CN102335167A - Application of captopril to inhibition of scar hyperplasia - Google Patents
Application of captopril to inhibition of scar hyperplasia Download PDFInfo
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- CN102335167A CN102335167A CN2010102396749A CN201010239674A CN102335167A CN 102335167 A CN102335167 A CN 102335167A CN 2010102396749 A CN2010102396749 A CN 2010102396749A CN 201010239674 A CN201010239674 A CN 201010239674A CN 102335167 A CN102335167 A CN 102335167A
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Abstract
The invention relates to application of captopril to the preparation of medicaments for treating and/or inhibiting scar hyperplastic diseases. Particularly, the hyperplastic diseases comprise hyperplastic scar, cheloid, urethral scar stricture and silicon gel breast augmentation prosthesis postoperative capsular contracture. When the diseases are treated, the captopril is used as an active ingredient, clinically-used emulsifiable paste, gel, injection and the like in different formulations are prepared by the conventional preparation process. The study indicates that the captopril can reduce the capacity of synthesizing pathologic scar fibroblast collagen and secreting the collagen, weaken the multiplication capacity of fibroblasts and reduce the expression of transforming growth factor-beta 1 (TGF-beta 1), and has a good treatment or prevention effect on pathologic scars. Simultaneously, the captopril acts on scar tissue directly, has the advantages of small dose, high curative effect, small side effect, mature raw material process, readily available materials, low cost and the like, and is expected to become a main medicament for treating and preventing the scars clinically.
Description
Technical field
What the present invention relates to is a kind of new purposes of captopril, and specifically captopril is applied in the treatment of preparation inhibition scar hyperplasia or the new purposes in the prophylactic agent.
Background technology
Captopril (Captopril) is claimed captopril again, i.e. 1-(3-sulfydryl-2-D-methylpropionyl)-L-proline, and structure is:
Be white or off-white color crystalline powder, the special smelly of similar Bulbus Allii arranged, salty in the mouth is slightly soluble in water, is soluble in ethanol.Captopril is to be applied to clinical angiotensin-convertion enzyme inhibitor the earliest; Along with further investigation to renin-angiotensin system; Recognize that angiotensin not only is present in the blood circulation; But also be present in various tissues, like blood vessel, kidney, adrenal gland, brain, hypophysis and uterus etc., bringing into play various physiological actions.Since coming out the nineties in 20th century. captopril develops to the clinical application of diseases such as other cardiovascular disease of treatment, cirrhotic ascites, rheumatoid arthritis, hyperthyroidism, idiopathic edema from treatment hypertension special-purpose medicaments, and has obtained good clinical effectiveness.Above result all points out ACE-I class medicine that many-sided biological function is arranged in body, and its effect can't explain that antihypertensive effect only is the part of its effect with blood pressure lowering.
Pathologic scar comprises hypertrophic cicatrix and keloid; It is one of focal issue of plastic surgery and even whole outer scientific cirle research always; Although existing The experimental results shows; Numerous complicated cytokines and gene have been participated in the generation of pathologic scar, but its clear and definite etiology mechanism is still unclear so far, also do not have a kind of general effectively clinical treatment method.Yet comprehensive at present for the result of pathologic scar Mechanism Study, TGF-β 1 cytokine becomes one of of paramount importance factor in the keloid generting machanism of generally acknowledging now.TGF-β 1 not only can induce self and other factors (TNF-α; IL-1 β; PDGF etc.) expression, but also can make the fibroblast activation, breed and be converted into myofibroblast, promote the deposition of extracellular matrix compositions such as fibronectin, glycoprotein and collagen.TGF-β 1 can also collagenase produces and increase MMP inhibiting substances (TIMP, PAI, α-macroglobulin) generation suppresses precollagenous degraded through suppressing simultaneously, causes collagen deposition to increase.Experimentation confirms in recent years, and captopril has the effect that suppresses TGF-β 1.Captopril all has the effect of good fibrosis to heart, kidney and liver.Yet, current few as the correlational study and the report of the preventive and therapeutic effect of the captopril of the fibrotic disease of skin to pathologic scar.
Summary of the invention
The objective of the invention is to provide a kind of new purposes of captopril to the research direction of above-mentioned frontier.
Research of the present invention shows that captopril has the effect that suppresses scar hyperplasia, is applied to prepare in the medicine that treats and/or prevents scar hyperplasia property disease.
Specifically, captopril of the present invention is suppressing the application in the medicine that treats and/or prevents of hypertrophic cicatrix; Suppressing the application in the medicine that treats and/or prevents of keloid; Said captopril also can be made gel, is applied in treating and/or preventing of urethra cicatricial stricture; Said captopril is made into injection and is applied to silicon gel prosthese the treating and/or preventing of postoperative capsule contracture of enlarging the bosom.
