CN1208061C - Artesunate and dihydroarteannuin medicine preparation for proofing formation of blood vessel and use thereof - Google Patents
Artesunate and dihydroarteannuin medicine preparation for proofing formation of blood vessel and use thereof Download PDFInfo
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Abstract
The present invention relates to an artesunate and dihydroartemisinin medicine preparation for resisting angiogenesis and an application thereof. The medicine preparation principally contains artesunate or dihydroartemisinin, and the dosage form principally is a microsphere injection. The medicine preparation provided by the present invention has activity in resisting tumor angiogenesis and can be used for treating tumor angiogenesis and other diseases relevant to angiogenesis, and for therapies, such as tumour chemotherapies and/or adjuvant chemotherapies. The preparation slowly releases medicine and absorbs in administration sites and prolongs medicine action time. The present invention uses an angiogenesis theory as a background, researches and states traditional Chinese medicine effective monomer ingredient action and mechanisms, is new and important direction for developing Chinese medicine theories, provides important reference for discovering new theories and medicine action new targets and provides reference for the development of the new applications of artemisinin medicine.
Description
Technical field
The invention belongs to medicinal application, relate to arteannuin and derivant thereof the medicinal usage aspect blood vessel formation against function.
Background technology
Angiogenesis is meant that already present blood vessel (blood capillary and venule) is by sprouting or splitted mode produces new blood vessel.Under physiology and the pathological conditions, take place as the embryo, processes such as female reproduction cycle, inflammatory reaction, wound healing, tumor generation are all being carried out angiogenesis.Particularly under the pathological conditions, according to statistics, the rise of about 20～40 kinds of human diseasess and angiogenesis or reduce relevant.1971, Folkman has set up the theory of getting in touch between angiogenesis and tumor growth, propose angiogenesis and not only can keep its vigorous metabolism, created advantageous conditions for tumor cell leaves primary lesion by blood transfer again simultaneously for tumor cell provides abundant nutrition.Many tumors are not having can only to grow several millimeters sizes before the new vessels generation, and angiogenesis is suppressed, though tumor cell is carrying out apoptosis fast, so can suppress growth of tumor and transfer effectively simultaneously still breeding at a high speed.Therefore, seek the new vessels growth inhibitor and become in the world neoplasm growth and the another important direction that shifts treatment in recent years.Anti-angiogenic medicaments and other cancer therapy drugs relatively have many advantages, and as seldom producing drug resistance, side effect is little, the efficient height, and the whole world above drugmaker of existing 40 families is developing anti-angiogenic agent.
Since angiogenesis inhibitor treatment in 1988 entered clinical trial, approximately kind of an angiogenesis inhibitor entered clinical trial surplus in the of existing 20, wherein had plenty of at the special molecular such as the interferon-ALPHA that participate in neovascularization; The cell signalling such as the calcium channel blocker of the inhibition calcium mediation that has; Function that then directly suppresses endotheliocyte that has or reaction are as aspergillus fumigatus cedrol (TNP-470).The above-mentioned mechanism of action of analysis-by-synthesis, the better target spot that suppresses angiogenesis is an endotheliocyte, by sealing or reduce its surperficial angiogenic growth factor receptor, suppresses the growth of endotheliocyte, migration and tube chamber form, and can destroy new vessels efficiently and form.And,, act on the receptor of the other vascular endothelial cell of tumor because many malignant tumor cells itself can be secreted angiogenic growth factor for neonate tumour blood vessel, promote tumor vascular growth.So the angiogenesis factor protein expression in the downward modulation tumor cell suppresses the secretion of its angiogenesis factor, also can reach antineoplastic vascular growth effect.
The seventies, Chinese scholar is isolated antimalarial arteannuin (artemisinin) in Chinese herbal medicine Hemerocallis citrina Baroni Artemisia after, Artemether, artesunate (artesunate) and dihydroartemisinine effective derivants such as (dihydroartemisinin) have been synthesized again successively.New milestone is set up in the appearance of this class medicine on the antimalarial agent research history.In up to a million malaria infection were used all over the world, artemisinin-based drug is evident in efficacy, and was little to the human body toxic and side effects, and do not see as yet that so far Drug resistance occurs, and is the important antimalarial of highly effective and safe by world health organisation recommendations.The various countries scholar is to finding that this class medicine also has stronger antitumor action except its special significant malaria curative effect in the research in surplus the artemisinin-based drug ten year.
