CN101112369B - Application of tanshinol in the preparation of medicine for treating and preventing chronic renal failure and kidney fibrosis - Google Patents
Application of tanshinol in the preparation of medicine for treating and preventing chronic renal failure and kidney fibrosis Download PDFInfo
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- CN101112369B CN101112369B CN2006100697571A CN200610069757A CN101112369B CN 101112369 B CN101112369 B CN 101112369B CN 2006100697571 A CN2006100697571 A CN 2006100697571A CN 200610069757 A CN200610069757 A CN 200610069757A CN 101112369 B CN101112369 B CN 101112369B
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Abstract
The present invention provides a new usage of salvianic acid A drugs, and particularly provides the application of the salvianic acid A in preparation of the drugs which can treat or prevent the chronic renal failure and renal fibrosis. The range of the dosage of salvianic acid A during the oral administration in the application is 100mg to 2000mg, while 100 to 1000mg is preferred. The present invention also provides a drug compound which takes the salvianic acid A as the active component.
Description
Technical field
The present invention relates to the new medicine use of danshensu, relate to the application of danshensu in the medicine of preparation treatment or prevention chronic renal failure and renal fibrosis particularly.
Background technology
Danshensu (chemistry β by name-3,4-dihydroxyphenyl lactic acid) extracts from Radix Salviae Miltiorrhizae and obtains, and is the effective ingredient of Radix Salviae Miltiorrhizae.The bibliographical information danshensu has certain protection effect [Jiang Wende aspect cardiovascular and cerebrovascular disease; Chen Yuhua, Wang Yingping is etc. danshensu and two kinds of water solublity Radix Salviae Miltiorrhizae composition resisting myocardial ischemias with to research coronarius. the Shanghai first medical college journal; 1982,9 (1): 13-94.; Tension force, Wang Xiaoming, Liang Dianquan, etc. danshensu causes the influence of mitochondrion variation and the discussion of the mechanism of action thereof to the rat heart muscle ischemia/reperfusion. Chinese Journal of Pathophysiology, 1990,6 (6): 420-423.; Chang Yingzi, Liang Dianquan, Wang Xiaoming, etc.].The inventor has found the application of danshensu in the medicine of preparation treatment or prevention chronic renal failure and renal fibrosis through a large amount of experimentatioies.
Summary of the invention:
The invention provides the application of danshensu in the medicine of preparation treatment or prevention chronic renal failure.
The invention provides the application of danshensu in the medicine of preparation treatment or prevention renal fibrosis.
The invention provides with the danshensu is the pharmaceutical composition that is used for chronic renal failure and renal fibrosis of active component.
Its content of danshensu of the present invention can get with the preparation of pharmacy conventional method more than 90%, and be preferably: get the Radix Salviae Miltiorrhizae crude drug and pulverize, the NaOH that adds 12 times of amounts 0.5% decocts twice; Each 1.5 hours, filter merging filtrate; Adsorb (the volume ratio 3:1 of extracting solution and resin) with the alkalescence macroporous adsorbent resin, with deionized water eluting 3-5 column volumes, 2 column volumes of the NaOH eluting of reuse 0.4%; Collect eluent, the adjusting pH value is 2-5, adsorbs (the volume ratio 3:1 of extracting solution and resin) with low pole or nonpolar macroporous adsorption resin; With washing 5 column volumes again behind 1-2 column volume of deionized water eluting, collect eluent, concentrate; Add an amount of HCl and transfer pH to acid, crystallization promptly gets.Wherein alkalescence macroporous resin, low pole or non-polar macroporous resin are preferably the AB-B macroporous resin.
Pharmaceutical composition provided by the invention is when being used for chronic renal failure and renal fibrosis, and the using dosage scope is 100mg～2000mg when oral; Preferred 100～1000mg.
