CN1073416C - New use of caffeic acid and ferulic acid antagonistic endotheliolysin biological effect - Google Patents
New use of caffeic acid and ferulic acid antagonistic endotheliolysin biological effect Download PDFInfo
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- CN1073416C CN1073416C CN98100877A CN98100877A CN1073416C CN 1073416 C CN1073416 C CN 1073416C CN 98100877 A CN98100877 A CN 98100877A CN 98100877 A CN98100877 A CN 98100877A CN 1073416 C CN1073416 C CN 1073416C
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- caffeic acid
- endothelin
- ferulic acid
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Abstract
The present invention discloses new applications of caffeic acid and ferulic acid and specifically relates to applications of caffeic acid or ferulic acid to the preparation of medicines with antagonistic effect on endothelin. The applications comprise an application of caffeic acid or ferulaic acid to the preparation of medicines which have protective action on a mouse's acute death caused by endothelin, an application of caffeic acid or ferulaic acid to the preparation of medicines which have antagonistic action on vasoconstrictive effect caused by endothelin, an application of caffeic acid or ferulaic acid to the preparation of medicines which have antagonistic action on blood pressure rising effect caused by endothelin, an application of caffeic acid or ferulaic acid to the preparation of medicines which have antagonistic action on the proliferation effect of vascular smooth muscle cells caused by endothelin.
Description
The invention relates to the pharmaceutic usage invention of caffeic acid, ferulic acid, specifically caffeic acid, the application of ferulic acid in preparing the medicine that the endothelin-1 biological effect is had antagonism belong to drug world.
Caffeic acid and ferulic acid are chemically all belonging to styrene type compounds, and the difference of the two is the group on 3 of the phenyl ring, are hydroxyls on 3 of the caffeinic phenyl ring, and are to be methoxyl group on 3 of the phenyl ring of ferulic acid.Caffeic acid and ferulic acid are the important component of promoting blood flow and remove blood stasis drug in China's tradition Chinese medicine, and be more as content in the medical materials such as Radix Angelicae Sinensis, ligustrazine.
Endothelin is a kind of bioactive substance of latest report in the world.The generation development and the Endothelin of many cardiovascular and cerebrovascular diseases have confidential relation, and as hypertension, coronary heart disease, cerebrovascular accident, heart failure etc., Endothelin participates in pathology, the physiological process of these diseases.Many countries are the pathological index of Endothelin as diseases such as hypertension, coronary heart disease, cerebrovascular accident, heart failure, and treat above-mentioned disease by the biological agent of regulating Endothelin.Endothelin is also relevant with chronic rejection, eclamposia, hepatitis etc. after other diseases such as the organ transplantation in addition.Therefore, screening is a kind of can the bioactive medicine of antagonism Endothelin be present extremely important and significant thing.
The inventor has found caffeic acid and the ferulic acid antagonism to Endothelin, thereby has finished the present invention based on a large amount of experimentatioies.
Therefore, the object of the invention provides the pharmaceutic usage of caffeic acid and ferulic acid.
As mentioned above, caffeic acid and ferulic acid are chemically all belonging to styrene type compounds, and its structural formula is respectively:
The chemical structural formula of caffeinic chemical structural formula ferulic acid
The inventor studies have shown that by experiment caffeic acid, ferulic acid have good antagonism to the biological effect of endothelin-1 (ET-1), mainly show:
(1) caffeic acid, ferulic acid cause the protective effect of death of mice to endothelin-1 (ET-1).
(2) caffeic acid and ferulic acid are to the contract antagonism of vascular effect of ET-1.
(3) caffeic acid and ferulic acid rise the antagonism of blood pressure effect to ET-1.
(4) caffeic acid and ferulic acid are to the antagonism of ET-1 hyperamization pipe smooth muscle cell proliferation effect.
Caffeic acid and ferulic acid are two kinds of structurally very approaching chemical compounds, according to the pharmaceutical preparation technology of routine, can add conventional excipient with it as effective ingredient, are prepared into any pharmaceutical preparation that is suitable for using clinically.For example, pill, tablet, capsule, oral liquid, injection, powder, unguentum, aerosol etc.Preparing these pharmaceutical preparatioies is those of ordinary skills' technical activity routinely.
