CN104188957B - Medicine for preventing and curing restenosis, and preparation method and using method thereof - Google Patents
Medicine for preventing and curing restenosis, and preparation method and using method thereof Download PDFInfo
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- CN104188957B CN104188957B CN201410232851.9A CN201410232851A CN104188957B CN 104188957 B CN104188957 B CN 104188957B CN 201410232851 A CN201410232851 A CN 201410232851A CN 104188957 B CN104188957 B CN 104188957B
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Abstract
The invention discloses a medicine for preventing and curing restenosis and a preparation method and a using method thereof. The effective components of the medicine include guaianese squiterpenes compounds P1, P2 and P3, wherein P1 is Zedoalactone B; P2 is a stereoisomer of P1; P3 is Zedoarondiol; and the effective components are extracted from Curcum lump powder by water bath, ultrafiltration separation, nanofiltration concentration, chromatographic purity analysis and nuclear magnetic resonance structure comparison. The using method of the medicine is to coat a carrying device with the medicine taking the compounds P1, P2 and P3 as the effective components. The medicine can prevent and cure restenosis, and compared with a conventional sirolimus-eluting stent, the medicine can inhibit the proliferation of vascular smooth muscle cells and inflammatory responses of vascular walls. Besides, the medicine can promote healing of vascular endothelial cells, avoids long-term thrombotic complications; and the dose is low, the cost is low and toxic or side effects are avoided.
Description
Technical field
The present invention relates to Chinese medicine extract field, and in particular to it is a kind of with guainane type sesquiterpenoid for it is effective into
Point preventing and treating restenosiss medicine, the method for the medicine and the using method of the medicine are prepared with Rhizoma Curcumae.
Background technology
At present, PCI (percutaneous coronary intervention, PCI) is treatment
The main method of coronary heart disease, but the major defect of such method is the postoperative restenosis for discharging support portions.And Ink vessel transfusing blood
Bolt formation, elastical retraction, Artery Remodeling, neointimal hyperplasia, smooth muscle hyperplasia, vascular remodeling and inflammation etc. are to cause
The principal element that restenosiss occur.
In order to solve the problems, such as restenosiss, recent domestic is generally pressed down using the coated medicament layer on traditional support
The generation of restenosiss phenomenon processed, such as medicine such as rapamycin, paclitaxel figure layer support, after prevention coronary artery balloon expandable
Restenosiss aspect obtains remarkable break-throughs, but because such medicine can suppress the healing of blood vessel injury inner membrance after balloon expandable, it is at a specified future date
Thrombus complication substantially increases, and several clinical trials and meta-analysises result show that such bracket for eluting medicament may increase extremely
Die or incidence rate of myocardial infarction (Thrombosis in sten), long-term prognosis are not better than conventional bare metal stent, Acute myocardial
Infarction PTCA or and STENTS the events of heart attack incidence rate annual 20% or so, and using the incidence rate of restenosiss after Western medicine coating bracket
Still 10% or so.Additionally, coating stent of medicine is expensive, one piece of import support is up to 2.0 ten thousand or so, it is impossible to be adapted to state of China
Feelings Popularization And Development, has been significantly greatly increased the financial burden of medical treatment cost and patient.
For the pathophysiological mechanism of restenosiss, the antithrombotic having in theory, antiinflammatory and anti-cell migration, propagation are made
Medicine should all have the effect of prevention of restenosis, but the result of study of the postoperative whole body applications of Jing PCI these medicines makes us losing
Hope, the effect for not only reducing restenosiss is limited, it is important to which the toxic action of some of which medicine and side reaction are serious.
The content of the invention
In order to overcome above-mentioned the deficiencies in the prior art, the invention provides a kind of medicine of preventing and treating restenosiss, and
Accordingly there is provided the method for preparation and use of the medicine, the medicine can not only prevent and treat restenosiss, and with existing rapamycin
Support etc. is compared, and can suppress the inflammatory reaction of vascular smooth muscle cell proliferation, blood vessel wall, can also promote blood vessel endothelium thin in addition
The healing of born of the same parents, it is to avoid thrombus complication at a specified future date, and consumption is few, low cost, have no toxic side effect.