Arteannuin (Artemisinin) is the sesquiterpene lactones with new structure that China scientist proposed from feverfew Herba Artemisiae annuae (Artemisia annua Linn) first in 1971.It has very good malaria effect, comprises that those have chemical sproof falciparum infection to chloroquine.Cause worldwide attention immediately, owing to exist Orally active low, water-soluble degree is little, and shortcomings such as relapse rate height make to enlarge to use to be restricted.Therefore China scientist has synthesized a large amount of derivants, is dihydroartemisinine (Dihydroartemisinin) according to arteannuin reductive metabolites in vivo, with arteannuin C
10Carbonyl reduction gets dihydroartemisinine, and anti-Mus malaria (P.berghei) is stronger one times than arteannuin.Dihydroartemisinine is carried out esterification get artesunate (Artesunate), chemistry dihydroartemisinine by name-10-α-succinate monoester, its sodium salt is made injectable powder, for quiet notes, the plasmodium phorozoon is had stronger killing action.Artesunate is converted into dihydroartemisinine, i.e. dihydroartemisinine immediately in body.Because dihydroartemisinine is water insoluble, and blood plasma and histone are had stronger adhesion, make medicine rapidly to whole body each tissue transhipment and removing.Therefore, that artesunate has is efficient, quick-acting, low toxicity, be difficult for producing characteristics such as tolerance, all effective to tertian malaria, subtertian malaria, cerebral malaria, the clinical treatment that mainly is applicable to cerebral malaria and various critical malaria.
The dihydroartemisinine artesunate
Summary of the invention
An object of the present invention is to provide the application in anti-angiogenic medicaments of artesunate and/or dihydroartemisinine.
Artesunate provided by the invention or dihydroartemisinine also can be in the application aspect chemotherapy of tumors and/or the adjuvant chemotherapy.
The present invention has the following advantages:
(1) artesunate and dihydroartemisinine are the most representative medicines in the traditional Herba Artemisiae Annuae class antimalarial, be used for the malaria treatment all the time, characteristics of the present invention are to propose artesunate first and dihydroartemisinine has blood vessel formation against function, and with their medicine as the disease treatment that is used for tumor-blood-vessel growth and other associated angiogenesis.Human numerous disease and associated angiogenesis, artemisinin-based drug will obtain important use as angiogenesis inhibitor in these treatment of diseases.
(2) the present invention provides pharmacodynamics and Its Mechanisms foundation for the artemisinin-based drug exploitation becomes antitumor drug, has the value with artemisinin-based drug exploitation becoming class medicines such as chemotherapy of tumors and/or adjuvant chemotherapy.
(3) the present invention is a background with the angiogenesis theory, studies and illustrate effect of Chinese medicine effective monomer component and mechanism, is the new important directions of developing Chinese medicine pharmacology opinion, provides important evidence for finding the new target spot of new theory and drug effect.
Description of drawings
Fig. 1. be the influence of artesunate to the chick chorioallantoic membrane angiogenesis.
Fig. 2 .1a is HE dyeing (Yihong-haematoxylin dyeing).
Fig. 2 .1b is blood vessel CD
31Dyeing.
Fig. 2 .2. is the influence of artesunate to vegf expression.
Fig. 2 .3. is the influence of artesunate to the KDR/flk-1 expression of receptor.
Fig. 3. be transplanted tumor in nude mice change in volume during the medication.
Fig. 4 is the influence to vascular endothelial cell proliferation of artesunate and dihydroartemisinine.
Fig. 5 is the influence to migration of vascular endothelial cells of artesunate and dihydroartemisinine.
Fig. 6 is the influence to the molding of vascular endothelial cell tubule of artesunate and dihydroartemisinine.
Fig. 7 .1 is the influence of dihydroartemisinine to migration of vascular endothelial cells.
Fig. 7 .2 is the influence of dihydroartemisinine to the molding of vascular endothelial cell tubule.
The specific embodiment
The present invention is described further with accompanying drawing in conjunction with specific embodiments.Should be understood that these embodiment only are used for illustration purpose, and be not used in the restriction scope of the invention.