Because the inventor has discovered the above-mentioned new pharmacological action of caffeic acid and ferulic acid by experiment, therefore, according to the made any pharmaceutical dosage form that is suitable for clinical use of the conventional formulation technology of pharmaceutical field, all has following effect:
(1) endothelin-1 is caused the protective effect of death of mice.
(2) to the contract antagonism of vascular effect of ET-1.
(3) ET-1 is risen the antagonism of blood pressure effect.
(4) to the antagonism of ET-1 hyperamization pipe smooth muscle cell proliferation effect.
Therefore, the invention provides the following pharmaceutic usage of caffeic acid, ferulic acid:
Caffeic acid, the application of ferulic acid in preparing the medicine that Endothelin is had antagonism;
Caffeic acid, ferulic acid cause to endothelin-1 that in preparation death of mice has the application in the medicine of protective effect;
Caffeic acid, ferulic acid have application in the medicine of antagonism at preparation endothelin-1 is contracted vascular effect;
Caffeic acid, ferulic acid rise application in the medicine that blood pressure effect has antagonism in preparation to endothelin-1;
Caffeic acid, the application of ferulic acid in preparing the medicine that endothelin-1 hyperamization pipe smooth muscle cell proliferation effect is had antagonism.
Caffeic acid, ferulic acid can add the medicine excipient when being prepared into medicament, as, filler, disintegrating agent, solvent, antiseptic, correctives, thickening agent, emulsifying agent etc.
With caffeic acid, ferulic acid when being prepared into medicament, the amount of contained caffeic acid or ferulic acid effective ingredient is generally the treatment effective dose that is used for human body in the medicament.
The said pharmacy optimization of the present invention contains the caffeic acid or the ferulic acid of 0.1-99.9% weight portion;
The said pharmacy optimization of the present invention contains the caffeic acid or the ferulic acid of 10-90% weight portion;
The said pharmacy optimization of the present invention contains the caffeic acid or the ferulic acid of 15-80% weight portion;
The said pharmacy optimization of the present invention contains the caffeic acid or the ferulic acid of 20-70% weight portion;
The method of the said caffeic acid of the present invention or ferulic acid being made capsule is:
Get the pure product of caffeic acid or ferulic acid, add excipient, go into the blender mixing, encapsulated, make capsule.
The method of the said caffeic acid of the present invention or ferulic acid being made tablet is:
Get the pure product of caffeic acid or ferulic acid, add excipient, mix homogeneously, pelletize, granulate, tabletting, sugar coating gets tablet.
Following pharmacological evaluation further illustrates the pharmaceutic usage of caffeic acid or ferulic acid.
Experimental example 1 caffeic acid, ferulic acid cause the protective effect of death of mice to endothelin-1
90 of Kunming mouses (available from the department of the Chinese Academy of Sciences of laboratory animal section of Beijing Medical University), male and female half and half, body weight 20 ± 2.0g, fasting be can't help water after 16 hours, (dosage range of administration is 0.1～100mg/kg) after 30 minutes from lumbar injection caffeic acid, ferulic acid, from tail vein injection ET-1 12nmol/kg, death toll and the death time of record animal; Matched group behind the normal saline of lumbar injection and disposition of drug group equal parts 30 minutes, from tail vein injection ET-112nmol/kg, death toll and the death time of record animal, and data are done statistical procedures.
Caffeic acid and ferulic acid all effectively antagonism ET-1 cause the death of mice effect, the death time has been compared the significance meaning with matched group; In dosage was the scope of 0.1～100mg/kg, this made the apparatus dose dependent; When drug level was identical, the antagonism usefulness of ferulic acid was greater than caffeic acid.
Table 1. caffeic acid and ferulic acid antagonism ET-1 cause the protective effect of death of mice
| Medicine | Dosage | Number of animals (only) | Death time of animal (min) |
| ET-1 caffeic acid+ET-1 ferulic acid+ET-1 | 12nmol/kg 100mg/kg 10mg/kg 1mg/kg 0.1mg/kg 100mg/kg 10mg/kg 1mg/kg 0.1mg/ | 10 10 10 10 10 10 10 10 10 | 2.24±1.02 12.72±3.11 *** 3.19±0.88 * 2.58±0.21 * 2.33±0.19 * 14.37±1.89 *** 5.54±1.06 ** 4.04±0.50 ** 3.33±1.84 * |
Experimental example 2 caffeic acids and ferulic acid are to the contract antagonism of vascular effect of ET-1
Male SD rat, body weight 230 ± 10g with winning thoracic aorta fast after the rat stunning, after separating connective tissue, is cut into the wide vascular ring of 2～3mm, places Krebs-Henseleit physiological solution (K-H liquid, pH7.40 ± 0.05,95%O respectively
2+ 5%CO
2, 37.0 ± 0.5 ℃) in, add 2g basis tension force, with 10
-7The mol/L norepinephrine swash in advance secondary, balance, stable after, add ET-1 10
-9Mol/L, after waiting to reach the maximum collapse effect, (with 2%DMSO is solvent to add caffeic acid, ferulic acid and the CA-1201 of variable concentrations respectively, experiment compares with 2%DMSO), connect desk-top balance recorder (Shanghai Dahua Instrument and Meter Plant) through tonotransducer, record blood vessel isotonic contraction and diastole situation.
