CN102973593A - Application of dextran sulfate in preparing medicament for treating hepatic fibrosis - Google Patents
Application of dextran sulfate in preparing medicament for treating hepatic fibrosis Download PDFInfo
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- CN102973593A CN102973593A CN2012104863129A CN201210486312A CN102973593A CN 102973593 A CN102973593 A CN 102973593A CN 2012104863129 A CN2012104863129 A CN 2012104863129A CN 201210486312 A CN201210486312 A CN 201210486312A CN 102973593 A CN102973593 A CN 102973593A
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- dextran sulfate
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Abstract
The invention discloses novel application of dextran sulfate in preparing a medicament for treating hepatic fibrosis. The medicament can be used for inhibiting inflammatory reaction in hepatic fibrosis attaching process, so that attack or symptom worsening of hepatic fibrosis can be inhibited. Dextran sulfate has good curative effect in a carbon tetrachloride induced animal model; and the medicaments used in the application can be easily acquired, low in price and stable in properties, are convenient to store and transport, and have wide application prospect.
Description
Technical field
The invention belongs to the biological medicine technology field, be specifically related to the application of dextran sulfate in the medicine of preparation treatment hepatic fibrosis.
Background technology
Hepatic fibrosis is the disease that has a strong impact on people's life health.In recent years along with people life style, the variation of dietary habit, and the impact of chronic viral hepatitis, the serious symptom sickness rate has continuous rising, and the direct result of hepatic fibrosis is liver cirrhosis and liver failure, the patient death rate is high, lack simultaneously effective medicine, be replaced into therapeutic regimen with liver clinically, but liver donor wretched insufficiency, overwhelming majority patient can't treat, and it is significant to the treatment of this disease therefore to develop effective medicine.
The predisposing factors of hepatic fibrosis is a lot, virus, and medicine, ethanol etc. all might cause the outbreak of hepatic fibrosis.The biological mechanism of its morbidity is the overactivity that is into stellate cells by the people, the excessive mediation tissue fibering that a large amount of secretion collagens cause, the metal matrix protease of liver macrophage secretion is the negative growth factor of collagen tissue, can play the effect that alleviates hepatic fibrosis.
Dextran sulfate Dextran sulfate, molecular weight 2KD ~ 600KD does not wait, and it is the polyanionically-derivatised thing of glucosan, is formed by the esterification of glucosan and chlorosulfonic acid, and at present, it is mainly used in blood fat reducing and antiatherosclerotic.
Summary of the invention
Purpose of the present invention namely is to provide the application of a kind of dextran sulfate in preparation treatment hepatic fibrosis medicines, dextran sulfate of the present invention can demonstrate the activation of strong inhibition spider cell in related experiment, promote the character of macrophage secretion metal matrix protease, on the principle, dextran sulfate can reduce hepatic fibrosis morbidity collagen by these mechanism and produce, and alleviates the symptom of hepatic fibrosis.Therefore, dextran sulfate can develop into a kind of medicine for the treatment of hepatic fibrosis on the principle.
The application of dextran sulfate of the present invention in preparation treatment hepatic fibrosis medicines, wherein, described dextran sulfate is alpha-glucans, molecular weight is 3.6 kD ~ 300 kD.