Embodiment 1: a kind of method of preparation artesunate microsphere injection liquid
(Polycaprolactone PCL) grinds artesunate, and the melting mixing liquid that is prepared into is made microsphere injection liquid with biocompatibility and Biodegradable polymer with release polymer.Used polymer release posthydrolysis is harmless degradation product (water and carbon dioxide).After this microsphere injection liquid intramuscular injection, slowly discharge medicine and absorption, prolonged action time, can be used for the disease treatment of tumor and other associated angiogenesis at medicine-feeding part.
Embodiment 2: the whole angiogenesis that suppresses of artesunate microsphere injection liquid is tested
(1) suppresses the chick chorioallantoic membrane angiogenesis
Experiment material: artesunate (crude drug is provided by Guilin second pharmaceutical factory) adopts microsphere injection liquid of the present invention; Hydrocortisone (Xianju, Zhejiang pharmaceutical factory product); Hatching egg (purchasing) in Hangzhou Ilex purpurea Hassk.[I.chinensis Sims name chicken plant.
Method: 7-8 days Embryo Gallus domesticus is windowed, add artesunate, positive reference substance (hydrocortisone) and solvent control product (blank microsphere injection liquid) respectively, behind the hatching 24h, with the fixing chick chorioallantoic membrane of 1: 1 mixed liquor of methanol, acetone, make specimen, counting blood vessel number under anatomic microscope.
The result:
The angiogenesis suppression ratioArtesunate is respectively 50%, 55.6%, 87.5% and 100% to chick chorioallantoic membrane angiogenesis suppression ratio when dosage 15,30,60,80 μ g/ embryos.The suppression ratio 66% of positive controls hydrocortisone 30 μ g/ embryos, the suppression ratio 0% of the blank microsphere injection liquid/embryo of solvent control group isometric(al).Every embryo administration volume 100 μ l.The results are shown in Table 1.
Table 1 artesunate is to the inhibitory action of chick chorioallantoic membrane angiogenesis
Dosage
The tunica vasculose number positiveTunica vasculose tunica vasculose suppression ratio
Medicine (μ g/ embryo)+++ negative number survival number %
Blank microsphere liquid 30 00 10 10 0
Artesunate 15 909 18 50.0
Artesunate 30 828 18 55.6
Artesunate 60 3 11 2 16 87.5
Artesunate 80 0 10 0 10 100.0
Vascular countsThe vessel density of solvent control group, branch are obviously more than the administration group, and caliber is thicker, referring to Fig. 1, wherein: (a) solvent control, (b) artesunate 30 μ g/ embryos, (c) hydrocortisone 30 μ g/ embryos.During the high concentration administration, have only the tiny blood vessel of only a few caliber, do not have obvious branch-like, even do not see and haemolysis occurs by blood vessel, indivedual chicken embryo deaths.When artesunate dosage 60,30,15 μ g/ embryos, vascular counts is respectively 3.8,9.7,27.1,19.5 of positive controls, 40.5 of solvent control groups.Compare with the solvent control group, each is organized data and is significant difference (P＜0.01).The results are shown in Table 2.
Table 2 artesunate is to the influence of chick chorioallantoic membrane angiogenesis
Drug dose (μ g/ embryo) n counts blood vessel number (x ± s)
Blank microsphere liquid 30 15 40.6 ± 2.3
Artesunate 15 15 27.1 ± 8.5
*
Artesunate 30 15 9.7 ± 2.7
*
Artesunate 60 15 3.8 ± 1.6
*
*The blank microsphere liquid of P＜0.01vs3%, t test
(2) suppress human ovarian cancer transplanted tumor in nude mice angiogenesis
Experiment material: artesunate (crude drug is provided by Guilin second pharmaceutical factory) adopts microsphere injection liquid of the present invention.HO-8910 human oophoroma cell line (providing) by the institute of oncology, Zhejiang Province, 32 of BALB/C nude mouses, body weight (20 ± 2) g, male, 6～8 ages (providing) in week by the Shanghai Inst. of Tumor.The RPMI-1640 cell culture fluid that contains 10% calf serum.VEGF (VEGF) polyclonal antibody (the anti-people of rabbit, U.S. Santa Cruz company), VEGFR-2 (KDR/flk-1 receptor) polyclonal antibody (the anti-people of rabbit, U.S. Santa Cruz company), CD
31Factor monoclonal antibodies (rat anti-mouse, U.S. Santa Cruz company).