A kind of medicine of preventing and treating restenosiss that the present invention is provided, effective ingredient includes guainane type sesquiterpenoid
P1, P2 and P3；
The P1 is Zedoalactone B, and its structural formula is：
The P2 is the stereoisomer of the P1, and its structural formula is：
The P3 is Zedoarondiol, and its structural formula is：
The mass ratio of described guainane type sesquiterpenoid P1, P2, P3 is：P1:P2:P3=(16～64):(2.5
～10):(25～100)
The mass ratio of described guainane type sesquiterpenoid P1, P2, P3 is：P1:P2:P3=32:5:50.
A kind of preparation method with the medicine for preparing above-mentioned preventing and treating restenosiss, including the step for extracting its effective ingredient as follows
Suddenly：
(1) first Rhizoma Curcumae block powder Jing water-baths extraction will be extracted into the centrifugation of sample liquid pipeline, obtains CEF；
(2) and then by CEF ultra-filtration and separation is carried out, obtains ultrafiltration permeate and ultra-filter retentate；
(3) again ultrafiltration permeate carried out into nanofiltration concentration, obtains nanofiltration liquid；
(4) chromatographic purity analysis and NMR structure contrast are finally carried out to nanofiltration liquid, compound P1, P2, P3 is obtained.
The Rhizoma Curcumae is zingiberaceous plant Rhizoma Curcumae (Curcum a phaeocaulis.Val1), Guangxi zedoary (Curcum a
Kw angsiensis S.G.Lee et C.F.Liang) and RADIX CURCUMAE (Curcum a wenyujin Y.H.CHen et
C.Ling dry rhizome).Herbaceos perennial, mainly originates in the ground such as Guangxi, Yunnan, Sichuan.
A kind of using method of the medicine of above-mentioned preventing and treating restenosiss, is that compound P1, P2, P3 are coated in into a carrying apparatus
On.
Preferably, the carrying apparatus is internal lumen inner bracket.
Preferably, the drug loading of the internal lumen inner bracket is (0.7-0.9) μ g/mm2.
Preferably, the internal lumen inner bracket is mounted in advance on rapid-exchange version foley's tube.
Preferably, above-mentioned using method also includes carrying out the internal lumen inner bracket process of 60Coradiation sterilizing.
The present invention has the advantages that：
(1) inflammatory reaction of vascular smooth muscle cell proliferation and blood vessel wall can be suppressed, particularly with existing medicine phase
Than the healing that can also promote vascular endothelial cell, it is to avoid thrombus complication at a specified future date, the incidence rate of restenosiss is reduced；
(2) carry out extracting the effective ingredient of medicine by natural Chinese medicine Rhizoma Curcumae, the chemical constitution of effective ingredient understands, makes
For technical maturity, extraction ratio is high, facilitate large-scale production, saves production cost；
(3) medicinal application for providing the present invention is when the internal lumen inner bracket, under the conditions of drug loading is less
The effect that effectively preventing and treating restenosiss occur is reached, cost is not only reduced and is also avoided that the adverse effect excessively brought because of consumption；
(4) with the preventing and treating restenosis medicaments ratio such as existing rapamycin without other toxic and side effects.
Description of the drawings
Figure 1A is the cross-sectional view of vessel segment when drug stent of the present invention (ZES) is implanted into 30 days；
Figure 1B is the cross-sectional view of vessel segment when rapamycin support (SES) is implanted into 30 days；
Fig. 1 C are the cross-sectional view of vessel segment when bare metal stent (BMS) is implanted into 30 days；
Fig. 2A is the cross-sectional view of vessel segment when drug stent of the present invention (ZES) is implanted into 90 days；
Fig. 2 B are the cross-sectional view of vessel segment when rapamycin support (SES) is implanted into 90 days；
Fig. 2 C are the cross-sectional view of vessel segment when bare metal stent (BMS) is implanted into 90 days；
Fig. 3 A are scanning electron microscope analysis figure when drug stent of the present invention (ZES) is implanted into 90 days；
Fig. 3 B are scanning electron microscope analysis figure when rapamycin support (SES) is implanted into 90 days；
Fig. 3 C are scanning electron microscope analysis figure when bare metal stent (BMS) is implanted into 90 days；
Fig. 4 is the cross-sectional structure schematic diagram of drug stent of the present invention (ZES)；
Fig. 5 is the overall structure diagram of drug stent of the present invention (ZES)；
In figure：1st, rest body 2, medication coat.
