CN101904831B - Application of alkannin and compositions thereof - Google Patents
Application of alkannin and compositions thereof Download PDFInfo
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- CN101904831B CN101904831B CN2010102477784A CN201010247778A CN101904831B CN 101904831 B CN101904831 B CN 101904831B CN 2010102477784 A CN2010102477784 A CN 2010102477784A CN 201010247778 A CN201010247778 A CN 201010247778A CN 101904831 B CN101904831 B CN 101904831B
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- shikonin
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- NEZONWMXZKDMKF-JTQLQIEISA-N Alkannin Chemical compound C1=CC(O)=C2C(=O)C([C@@H](O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-JTQLQIEISA-N 0.000 title claims abstract description 52
- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 239000000203 mixture Substances 0.000 title abstract description 11
- 239000004229 Alkannin Substances 0.000 title abstract 4
- 235000019232 alkannin Nutrition 0.000 title abstract 4
- 239000003814 drug Substances 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 15
- 241001071917 Lithospermum Species 0.000 claims description 47
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- 238000000034 method Methods 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 4
- 235000012424 soybean oil Nutrition 0.000 claims description 4
- 239000003549 soybean oil Substances 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
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- WNFXUXZJJKTDOZ-HNNXBMFYSA-N [(1s)-1-(5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl] acetate Chemical compound C1=CC(O)=C2C(=O)C([C@@H](OC(C)=O)CC=C(C)C)=CC(=O)C2=C1O WNFXUXZJJKTDOZ-HNNXBMFYSA-N 0.000 description 2
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- WNFXUXZJJKTDOZ-UHFFFAOYSA-N shikonin acetate Natural products C1=CC(O)=C2C(=O)C(C(OC(C)=O)CC=C(C)C)=CC(=O)C2=C1O WNFXUXZJJKTDOZ-UHFFFAOYSA-N 0.000 description 2
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- MXANJRGHSFELEJ-MRXNPFEDSA-N [(1r)-1-(5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl] 3-hydroxy-3-methylbutanoate Chemical compound C1=CC(O)=C2C(=O)C([C@H](OC(=O)CC(C)(C)O)CC=C(C)C)=CC(=O)C2=C1O MXANJRGHSFELEJ-MRXNPFEDSA-N 0.000 description 1
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- MXANJRGHSFELEJ-UHFFFAOYSA-N beta:-hydroxy isovaleryl shikonin Natural products C1=CC(O)=C2C(=O)C(C(OC(=O)CC(C)(C)O)CC=C(C)C)=CC(=O)C2=C1O MXANJRGHSFELEJ-UHFFFAOYSA-N 0.000 description 1
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses application of alkannin and compositions thereof in preparing medicaments for preventing and treating vessel and local tissue injury caused by extravasation of chemotherapeutic agents. The rat in-vivo pharmacological research and clinical research show that the alkannin has obvious effects of treating the vessel and local tissue injury caused by extravasation of chemotherapeutic agents and promoting healing and can obviously shorten the time of eliminating the swelling of the local tissues and accelerate the healing of the local tissue injury, and also show that the alkannin and compositions thereof can be used for preparing the medicaments for preventing and treating the vessel and local tissue injury caused by the extravasation of the chemotherapeutic agents.
Description
Technical field
The present invention relates to medical technical field, be specifically related to the application of shikonin and compositions thereof.