Caffeic acid and ferulic acid be the vascular effect that contracts of antagonism ET-1 significantly, and gives antagonism tool dose dependent; Drug dose-effect curve is after the match of sigmiodal method (referring to Fig. 1), and from the effect kinetic parameter that drawn as seen, ferulic acid antagonism ET-1 contracts the usefulness of blood vessel than caffeic acid strong (p＜0.05).
Table 2. caffeic acid and the ferulic acid antagonism ET-1 vascular effect kinetic parameter that contracts
| Medicine | Kinetic parameter | |
| Emax(％) | IC 50(×10 -6mol/L) | |
| The caffeic acid ferulic acid | 70.95±6.30 92.10±0.81 | 1.80±0.80 0.063±0.005 |
Experimental example 3 caffeic acids and ferulic acid rise the antagonism of blood pressure effect to ET-1
Male SD rat, body weight 230 ± 10g,, after water 18h is can't help in fasting, behind caffeic acid and the ferulic acid various dose tail vein injection, measure from tail vein injection ET-1 by 6 μ g/kg immediately, change (SBP) with Impedance Determination rat arteria caudalis systolic pressure; Matched group is handled the ET-1 of back tail vein injection and disposition of drug group same dose with the equivalent normal saline; And with systolic pressure changing value and matched group comparison.
Caffeic acid and ferulic acid significantly after the antagonism ET-1 intravenous injection to the blood pressure effect that rises of rat; Compare with matched group, in 30 minutes, pressor effect obviously weakens after giving ET-1, and there was no significant difference (p＞0.05) (referring to Fig. 2) is compared in its effect in the later time with matched group.
Experimental example 4 caffeic acids and ferulic acid are to the antagonism of ET-1 hyperamization pipe smooth muscle cell proliferation effect
Getting rabbit aortic smooth muscle cells (RAVSMC) that the 5th generation grew up to fine and close monolayer, to adjust cell number with the culture method that goes down to posterity be 1 * 10
5Ml
-1, be inoculated in 96 well culture plates (100 μ, 1 hole
-1), 37 ℃, 5%CO
2Hatch 24h, inhale and remove culture fluid, change DMEM culture fluid, add ET-1 (10nmolL with 1% calf serum
-1) after continue to hatch different time after, obtain time-effect curve of ET-1 effect and RAVSMC; Investigate it behind adding caffeic acid and the ferulic acid and ET-1 is caused the proliferation function of smooth muscle cell.To measure each hole optical density (OD) value at the 570nm place with enzyme mark detector after the violet staining.4.1 cellular morphology is observed
After the fixing painted culture plate of crystal violet dries, directly under inverted microscope, observe, do not see that tangible cellular morphology changes.4.2 ET-1 stimulates the time-effect relation of RAVSMC propagation
Table 3.ET-1 causes the time effect of RAVSMC propagation
| Time (d) | The rate of increase (%) |
| 1 2 7 | 33.3±25.0 ** 50.0±13.6 *** 40.0±9.28 ** |
*p＞0.05；
**p＜0.05；
***p＜0.01
By table 3 as seen, ET-1 can stimulate RAVSMC propagation, and in the 2nd day peaking, the 1st, 2 compared with matched group with the 7th day numerical value, and the increase of cell proliferation rate has the significance meaning; This effect is time dependence.4.3 caffeic acid and ferulic acid antagonism ET-1 cause RAVSMC propagation
Cause time-effect relation that RAVSMC breeds, 10nmolL by ET-1
-1ET-1 and caffeic acid, ferulic acid and CA-1201 are incubated altogether and were measured OD (570nm) value on the 2nd day, the results are shown in Table 4.
