CN103690548B - Stilbene glucoside has the application suppressed in pressure load type remodeling ventricle medicine in preparation - Google Patents
Stilbene glucoside has the application suppressed in pressure load type remodeling ventricle medicine in preparation Download PDFInfo
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- CN103690548B CN103690548B CN201410017906.4A CN201410017906A CN103690548B CN 103690548 B CN103690548 B CN 103690548B CN 201410017906 A CN201410017906 A CN 201410017906A CN 103690548 B CN103690548 B CN 103690548B
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Abstract
The present invention relates to field of medicaments, provide stilbene glucoside and pharmaceutically acceptable salt or ester thereof and there is in preparation the application suppressed in pressure load type remodeling ventricle medicine.The present invention has opened up the new application of stilbene glucoside one, for new drug development provides new thinking and theoretical foundation.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to stilbene glucoside and pharmaceutically acceptable salt or ester thereof and there is in preparation the application suppressed in pressure load type remodeling ventricle medicine.
Background technology
As the Chinese medicine of 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, main containing three effective constituents: hexichol alkene glycosides compound, hydroxyanthraquinone compounds, phospholipid and containing multiple important trace element.2,3,4 ', 5-tetrahydroxystilbene-2-0-β-D glucosides (being called for short: stilbene glucoside) are the primary water-soluble composition of natural drug Radix Polygoni Multiflori, and its content is the quality control index that " Chinese Pharmacopoeia " specifies this medical material and preparation.
Modern pharmacological research shows, stilbene glucoside is the main effective active effect composition of 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.Base application research about Radix Polygoni Multiflori pharmaceutically-active ingredients stilbene glucoside has become the focus of researches on natural drugs and exploitation.And it has no bibliographical information in suppression pressure load type remodeling ventricle.
Pressure load is overweight is common in hypertension, aortic stenosis, pulmonary hypertension, pulmonary stenosis etc., and the disease that Ventricular SD resistance increases.The increase of heart continuous pressure over loading easily causes remodeling ventricle, and its characteristic changes into left ventricular hypertrophy and myocardial fibrosis, be independent of blood pressure outside increase incidence of cardiovascular disease and the risk factor of case fatality rate.Current pressure load type remodeling ventricle medicine mainly comprises antihyperalgesic, matrix metallo-proteinase inhibitor, Endothelin receptor antagonist, prolyl hydroxylase inhibitors, stem-cell therapy etc., but curative effect is not good enough, the medicine 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 suppressed 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 or ester thereof there is in preparation the application suppressed 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 pharmaceutically acceptable carrier.
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 salt is 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 alone or use with the form of pharmaceutical composition.Pharmaceutical composition comprises as the stilbene glucoside of active component and pharmaceutically acceptable salt thereof or ester and pharmaceutically suitable carrier.Preferably, pharmaceutical composition of the present invention has the stilbene glucoside as active component of 0.1-99.9% percentage by weight and pharmaceutically acceptable salt thereof or ester." pharmaceutically suitable carrier " can not destroy the pharmaceutical active of compound or pharmaceutically acceptable salt thereof of the present invention, simultaneously its effective dose, and consumption when namely can play pharmaceutical carrier effect being is to human non-toxic.
" 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 of the pharmaceutical preparatioies such as tween or other similar polymerisation mediums, 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 such as the hydroxyalkyl cyclodextrin such as 2-and 3-HP-β-CD or other soluble derivatives etc. through chemical modification all can be used for the drug delivery promoting compound of the present invention, its pharmaceutical salts or prodrug.
Other pharmaceutically acceptable auxiliaries such 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. also can add in pharmaceutical composition of the present invention.
The stilbene glucoside of the invention described above and pharmaceutically acceptable salt thereof or ester and pharmaceutical composition are by intestinal or parenteral administration.Non-intestinal drug delivery agent comprises injection, cream, ointment, patch, spray etc.Route of administration comprises in subcutaneous, Intradermal, intra-arterial, intravenous, intramuscular, intraarticular, synovial fluid, in breastbone, in sheath, intralesional, intracranial injection or infusion, or, oral, locally, rectum, per nasal, through cheek, vagina, Sublingual, Intradermal, mucosa, trachea, urethral administration, or by suck aerosol or implant accumulation or the administration of acupuncture mode.
The treatment effective dose of the stilbene glucoside of the invention described above and pharmaceutically acceptable salt or ester and pharmaceutical composition is between 0.001-100mg/kg/d, can be used for single drug or the drug combination treatment of relevant disease, is the scope that those skilled in the art can understand.
Stilbene glucoside of the present invention can adopt prior art to prepare, if application number is 201310045725, method disclosed in the Chinese patent literature that name is called " a kind of method extracting stilbene glucoside from Radix Polygoni Multiflori ", or as application number be 99119853.0, method disclosed in the Chinese patent literature that name is called " a kind of Tetrahydroxydiphenylglycosides glycosides compounds 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 area (CSA) statistical result of pressure load type remodeling ventricle rat model cardiomyocytes cross-sectional.