Background technology
Along with constantly increasing of cancer morbidity, chemotherapeutics in Clinical Application also more and more widely.Chemotherapy is one of means of the various cancers of clinical treatment, leukemia, immune disease; Chemotherapeutics extravasation is a kind of relatively common complication; Most chemotherapeutics all have stronger stimulation to local organization; Can cause phlebitis, chemotherapeutics that has such as vincristine etc. can cause the neurotoxicity infringement.After the chemotherapeutics intravenous injection was exosmosed, the lighter can cause the slight erythema of surrounding tissue, local pain swelling, scorching hot, and weight person can cause surrounding tissue necrosis, skin ulcer and DEEP STRUCTURE such as tendon and joint injury.Take positive treatment measures behind the drug extravasation, to prevent local tissue necrosis and ulcer, the generation of the complication of protecting from infection, it is significant to alleviate the patient suffering.According to statistics, the percolation ratio of chemotherapy is 0.1%～0.6%, and actual incidence rate is then higher.The occurrence cause of chemotherapeutics extravasation mainly is that the zest and the patient vessel of chemotherapeutics itself is second-rate.Because chemotherapeutics stimulates blood vessel wall, cause that vascular permeability increases, organize inflammatory exudation, vasomotor disturbance reasons such as (contracture or expansions), tumor patient is everlasting and phlebitis is taken place after the chemotherapy, and the lighter shows as local red and swollen distending pain, blood vessel hardening or become streak.Severe patient can form blister, ulcer, even tissue necrosis.
Chemotherapeutics seepage injured blood vessel and local organization belong to the traditional Chinese medical science " skin infection " category.The traditional Chinese medical science thinks, the many duties of primary disease impaired in local venation accumulates in blood oozing from the body openings or subcuta neous tissue skin or the heat in blood and the part to occur rubescent; QI and blood is not smooth, the then swelling of being obstructed of cohesion skin, the defeated cloth of body fluid; Accumulate with the passing of time then local pyrexia of heat-transformation in the blood stasis; The venation hematogenous blockage, stagnation of blood stasis, stagnation of QI and blood may bring about pain, blood stasis then run through it all the time.In a word, this disease be that pyretic toxicity pents up because of exopathogen invasion, stagnation of QI-blood forms, and controls suitable removing pathogenic heat from blood and toxic substance from the body, promoting blood circulation to remove obstruction in the collateral, blood-activating analgetic.
Radix Arnebiae (Radix Lithospermi) (Radix Arnebiae) is the dry root of comfrey lithospermum euchromum Royle Arnebia educhroma (Royle) Johnst, Radix Arnebiae (Radix Lithospermi) Lithospermum erythrorhizon Sieb.et Zucc. or arnebia guttata Bunge Arnebia guttataBunge.Radix Arnebiae (Radix Lithospermi) is claimed Lacca, mountain Radix Arnebiae (Radix Lithospermi), Zi Dan, Radix Arnebiae (Radix Lithospermi), red stone root again.Main product in Xinjiang, ground such as Tibet, Gansu, Heilungkiang, Jilin, Liaoning, Hebei, Henan, Guangxi.The Radix Arnebiae (Radix Lithospermi) nature and flavor are sweet, salty, cold, GUIXIN, Liver Channel.The function removing heat from blood is invigorated blood circulation, the detoxifcation rash.Cure mainly the heat in blood poison and contain, macule is purple black, measles without adequate eruption, skin infection, eczema, burn due to hot liquid or fire etc.Radix Arnebiae (Radix Lithospermi) mainly contains shikonin (shikonin), acetylshikonin (acetylshikonin), beta-hydroxyisovalerylshiderivative (β-hydro-xyisovalerylshikonin), β; β '-dimethylacrylshikonin (β, β '-dimethylacrylshikonin) etc.
Wherein, the shikonin molecular weight is 288.30, molecular formula C
16H
16O
5, another name is 5,8-dihydroxy-2-[(1R)-and 1-hydroxy-4-methyl penta-3-thiazolinyl] naphthalene-1, the 4-diketone, structure is as shown in Figure 1, is puce acicular crystal, 147 ℃ of fusing points, optical rotation α
D 20=+135 ° (benzene).Be dissolved in ethyl phenyl ether, acetone, chloroform, methanol, ethanol, glycerol, vegetable and animals oils and alkaline aqueous solution, water insoluble.Tone changes with pH value, and pH value 4～6 takes on a red color, and pH value 8 is purple, and it is blue that 10～12 of pH value then are.Fast light, heat-resisting, oxidative resistance is good, and is unstable to reduction dosage, meet iron ion and be darkviolet.These article have certain anticancer, antiinflammatory, effect such as antibiotic.Clinically be used to treat acute and chronic hepatitis, liver cirrhosis (ascites).Department of dermatologry is used to treat verruca plana, psoriasis, topical application treatment burn and promotion wound healing.Eye drop is used to treat herpes simplex keratitis, and epitheliated type dendroid and shallow essential layer dendritic keratitis are had certain curative effect; Oil preparation is used to treat baby's dermatitis, eczema, vaginitis, cervicitis etc.; The toothpaste that contains shikonin can be prevented and treated dental caries and gingivitis; Shikonin also can be used for the coloring agent of medicine, cosmetics and food in addition.But the shikonin monomer is not seen bibliographical information as yet in the effect and the effect of control chemotherapeutics seepage injured blood vessel and local organization.