Method:
Suppress human ovarian cancer transplanted tumor in nude mice modelling and dosage regimen Add 10% calf serum with RPMI-1640 and cultivate the HO-8910 Proliferation of Human Ovarian Cell.Cell is by 1 * 10
7/ ml is suspended in the serum-free medium, every mice left side axil subcutaneous vaccination 0.2ml.Can form macroscopic tumor piece, tumor formation rate 100% in about about 4 days.Beginning administration in the 3rd day is divided into 4 groups: artesunate high dose group 100mg/ (kgd), middle dosage group 50mg/ (kgd), low dose group 10mg/ (kgd) and blank microsphere injection liquid group at random after the one-tenth tumor.Every group 8, administered intramuscular, every day 1 time, successive administration 10 days, matched group wait the blank microsphere injection liquid of capacity.After the last administration 24 hours, put to death animal, take out the tumor piece.
The toxic and side effects of gross tumor volume variation and medicineObserve ordinary circumstance and the growth of xenografted situation of nude mouse during the administration, gross tumor volume of per 3 days mensuration.Measuring method is: with vernier caliper measurement tumor major axis (a), minor axis (b) is according to formula V=0.5ab
2Calculate gross tumor volume, draw the gross tumor volume growth curve.Measure the nude mice body weight simultaneously.
HE dyeing and SABCAbove-mentioned tumor tissues specimen is made the thick paraffin section of 5 μ M after routine is handled, HE dyeing, and referring to Fig. 2 .1a, conventional index is observed.With SABC SABC method, adopt mouse-anti Mus CD
31Factor antibody, rabbit anti-people VEGF antibody and rabbit human VEGFR-3 resistant-2 antibody test tumor specimen medium vessels generate, and VEGF and KDR/flk-1 expression of receptor replace an anti-feminine gender of doing with BPS.1. vascular counts: select 6 visuals field to observe blood vessels and counting under every section high power lens (* 200) at random, averaging is the end value of every example.2. VEGF and KDR/flk-1 expression of receptor: select 6 visuals field at random under every section high power lens (* 400), the number of cells of VEGF and KDR/flk-1 receptor positive in 200 cells of counting in each visual field, less than 10% positive cell negative (-), 10%-30% is the weak positive (+), 30%-70% is the middle positive (++), and 70%-100% is strong positive (+++).VEGF expresses in the tumor cell slurry, and the KDR/flk-1 receptor all has expression in tumor cell and vascular endothelial cell, and the expressive site immunohistochemical staining is pale brown color.
The result:
Vascular countsHigh dose group (100mg kg
-1d
-1), middle dosage group (50mg kg
-1d
-1) and low dose group (10mg kg
-1d
-1) blood vessel CD
31Dyeing, the result is referring to Fig. 2 .1b.Vascular counts is respectively 11.61 ± 4.32,27.75 ± 8.04,47.92 ± 11.49, blank microsphere injection liquid group is 48.98 ± 9.40, compare higher, middle dosage group vascular counts with blank microsphere injection liquid matched group and all obviously reduce (P＜0.01), low dose group no significant difference (P＞0.05).Referring to table 3.
Table 3 artesunate is to the influence of transplanted tumor in nude mice vessel density
Group (mg/kgd) number of animals (n) vessel density (x ± s)
Blank microsphere (10ml/kg.d) 8 48.98 ± 9.40
*P＜0.05,
*The blank microsphere group of P＜0.01vs, the t check
VEGF, the KDR/flk-1 protein expressionTreatment group and blank microsphere injection liquid group VEGF, the KDR/flk-1 receptor in tumor cell and vascular cell The positive expression rate referring to Fig. 2 .2, Fig. 2 .3, among Fig. 2 .2: (a) dosage group, (c) negative control group in blank microsphere injection liquid group, (b) artesunate, among Fig. 2 .3: (a) dosage group, (c) artesunate high dose group in blank microsphere injection liquid group, (b) artesunate.High dose group (100mg/kgd), middle dosage group (50mg/kgd) and low dose group (10mg/kgd) VEGF, flt-1 immunohistochemical staining positive rate compare with matched group all notable difference (P＜0.05).See Table 4.
