30mg/kg/day dosage group, 4 is stilbene glucoside 60mg/kg/day dosage group, 5 be stilbene glucoside 120mg/kg/day dosage group .* with sham operated rats than P<0.05, * * compares P<0.01 with sham operated rats; ## compares P<0.01 with model group.There were significant differences for P<0.05, P<0.01 have highly significant difference).Collagen volume fraction around the myocardium interstitial collagen fraction by volume of sirius red dyeing and myocardial vascular is added up, and result as shown in Figure 4 and Figure 6.Result demonstration, around collagen is less for sham operated rats cardiac muscle interstitial and blood vessel; Visible more collagen between model group myocardial cell, cardiac muscle fiber arrangement disorder, blood vessel around collagen is radial and increases, statistical result showed, compare with sham operated rats, the myocardium interstitial collagen fraction by volume of model group and blood vessel around collagen volume fraction significantly increase; High dose TSG significantly reduces myocardium interstitial and the blood vessel deposition of collagen around, compares with model group, and its myocardium interstitial collagen fraction by volume and blood vessel around collagen volume fraction reduce respectively 40.7% and 42.6%.Above result demonstration, stilbene glucoside can effectively suppress pressure load type remodeling ventricle, alleviates myocardial hypertrophy and myocardial fibrosis degree.
Claims (2)
1. there is the stilbene glucoside of following structural and pharmaceutically acceptable salt thereof or ester and there is in preparation the application suppressing in pressure load type remodeling ventricle medicine
2. application as claimed in claim 1, is characterized in that described medicine is containing stilbene glucoside and pharmaceutically acceptable salt or ester and one or more pharmaceutically acceptable carrier.
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| CN201410017906.4A CN103690548B (en) | 2014-01-15 | 2014-01-15 | Stilbene glucoside has the application suppressed in pressure load type remodeling ventricle medicine in preparation |
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| CN201410017906.4A CN103690548B (en) | 2014-01-15 | 2014-01-15 | Stilbene glucoside has the application suppressed in pressure load type remodeling ventricle medicine in preparation |
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| CN103690548B CN103690548B (en) | 2015-10-28 |
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Non-Patent Citations (2)
| Title |
|---|
| 王静 等: "二苯乙烯苷通过降低钙调神经磷酸酶的活性抑制心肌成纤维细胞的增殖", 《南通大学学报（医学版）》, 31 August 2013 (2013-08-31), pages 258 - 259 * |
| 甘受益 等: "二苯乙烯苷对实验性糖尿病大鼠心肌保护作用研究", 《中药药理与临床》, 31 August 2011 (2011-08-31), pages 14 * |
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