Specific embodiment
In order that those skilled in the art more fully understand the present invention program, with reference to the accompanying drawings and detailed description
The present invention is described in further detail.
Embodiment 1
The effective ingredient of the medicine of present invention preventing and treating restenosiss is extracted from Rhizoma Curcumae, concrete extracting method is：
1. sample pretreatment process
Extract：(1-10) Kg Rhizoma Curcumae bulk powders are weighed, is extracted in two batches.Add 10L, 95 DEG C of water-baths to rotate 2 hours, carry
Take 3 times.The sample liquid of extraction is merged and is centrifuged, obtain about 43.5L CEFs, 50mL is taken respectively and is kept sample analysis.
Ultra-filtration and separation:43.5L CEFs are added in the material fluid bath of membrance separation instrument, ultra-filtration and separation is carried out (hollow
Fibrous membrane UF, model PS06, membrane area 4.0M2, numbering 09-0114), (reason is before ultrafiltration to obtain ultrafiltration permeate 43L or so
Do not drain water), ultra-filter retentate 3.5L takes respectively 50mL and keeps sample, analyzes.
Nanofiltration is concentrated:43L ultrafiltrate permeate is added in nanofiltration instrument, frequency is adjusted to 20Hz, adjusts liquid outlet
Pressure is 0.5MPa, obtains nanofiltration retentate fluid 3.9L, and nanofiltration permeate liquid 40.1L takes respectively 50mL and keeps sample, analyzes.
2. the preparation X1 of Rhizoma Curcumae guainane type sesquiterpene Chinese medicine is prepared (prepared by the first dimension)
Chromatographic column is activated with 95% ethanol of 3 times of column volumes, then process is balanced with the water of 2 times of column volumes,
Then take 1.9L nanofiltration liquid loadings, then Jing washings, 3 times of column volumes 10%-50% ethanol repeatedly drip washing 5 times, eluting, wash post,
Fraction merging obtains F6, F7, F8, F9, F11, F12, F16 fractions, and main peak target is P1, P2, P3.
3. the C18HC posts of Rhizoma Curcumae guainane type sesquiterpene Chinese medicine are prepared (prepared by the second dimension)
It is prepared by peak P1：
Sample preparation：Take Rhizoma Curcumae F6 sample 190mg to be dissolved in 10mL water, concentration is about 20mg/mL；F7-9 sample 400mg
In being dissolved in 20mL water, concentration is about 20mg/mL.Preparation condition：Chromatographic column：C18HC (20 × 250mm, 10m, numbering
12041901A)；Flow velocity：20mL/min, detector：275nm, 240nm；Sample size：5mL.Peak P1 prepares elution requirement and is shown in Table 1.
The peak P1 of table 1. prepares elution requirement
Peak P2 is prepared (F11 samples)
Sample preparation：Take Rhizoma Curcumae F11, F12 sample 350mg to be dissolved in 10mL water, concentration is about 35mg/mL, then Jing water
Membrane filtration mistake.Chromatographic column：C18HC (20 × 250mm, 10m, numbering 12041901A)；Flow velocity：20mL/min；Detector：275nm,
240nm；Sample size：1mL.Actual conditions is shown in Table 2.
The peak P2 of table 2. prepares elution requirement
Peak P3 is prepared (F16 samples)
Sample preparation：Take Rhizoma Curcumae F16 sample 350mg to be dissolved in 20mL water, concentration is about 17mg/mL, then the filter of Jing moisture films
Cross.Chromatographic column：C18HC (20 × 250mm, 10m, numbering 12041901A)；Flow velocity：20mL/min；Detector：275nm,
240nm；Sample size：1mL.Actual conditions is shown in Table 3.
The peak P3 of table 3. prepares elution requirement
The purity analysis and structural characterization of 4.P1, P2 and P3
Chromatographic purity is analyzed：
Instrument：Alliance6；Chromatographic column：C18TDE (4.6 × 150mm, 5m, numbering 110517-5), flow velocity：1mL/
min；Detector：275nm、240nm；Sample size：50L；Elution requirement：Gradient elution.Elution requirement is shown in Table 4.