When treating and/or preventing scar hyperplasia property disease, be active component with the captopril, with the preparation process of routine, be prepared into the medicine of operable various different dosage forms clinically.Like emulsifiable paste, gel, injection and various external preparation etc.
Research of the present invention shows that captopril can reduce pathologic scar fibroblast collagen protein synthesis and secretion collagen protein ability, weakens the fibroblasts proliferation ability, and downward modulation TGF-β 1 expresses.Captopril ointment has good curing or preventive effect for pathologic scar.
This Application Research captopril is intervened fibroblasts in keloid, finds that captopril has direct inhibition proliferative effect for fibroblast.Captopril is made into emulsifiable paste, gel or injection, after pathologic scar being carried out the exploration treatment, shows that the synthetic collagen content of fibroblast reduces and secretion collagen protein ability drop; Corresponding downward modulation expression has taken place with the relevant important cytokine TGF-β 1 of keloid generation in some simultaneously.Through the pathologic scar patient being carried out the external of captopril emulsifiable paste, can effectively alleviate the symptoms such as aching, itch of cicatrix clinically; The cicatrix color and luster is thin out; The height that significantly reduces cicatrix plays the skin surface height.Through the prophylactic use of adversary's postoperative patient wound, do not find that wound site pathologic scar occurs and takes place.
The present invention has the following advantages: 1, treatment has specificity to pathologic scar pathogenic factors important cytokine TGF-β 1; 2, adopt external preparation such as cream, directly act on scar tissue, so dosage is little, the curative effect height, side effect is little; 3, captopril belongs to conventional cardiovascular drugs, and characteristics such as have low price, technical maturity, be easy to get are applied to the fibrosis treatment and belong to old medicine usefulness newly, are expected to become main clinically scar treatment and prevention method.
Description of drawings
Fig. 1 is expressed in the fibroblast kytoplasm for Captopril group TGF-β 1mRNA, and kytoplasm is light to dye (* 200)
Fig. 2 is expressed in the fibroblast kytoplasm for non-Captopril group TGF-β 1mRNA, and kytoplasm is dense to dye (* 200)
Fig. 3 expresses for the Captopril group type i collagen, and collagen content is few, marshalling (* 200)
Fig. 4 is that non-Captopril group type i collagen is expressed, and collagen content is many, arrangement disorder (* 200)
The specific embodiment
Following examples only are used to set forth the present invention, and protection scope of the present invention is not only to be confined to following embodiment.Disclosure of the present invention more than the those of ordinary skill foundation of said technical field all can realize the object of the invention.
The preparation of captopril emulsifiable paste:
Substrate: by weight stearic acid 4-10%, span 1-2%, octadecanol 4-10%, liquid paraffin 6-12%, white vaseline 4-10% obtain solution first; Tween 3-10%, glycerol 4-20%, sorbic acid 0.2%, distilled water 50-70% obtain solution second.First, second two liquid are heated to 80 ℃ respectively, second liquid is slowly added in the first liquid, be stirred near coagulating, it is subsequent use to get substrate.
By weight distilled water 80-88% is dissolved captopril 6-20%; In this solution, add equivalent substrate, condensation had both got 3-10% captopril emulsifiable paste.
Experimental example
It is following that the captopril cream products that makes in the above-mentioned embodiment is implemented the gained experimental result to the different situations case:
Experimental example 1: pathologic scar patient's clinical treatment is used
Pathologic scar patient's 30 examples of selecting hospital for plastic surgery to go to a doctor, BIAO and BEN needs the BIAO and BEN through plastic surgery treatment for 5-8 month pathologic scar in burn back, male's 12 examples wherein, women's 18 examples; Age 17-39 year; The cicatrix position is respectively ear-lobe, chest, shank.Method for using: 5% captopril emulsifiable paste external cicatrix position, 3 times/day, each 5-100mg/cm
2Use the back respectively at 0.5 hour, 1 hour, 2 hours monitoring blood pressures; Use after 3 months evaluation scar treatment situation, be respectively that effect is good, improvement, invalid, serious.Anaphylaxis and other untoward reaction of skin do not take place after using 3-7 month in the patient, do not monitor the blood pressure situation that obviously fluctuates.The visible cicatrix color and luster through the captopril treatment of gross examination of skeletal muscle and histological observation is dark red, surface elevation, and quality is softer; But not the cicatrix color of captopril treatment is redder, rough surface, and quality is harder.The visible pathologic scar collagen content through the captopril treatment of histological observation is less, marshalling; But not the pathologic scar collagen content of captopril treatment is many, arrangement disorder.The cicatrix evaluation result is that 22 routine patient's effects are good, and 8 examples are effect improved.Improvement rate 100%, obviously improvement rate 73.3%.
