CN1605343A - Application of skimming in the preparing process of medicine for preparing and treating kidney function failure - Google Patents
Application of skimming in the preparing process of medicine for preparing and treating kidney function failure Download PDFInfo
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- CN1605343A CN1605343A CN 200310100220 CN200310100220A CN1605343A CN 1605343 A CN1605343 A CN 1605343A CN 200310100220 CN200310100220 CN 200310100220 CN 200310100220 A CN200310100220 A CN 200310100220A CN 1605343 A CN1605343 A CN 1605343A
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- skimmin
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses the application of skimmin in preparing medicine for preventing and treating kidney incompetence. The present invention has the advantages of wide source and low toxic side effect.
Description
Technical field
The present invention relates to skimmin and prevent and/or treat application in the renal insufficiency medicine in preparation.
Background technology
Chronic renal disease (comprising all kinds of chronic nephritiss, diabetic nephropathy and hypertensive cerebral renal damage etc.) is a kind of the most common chronic refractory disease.Natural crowd's annual morbidity of chronic renal failure (CRF) is 98～19,8/1,000,000 populations, the sickness rate of the developed country such as the U.S. and Japan is up to 800～1,000 ten thousand/1,000,000 populations, be the trend that index rises over past ten years, the definite sickness rate of China CRF still lacks statistics, is about annual 100/1000000 populations.Along with the continuous variation of China's economic situation and spectrum of disease, the sickness rate of diabetes and the relevant nephropathy of hypertension has demonstrated surprising ascendant trend year by year.The diabetes aspect, the sickness rate 97 of China is 3.2%, the sickness rate that WHO predicts diabetes in 2010 will increase to 14%, what wherein develop into diabetic nephropathy at last is 40%, promptly from 97 years 1,500 ten thousand be increased to 2010 7,000 ten thousand.The hypertension aspect, China has reached 11.26% the beginning of the nineties, just increases sharply with the speed of increases in per 10 years more than 20% at present.Diabetes are since insulin is used, the acute complication of diabetes such as the mortality rate of ketoacidosis significantly descend, but along with diabetes patient's life-time dilatation, diabetic nephropathy may take place in the diabetic about 40%, and in case kidney damage takes place, albuminuria, hypertension and the renal insufficiency of progress then occur continuing, the state of an illness is often irreversible, often carries out sexual development until end stage renal failure.Predict to the year two thousand twenty that according to WHO above-mentioned non-infective disease disease will become the first place of China's population cause of death, and latter stage at end, CRF was one of most important cause of death.
No matter all can making progress gradually from early lesion, which kind of cause of disease, nephridial tissue pathological changes be the pathological changes in late period of glomerular sclerosis and/or kidney region fibrosis.If can not get effective treatment, cause chronic renal insufficiency and irreversible end stage renal failure (being uremia) at last.
The pathophysiological mechanism of the progress of chronic kidney disease renal fibrosis is very complicated, comprise that former paathogenic factor (as immune inflammation, metabolism disorder etc.) interacts to abnormal hemodynamics, the cytokine of the effect of kidney various kinds of cell and secondary thereof and extracellular matrix (ECM) synthetic unbalance or the like with degraded.
Treatment chronic kidney hypofunction method commonly used has dialysis and transplants two kinds at present, but is the treatment means of CRF in latter stage at end.Renal transplantation, internal organs sources is limited, the financial burden height, the people that can carry out kidney transfer operation seldom only has the nephrotic of 2-5% to have an opportunity to implement operation approximately, and postoperative is taken immunosuppressant in addition for a long time.Though dialysis treatment can reach the purpose that substitutes kidney, rely on dialysis machine, medical condition require high, and exist cardiovascular intercurrent disease height, patient has risk of infection, poor compliance, financial burden is heavy, uses very limited in China.Can have ready conditions and dialyse or the patient of renal transplantation only is only a few.Therefore, a large amount of patients press for the active drug that can delay and stop the renal insufficiency progress, and it is particularly important that the development of newtype drug and exploitation seem.