Table 4 artesunate to tumor tissues VEGF and
KDR/The influence that flt-1 expresses
Group number of animals vegf expression
KDR/Flk-1 expresses
(mg/kgd) (n) tumor cell tumor cell vascular endothelial cell
Blank microsphere 8 +++(8) +++(7) ++ (1) +++(8)
10 8 +++(4)++(4) +++(3)++(5) +++(2)++(6)
*
50 8 ++(1)+(4)-(3)
** ++(4)+(3)-(1)
** ++(2)+(4)-(2)
**
100 8 ++(1)+(2)-(5)
** ++(2)+(2)-(4)
** ++(1)+(2)-(5)
**
*P＜0.05,
*The blank microsphere group of P＜0.01vs, x
2Check
The toxic and side effects of gross tumor volume variation and medicineGrowth of xenografted and change in volume are referring to Fig. 3, and when becoming tumor (inoculating after 4 days), treatment group and blank microsphere injection liquid group tumor body difference in size do not have significance (P＞0.05).In the medication process, treatment group tumor growth is slower, and medication the 1st, 4 was measured gross tumor volume in 7,10 days, and height, middle dosage group gross tumor volume have significant difference (P＜0.05) all less than matched group.During the medication, four groups of tumor bearing nude mices are movable good, do not see special untoward reaction, and none example is dead.Medication is matched group and height after 10 days, in, low treatment group on average goes tumor Mus heavy (g) to be respectively 22.1 ± 1.86,22.62 ± 2.4, and 21.83 ± 2.1,22.25 ± 2.36, treatment group and blank microsphere injection liquid matched group relatively do not have significant difference (P＞0.05).
Embodiment 3: artesunate and the experiment of dihydroartemisinine vitro inhibition angiogenesis
Experiment material: artesunate, dihydroartemisinine (crude drug is provided by Guilin second pharmaceutical factory)
Method:
(1) Human umbilical vein endothelial cells (HUVEC) is cultivated
Get the fetal cord of fresh and healthy, pour into 5% collagenase, 37 ℃ of water-bath 15～20min are with PBS liquid flushing umbilical vein, centrifugal, abandon supernatant, use the culture fluid suspension cell, put in the culture bottle and cultivate, change liquid every other day once, culture fluid is that DMEM contains 15% calf serum and the VEGF of 10ng/ml.Use with getting the cell confession research of the 2nd～3 generation after the evaluation of the anti-people VIII of rabbit factor antibody row SABC.
(2) HUVEC propagation suppresses
With HUVEC with 5 * 10
4Individual/ml density is inoculated in 24 well culture plates, puts incubator 5%CO
2, 37 ℃ hatch treated in 24 hours fully adherent after, add medicine (artesunate or dihydroartemisinine), and establish normal saline and DMSO matched group.Establish 3 multiple holes for every group, act on after 48 hours, detect cell survival rate with mtt assay.
(3) the HUVEC migration suppresses
Be grown in the HUVEC that has been fused to monolayer in the 35mm plastic culture dish with the blade damage,, add the DMEM culture fluid that contains 15% calf serum, add testing drug (artesunate or dihydroartemisinine) then, put 5%CO with PBS liquid flushing 3 times
2, in 37 ℃ of incubators, the HUVEC number that from injured edge continuous counter (500 * 250) μ M section, moves after 24 hours, 10 of numeric representations are the cell number average in the visual field at random.
(4) the HUVEC tubule forms and suppresses
Type i collagen (Sigma, Bomem Belgium), DMEM (* 10), 0.05M NaOH+0.2MHEPES+0.26MNaHCO
2With volume ratio 8: 1: 1: mix rapidly down in ice bath, coat 24 well culture plates bottom, put 37 ℃ and form collagen gels, with HUVEC with 5 * 10
4The density of individual/ml is suspended in the 10% calf serum DMEM culture fluid, and every hole adds 0.5ml, and used medicine (artesunate or dihydroartemisinine) also adds with certain concentration at this moment, at 5%CO
2, cultivated 48 hours in 37 ℃ of incubators, (* 200) measure the total length of tubule in 10 visuals field at random with trisquare under inverted microscope.