Experimental example 2: postoperative patient prophylactic use
Patient with operation 30 examples of selecting hospital for plastic surgery to go to a doctor are carried out prophylactic use to wound site.Male's 15 examples wherein, women's 15 examples, age 6-33 year.Method for using 5% captopril emulsifiable paste external surgical wound position, 3 times/day, each 5-100mg/cm
2Use the back respectively at 0.5 hour, 1 hour, 2 hours monitoring blood pressures; Use evaluation scar treatment situation after 3-6 month, be respectively that scar hyperplasia is serious, moderate hypertrophy, no hypertrophy.Anaphylaxis and other untoward reaction of skin do not take place after using 3-7 month in the patient, do not monitor the blood pressure situation that obviously fluctuates.Scar hyperplasia does not take place in 29 examples, and 1 routine patient's wound moderate hypertrophy continues to use after 3 months doing well,improving to occur.Prevention hypertrophy effect is very obvious.
Experimental example 3:MTT detects
Experiment is divided into 4 groups, and K0 represents matched group, and it is the experimental group of 1,5,10 μ g/L that K1, K5, K10 represent drug level respectively, and MTT1-5 represents the fibroblast of 5 keloid samples respectively.After experiment was divided into groups, it is unicellular that (1) becomes it with 0.25% trypsin digestion and cell, and the RPMI RPMI-1640 that usefulness contains 10% hyclone is made into the single cell suspension of 1 * 109 cell/L, with cell inoculation in 96 well culture plates, every hole 100 μ L.(2) culture plate is put in the CO2 incubator, under 37 ℃ of 5%CO2 conditions, cultivated 3～5 days.(3) cultivate after 3～5 days, every hole adds MTT solution and (MTT is dissolved in 0.01mol/L by 5mg/mL, among the PBS of pH7.2; Piping and druming is dissolved to whole gently, filtration sterilization, and 4 ℃ keep in Dark Place; Holding time generally was no more than for two weeks) 10 μ L, continue to put incubator and hatched 3～6 hours, stop cultivating; Add 37 ℃ of numbers in 10%SDS-HCl100 μ L/ hole hour, make in the cell and fully dissolve with pericellular MTT granule.(4) measure each hole absorbance value (OD) with enzyme-linked immunosorbent assay instrument, select wavelength 490nm, on enzyme-linked immunosorbent assay instrument, measure each hole absorbance.Data show that the medicine cell growth has direct repression, along with dosage increases, and MTT numerical value decline (table 1).
The MTT value of table 1 different pharmaceutical concentration
| Experimental group | MTT1 | MTT2 | MTT3 | MTT4 | MTT5 |
| K0 | 0.1206 | 0.081 | 0.068 | 0.0812 | 0.5462 |
| K1 | 0.1234 | 0.0638 | 0.0734 | 0.0634 | 0.4814 |
| K5 | 0.1094 | 0.0516 | 0.0558 | 0.0428 | 0.4566 |
| K10 | 0.1042 | 0.045 | 0.057 | 0.041 | 0.4324 |
Experimental example 4: in situ hybridization
TGF-β 1mRNA in situ hybridization test kit gets company available from the Wuhan doctor.BIAO and BEN-70 ℃ refrigerator takes out, concentrate the section of freezing 10 μ m series after, through the fixing 15min of 40g/L paraformaldehyde-phosphate buffer; Include 0.4g/L baycovin (DEPC), pollute, adopt TGF-β 1mRNA in situ hybridization test kit to eliminate the exogenous rna enzyme; Operation is undertaken by the test kit description, and all vessel are all used the DEPC water treatment of 1g/L in the operation, and 200 ℃ of high temperature 4 hours; Sterilization enzyme inactivation is established the negative control that does not add probe simultaneously.TGF-β mRNA mainly is expressed in the fibroblast endochylema in the pathologic scar, and few part is expressed in the basal layer cell endochylema.Analysis result demonstration shown in Figure 1 TGF-β 1mRNA in the case property cicatrix of captopril treatment expresses obviously and reduces, and kytoplasm is light to be dyed, and with non-captopril treatment group TGF-β 1mRNA expression shown in Figure 2 significant difference (P＜0.01) is arranged on the statistics.