Pharmaceutical composition provided by the invention can exist with forms such as tablet, pill, granule, capsule, syrup, soft capsules, is preferably soft capsule and tablet.Various dosage form provided by the invention all can adopt the pharmacy conventional method to be prepared from.
The inventor has carried out following test and has confirmed to treat or prevent the application in the medicine of chronic renal failure and renal fibrosis.(following embodiment is used for explaining in more detail the present invention, but and does not mean that the present invention only limits to this).
The practical implementation instance:
The preparation for preparing routine 1 danshensu
Get Radix Salviae Miltiorrhizae 10kg crude drug and pulverize, the NaOH that adds 12 times of amounts 0.5% decocts twice, each 1.5 hours, filters; Merging filtrate adsorbs (the volume ratio 3:1 of extracting solution and resin) with AB-8 property macroporous adsorbent resin, with deionized water eluting 3-5 column volumes, and 2 column volumes of the NaOH eluting of reuse 0.4%; Collect eluent, the adjusting pH value is 2-5, adsorbs (the volume ratio 3:1 of extracting solution and resin) with the AB-8 macroporous adsorbent resin, with washing 5 column volumes again behind 1-2 column volume of deionized water eluting; Collect eluent, concentrate, add an amount of HCl and transfer pH to acid; Crystallization gets danshensu sodium 9.356g, and purity is 91.5%.
The preparation for preparing routine 2 danshensu tablets
Cross 100 mesh sieves after taking by weighing 100.0g danshensu, 170.0g Icing Sugar, 80.0g lactose and the abundant mix homogeneously of 46.0g carboxymethyl starch sodium, add 3%PVP
K30Aqueous solution is made soft material in right amount, and 20 mesh sieves are granulated, 60 ℃ of dryings 3 hours, and 18 mesh sieve granulate add the 4.0g magnesium stearate, press 1000 behind the mix homogeneously, and every agreement that contracts a film or TV play to an actor or actress 400mg promptly gets.
The preparation for preparing routine 3 radix salviae miltiorrhizae essence capsules
Cross 100 mesh sieves after taking by weighing 50.0g danshensu, 85.0g Icing Sugar, 40.0g lactose and the abundant mix homogeneously of 23.0g carboxymethyl starch sodium, add 3%PVP
K30Aqueous solution is made soft material in right amount, and 20 mesh sieves are granulated, 60 ℃ of dryings 3 hours, and 18 mesh sieve granulate add the 2.0g magnesium stearate, the encapsulating capsule, every about 200mg promptly gets.
Test Example 1 danshensu causes the influence of rat chronic renal failure and renal fibrosis to adenine
1.1 material:
Regular grade Wistar rat, male, body weight 150-200g, the SD rat, Shandong greenery natural drug Societe Principia Research Development Experimental Animal Center provides qualifier: SYXK (Shandong) 20030020.
Danshensu: Shandong natural drug Societe Principia Research Development modern Chinese medicine chamber provides, content 95%, lot number: 040218; Adenine: Changzhou China Tonghua worker company, lot number: 040611; Prednisolone, Belgian Pharmacia S.P.A., lot number: 040706; Creatinine and blood urea nitrogen test kit: give birth to scientific & technical corporation, lot number: 050606 in Beijing;
The hydroxyproline test kit: biotech firm is built up in Nanjing, lot number: 050906.
1.2 test method and result: 90 of rats, body weight 150-200g in 1 week of animal feeding, is divided into 9 groups with animal; Be normal group, model group, prednisolone (12mg/kg) group, danshensu is irritated stomach low dose of (5mg/kg) group, and danshensu is irritated dosage (10mg/kg) group in the stomach; Danshensu is irritated stomach heavy dose of (20mg/kg) group 1, and danshensu is irritated stomach heavy dose of (50mg/kg) group 2, and danshensu is irritated stomach heavy dose of (100mg/kg) group 3, and danshensu is irritated stomach heavy dose of (200mg/kg) group 4; Except that normal group, every rat ip adenine 150mg/kg gives 2 days continuously, stops 2 days; Continued the ip adenine 150mg/kg2 days, after 3 days, big rathole frame is got blood, serum creatinine, blood urea nitrogen, hydroxyproline; Observe the modeling situation, since administration in the 8th day, successive administration 14 days was got blood from eye socket; Measure serum creatinine, blood urea nitrogen, hydroxyproline, put to death and do the pathology section, observe the pathological change of renal function.