Summary of the invention
The object of the present invention is to provide a kind of new medical use of shikonin, particularly, provide the application of shikonin in the medicine of blood vessel that preparation control/treatment chemotherapeutics seepage causes and local tissue damage.
Another object of the present invention is to provide a kind of new medical use of shikonin compositions, particularly, provide the application of shikonin compositions in the medicine of blood vessel that preparation control/treatment chemotherapeutics seepage causes and local tissue damage.
The present invention uses shikonin the rat chemotherapeutics seepage damage model that adopts amycin etc. to cause is handled; Using shikonin handles the chemotherapeutics damage patient that amycin etc. causes; Confirm that shikonin has significant therapeutical effect, so shikonin and compositions thereof all can be used in preparation and have the blood vessel that control causes because of the chemotherapeutics seepage and the medicine of local tissue damage effect.
Description of drawings
Fig. 1 is the structural formula of shikonin.
Fig. 2 is a rat back state picture; Picture when wherein a1 and a2 are untreated fish group 7 days and 14 days; Picture when the picture when b1 and b2 are Semen sojae atricolor line of oils 7 days and 14 days, c1 and the c2 picture during for happiness distant appropriate group of 7 days and 14 days, d1 and d2 are shikonin group 7 days and 14 days.
Fig. 3 is HE dyeing microscope picture, and wherein a1 and a2 are the pictures of untreated fish group 3 days during with 7 days, and the picture when b1 and b2 are Semen sojae atricolor line of oils 3 days and 7 days, c1 and c2 are the picture when liking distant appropriate group of 3 days and 7 days, the picture when d1 and d2 are shikonin group 3 days and 7 days.
The specific embodiment
Below in conjunction with specific embodiment, the present invention is further specified.Should be understood that following examples only are used to the present invention is described but not are used to limit scope of the present invention.Shikonin according to the invention can extract from Radix Arnebiae (Radix Lithospermi) and get, and the method that also can use disclosed synthetic in the prior art obtains.In following examples, to be that the shikonin that extraction gets from Radix Arnebiae (Radix Lithospermi) is an example, carried out series in body pharmacology and clinical research, the new purposes of preventing and treating chemotherapeutics seepage injured blood vessel and local organization for the developing shikonin provides scientific basis.Those skilled in the art can know that the shikonin of using the method acquisition of disclosed synthetic in the prior art also has identical purposes.
The preparation of embodiment 1 shikonin
Collect dry Radix Arnebiae (Radix Lithospermi) 5kg, pulverize, with 95% ethanol ultrasonic extraction 3 times, extracting solution merges; Concentrating under reduced pressure, behind the petroleum ether ultrasonic degreasing, the reuse ethyl acetate extraction filters; The acetic acid ethyl acetate extract decompression concentrates, and drying gets crude extract; (follow the tracks of with TLC and to detect, to merge for granularity 200-300 order, 10cm * 20cm) by petroleum ether-ethyl acetate (1: 9～1: 5) gradient elution through silica gel column chromatography 1400g for the ethyl acetate crude extract; The decompression of the 8th part of fraction, be concentrated into dried, again through methanol drip washing, to remove impurity.Behind the vacuum drying the shikonin powder, detect through HPLC, purity is greater than 95%, is used for subsequently clinical and in the body pharmacological evaluation.