What the chromatographic purity of table 4. was analyzed prepares elution requirement
| Time (min) | Acetonitrile mass percent | 0.1% formic acid-water quality percentage ratio |
| 0 | 5 | 95 |
| 20 | 40 | 75 |
| 25～30 | 95 | 5 |
The structural characterization of P1, P2 and P3：P1=20mg, P2=2.7mg, P3=25.5mg are obtained after eluting.With respect to peak face
Product purity analysis result shows that the purity of P1 is 98.44% for the purity of 96.26%, P3 for the purity of 99.06%, P2.
Understand that these three compounds are guainane type sesquiterpene with the contrast of document nuclear magnetic data, wherein P1 is
Zedoalactone B, P2 are the stereoisomer of P1, and P3 is Zedoarondiol, and its structural formula is as follows：
Test example 1
Zoopery
1st, animal and packet：Using regular grade Chinese miniswine 36, provided by China Agricultural University, male and female half and half, body
Weight (25-30) kg, is randomly divided into Rhizoma Curcumae extract coating bracket group (ZES), rapamycin eluting stent group (SES) and bare metal
Three groups of support (BMS), 12 per group.
2nd, prepared by Rhizoma Curcumae extract coating bracket：Based on 316L stainless steel metal nanometer micropore bare brackets, surface applies
The medicine provided in embodiment 1 is covered, the consumption of P1, P2, P3 is followed successively by medicine：32mg, 5mg, 50mg, the medicine of mixing is added
Enter corresponding ultrapure aqueous solvent, be configured to the solution of 2.5% concentration, be sprayed on support, nominal drug loading is 0.83 μ g/mm2。
Support is mounted in advance on rapid-exchange version foley's tube.All stent lengths are 15mm, 2.5～3.0mm of diameter, using Co 60 spoke
According to sterilizing.316L stainless steel metal nanometer micropore bare brackets and rapamycin Nano supports (nominal drug loading 2-20 μ g/mm2,
Frame matrix is also 316L stainless steel metal nanometer micropore supports) prepared and carried by general (Beijing) Medical Devices Co., Ltd. of pleasure
For.The structural representation of support refer to Fig. 4, and support is by rest body 1 and said medicine coating 2 (Rhizoma Curcumae extract coating) group
Into.The overall structure of support refers to Fig. 5, naturally it is also possible to make adaptability tune to the planform according to actual needs
It is whole.
3rd, experimentation：Start within preoperative 3 days to give aspirin 300mg daily, clopidogrel 50mg is daily.Set up vein to lead to
Road, after weighing, using intramuscular injection pentobarbital 0.5mg/kg and ketamine 10mg/kg intravenous injection combined anesthesias.Coronary angiography with
Seldinger methods puncture pig femoral artery and are placed into 6F arterial sheaths, and Jing sheaths give heparin 200U/kg, row selectivity coronary artery
Radiography.Stent Implantation diameter is 1.2 with target vessel diameter ratio:1, it is implanted in anterior descending branch, Circumflex branch and right arteria coronaria respectively same
Support is each one piece.As left Circumflex branch diameter it is less, then by the right arteria coronaria of two pieces of stenter to implant, continuous cardiac monitoring in art.It is postoperative
The common grain trough of single cage feeds observation, aspirin 100mg once a day, clopidogrel 50mg once a day, until experiment
Terminate.
4th, prepared by specimen：Anesthesia put to death laboratory animal after open immediately breast take out heart after, be put into containing 25000 units heparins,
In the 1000ml normal saline of 60mg papaverine, stretch into 7F from ascending aorta and expand pipe respectively to left and right coronary opening, use the liquid
Flushing arteria coronaria 3-4 time.Free heart Jing ascending aortas are stretched into into 7F and expands pipe to left ventricle, pricked heart with mosquito forcepss envelope and respectively go out
Mouthful, with pressue device with the pressure continuous pouring 15 minutes of 100mmHg under pressure monitoring.Separation anterior descending branch, Circumflex branch, the right side are coronal
Arterial bracket inserts place's vessel segment, and specimen of drawing materials includes support and support both sides 5mm inner regions.Proximal segment specimen Jing 2.5% penta
After dialdehyde fixes 24 hours, rinsed 3 times with 1/15M phosphate buffers, with fixing 2 hours after 1% osmic acid, respectively with 30%,
50%th, 70%, 90% ethanol and 90% ethanol acetone, 90% acetone are respectively dehydrated 10 minutes, row electron microscopic observation after dehydration；Distal section mark
After the neutral buffered formalin enhancing perfusions of this Jing 10% fix 24 hours, after row plastic embedding, continuously cutting for 5um thickness is made
Piece, row om observation after the dyeing of conventional H E.