Though the hormone that tradition is used, immunosuppressant, blood sugar lowering treatment etc. at the therapeutical effect that has shown aspect anti-inflammatory, adjusting immunity and the metabolism protopathy, are being difficult to prove effective aspect the control chronic kidney disease change progress.Drug therapy does not worsen most important to delaying the CRF patients " renal function entirely.At present, the active drug that is widely used in the treatment renal insufficiency in the world wide mainly contains two classes: a class is an angiotensin converting enzyme inhibitor, be ACEI, comprise Captopril, Benazapril, Ramipril etc., it is synthetic that its main mechanism of action is to block AII, thereby reduce the generation of hypertension, the interior high filtration pressure of glomerule and short hardening factor TGF-β 1 that AII caused.Another kind of is Angiotensin II 1 receptor antagonist, and promptly AT1RA comprises Losartan, Irbsartan, Versartan etc., and its main mechanism of action is to reduce by the blocking-up aii receptor the above-mentioned effect of AII.External by a large amount of studies show that, can bring really all kinds of chronic renal disease patients' early stage active drug treatment significantly to delay the effect that renal insufficiency worsens, and have remarkable social benefit and economic benefit.
If be used for the treatment of the drug main Benazepril and the Losartan of renal insufficiency at present clinically, but main dependence on import, this class drug price costliness, toxic and side effects is bigger.As cause part patient hyperkalemia, unsurmountable cough, hypotensive activity strong inadequately etc.Therefore, be difficult to be used for for a long time the chronic renal failure patients as Captopril because of easily causing hyperkalemia clinically, 5-15% patient is forced to stopped treatment because of the cough due to the Benazapril, the patient of many constitutionales or renal hypertension must add with multiple other antihypertensive drugs simultaneously in order to reach ideal bp when using said medicine.
Skimmin (Skimmin) shown in (I), is a compound known, is distributed widely in various plants and the citrus fruit and (sees 1.Doi, Kayo; Kojima, Takashi; Makino, Mitsuko; Kimura, Yumiko; Fujimoto, Yasuo Studies on theconstituents of the leaves of Morus alba L.Chem.Pharm. Bull., 49 (2), 151-153 (English) 2001; 2.Kwaon, Yong-Soo; Cho, He-Young; Kim, Chang-Min, The chemical constituents from Heracleummoellendorffii roots.Yakhak Hoechi, 44 (6), 521-527 (Korean) 2000; 3.Moon, Hyung In; Oh, Joa Sub; Kim, Jong Sik; Chen, Pei Chun; Zee, Ok Pyo.Phytochemical compounds from the underground parts ofGardenia jasminoides var.radicans Makino.Saengyak Hakhoechi, 33 (1), 1-4 (Korean) 2002.; 4.Runkel, M.; Bourian, M.; Legrum, W., Scopolin and skimmin as constituents of citrus fruits.FruitProcess., 7 (6), 213-216 (English) 1997).Can separate obtaining pure product skimmin from various plants (as Folium Mori), separation method (is seen Doi, Kayo; Kojima, Takashi; Makino, Mitsuko; Kimura, Yumiko; Fujimoto, Yasuo Studies on theconstituents of the leaves of Morus alba L.Chem.Pharm Bull., 49 (2), 151-153 (English) 2001; ).
Summary of the invention
In order to overcome the shortcoming of prior art, the invention provides a kind of new skimmin shown in general formula (I) and prevent and/or treat application in the medicine of renal insufficiency in preparation.
(I)
Another object of the present invention is to provide a kind of new pharmaceutical composition that prevents and/or treats renal insufficiency, its contain the treatment effective dose suc as formula skimmin and the pharmaceutical carrier shown in (I).
The present invention shows by pharmacological evaluation, causes after the chmice acute injury of kidney 3 days with cisplatin, and model group serum creatinine, blood urea nitrogen significantly raise.Skimmin 12.5mg/kg dosage group can reduce serum creatinine, urea nitrogen levels, reduces by 37.2% and 51.8% respectively, and its action intensity is suitable with positive drug Benazepril10mg/kg dosage group.