Find out from table 1, danshensu irritate in the stomach dosage (10mg/kg) group reduce rat chronic renal failure serum creatinine, blood urea nitrogen, hydroxyproline (with model group relatively, p 0.05); Prednisolone (12mg/kg) group; Danshensu is irritated stomach heavy dose of (20mg/kg) group 1; Danshensu is irritated stomach heavy dose of (50mg/kg) group 2; Danshensu is irritated stomach heavy dose of (100mg/kg) group 3, danshensu irritate stomach heavy dose of (200mg/kg) group 4 obviously reduce rat chronic renal failure serum creatinines, blood urea nitrogen, hydroxyproline (with model group relatively, p 0.01).
Pathologic finding: normal control group nephridial tissue structure is normal, and model group has obvious nephridial tissue crystalline deposit thing, and renal tubules destroys; Atrophy, tube chamber diminishes, wherein visible lymphocytic infiltration and local proliferation of fibrous tissue; The glomerule enlargement, the degeneration of glomerular epithelium cell formation of vacuoles, a large amount of unconsolidated materials appear down in endotheliocyte; Basement membrane thickened, quantitative analysis renal tubules area and glomerular volume, model group and normal control group relatively have significant difference.Danshensu is respectively organized each dose groups and is obviously alleviated with dosage increase degree of injury, but returns to normal level not yet.
Table 1 danshensu is to the influence (n=10) of rat chronic renal failure serum creatinine, blood urea nitrogen, hydroxyproline
*, p<0.05,
*, p<0.01, compare with model group
Test 2 danshensus cause the rat chronic renal failure to the nephrectomy influence
2.1 material
Laboratory animal regular grade Wistar rat, male, body weight 150-200g, the SD rat, Shandong greenery natural drug Societe Principia Research Development Experimental Animal Center provides qualifier: SYXK (Shandong) 20030020.
The medicine danshensu, Shandong natural drug Societe Principia Research Development modern Chinese medicine chamber provides, content 95%, lot number: 040218; Prednisolone, Belgian Pharmacia S.P.A., lot number: 040706; The hydroxyproline test kit, biotech firm is built up in Nanjing, lot number: 050906.Creatinine and blood urea nitrogen test kit are given birth to scientific & technical corporation, lot number: 050606 in Beijing;
2.2 test method and result
135 of rats, body weight 150-200g in 1 week of animal feeding, is divided into 9 groups with animal; Be normal group, model group, prednisolone (12mg/kg) group, danshensu is irritated stomach low dose of (5mg/kg) group, and danshensu is irritated dosage (10mg/kg) group in the stomach; Danshensu is irritated stomach heavy dose of (20mg/kg) group 1, and danshensu is irritated stomach heavy dose of (50mg/kg) group 2, and danshensu is irritated stomach heavy dose of (100mg/kg) group 3, and danshensu is irritated stomach heavy dose of (200mg/kg) group 4; Except that normal group, rat is processed the chronic kidney hypofunction model with 5/6 nephrectomy method, for the first time excision left side kidney 2/3; The right kidney of the one week back row excision second time, operation back one all beginning administrations for the second time, administering mode is gastric infusion or intraperitoneal injection; 4 weeks after the administration, 8 weeks, big respectively rathole frame was got blood, measured serum creatinine and blood urea nitrogen, and 4 weeks were put to death 5 after the administration; Off-test is put to death 10, does the pathology section, observes the pathological change of renal function.