The result:
(1) influence that HUVEC is bred
Normal saline matched group and DMSO matched group OD value are 0.71 ± 0.05 and 0.72 ± 0.05.Compare with the corresponding solvent matched group, all not obvious to the HUVEC inhibited proliferation when drug level is 0.5 μ mol/L, the OD value of artesunate and dihydroartemisinine is 0.70 ± 0.04 and 0.69 ± 0.07 (P＞0.05); When concentration was 2.5 μ mol/L, the OD value of dihydroartemisinine was 0.66 ± 0.04 (P＜0.05), and the propagation of HUVEC is had inhibitory action; When concentration was 12.5 and 50 μ mol/L, two kinds of medicines all had tangible inhibited proliferation (P＜0.01) to HUVEC, and the OD value is respectively 0.59 ± 0.04,0.42 ± 0.03 (artesunate) and 0.50 ± 0.04,0.36 ± 0.03 (dihydroartemisinine); The OD value descend have dose dependent, each medication group difference have significance (P＜0.05, n=3).Drug level (μ mol/L) is seen ginseng Fig. 4 (n=3), wherein (▲) artesunate, (■) dihydroartemisinine with the relation of cell survival rate (%).
(2) influence that HUVEC is moved
The cell migration experimental result shows, under the effect of artesunate and dihydroartemisinine, the quantity that the HUVEC migration enters injured exposed area obviously reduces, referring to Fig. 5, Fig. 7 .1, among Fig. 5: (▲) artesunate, (■) dihydroartemisinine, among Fig. 7 .1: (a) solvent control, (b) 2.5 μ M dihydroartemisinines, (c) 50 μ M dihydroartemisinines.
The cell number of normal saline and DMSO matched group HUVEC migration is 256 ± 28 and 258 ± 29.When drug level was 0.5 μ mol/L, the migration inhibitory action was not obvious, and artesunate and dihydroartemisinine group cell migration number are 252 ± 46 and 241 ± 23 (P＞0.05); When concentration is 2.5,12.5,50 μ mol/L, significant difference (P＜0.01) is arranged between medication group and the matched group, artesunate and dihydroartemisinine group migrating cell number are respectively 182.6 ± 25,88.7 ± 11,7.6 ± 6 and 147 ± 18,45 ± 9,1.5 ± 1.The relation of drug level (μ mol/L) and cell migration rate (%) is referring to Fig. 5 (n=3).
(3) artesunate and dihydroartemisinine are to the influence of HUVEC tubule molding
HUVEC grew in collagen gel substrate 2 ~ 3 days the time, and cell becomes spindle shape by original polygon, and in gel-type vehicle elongation growth, be linear array and form tubular structure, a plurality of tubular structures are interconnected to form tridimensional network.Referring to Fig. 6, Fig. 7 .2, among Fig. 6: (▲) artesunate, (■) dihydroartemisinine, among Fig. 7 .2: (a) solvent control, (b) 12.5 μ M dihydroartemisinines, (c) 50 μ M dihydroartemisinines.
Behind the 48h, the tubule total length is 4.90 ± 0.55mm and 5.18 ± 0.65mm in normal saline and each visual field of DMSO matched group; When drug level was 0.5 μ mol/L, little length of tube of medication group and matched group did not more all have significant difference (P＞0.05); When drug level was 2.5 μ mol/L, dihydroartemisinine group tubule total length was 3.85 ± 0.35mm, presented obvious suppression effect (P＜0.05); When concentration was 12.5,50 μ mol/L, two kinds of medicines all had significant tubule inhibitory action (P＜0.01).Artesunate and dihydroartemisinine group tubule total length are respectively 3.47 ± 0.32mm, 1.30 ± 0.08mm and 1.65 ± 0.73mm, 0.42 ± 0.02mm.Relation between drug level (μ mol/L) and the tubule formation rate (%) is referring to Fig. 6 (n=3).The partial reference document that the present invention relates to:
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[8]Satake?S，Kuzuya?M，Ramas?MA，et?al.Angiogenic?stimuli?are?essential?forsurvival?of?vascular?endothelial?cells?in?three-dimensional?collagen?lattice.Biochem?Biophys?Res?Commun?1998，244：642-646.
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All documents that the present invention mentions are all quoted in application as a reference, are just all quoted as a reference separately as each piece document.Should understand in addition, the present invention is described in conjunction with most preferred embodiment, yet after having read foregoing of the present invention, those skilled in the art can make various changes or modifications the present invention, and these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (1)
1. artesunate and/or the dihydroartemisinine application in the preparation anti-angiogenic medicaments.
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