Behind the modeling type 5 days, model group serum creatinine, blood urea nitrogen still kept higher level.Skimmin 12.5mg/kg dosage group can reduce serum creatinine 55.6%, obviously is better than positive drug Benazepril10mg/kg dosage group.Skimmin 6.25mg/kg dosage group reduces the blood urea nitrogen level and reaches 49.4%, and is suitable with the effect of positive drug Benazepril 5mg/kg dosage group.
Behind the modeling type 7 days, model group and each administration group serum creatinine level were recovered normal (Benazepril10mg/kg dosage group serum creatinine level is lower than normal level).But model group blood urea nitrogen level still is significantly higher than negative control group, and skimmin 6.25mg/kg, 12.5m/kg dosage group can reduce the blood urea nitrogen level, are respectively 67.1% and 69.4%, are better than positive drug Benazepril.
Experimental result shows that skimmin has the certain protection effect to the mice injury of kidney that cisplatin causes, and acts on suitable with positive control drug Benzaepril.
Skimmin of the present invention source is abundant, is suitable for suitability for industrialized production, and production cost is low.To the similar effect of above-mentioned synthetic drug, close action intensity, but production cost is low, and toxicity is little,
According to the invention still further relates to the preparation of drug combination method.When being used for this purpose, if desired, active component and one or more solids or liquid medicine excipient and/or adjuvant can be combined, make and can be used as suitable administration form or the dosage form that people's medicine uses.
Pharmaceutical composition of the present invention can the unit dosage form administration, and route of administration can be intestinal or non-intestinal, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritoneum or rectum etc.
The route of administration of pharmaceutical composition of the present invention can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection therapy etc.
Form of administration can be liquid dosage form, solid dosage forms.As liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other dosage forms are tablet, capsule, drop pill, aerosol, pill, powder, solution, suspensoid, Emulsion, granule, suppository, lyophilized injectable powder etc. for example.
Compositions of the present invention can be made ordinary preparation, also can be slow releasing preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier is, for example diluent and absorbent are as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, carbamide, calcium carbonate, kaolin, microcrystalline Cellulose, aluminium silicate etc.; Wetting agent and binding agent are as water, glycerol, Polyethylene Glycol, ethanol, propanol, starch slurry, dextrin, syrup, Mel, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.; Disintegrate inhibitor, for example sucrose, glyceryl tristearate, cocoa butter, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example Pulvis Talci, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, Polyethylene Glycol etc.Tablet further can also be made coated tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.
For pill is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example diluent and absorbent are as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, Kaolin, Pulvis Talci etc.; Binding agent is as arabic gum, Tragacanth, gelatin, ethanol, Mel, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.
For suppository is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example the ester of Polyethylene Glycol, lecithin, cocoa butter, higher alcohol, higher alcohol, gelatin, semi-synthetic glyceride etc.
For capsule is made in the administration unit, effective ingredient is mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard gelatine capsule or soft capsule.Also effective ingredient can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.
For example, compositions of the present invention is made injection preparation, as solution, suspensoid solution, Emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can contain acceptable carrier, diluent, binding agent, lubricant, antiseptic, surfactant or dispersant on a kind of and/or multiple pharmacodynamics.Can be selected from water, ethanol, Polyethylene Glycol, 1 as diluent, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection, can in injection preparation, add proper amount of sodium chloride, glucose or glycerol, in addition, can also add conventional cosolvent, buffer agent, pH regulator agent etc. in order to prepare etc.These adjuvants are that this area is commonly used
In addition, as needs, also can in pharmaceutical preparation, add coloring agent, antiseptic, spice, correctives, sweeting agent or other material.