Described dextran sulfate can be the commercially available prod, also can synthesize with commercial available dextran sulfate modification, the glucosan of modifying the different molecular weight size as passing through chlorosulfonic acid-pyridine method obtains, preparation method as: pyridine is added in the three-necked bottle with condensing tube and agitating device, place cryosel to bathe, dropwise add chlorosulfonic acid, 10 min dropwise, add again alpha-glucans, immediately it is moved in the oil bath of preheating in 400-1000 degree centigrade of isothermal reaction.React complete after, in reactant liquor impouring frozen water.Transfer to pH neutrality with 10 mol/LNaOH.With deionized water 48 h that dialyse, dialysis solution concentrates precipitate with ethanol, redissolution, lyophilizing, namely gets dextran sulfate (Richetts CR. Preparation of dextran sulphate and tracer experiments in the rabbit. Biochem J. 1954; 58:523. the favorable to the people pharmaceutical factory in Guangdong. dextran sulfate: pyridine-chlorosulfonic acid esterification process brief introduction. Chinese Journal of Pharmaceuticals, 1975; 3:1.）。The control reaction temperature can obtain different modification rates.The different modifying rate is as follows with corresponding reaction temperature synopsis among the present invention:
| Molecular weight and modification rate | Reaction temperature |
| 3.6 the KD dextran sulfate, 5% modifies | 400 degrees centigrade |
| 3.6 the KD dextran sulfate, 27% modifies | 690 degrees centigrade |
| 40 KD dextran sulfates, 7% modifies | 570 degrees centigrade |
| 40 KD dextran sulfates, 22% modifies | 750 degrees centigrade |
| 70 KD dextran sulfates, 8% modifies | 630 degrees centigrade |
| 70 KD dextran sulfates, 24% modifies | 860 degrees centigrade |
| 70 KD dextran sulfates, 43% modifies | 970 degrees centigrade |
| 110 KD dextran sulfates, 6% modifies | 790 degrees centigrade |
| 110 KD dextran sulfates, 18% modifies | 940 degrees centigrade |
| 300 KD dextran sulfates, 4% modifies | 880 degrees centigrade |
| 300 KD dextran sulfates, 14% modifies | 1000 degrees centigrade |
Adopt dextran sulfate of the present invention to combine with multiple pharmaceutically acceptable carrier for soluble salt such as the dextran sulfate sodium salt of dextran sulfate, by such as oral cavity, vein, nasal cavity, rectum or other any administering modes that can carry the active substance of effective dose, can be prepared into various liquid preparations such as injection, oral liquid formulations etc., also can be prepared into various effectively and be easy to solid preparation such as capsule, the suppository etc. of administration.Wherein, be used for injection or liquid preparation for oral use, its required carrier can be the medically acceptable carriers such as sterilized water, Sterile Saline or water solublity organic carrier such as cyclodextrin, Semen Maydis oil, olive oil, ethyl oleate, glycols; The solid drug-delivery preparation can add solid preparation adjuvant commonly used such as excipient glucose, lactose, cellulose etc. in preparation, also can add lubricant Polyethylene Glycol, magnesium stearate etc., and the required adjunct ingredients of solid preparation such as binding agent, correctives, again by operation molding such as mixing, granulations.The effective dose of the active substance in above-mentioned these preparations is the amount that hepatic fibrosis is obviously reduced, research worker with routine techniques can be determined the most effective dosage and the time consideration administering mode of the reagent that this invention provides, drug metabolism, and some other pharmacokinetic parameter drug distribution for example, clearance rate etc.All right and for example medication combined administration of conventional hepatoprotective of other reagent of reagent provided by the present invention is so that the hepatic fibrosis occurring degree effectively reduces.
The present invention carries out illustration by the Liver Fibrosis Model to tetrachloro-methane induction in the body.Animal herein includes, but are not limited to: mice, rat, performing animal includes, but are not limited to cat, Canis familiaris L., and some other animal for example but be not limited to cattle, sheep, pig, horse, primate for example but be not limited to monkey and people.
The present invention proposes the new application of dextran sulfate in preparation treatment hepatic fibrosis medicines, this medicine can pass through the inflammatory reaction in the inhibition hepatic fibrosis pathogenic process, thereby suppresses outbreak or the sx↑ of hepatic fibrosis.Obtain good curative effect in the animal model of dextran sulfate tetrachloro-methane induction, simultaneously, medicine used in the present invention is easy to obtain, and is cheap, and stable in properties is convenient to storage and transport, has broad application prospects.
The specific embodiment
The zoopery example
(dextran sulfate injection solution preparation is to the treatment of the Liver Fibrosis Model of tetrachloro-methane induction)
The dextran sulfate of different molecular weight and different modifying rate is for subsequent use with the injection that physiological saline solution is made into 2.0mg/ml, regulate pH value to 7.0 with 10 mol/L NaOH solution.Get 78 of female new ICR mices, body weight 18 g-20 g are divided into 13 groups at random with animal, and 6 every group, i.e. Normal group, Liver Fibrosis Model group, respectively with the treatment group of the dextran sulfate treatment of different molecular weight and modification rate.The foundation of model is 20% Oleum Camelliae solution by the carbon tetrachloride of subcutaneous injection 5 ml/kg body weight, and per 5 days once, and continuous 3 months, treatment group weekly lumbar injection dextran sulfate was treated, and the model group of drug treatment is not injected isopyknic normal saline.After 3 months, measure the content of the hydroxyproline in the hepatic tissue in the experiment beginning by the aqueous alkali method.Experimental result is as shown in table 1.
