CN104224795A - Application of chlorhematin in preparation of medicine for protecting vascular injury caused by smoking - Google Patents
Application of chlorhematin in preparation of medicine for protecting vascular injury caused by smoking Download PDFInfo
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- CN104224795A CN104224795A CN201410452768.2A CN201410452768A CN104224795A CN 104224795 A CN104224795 A CN 104224795A CN 201410452768 A CN201410452768 A CN 201410452768A CN 104224795 A CN104224795 A CN 104224795A
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Abstract
The invention relates to an application of chlorhematin in preparation of a medicine for protecting vascular injury caused by smoking. Lots of experiments prove that the chlorhematin can obviously alleviate a vascular inflammation reaction caused by smoking and has an effect of protecting the blood vessels in a smoking state. Therefore, the chlorhematin can treat the vascular inflammation injury caused by smoking and also has a protective effect of preventing the vascular inflammation injury caused by smoking. The chlorhematin is a medicine applied to clinical test, the administration route is convenient and safe, and a novel drug is increased for protecting the vascular injury caused by smoking.
Description
Technical field
The present invention relates to a kind of chlorhematin and cause application in blood vessel injury medicine in preparation protection smoking; specifically chlorhematin can either damage therapeutical effect to the vascular inflammation that smoking causes; the protective effect of the vascular inflammation damage that also having prevents to smoke causes, belongs to field of medicaments.
Background technology
Large quantity research confirms, smoking is the Major Risk Factors of many Cardial or cerebral vascular diseases and peripheral vascular disease.The sickness rate of the coronary heart disease of smoker, hypertension, cerebrovascular and peripheral angiopathy all obviously raises.Statistics shows, in coronary heart disease and patients with hypertension, 75% has smoking history.Comparatively non-smoker is high 3.5 times for the Incidence of CHD of smoker, the case fatality rate of coronary heart disease the former comparatively the latter is high 6 times, the sickness rate of myocardial infarction the former comparatively the latter is high 2 ~ 6 times.Pathological anatomy also finds, comparatively non-smoker is extensively serious for the coronary artery lesion of smoker.In cardiovascular disease death toll 30% ~ 40% is caused by smoking, and the growth of mortality rate is directly proportional to smoking capacity.
Well-known smoking can cause atherosclerosis, can vascular endothelial cell injury, and causes serum high-density LP to reduce, and low density lipoprotein, LDL raises, T-CHOL raises, prostaglandin I
2level reduces, thromboxane A
2increase, carboxyhemoglobin increases, compensatory polycythemia, blood flow slow down, microcirculation disturbance, plasma fibrinogen level increase, and Platelet increases, blood viscosity increases, blood coagulability increases and many illeffectss such as vital organ anoxia.The comprehensive long-term results of the multiple illeffects that these smokings above-mentioned cause causes atherosclerosis exactly.
Smoking mainly causes inflammation damnification and the oxidative damage of blood vessel, and then can cause atherosclerotic generation.If the statins of the atherosclerotic drug main adjusting blood lipid of the treatment of current extensive use.Say that statins may have certain preventive effect to the blood vessel injury that smoking causes from the atherosclerotic angle for the treatment of.But statins can only be applied to occurred atherosclerosis or with hyperlipemia smoker and there is certain side effect as the infringement of liver function and bring out rhabdomyolysis etc., simple smoker can not be applied to, as the smoker of the youth without any disease.And do not indicate in the description of statins and can be applied to the blood vessel injury alleviating smoking and cause.Strictly say still there is no a kind of medicine to clearly state can be used for the blood vessel injury protecting smoking to cause at present.
Certain smoking cessation is directly the most basic method, but current most people still cannot give up smoking.Have statistics show that the people in the whole world 20% is in smoking, and in Chinese Adult the people of 60% in smoking.The object that we study this medicine is exactly want these crowds that cannot give up smoking are benefited.
Chlorhematin is a kind of chemicals of synthetic, is the chloride of natural pigment haemachrome.English name is hemin.Another name: Chloro (protoporphyrinato) iron (III); Chlorohemin; Chloroprotoporphyrin IX iron (III); Ferriprotoporphyrin IX; Chloride Hemin (chloride); Ferrous porphyrin; Hydrochloric acid haemachrome; Protohemin; Protoferriheme; Hemin.Molecular formula is C
34h
32clFeN
4o
4, molecular weight is 651.94.Chlorhematin generally extracts from Sanguis sus domestica, is widely used in medicine, food, health product, and it is a kind of important medicine, health product and food additive.