5th, pathological analysis：
(1) after cutting into slices with HE dyeing, with LEIKA DFC300FX observation by light microscope brace sections vascular inflammations, thrombosis, interior
Film is bred.
(2) vessel wall inflammation reaction is integrated using inflammation：
0 point：NIP cell；
1 point：It is dispersed in inflammatory cell；
2 points：Support point in 25%-50% blood vessel Zhou Jing wraps 50% by inflammatory cell；
3 points：Support point in 25%-50% blood vessel Zhou Jing is wrapped completely by inflammatory cell.
(3) vascular damaged degree application lesion extent：
0 point：Interior elastic membrane is complete；
1 point：Interior Elastic membrane damage；
2 points：Interior elastic membrane and middle membrane damage；
3 points：Outer Elastic membrane damage.
(4) endothelialization is integrated：
1 point：25% luminal surface has endothelium to cover；
2 points：25%-75% luminal surfaces have endothelium to cover；
3 points：The luminal surfaces of ＞ 75% have endothelium to cover.
(5) using lightlab optical coherence tomographies (Optical Coherence Tomography, OCT) system
Ink vessel transfusing scanning imagery, measurement lumen of vessels and tunica adventitia diameter, calculated diameter stenosis rate and area stenosis rate are carried out, it is qualitative to comment
Valency support endothelium is repaired and thrombus in stents.
6th, statistical analysis：All continuous datas are represented using mean scholar's standard deviation, compare between measurement data group and use
ANOVA is checked.Enumeration data represents that enumeration data adopts X 2 test using median/percentile.Jing inspections meet normal state
Distribution, with SPSS13.0 statistical softwares data processing, P are carried out<0.05 is that difference is statistically significant.
Experimental result
1st, OCT morphological analysis 30 and ZES and SES support group average lumen diameters, average Lumen Area when 90 days, bright
It is aobvious to be more than BMS support group (P<0.05).Diameter stenosis rate, area stenosis rate are significantly lower than BMS group (P<0.05).ZES supports
Compared with SES, every Morphologic Parameters have no notable difference (P ＞ 0.05) to group, and concrete data are shown in Table 5.
The Rhizoma Curcumae extract support of table 5. inserts 30 and 90 days histomorphometric analysis results
Term is explained：ZES, SES, BMS are respectively Rhizoma Curcumae support, rapamycin support and bare metal stent, and VD is reference
Blood vessel diameter, LD are average blood vessel diameter, EELD is average adventitia diameter, Diameter stenosis are diameter stenosis rate, LA
For average Lumen Area, EELA be average adventitia area, Area stennosis be area stenosis rate, p ＜ 0.01 are compared with BMS
2nd, changes in histopathology analysis
Figure 1A -1C, 2A-2C, 3A-3C are refer to, BMS stented vessels neointimal hyperplasia substantially, occurs when being implanted into 30 and 90 days
Obvious restenosiss phenomenon, but have no that inner membrance bleed bottom and mural thrombus are formed, reconstruct without Aneurysmformation and blood vessel positivity.
Though SES supports have no restenosiss, visible part rack beam is exposed to be covered in lumen of vessels without endothelium, and has leukocyte, acidophilus
Granulocyte and a small amount of lymphocyte aggregation.Not only there is no restenosiss phenomenon in ZES, and support endothelium covers complete, has no
Thrombosiss and leukocyte and acidophil aggregation.
Above-mentioned comparing result can also be obtained by the integration of the inflammation in table 6, lesion extent and endothelialization integration data：With
SES groups compare, and ZES groups and BMS groups inflammation integration are substantially reduced；Endothelialization integrates significantly raised (P<0.05).3 groups of lesion extents
No significant difference (P ＞ 0.05).