Can find out from table 2, table 3 result, danshensu irritate in the stomach dosage (10mg/kg) group reduce rat chronic renal failure serum creatinine, blood urea nitrogen, hydroxyproline (with model group relatively, p 0.05); Prednisolone (12mg/kg) group; Danshensu is irritated stomach heavy dose of (20mg/kg) group 1; Danshensu is irritated stomach heavy dose of (50mg/kg) group 2; Danshensu is irritated stomach heavy dose (100mg/kg) and is organized 3, danshensu filling stomach heavy dose of (200mg/kg) group 4 obvious reduction rat chronic renal failure serum creatinines and blood urea nitrogen (compare with model group, p 0.01); Stomach heavy dose of (100mg/kg) group 3 of irritating danshensu reduces rat chronic renal failure serum creatinine and blood urea nitrogen and danshensu and irritates stomach heavy dose of (200mg/kg) group 4 relatively, there was no significant difference.
Pathological change: see that glomerule has compensatory hypertrophy in various degree under administration the 4th all model group light microscopics, proliferation of mesangial cells, mesentery substrate increases, and the glomerular capillary button loop is lobulated; Part glomerule blister cavities disappears, and the blood capillary tube wall thickens, and renal tubules swelling, expansion have proteinosis in the tube chamber; The little shrink tube of part, a matter has inflammatory cell infiltration, and each administration group is also seen above-mentioned change; But lesion degree is lighter, increases with dosage, and lesion degree alleviates; See proliferation of mesangial cells under administration the 8th all model group light microscopics, the substrate showed increased, the blood capillary tube wall subsides; The blood capillary segmented sclerosis, the harden zone many near blood vessel wall the circular PAS of the visible homogenizing wine-colored deposit that dyes in the hardened glomerule, indivedual glomerule have focal sacculus adhesion; Focal crescent forms, and a matter visible inflammatory cell soaks into, proliferation of fibrous tissue; Each organizes the glomerular sclerosis varying degree, increases with dosage, and lesion degree alleviates.
Table 2 danshensu is to the influence (n=10) of kidney of rats excision chronic kidney hypofunction administration 4 all serum creatinines and blood urea nitrogen
*, p<0.05,
*, p<0.01, compare with model group
Table 3 danshensu is to the influence of kidney of rats excision chronic kidney hypofunction administration 8 all serum creatinines and blood urea nitrogen
*, p<0.05,
*, p<0.01, compare with model group
Test of the influence of 3 danshensus to one-sided ureter ligation kidney of rats interstitial fibrosis
3.1 material
Laboratory animal regular grade Wistar rat, male, body weight 150-200g, the SD rat, Shandong greenery natural drug Societe Principia Research Development Experimental Animal Center provides qualifier: SYXK (Shandong) 20030020.
The medicine danshensu, Shandong natural drug Societe Principia Research Development modern Chinese medicine chamber provides, content 95%, lot number: 040218; Benazepril, Novartis Pharma AG produces, lot number: 040306; The hydroxyproline test kit, biotech firm is built up in Nanjing, lot number: 050906.
3.2 test method and result
90 of rats, body weight 150-200g, 1 week of animal feeding, each rat with 10% chloral hydrate 3.0mL/kg intraperitoneal injection of anesthesia after; The rat RAR is fixed on the operating-table, and with iodine tincture, 75% alcohol disinfecting field of operation, row left side abdomen otch successively cuts skin, muscle and each layer of stomach wall after the cropping; Expose and also to separate the left side ureter, sham operated rats is only cut abdominal cavity and free left side ureter, but not ligation with cut off, other respectively organize rat with 4-0 silk thread ligation twice; Last one ligation point is positioned at left inferior pole of kidney level, between twice ligation point, cuts off ureter then, and layer-by-layer suture is divided into 9 groups with animal; Be sham operated rats, model group, benazepril (10mg/kg) group, danshensu is irritated stomach low dose of (5mg/kg) group; Danshensu is irritated dosage (10mg/kg) group in the stomach, and danshensu is irritated stomach heavy dose of (20mg/kg) group 1, and danshensu is irritated stomach heavy dose of (50mg/kg) group 2; Danshensu is irritated stomach heavy dose of (100mg/kg) group 3, and danshensu is irritated stomach heavy dose of (200mg/kg) group 4, each group beginning administration of postoperative; Put to death each treated animal after 21 days after 10% chloral hydrate anesthesia, normal saline is left and taken left kidney after the lavation repeatedly, and nephridial tissue is fixed through 4% paraformaldehyde buffer.Cut an amount of nephridial tissue, press the explanation of hydroxyproline kit measurement and measure hydroxyproline.