Fig. 3 is pressure load type remodeling ventricle rat model Myocardial collagen network sirius red coloration result.
Fig. 4 is the statistical result of pressure load type remodeling ventricle rat model Myocardial collagen network fraction by volume.
Fig. 5 is collagen sirius red coloration result around pressure load type remodeling ventricle rat model myocardial vascular.
Fig. 6 is collagen volume fraction statistical result around pressure load type remodeling ventricle rat model myocardial vascular.
Detailed description of the invention
Concrete steps of the present invention are described by the following examples, but do not limit by embodiment.
Term used in the present invention, except as otherwise noted, generally has the implication that those of ordinary skill in the art understand usually.
Below in conjunction with specific embodiment and comparable data describes in further detail the present invention.Should be understood that these embodiments just in order to demonstrate the invention, but not limit the scope of the invention by any way.
In the examples below, the various process do not described in detail and method are conventional methods as known in the art.
Embodiment 1 pressure load type remodeling ventricle is tested
The rat pressure load type remodeling ventricle model of rat aorta ligation induction.Concrete scheme: rat random packet, often organizes 6: Sham-operated control group, model group, stilbene glucoside low (30mg/kg/day), in (60mg/kg/day), high (120mg/kg/day) three dosage groups.Use 4% Nembutal sodium solution, with 1mlKg
-1dosage intraperitoneal injection of anesthesia rat, rat lateral position, xiphoid-process median incision of lower abdomen, more than renal artery branch is separated ventral aorta, and No. 7 syringe needles are parallel to be placed on ventral aorta, and syringe needle is extracted in No. 4 silk thread ligation out, closes abdomen, sews up.Make rat aorta narrowed diameter to 0.7mm.Silk thread of performing the operation after sham operated rats opens abdomen is through ventral aorta, and except not ligation, other operations are identical with operation group.Postoperative penicillin 200,000 U/ only, lumbar injection once, prevention infection.Administration is started, administration 30 days in postoperative 3 days.
Table 1 stilbene glucoside is on the impact of 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 room; 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 room Chong Liang ∕ body weight.* P<0.01 is compared with sham operated rats than P<0.05, * * and sham operated rats; ## compares P<0.01 with model group.Namely there were significant differences, namely 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.Compared with model group, have significantly or highly significant difference.Compared with model group, the left cardiac index of the heavy exponential sum of the heart of TSG high dose group all significantly declines.
HE dyeing is carried out to pressure load type remodeling ventricle rat model myocardial cell, (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 is that stilbene glucoside 120mg/kg/day dosage group .* compares P<0.01 with sham operated rats than P<0.05, * * and sham operated rats; ## compares P<0.01 with model group.Namely there were significant differences for P<0.05, namely P<0.01 have highly significant difference).Add up the cardiomyocytes cross-sectional area (CSA) of HE dyeing, result as shown in Figure 2.Result shows that the middle and high dosage group of stilbene glucoside all can significantly reduce cardiomyocytes cross-sectional area.Compared with model group, have significantly or highly significant difference.
Sirius red dyeing is carried out to collagen around pressure load type remodeling ventricle rat model Myocardial collagen network and myocardial vascular, (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 is that stilbene glucoside 120mg/kg/day dosage group .* compares P<0.01 with sham operated rats than P<0.05, * * and sham operated rats; ## compares P<0.01 with model group.Namely there were significant differences for P<0.05, namely P<0.01 have highly significant difference).To sirius red dyeing Myocardial collagen network fraction by volume and myocardial vascular around collagen volume fraction add up, result is as shown in Figure 4 and Figure 6.Result show, sham operated rats cardiac interstitium and perivascular collagen less; Collagen more as seen between model group myocardial cell, cardiac muscle fiber arrangement disorder, perivascular collagen radially increases, statistical result showed, compared with sham operated rats, Myocardial collagen network fraction by volume and the perivascular collagen fraction by volume of model group significantly increase; High dose TSG significantly reduces the deposition of cardiac interstitium and perivascular collagen, and compared with model group, its Myocardial collagen network fraction by volume and perivascular collagen fraction by volume reduce by 40.7% and 42.6% respectively.Above result display, stilbene glucoside effectively can suppress pressure load type remodeling ventricle, alleviates myocardial hypertrophy and degree of myocardial fibrosis.
Claims (2)
1. there is the stilbene glucoside of following structural and pharmaceutically acceptable salt or ester thereof there is in preparation the application suppressed in pressure load type remodeling ventricle medicine
2. apply as claimed in claim 1, it is characterized in that described medicine is containing stilbene glucoside and pharmaceutically acceptable salt thereof or ester and one or more pharmaceutically acceptable carrier.
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| CN103690548B true CN103690548B (en) | 2015-10-28 |
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Non-Patent Citations (2)
| Title |
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| 二苯乙烯苷对实验性糖尿病大鼠心肌保护作用研究;甘受益 等;《中药药理与临床》;20110831;第14页 * |
| 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;王静 等;《南通大学学报（医学版）》;20130831;第258-259页 * |
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