Experimental example 5: immunohistochemical staining
The type i collagen multi-resistance gets company available from the Wuhan doctor, and two anti-are EnVision system of Denmark DAKO company.Germany KONTRON IBAS 2.5 automated image analysis systems, Japanese TVC ky-F30B 3-CCD chromatic image is shot with video-corder the input appearance.BIAO and BEN is through FFPE, and I, III Collagen Type VI multi-resistance are adopted in the section of 4 μ m series.The two step method immunohistochemical staining is adopted in concrete operations, and the paraffin section routine dewaxes to water, and 3%H2O2 room temperature is hatched 20min, to eliminate endogenous peroxidase activity.Distillation washing 3 times, the antigen microwave is repaired 3min, phosphate buffer (PBS, 0.1mmo1/L, pH7.2) washing 3 times, it is anti-and two anti-to drip the type i collagen one of dilution in 1: 300, and PBS washes 3 times, and diaminobenzidine (DAB) develops the color, and haematoxylin is redyed, conventional mounting.Microscopically is observed, and dyes the positive unit of pale brown color, establishes simultaneously not add an anti-non-specific contrast.Light microscopic is observed down in situ hybridization and SABC result, and German KONTRON IBAS 2.5 automated image analysis systems are adopted in 10 visuals field of every section picked at random, carry out quantitative analysis, calculate average positive unit (PU) value according to positive area and gray scale.The more little positive unit of PU value is big more.Light the dying of positive expression of type i collagen in the pathologic scar of captopril treatment; Analysis result shown in Figure 3 shows that type i collagen content is less; And dense the dying of positive expression of attaching type i collagen in the pathologic scar that non-captopril is treated shown in 4; Collagen content is many, and this and Captopril group have significant difference (P＜0.05).
Claims (5)
1. captopril treats and/or prevents the application in the medicine of scar hyperplasia property disease as preparation.
2. the application of captopril as claimed in claim 1 is characterized in that: described disease is a hypertrophic cicatrix.
3. the application of captopril as claimed in claim 1 is characterized in that: described disease is a keloid.
4. the application of captopril as claimed in claim 1 is characterized in that: described disease is the urethra cicatricial stricture.
5. the application of captopril as claimed in claim 1 is characterized in that: described disease is the silicon gel prosthese postoperative capsule contracture of enlarging the bosom.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432145A (en) * | 2013-07-01 | 2013-12-11 | 宁夏医科大学 | Scar treatment external application western medicine composition preparation and application thereof |
| CN107617107A (en) * | 2017-09-18 | 2018-01-23 | 浙江大学 | A kind of anti-scar preparation of compound Angiotensin-Converting class |
| CN107648611A (en) * | 2017-09-18 | 2018-02-02 | 浙江大学 | The anti-cicatrix externally used preparation of compound Angiotensin-Converting class |
| CN113209312A (en) * | 2021-05-06 | 2021-08-06 | 吉林大学 | Application of reagent for inhibiting expression of transcription factor MEF2C in preparation of medicine for treating keloid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1668312A (en) * | 2002-05-13 | 2005-09-14 | 洛杉矶儿童医院 | Treatment and prevention of abnormal scar formation in keloids and other cutaneous or internal wounds or lesions |
-
2010
- 2010-07-28 CN CN2010102396749A patent/CN102335167A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1668312A (en) * | 2002-05-13 | 2005-09-14 | 洛杉矶儿童医院 | Treatment and prevention of abnormal scar formation in keloids and other cutaneous or internal wounds or lesions |
Non-Patent Citations (2)
| Title |
|---|
| 肖刚等: "转化生长因子β1对病理性瘢痕中成纤维细胞增殖及凋亡水平的影响", 《实用医学杂志》, vol. 24, no. 13, 31 December 2008 (2008-12-31), pages 2242 - 2245 * |
| 郭倩玉等: "卡托普利和氯沙坦对自发性高血压大鼠TGF-β1表达的影响", 《天津医药》, vol. 33, no. 10, 31 October 2005 (2005-10-31), pages 657 - 659 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432145A (en) * | 2013-07-01 | 2013-12-11 | 宁夏医科大学 | Scar treatment external application western medicine composition preparation and application thereof |
| CN107617107A (en) * | 2017-09-18 | 2018-01-23 | 浙江大学 | A kind of anti-scar preparation of compound Angiotensin-Converting class |
| CN107648611A (en) * | 2017-09-18 | 2018-02-02 | 浙江大学 | The anti-cicatrix externally used preparation of compound Angiotensin-Converting class |
| CN113209312A (en) * | 2021-05-06 | 2021-08-06 | 吉林大学 | Application of reagent for inhibiting expression of transcription factor MEF2C in preparation of medicine for treating keloid |
| CN113209312B (en) * | 2021-05-06 | 2022-06-03 | 吉林大学 | Application of reagent for inhibiting expression of transcription factor MEF2C in preparation of medicine for treating keloid |
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Application publication date: 20120201 |