In this embodiment, laboratory animal is: 60 of 3 monthly age SPF level SD male rats, and body constitution amount 180-200g is provided by The 2nd Army Medical College zoopery center, and the quality certification number is SCXK [Shanghai 2007-0003].Main medicine is: the hydrochloride for injection doxorubicin (is called for short amycin, Shenzhen ten thousand happy medicinal liquid company limiteies, the accurate word of traditional Chinese medicines: H44024359); (it is appropriate to be called for short happiness the Liao Dynasty, and Germany three is Pharmaceutical altogether, authentication code: H20030014) for many sulfonic acid mucopolysaccharide emulsifiable paste; Soybean oil (Jiangxi Jinhaitang Medicinal Oil Co., Ltd., authentication code: the accurate word 20050003 of Jiangxi food medicine), shikonin (from Radix Arnebiae (Radix Lithospermi), extract and obtain); Normal saline, 10% formaldehyde.Method for preparation of drug is: the 10mg amycin is diluted to the 1.67mg/ml solution for standby with the 6ml normal saline, with soybean oil shikonin is diluted to the 4mg/ml suspension, and 4 ℃ of preservations are subsequent use.
2.1 modeling and grouping
After adopting shears and electric hair cutter with the depilation of SD rat,, process chemotherapeutics seepage injured animal model in every the left back back of rat subcutaneous injection 0.4ml (1.67mg/ml) amycin.Numbering back is divided into 4 groups by the table of random number method with 60 SD rats at random, i.e. untreated fish group, soybean oil adjuvant group, shikonin experimental group and like distant appropriate positive controls, 15 every group.
2.2 intervening measure
Carry out corresponding intervention behind the modeling 30min, except that untreated fish group was left intact, other groups were embrocated at injury region with relative medicine.External application area diameter is 15～20mm, evenly is coated with the full degree that is.External application every day 2 times, 3 weeks of continuous use.
2.3 observe
The skin color of observing at every turn and write down every group of rat local organization before changing dressings changes; Swelling or blood stasis regression time; With oil ga(u)ge kind of calliper local eminence area; Calculate and respectively organize the swelling index (index that disappears=local eminence area/protuberance disappear fully required time, swelling area=π/4 * major diameter * minor axis) that disappears.And measure and respectively organize subcutaneous rat scleroma and ulcer area size (major diameter and minor axis), selectivity is taken pictures, and the result is as shown in Figure 2.In addition, in the 1st, 3,5,7 day that changes dressings every group get 1 execution, be the center with point of puncture and apart from point of puncture 1cm place respectively; Downcut the skin histology of 0.25cm; 10% formaldehyde fixed 24h, routine pathology film-making, HE dyeing; The light microscopic histological observation is also analyzed pathological manifestations such as cell infiltration, edema, necrosis, hemorrhage, thrombosis and proliferation of fibrous tissue, and the result is as shown in Figure 3.That the pathology degree is divided is light, in, weigh 3 grades.Slightly: the dispersivity cell infiltration, epidermis is intact; Moderate: tissue edema, be dispersed in hemorrhage, obvious inflammatory cell infiltration; Severe: ulcer, tissue necrosis is hemorrhage.Gross examination of skeletal muscle mainly be skin lesion pale red or turn white, dark red, edema and ulcer.
3.4 statistical analysis
Adopt SPSS 13.0for Windows software to carry out statistical analysis; All enumeration datas relatively adopt paired t-test with mean ± standard deviation
expression between group.P＜0.05 expression difference has statistical significance.
The result is shown in table 1～table 3.
The table 1 swelling index that disappears
* P＜0.05, the vs untreated fish group.