Can find out from table 4 result, the one-sided ureter ligation kidney of rats hydroxyproline content of dosage (10mg/kg) group reduction in the danshensu filling stomach (compare with model group, p 0.05); Benazepril (10mg/kg) group; Danshensu is irritated stomach heavy dose of (20mg/kg) group 1; Danshensu is irritated stomach heavy dose of (50mg/kg) group 2; Danshensu is irritated stomach heavy dose (100mg/kg) and is organized 3, the one-sided ureter ligation kidney of rats hydroxyproline content of danshensu filling stomach heavy dose of (200mg/kg) group 4 obvious reductions (compare with model group, p 0.01); Danshensu irritates stomach heavy dose of (100mg/kg) the group 3 one-sided ureter ligation kidney of rats hydroxyproline contents of reduction and danshensu is irritated stomach heavy dose of (200mg/kg) group 4 relatively, there was no significant difference.
Routine pathology is learned and checked 1. macroscopy: sham operated rats kidney color is scarlet, smooth surface, peplos gloss, no adhesion.Other respectively organize the increase of kidney volume, and color is pale, and the surface is graininess, similar human body branny kidney, the adhesion of few regions kidney peplos.2. light microscopy checking: sham operated rats nephron clear in structure, glomerular capsule do not have expansion or dwindle, and renal cells does not have obvious degeneration and necrosis, do not have come off epithelial cell or cast, no vasodilation or cell infiltration in the matter in the tube chamber.The large stretch of renal tubular necrosis of model control group, the hyperplasia of kidney interstitial fibers, tubular ectasia, in a large amount of pale brown color refractive power materials or the downright bad epithelial cell that comes off are arranged, the glomerule decreased number, part glomerule fibrosis and with the adhesion of bag Man cyst wall, blister cavities disappears.Administration respectively organizes pathological changes and model control group is similar, but all has morphology in various degree to improve, and irritates heavy dose of each group of stomach significantly with danshensu especially, with model control group notable difference is arranged relatively.
Table 4 danshensu is to the influence of one-sided ureter ligation kidney of rats hydroxyproline content
*, p<0.05,
*, p<0.01, compare with model group
Claims (2)
1. danshensu is as the application of unique active component in the medicine of preparation treatment or prevention chronic renal failure.
2. danshensu is as the application of unique active component in the medicine of preparation treatment or prevention renal fibrosis.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1242986A (en) * | 1999-07-05 | 2000-02-02 | 济南三九益民制药有限责任公司 | Use of B magnesium tanphenolate in pharmacy |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1242986A (en) * | 1999-07-05 | 2000-02-02 | 济南三九益民制药有限责任公司 | Use of B magnesium tanphenolate in pharmacy |
Non-Patent Citations (3)
| Title |
|---|
| 余世春等.丹参的化学成分和药理活性研究概况（综述）.安徽卫生职业技术学院学报.2002,1(2),43-47. * |
| 周世良.丹参在肾脏病中的临床应用.临床荟萃.1993,8(20),955-957. * |
| 张文欣.丹参治疗肾脏病的研究进展.医学综述.1998,4(12),643-644. * |
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