The support of table 6. inserts 30 and 90 days histopathological analysis results
| Packet | Days | Inflammation is integrated | Lesion extent | Endothelialization is integrated |
| ZES | 30day | 0.93±0.41 | 2.36±0.63 | 3.00±0.00 |
| 90day | 0.88±0.39 | 2.17±0.45 | 3.00±0.00 | |
| SES | 30day | 1.23±0.82# | 2.33±0.52 | 2.69±0.42# |
| 90day | 1.36±0.77# | 2.26±0.44 | 2.83±0.39# | |
| BMS | 30day | 1.01±0.41 | 2.19±0.75 | 3.00±0.00 |
| 90day | 0.88±0.43 | 2.00±0.53 | 3.00±0.00 |
Note：With ZES compared with BMS, #p ＜ 0.05
Experiment conclusion
The study show that, Chinese medicine support ZES made by with Rhizoma Curcumae extract as effective ingredient, when observing for 30 days and 90 days
Substantially suppress smooth muscle cell proliferation, restenosis rate is low；Endothelium healing is complete, has no obvious thrombus in stents event.And nothing
By rapamycin or Paclitaxe-eluting stent, clinical trial all observes that implantation after-poppet sections endothelialization postpones, very
To the generation for late period thrombus in stents occur, it is possible to cause the serious consequences such as death, myocardial infarction.Additionally, in the present invention
Effective ingredient is extracted by natural Rhizoma Curcumae, and cost is relatively low, and drug loading is 0.83 μ g/mm2Left and right, not yet finds obvious
Toxic and side effects.
The said medicine coating bracket that the present invention is provided can also scribble medication coat of the present invention when actually used by above-mentioned
Support be mounted in advance on rapid-exchange version foley's tube, and carry out being used after 60Coradiation sterilization treatment.
The medicine and its preparation and application of a kind of preventing and treating restenosiss provided by the present invention have been carried out in detail above
Introduce.Specific case used herein is set forth to the principle invented and embodiment, and the explanation of above example is only
It is the core concept for being used to help understand the present invention.It should be pointed out that for those skilled in the art, not
On the premise of departing from the principle of the invention, some improvement and modification can also be carried out to the present invention, these are improved and modification also falls into
In the protection domain of the claims in the present invention.
Claims (2)
1. it is a kind of preventing and treating restenosiss medicine, it is characterised in that the effective ingredient of the medicine is by guainane type sesquiterpene
Compound P1, P2 and P3 are constituted；
The P1 is Zedoalactone B, and its structural formula is：
The P2 is the stereoisomer of the P1, and its structural formula is：
The P3 is Zedoarondiol, and its structural formula is：
The mass ratio of described guainane type sesquiterpenoid P1, P2, P3 is：P1:P2:P3=(16～64):(2.5～
10):(25～100).
2. it is according to claim 1 preventing and treating restenosiss medicine, it is characterised in that the guainane type sesquiterpene chemical combination
The mass ratio of thing P1, P2, P3 is：P1:P2:P3=32:5:50.
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| CN113347985A (en) * | 2019-01-30 | 2021-09-03 | 帝斯曼知识产权资产管理有限公司 | Use of a fraction of laurel extract for combating air pollution related diseases |
| CN116602946A (en) * | 2020-08-11 | 2023-08-18 | 中国中医科学院西苑医院 | Application of guaiane type sesquiterpene compound curcuma zedoary olone diol |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424117A (en) * | 2002-12-30 | 2003-06-18 | 中国中医研究院西苑医院 | Internal cavitary and vessel stent with medicinal coating against spinal canal restenosis and production thereof |
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2014
- 2014-05-28 CN CN201410232851.9A patent/CN104188957B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424117A (en) * | 2002-12-30 | 2003-06-18 | 中国中医研究院西苑医院 | Internal cavitary and vessel stent with medicinal coating against spinal canal restenosis and production thereof |
Non-Patent Citations (2)
| Title |
|---|
| 温郁金化学成分及药理活性研究进展;尹国平等;《中国中药杂志》;20121130;第37卷(第22期);第3354-3360页 * |
| 莪术组分涂层支架预防猪冠状动脉再狭窄的实验研究;赵福海等;《2011·中国医师协会中西医结合医师大会论文集》;20111125 * |
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