Chlorhematin as iron strengthen, have bioavailability high, without the advantage of the untoward reaction such as ferrum accumulate poisoning and gastrointestinal irritation in body.This is because chlorhematin absorbs with molecular forms, can directly be absorbed by intestinal mucosa.Chlorhematin is the biological source of iron of preventing and treating iron deficiency anemia that modern medicine is generally acknowledged.Its feature be absorbance high, effective, without iron taste, not stimulating gastrointestinal, be infant, the iron supplement of anemia of pregnant woman's first-selection enrich blood product.
Large quantity research has confirmed that chlorhematin has powerful antiinflammatory and anti-oxidative damage and cytoprotection.Can the generation of DELTA rHO-1 in inductor, and then haemachrome can be decomposed into bilirubin, nitric oxide and bivalence free iron.These materials all have the effect of powerful antiinflammatory, anti-oxidative damage and cytoprotective in vivo.In a word, chlorhematin, as a kind of important medicine and health product, not only has the effect for the treatment of and prevention iron deficiency anemia, and have potential using value in cell and Organoprotective.But chlorhematin carries out protection to the blood vessel injury that smoking causes there is no reported in literature.
Summary of the invention
The object of the invention is, according to chlorhematin, there is powerful antiinflammatory and anti-oxidative damage and cytoprotection and provide chlorhematin preparing the application in the blood vessel injury medicine protecting smoking to cause, thus being that the blood vessel injury that protection smoking causes increases new medicine.
The object of the invention is to be realized by following technical proposal:
Chlorhematin causes the application in blood vessel injury medicine in preparation protection smoking, described chlorhematin structural formula is as shown in formula I:
Formula I.
Medicine of the present invention can make the various ways such as tablet, powder, granule, capsule, oral liquid, unguentum.The medicine of above-mentioned various dosage form all can be prepared according to the conventional method of pharmaceutical field.
One or more pharmaceutically acceptable carriers can also be added in medicine of the present invention.Described carrier comprises the diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, absorption carrier etc. of pharmaceutical field routine, can also add flavouring agent, sweeting agent if desired.
Due to take technique scheme make the technology of the present invention have technology with oneself compared with tool have the following advantages and effect:
A (), chlorhematin can either damage therapeutical effect to the vascular inflammation that smoking causes, the protective effect of the vascular inflammation damage that also having prevents to smoke causes;
B () chlorhematin obviously can alleviate the vascular inflammation reaction of smoking induction, shield to the blood vessel under smoking state;
C () chlorhematin has been applied to clinical oral healthcare medicine, route of administration is convenient, safety.
Accompanying drawing explanation
Fig. 1 is the expression that chlorhematin suppresses NF-κ B in lung of smoking rats carotid artery;
Fig. 2 is the expression of NF-κ B in each group of rat carotid artery;
Fig. 3 is the expression that chlorhematin suppresses MCP-1, ICAM-1, VCAM-1 in lung of smoking rats carotid artery;
Fig. 4 is the expression of MCP-1, ICAM-1, VCAM-1 in each group of rat carotid artery;
Fig. 5 is the expression that chlorhematin suppresses IL-1 β, IL-6, TNF-α in lung of smoking rats carotid artery;
Fig. 6 is the expression of IL-1 β, IL-6, TNF-α in each group of rat carotid artery;
Fig. 7 is the expression of eNOS in chlorhematin induction lung of smoking rats carotid artery;
Fig. 8 is the expression of eNOS in each group of rat carotid artery;
Fig. 9 is that chlorhematin suppresses thickening of the tunica intima that causes of smoking;
Figure 10 is the Intimal area of each group of rat carotid artery and the ratio situation of media area.
Detailed description of the invention
Embodiment 1:
1) experiment purpose
Smoking mainly causes inflammation damnification and the oxidative damage of blood vessel.This experiment mainly illustrates from the angle of inflammation damnification the infringement that smoking causes blood vessel, and the therapeutical effect of chlorhematin to the vascular inflammation damage that smoking causes is described, a series of inflammatory factor of this experiment carrys out the inflammation damnification of label vascular.Inflammatory factor comprises: NF-κ B, MCP-1, ICAM-1, VCAM-1, IL-1 β, IL-6, TNF-α.The Chinese of above inflammatory factor is followed successively by: nuclear transcription factor-kappa B, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, interleukin-1 ' beta ', interleukin-6, tumor necrosis factor-alpha.