Table 4. caffeic acid, 1 couple of ET-1 of ferulic acid cause the effect of RAVSMC inhibition of proliferation
| Group | OD value (* 10 2) | |||
| 10-11 | 10 -10 | 10 -9 | 10 -8 | |
| Blank ET-1 caffeic acid+ET-1 ferulic acid+ET-1 | 1.6±0.5 2.4±0.2Δ 1.2±0.1 *** 1.4±0.3 *** | 1.2±0.4 *** 1.5±0.7 *** | 1.2±0.8 *** 1.2±0.2 *** | 0.9±0.1 *** 1.2±0.4 |
Δ is compared with the blank group, p＜0.05:
*P＞0.05;
*P＜0.05;
* *P＜0.01
By table 4 as seen, but the RAVSMC that caffeic acid and ferulic acid significance ground antagonism ET-1 cause propagation, and this makes the apparatus dose dependent.
Infer that theoretically Endothelin may be one of cause of disease of traditional Chinese medical science stagnancy of qi and blood stasis.This experimental result can draw: caffeic acid, ferulic acid are endothelin antagonist, to the diseases related treatment of Endothelin and explore the origin cause of formation of qi stagnation blood stasis and its treatment is had very big design for development.
Get pure product 10 grams of caffeic acid, add 100 gram starch, go into the blender mixing, encapsulated, every powder charge powder 1 gram makes capsule.
Embodiment 2
Get pure product 100 grams of ferulic acid, add starch 500 grams, mix homogeneously, pelletize, granulate, tabletting, sugar coating gets tablet.
Accompanying drawing 1 is caffeic acid and the ferulic acid antagonism ET-1 blood vessel function dose-effect curve that contracts.
Accompanying drawing 2 is that caffeic acid and ferulic acid antagonism ET-1 rise blood pressure action time-effect curve.
Claims (5)
1, caffeic acid or the ferulic acid application in preparing the medicine that Endothelin is had antagonism.
2, caffeic acid or ferulic acid have application in the medicine of protective effect in preparation Endothelin arched death of mice.
3, caffeic acid or ferulic acid have application in the medicine of antagonism at preparation Endothelin contracted vascular effect.
4, caffeic acid or ferulic acid rise application in the medicine that blood pressure effect has antagonism in preparation to Endothelin.
5, caffeic acid or the ferulic acid application in preparing the medicine that Endothelin hyperamization pipe smooth muscle cell proliferation effect is had antagonism.
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| CN98100877A CN1073416C (en) | 1998-03-04 | 1998-03-04 | New use of caffeic acid and ferulic acid antagonistic endotheliolysin biological effect |
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|---|---|---|---|
| CN98100877A CN1073416C (en) | 1998-03-04 | 1998-03-04 | New use of caffeic acid and ferulic acid antagonistic endotheliolysin biological effect |
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| CN1192357A CN1192357A (en) | 1998-09-09 |
| CN1073416C true CN1073416C (en) | 2001-10-24 |
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| JP4520602B2 (en) * | 2000-09-05 | 2010-08-11 | 花王株式会社 | Antihypertensive agent |
| JP2002080354A (en) * | 2000-09-05 | 2002-03-19 | Kao Corp | Hypotensive agent composition |
| JP4641090B2 (en) * | 2000-09-05 | 2011-03-02 | 花王株式会社 | Antihypertensive agent |
| JP2002154977A (en) * | 2000-09-05 | 2002-05-28 | Kao Corp | Composition for drinking and eating |
| JP4666736B2 (en) * | 2000-09-05 | 2011-04-06 | 花王株式会社 | Antihypertensive agent |
| JP4520623B2 (en) * | 2000-11-08 | 2010-08-11 | 花王株式会社 | Antihypertensive agent |
| JP2002363075A (en) | 2001-06-05 | 2002-12-18 | Kao Corp | Preventive and treating agent for hypertension |
| JP2013516400A (en) * | 2009-12-30 | 2013-05-13 | パラファーム カンパニー リミテッド | Materials and methods for prevention and treatment of viral infections |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04234319A (en) * | 1990-12-28 | 1992-08-24 | Fujirebio Inc | Anti-hbv agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04234319A (en) * | 1990-12-28 | 1992-08-24 | Fujirebio Inc | Anti-hbv agent |
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