The dosage of Pharmaceutical composition of the present invention depends on many factors, for example to prevent or treat the character and the order of severity of disease, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, administration number of times etc., therefore therapeutic dose of the present invention can have large-scale variation.In general, the using dosage of Chinese materia medica composition of the present invention is well known to a person skilled in the art.The actual active drug quantity that can be according to the present invention be contained in the last preparation in the Pharmaceutical composition, in addition suitable adjustment to reach the requirement of its treatment effective dose, is finished the purpose of reverse multiple drug resistance of tumor of the present invention.Usually to the about 75 kilograms of patients of body weight, the daily dose of the chemical compound of giving or effective site be 0.001mg/kg body weight～500mg/kg body weight, preferred 0.1mg/kg body weight～10mg/kg body weight.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations, the dosage regimen that this is subject to administration doctor's clinical experience and comprises utilization chemotherapy, radiotherapy means.
Term: BUN: blood urea nitrogen
Cre: creatinine
The specific embodiment
The present invention is further illustrated for following examples.But the present invention is not limited to these embodiment.
1, the foundation of cisplatin induced mice acute injury of kidney model
Get male Kunming KM mice, 16g～18g is divided into solvent control group and cisplatin model group, administration group, totally 6 groups, 8 every group at random by body weight.Matched group intraperitoneal injection of saline, cisplatin are with physiological saline solution, and lumbar injection is pressed the 7mg/kg drug administration by injection.The compounds of this invention once a day, is administered five times altogether in injection cisplatin beginning in preceding 2 days oral administration; Positive control drug Benazepril (K), while oral administration when the injection cisplatin once a day, is administered three times altogether (in the too late administration simultaneously of effect of injection cisplatin beginning in preceding 2 days administration, too late three times of the effect that is administered five times), each administration volume is 0.4ml/20g more than.Behind the injection cisplatin the 3rd day, 5 days, 7 days respectively eyeball get blood, detect serum BUN, Cre with test kit, and weigh.
2. result of study
The protective effect of the mice injury of kidney that table 1. chemical compound causes cisplatin (after the modeling 3 days)
Sample concentration Cre Bun
(mg/kg) (mg/dL) reduce (%) and (mg/dL) reduce (%)
Negative control group 6.10 ± 2.22 19.77 ± 2.55
Cisplatin 7 12.83 ± 6.69 110.4 ↑ 67.21 ± 24.90 240 ↑
K+ cisplatin 5.0 * 3+7 8.90 ± 3.12 30.6 29.39 ± 28.44* 56.3
10.0×3+7 8.69±7.67 32.3 35.51±20.68* 47.2
Skimmin+ cisplatin 6.25 * 5+7 11.47 ± 7.00 10.6 20.24 ± 5.87* 69.9
12.5×5+7 8.06±4.37 37.2 32.37±24.30* 51.8
*: P＜0.05, compare with model group
The protective effect of the mice injury of kidney that table 2. chemical compound causes cisplatin (after the modeling 5 days)
Sample concentration Cre Bun
(mg/kg) (mg/dL) reduce (%) and (mg/dL) reduce (%)
Negative control group 2.34 ± 1.12 22.30 ± 3.83
Cisplatin 7 3.07 ± 2.39 31.3 ↑ 56.94 ± 15.43 155.3 ↑
K+ cisplatin 5.0 * 3+7 2.10 ± 1.40 31.6 23.91 ± 6.21* 58.0
10.0×3+7 2.37±3.12 22.7 76.05±47.61 33.6↑
Skimmin+ cisplatin 6.25 * 5+7 2.57 ± 1.29 16.1 28.83 ± 5.95* 49.4
12.5×5+7 1.36±0.60 55.6 31.38±10.52* 44.9
*: P＜0.05, compare with model group
The protective effect of the mice injury of kidney that table 3. chemical compound causes cisplatin (after the modeling 7 days)
Sample concentration Cre Bun
(mg/kg) (mg/dL) reduce (%) and (mg/dL) reduce (%)
Negative control group 1.31 ± 0.22 20.99 ± 4.83
Cisplatin 7 1.36 ± 0.12 4.0 ↑ 65.36 ± 18.47 211.4 ↑
K+ cisplatin 5.0 * 3+7 1.46 ± 0.50 7.4 ↑ 26.64 ± 10.60* 59.2
10.0×3+7 0.90±0.41 33.5 24.82±4.08* 62.0
Skimmin+ cisplatin 6.25 * 5+7 1.47 ± 0.34 8.4 ↑ 21.51 ± 2.18* 67.1
12.5×5+7 1.46±0.24 7.5↑ 20.03±2.42* 69.4
*: P＜0.05, compare with model group
Above-mentioned experimental result shows, behind the modeling type 3 days, model group serum creatinine, blood urea nitrogen significantly raise, Skimmin 12.5mg/kg dosage group can reduce serum creatinine, urea nitrogen levels, reduce by 37.2% and 51.8% respectively, effect is suitable with the effect of positive drug Benazepril 10mg/kg dosage group.