Table 1: the evaluation of pesticide effectiveness of dextran sulfate
| Group | Hydroxyproline (μ g/g liver) |
| Normal group | 125 |
| Model group | 369 |
| 3.6 the KD dextran sulfate, 5% modifies | 172 * |
| 3.6 the KD dextran sulfate, 27% modifies | 161 * |
| 40 KD dextran sulfates, 7% modifies | 181 * |
| 40 KD dextran sulfates, 22% modifies | 187 * |
| 70 KD dextran sulfates, 8% modifies | 162 * |
| 70 KD dextran sulfates, 24% modifies | 163 * |
| 70 KD dextran sulfates, 43% modifies | 172 * |
| 110 KD dextran sulfates, 6% modifies | 172 * |
| 110 KD dextran sulfates, 18% modifies | 183 * |
| 300 KD dextran sulfates, 4% modifies | 192 * |
| 300 KD dextran sulfates, 14% modifies | 185 * |
Data are shown with the form of meansigma methods that all significant difference is determined that by the ANOVA check * represents P≤0.05.Therapeutic outcome shows that the hydroxyproline content in the Hepatic Fibrosis of Animal model hepatic tissue after the dextran sulfate treatment obviously reduces, and illustrates and uses dextran sulfate can treat preferably hepatic fibrosis.
Claims (2)
1. the application of dextran sulfate in preparation treatment hepatic fibrosis medicines.
2. application according to claim 1 is characterized in that: described dextran sulfate molecular weight is 3.6 kD ~ 300 kD.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104863129A CN102973593A (en) | 2012-11-26 | 2012-11-26 | Application of dextran sulfate in preparing medicament for treating hepatic fibrosis |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012104863129A CN102973593A (en) | 2012-11-26 | 2012-11-26 | Application of dextran sulfate in preparing medicament for treating hepatic fibrosis |
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| CN102973593A true CN102973593A (en) | 2013-03-20 |
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| CN2012104863129A Pending CN102973593A (en) | 2012-11-26 | 2012-11-26 | Application of dextran sulfate in preparing medicament for treating hepatic fibrosis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107921055A (en) * | 2015-07-30 | 2018-04-17 | Tx医生公司 | The new application of dextran sulfate |
| SE2051132A1 (en) * | 2020-09-29 | 2022-03-30 | Tx Medic Ab | Treatment of fatty liver diseases |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6020326A (en) * | 1991-05-31 | 2000-02-01 | Gliatech Inc. | Method for inhibition of bone growth by anionic polymers |
| JP2006335717A (en) * | 2005-06-03 | 2006-12-14 | Kenji Tanmachi | Tissue fibrosis inhibitor and eating and drinking articles |
| WO2008011216A2 (en) * | 2006-05-16 | 2008-01-24 | Pro-Pharmaceuticals, Inc. | Galactose-pronged polysaccharides in a formulation for antifibrotic therapies |
-
2012
- 2012-11-26 CN CN2012104863129A patent/CN102973593A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6020326A (en) * | 1991-05-31 | 2000-02-01 | Gliatech Inc. | Method for inhibition of bone growth by anionic polymers |
| JP2006335717A (en) * | 2005-06-03 | 2006-12-14 | Kenji Tanmachi | Tissue fibrosis inhibitor and eating and drinking articles |
| WO2008011216A2 (en) * | 2006-05-16 | 2008-01-24 | Pro-Pharmaceuticals, Inc. | Galactose-pronged polysaccharides in a formulation for antifibrotic therapies |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107921055A (en) * | 2015-07-30 | 2018-04-17 | Tx医生公司 | The new application of dextran sulfate |
| JP2018521086A (en) * | 2015-07-30 | 2018-08-02 | ティーエックス メディック エービー | New use of dextran sulfate |
| US10478451B2 (en) | 2015-07-30 | 2019-11-19 | Tx Medic Ab | Use of dextran sulfate |
| SE2051132A1 (en) * | 2020-09-29 | 2022-03-30 | Tx Medic Ab | Treatment of fatty liver diseases |
| WO2022071841A1 (en) * | 2020-09-29 | 2022-04-07 | Tx Medic Ab | Treatment of fatty liver diseases |
| SE544447C2 (en) * | 2020-09-29 | 2022-05-31 | Tx Medic Ab | Treatment of fatty liver diseases |
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Application publication date: 20130320 |