Table 2 ecchymosis incidence rate
Table 3 cicatrix expulsion rate
Visible by above-mentioned chart, untreated fish group rat back skin lesion is dark red, edema, ulcer are obvious, and the edema extinction time obviously prolong, the cicatrix incidence rate is high but its expulsion rate is low, pathological section shows obvious ulcer, tissue necrosis, severe haemorrhage.Semen sojae atricolor line of oils rat back skin lesion is dark red, edema, ulcer, and the edema extinction time is longer, and the cicatrix incidence rate is high and its expulsion rate is relatively low, pathological section display organization edema, be dispersed in hemorrhage, inflammatory cell infiltration, part ulcer and tissue necrosis.Like that distant appropriate group of rat back skin lesion is dark red, edema, ulcer, and the edema extinction time obviously prolong, the cicatrix incidence rate is high and its expulsion rate is low, pathological section display organization edema, be dispersed in hemorrhage, obvious inflammatory cell infiltration, part ulcer, tissue necrosis.Shikonin group rat back skin lesion is pale red, Mild edema, ulcer are less, and the edema extinction time is shorter, and the cicatrix incidence rate is low and its expulsion rate is higher, and pathological section shows the dispersivity cell infiltration, and epidermis is intact.
In sum, shikonin has effects such as removing pathogenic heat from blood and toxic substance from the body, promoting blood circulation to remove obstruction in the collateral, blood-activating analgetic, and the chemotherapeutics seepage is caused that local tissue damage has good therapeutical effect.
Embodiment 3 shikonin cause the effect of local tissue damage because of chemotherapy to the patient
No. 1 Hospital Affiliated to No. 2 Military Medical Univ.,PLA is through patients undergoing chemotherapy; Because of causing blood vessel injury, the chemotherapeutics seepage causes phlebitis and local tissue damage, totally 122 people, random packet; Wherein 62 people are the distant appropriate matched group of happiness; To like appropriate evenly the embrocating at injury region of the Liao Dynasty, 60 people are shikonin treatment group, shikonin is dissolved in suitable substrate evenly embrocates at injury region.Be administered once every day, and utilize perusal and vernier caliper measurement damage location to change, and adopts digital photographing to combine Image-Pro Plus 5.0 image analysis software to analyze, and the result is as shown in table 4.
Table 4 shikonin compares with the distant appropriate effect in treating the patient who causes local tissue damage because of chemotherapy of happiness
Two groups of curative effects are carried out χ
2Check, P＜0.01, difference has statistical significance.
Visible from table 4 result, shikonin has therapeutical effect significantly to chemotherapeutic phlebitis and localized seepage's damage, and the distant appropriate effect of more existing most popular happiness is more obvious, shows that this chemical compound has treatment chemotherapeutics seepage damaging action.
The present invention is through finding in body pharmacological research and clinical research and the proof shikonin has and shortens the local organization edema extinction time that the chemotherapeutics seepage causes; Promote the local organization wound healing; Prevent cicatrization; The effect of treatment chemotherapeutics seepage injured blood vessel and local organization; For clinical guidance shikonin treatment chemotherapeutics seepage injured blood vessel and safer, the reasonable use of local organization provide certain experimental basis; Simultaneously also experiment basis is provided for shikonin is developed further into the medication of chemotherapeutics seepage injury in treating; Confirmation can select shikonin to prepare to have the blood vessel that control causes because of the chemotherapeutics seepage and the medicine of local tissue damage effect, and the shikonin corresponding compositions also can be used for preparing has the blood vessel that control causes because of the chemotherapeutics seepage and the medicine of local tissue damage effect, and said shikonin compositions contains shikonin and pharmaceutically acceptable carrier or excipient, like solvent, diluent etc.; Shikonin and one or more pharmaceutically acceptable carrier or mixed with excipients, thus the shikonin compositions formed.Shikonin prepares easy, and is with low cost, and with the medicine of its preparation control chemotherapeutics seepage injured blood vessel and local organization, market prospect is wide, is containing huge social and economic benefit.
Claims (1)
1. a shikonin is characterized in that as the application of unique active component, and preparation has the blood vessel that control causes because of the chemotherapeutics seepage and the medicine of local tissue damage effect; Method for preparation of drug is: with soybean oil shikonin is diluted to the 4mg/ml suspension, 4 ℃ of preservations are subsequent use.
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| 张丞 等.化疗性静脉炎的中医治疗进展.《浙江中医药大学学报》.2010,第34卷(第1期),124-125. * |
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