Behind the modeling type 5 days, model group serum creatinine, blood urea nitrogen still kept higher level, and Skimmin12.5mg/kg dosage group can reduce serum creatinine 55.6%, obviously is better than positive drug Benazepril10mg/kg dosage group.Skimmin 6.25mg/kg dosage group reduces the blood urea nitrogen level and reaches 49.4%, and is suitable with the effect of positive drug Benazepril 5mg/kg dosage group.
Behind the modeling type 7 days, model group and each administration group serum creatinine level are recovered normal (Benazepril10mg/kg dosage group serum creatinine level is lower than normal level), model group blood urea nitrogen level still is significantly higher than negative control group, Skimmin 6.25mg/kg, 12.5m/kg dosage group can reduce the blood urea nitrogen level, be respectively 67.1% and 69.4%, be better than positive drug Benazepril.
Experimental result shows that Skimmin has the certain protection effect to the mice injury of kidney that cisplatin causes, and acts on suitable with positive control drug Benzaepril.
Claims (3)
1, prevents and/or treats application in the medicine of renal insufficiency suc as formula chemical compound shown in (I) in preparation.
2, a kind of pharmaceutical composition that prevents and/or treats renal insufficiency is characterized in that, contain the treatment effective dose suc as formula chemical compound and the pharmaceutical carrier shown in (I).
According to the pharmaceutical composition of claim 2, it is characterized in that 3, described pharmaceutical composition comprises tablet, capsule, pill, injection, slow releasing preparation, controlled release preparation and various particulate delivery system.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310100220 CN1256093C (en) | 2003-10-10 | 2003-10-10 | Application of skimming in the preparing process of medicine for preparing and treating kidney function failure |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310100220 CN1256093C (en) | 2003-10-10 | 2003-10-10 | Application of skimming in the preparing process of medicine for preparing and treating kidney function failure |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1605343A true CN1605343A (en) | 2005-04-13 |
| CN1256093C CN1256093C (en) | 2006-05-17 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 200310100220 Expired - Lifetime CN1256093C (en) | 2003-10-10 | 2003-10-10 | Application of skimming in the preparing process of medicine for preparing and treating kidney function failure |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101397315A (en) * | 2007-09-24 | 2009-04-01 | 中国医学科学院药物研究所 | Tonka bean camphor glycosides compounds, preparation method thereof and medicament composition and use thereof |
| CN107158050A (en) * | 2016-03-15 | 2017-09-15 | 中国医学科学院药物研究所 | Hydrangea paniculata general coumarin glycosides, its preparation method and combinations thereof and purposes |
-
2003
- 2003-10-10 CN CN 200310100220 patent/CN1256093C/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101397315A (en) * | 2007-09-24 | 2009-04-01 | 中国医学科学院药物研究所 | Tonka bean camphor glycosides compounds, preparation method thereof and medicament composition and use thereof |
| CN107158050A (en) * | 2016-03-15 | 2017-09-15 | 中国医学科学院药物研究所 | Hydrangea paniculata general coumarin glycosides, its preparation method and combinations thereof and purposes |
| CN107158050B (en) * | 2016-03-15 | 2021-08-13 | 中国医学科学院药物研究所 | Hydrangea paniculata total coumarin glycoside, preparation method, composition and application thereof |
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| Publication number | Publication date |
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| CN1256093C (en) | 2006-05-17 |
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