2) experimental technique:
Select 15 SPF level male SD rats, the scale of construction 350 ± 20g, is provided by Beijing Vital River Experimental Animals Technology Co., Ltd., and BJ Union Hospital's Experimental Animal Center is raised.Experimental rat is divided into 3 groups at random, often organizes 5.Be grouped as follows: A group-matched group-control, B group-smoking group-smoking, C group-smoking also injects chlorhematin group-smoking and injected with melatonin.B group and C group rat are placed in smoking apparatus smoking, smoking every day 1 time, each smoking 10.Cigarette tar oil mass: 13mg/ props up, nicotine amount: 1.2mg/ props up, CO measures: 14mg/ props up.Light 2 medicated cigarettes, the rear rest 5min that burnt continues smoking more at every turn simultaneously.A group rat every day and B, C group rat are synchronously placed in independent smoking apparatus, but namely igniting cigarette is not exposed in air.C group rat, every other day lumbar injection chlorhematin 1 time, dosage is 50mg/kg.A group and B group rat inject the normal saline of equal volume every other day.Smoking is got each group of rat carotid artery specimen and is placed in liquid nitrogen and preserves after 21 days.
3) detection method:
Application Western blot method detects the expression of above-mentioned inflammatory factor and eNOS in each group of carotid artery specimen.The Chinese of eNOS is endothelial cell nitric oxide synthase, is a kind of vascular protection factor.Specific implementation method is: taken out from liquid nitrogen by each carotid artery tissue specimen and be placed in mortar, grinds to form tissue homogenate after adding 200 μ l Tissue lysates.Tissue homogenate 100 DEG C is boiled the centrifugal 10min of 12000rpm room temperature after 10 minutes, get its supernatant.BCA method is surveyed protein concentration and is calculated applied sample amount.10%SDS-PAGE electrophoretic separation albumen, every hole 20 μ g sample protein 140V electrophoresis 60min.Then by protein delivery on NC film, 330mA transferring film 60min.The bovine serum albumin of 5% closes NC film.Spend the night with the antibody incubation NC film of the above-mentioned factor at 4 DEG C.TBST rinses 3 times, and under room temperature, two of horseradish peroxidase-labeled anti-hatch 1h, and TBST develops after again rinsing 3 times.With the gray value of AlphaEaseFC software measurement band, by capable for the gray value of each group statistical analysis.
4) experimental result:
The expression of inflammatory factor in 4.1 each group carotid artery, in table 1
The expression of inflammatory factor in carotid artery respectively organized by table 1
Experimental result shows, and in B group-smoking group rat carotid artery, the expression of above-mentioned inflammatory factor is significantly higher than the carotid artery of A group-control rats.C group-smoking the expression of injecting inflammatory factor in chlorhematin group rat carotid artery are significantly lower than the carotid artery of B group-smoking group rat.These results display smoking can cause the increase of above inflammatory Cytokines Expression in blood vessel wall, shows that smoking causes the inflammation damnification of blood vessel.And after applying chlorhematin, in blood vessel wall, the expression of above inflammatory factor obviously reduces again, this illustrates that chlorhematin can alleviate the inflammation damnification of the blood vessel wall that smoking causes, and can play therapeutical effect to the blood vessel under smoking state.As shown in Figures 1 to 6, B group compared with A group or C group,
*p < 0.01,
#p < 0.05.
The expression of eNOS in 4.2 each group carotid artery, in table 2
The expression of eNOS in carotid artery respectively organized by table 2
Experimental result shows: in B group-smoking group rat carotid artery, the expression of eNOS is significantly lower than the carotid artery of A group-control rats.C group-smoking the expression of injecting eNOS in chlorhematin group rat carotid artery are significantly higher than the carotid artery of B group-smoking group rat.These results display smoking can cause the minimizing of the eNOS in blood vessel wall with protective effect, shows that smoking can cause the reduction of " the self-protection effect " of blood vessel, can cause damage to blood vessel.And after applying chlorhematin, the eNOS in blood vessel wall increases again, this shows that chlorhematin has protective effect to the blood vessel under smoking state.As shown in Figure 7, Figure 8, B group compared with A group or C group,
*p < 0.01.
Embodiment 2:
1) experiment purpose:
Blood vessel wall there will be the change of blood vessel morphology after sustaining damage and comprising mechanical injuries, inflammation damnification and oxidative damage, namely the thickening and tube chamber narrow of inner membrance.The damage that smoking causes blood vessel is nonmechanical injury and inflammation damnification and oxidative damage mainly, and this damage causes the narrow required time of thickening of tunica intima and tube chamber long, not too easily observes.By capable for rat carotid artery balloon injured, then carry out smoking to rat more on this basis, the blood vessel morphology change so just making smoking cause can display at short notice.And then on this animal model, observe the protective effect of chlorhematin to the blood vessel injury that smoking causes.
2) experimental technique:
Select 15 SPF level male SD rats, the scale of construction 350 ± 20g, is provided by Beijing Vital River Experimental Animals Technology Co., Ltd., and BJ Union Hospital's Experimental Animal Center is raised.Rat is divided into 3 groups at random, often organizes 5.Be grouped as follows: I group-matched group-balloon injured group-control, II group-balloon injured+smoking group-smoking, III group-balloon injured+smoking+injection chlorhematin group-smokingand injected with melatonin merely.II group and III group of rat are placed in smoking apparatus smoking, smoking every day 1 time, each smoking 10.Cigarette tar oil mass: 13mg/ props up, nicotine amount: 1.2mg/ props up, CO measures: 14mg/ props up.Light 2 medicated cigarettes, the rear rest 5min that burnt continues smoking more at every turn simultaneously.I group of rat every day and II, III group of rat are synchronously placed in independent smoking apparatus, but namely igniting cigarette is not exposed in air.III group of rat, every other day lumbar injection chlorhematin 1 time, dosage is 50mg/kg.I group and II group of rat inject the normal saline of equal volume every other day.Each group of rat, after 7 days, is implemented carotid thrombosis by smoking.Namely by the external carotid artery of rats with left, the Forgarty of 2F is got bolt conduit and be placed in common carotid artery, after injecting 0.05ml normal saline in sacculus, sacculus is dragged in common carotid artery 3 times back and forth with injured blood vessel endothelium.Continued to give smog and air exposure by each group of rat afterwards, scheme is the same.By each group of rat anesthesia after 14 days, the common carotid artery of balloon injured section is taken out, be placed in the fixing preservation of 4% paraformaldehyde.
3) detection method
With paraffin, each group of carotid artery specimen is embedded.Then by capable for paraffin mass 5um ultrathin section.Afterwards by each slice row Verhoeff-Van Gieson elastin dyeing.Section is placed in basis of microscopic observation and takes pictures.Region inside and outside blood vessel wall between elastic membrane is defined as film in blood vessel, and the region within interior elastic membrane is defined as tunica intima.With the area of Image Pro6.0 software measurement tunica intima and tunica media.The stenosis of blood vessel is represented with Intimal area/media area (i/m).Each group of carotid i/m value row statistical analysis is compared.
4) experimental result: in table 3
Ratio (i/m) situation of carotid Intimal area and media area respectively organized by table 3
Experimental result shows, and normal carotid tunica intima is very thin, and as shown in the normal carotid artery of Fig. 9, i/m is almost nil, and wherein i represents tunica intima, and m represents tunica media.The carotid artery of the I group-simple carotid tunica intima compared with normal of balloon injured group obviously thickens, and shows that the mechanical injuries of sacculus cause damage to blood vessel wall, causes the narrow of vessel lumen.The tunica intima of II group-balloon injured+smoking group obviously thickens compared with I group, and i/m value obviously increases compared with I group.This shows that the damage that II group of blood vessel is subject to obviously increases compared with I group, and that is smoking causes the damage of non-mechanical to blood vessel.The tunica intima of III group-balloon injured+smoking+injection chlorhematin group is obviously thinning compared with II group, and i/m value obviously reduces compared with II group.This illustrates that the damage that III group of blood vessel is subject to obviously reduces compared with II group, and that is chlorhematin alleviates the blood vessel injury that smoking causes.These results show the protective effect of chlorhematin to the blood vessel injury that smoking causes.As shown in Figure 9, Figure 10, II group compared with I group or III group,
*p < 0.01.
Claims (1)
1. chlorhematin causes the application in blood vessel injury medicine in preparation protection smoking, and described chlorhematin structural formula is as shown in formula I:
Formula I.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105854004A (en) * | 2016-05-05 | 2016-08-17 | 中国医学科学院病原生物学研究所 | Application of heme in resisting influenza virus |
-
2014
- 2014-09-05 CN CN201410452768.2A patent/CN104224795A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| ANNE BURKE ET AL.: "Oxidative Stress and Smoking-Induced Vascular Injury", 《PROGRESS IN CARDIOVASCULAR DISEASES》 * |
| BRIAN K. NORDSKOG ET AL.: "Matrix-Degrading and Pro-Inflammatory Changes in Human Vascular Endothelial Cells Exposed to Cigarette Smoke Condensate", 《CARDIOVASCULAR TOXICOLOGY》 * |
| 郭钰珍等: "氯血红素诱导人脐静脉内皮细胞血红素氧合酶表达及其对血管保护作用", 《中国医师杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105854004A (en) * | 2016-05-05 | 2016-08-17 | 中国医学科学院病原生物学研究所 | Application of heme in resisting influenza virus |
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Application publication date: 20141224 |
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