CN103169718B - Application of anthracene nucleus antibiotic and its pharmaceutical salt for treating neovascular glaucoma - Google Patents
Application of anthracene nucleus antibiotic and its pharmaceutical salt for treating neovascular glaucoma Download PDFInfo
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- CN103169718B CN103169718B CN201110431274.2A CN201110431274A CN103169718B CN 103169718 B CN103169718 B CN 103169718B CN 201110431274 A CN201110431274 A CN 201110431274A CN 103169718 B CN103169718 B CN 103169718B
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Abstract
The invention discloses an application of anthracene nucleus antibiotic and its pharmaceutical salt for treating neovascular glaucoma. The invention found that the anthracene nucleus antibiotic and its pharmaceutical salt have good effect on treatment of r neovascular glaucoma, and especially the anthracene nucleus antibiotics can be prepared to prolonged action preparations such as a nano preparation, a microballoon preparation, liposome and hydrogel, the toxicity of anthracene nucleus antibiotic is reduced, and the anthracene nucleus antibiotic enables ophthalmic administration, administration dosage is simultaneously enlarged, the duration time of drug effect is long, the medicament curative effect is stronger than that of the common preparations of the anthracene nucleus antibiotic, when the ophthalmic administration is carried out, the anthracene nucleus antibiotic has good treatment effect for treating retinal vein occlusion, and the blank that no medicine is good for treating neovascular glaucoma can be filled.
Description
Technical field
The present invention relates to a kind of medicine for the treatment of neovascular glaucoma, be specifically related to a series of traditional anti-tumor antibiotic anthracycline antibiotics and the novelty teabag of officinal salt in preparation treatment neovascular glaucoma medicine thereof, especially, described anthracycline antibiotics and officinal salt preparation thereof become the durative action preparations such as nanometer formulation, microball preparation, liposome and hydrogel.
Background technology
Neovascular glaucoma is a kind of insecondary glaucoma disease, to be mainly manifested in patient's eye newborn a large amount of blood vessel on iris, to show glaucomatous symptom.Cause the cause of disease of neovascular glaucoma a lot, but main what cause neovascular glaucoma is the retinal vein occlusion and diabetic retinopathy, these two kinds of oculopathy all secondary can go out neovascular glaucoma, and the neovascular glaucoma that these two kinds of oculopathy cause mainly accounts for 75% of neovascular glaucoma morbidity.The 25% remaining neovascular glaucoma caused by other a variety of causes, probably has and nearly more than 40 plants the anterior ocular segment anoxia that various disease extensively can involve oculi posterior segment anoxia or locality, cause neovascular glaucoma.
The retinal vein occlusion and diabetic renal papillary necrosis are the topmost reasons causing iris neovascularization and develop into neovascular glaucoma, and neovascular glaucoma has become one of main blinding cause of disease, and sickness rate increases with disease.Retinal microvascular disease causes retinal tissue to change, and inspire the activated angiogenesis factor of tool, these factors are to preocular diffusion, stimulate iris to form fibrovascular membranes, cross over eye anterior chamber angle, affect aqueous humor and discharge, cause intraocular pressure to raise, now show as open angle glaucoma.When fibrovascular membranes shrinks, eye anterior chamber angle adhesion, then become the severe complications such as neovascular glaucoma, causes angle closure glaucoma.Angle, neovascular glaucoma room closed-down period, intraocular pressure raises plain stubborn, and ophthalmalgia is violent and be difficult to control, and treats also very complicated and difficult simultaneously.Along with the progress of the state of an illness, ocular tissue and visual function often suffer serious, irremediable infringement, and eye is congested, and corneal edema, violent ophthalmalgia, headache, often cause blind.Treatment of neovascular glaucoma difficulty is large, therapeutic effect is poor, even if patients with terminal operative treatment is also difficult to control intraocular pressure, finally causes visual function to be lost.
Because new vessels easily breaks, repeatedly there is hyphema, adopt the means such as full retinal photocoagulation, full retina is freezing, iridocorneal angle light is solidifying at present clinically, due to can post-operation inflammatory be produced and pain is more serious, and often poor effect, often the progress of exacerbate inflammation and the new vessels formation of quickening angle, room, and suffer the criticism of many clinical workers and academia.The method of intraocular pressure lowering is mainly taked in the treatment of medicine, and these medicines are often cured the symptoms, not the disease, the medicine such as atropine, glucocorticoid is all respite eye symptoms, thoroughly can not treat neovascular glaucoma, therefore current temporary nothing clinically treatment means more effectively.
The cause of disease of current neovascular glaucoma and pathogenesis are still imperfect, and treatment aspect is also without definite effective method, and existing treatment means still exists many disputes.Neovascular glaucoma and the illness such as the retinal vein occlusion, diabetic eye in close relations.Blinding due to it, seriously will reduce the quality of life of patient.If a kind of medicine can be developed effectively can treat neovascular glaucoma, avoid that sb.'s illness took a turn for the worse, show than the better therapeutic effect of technique of surgical treatment means or thoroughly solving this persistent ailment will produce major and immediate significance.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of anthracycline antibiotics and the novelty teabag of officinal salt in preparation treatment neovascular glaucoma medicine thereof, especially described anthracycline antibiotics and officinal salt preparation thereof are become the durative action preparations such as nanometer formulation, microball preparation, liposome and hydrogel, better therapeutic effect can be obtained.
The concrete technical scheme that the present invention adopts is:
Anthracycline antibiotics of the present invention is the compound and stereoisomer thereof that structure is following:
Wherein, R1 is H, OH, CH
3, CH
2oH or OCH
3, R2 is COR1 or CR1R1, R3 is H, OH, CH
3, CH
2oH, OCH
3, pyridine radicals, furyl, pyrrole radicals, thienyl or pyranose.
More preferably, described anthracycline antibiotics is doxorubicin (being also called amycin), table doxorubicin, pyrans doxorubicin, mitoxantrone, daunorubicin (being also called daunomycin, rubidomycin), idarubicin, aclarubicin (being also called aklavine) or carminomycin (being also called the soft mycin of card, Carrninomycin I)
Above-claimed cpd can by prior art disclosed method prepare, some compounds can be bought by commercial sources and obtain.
Anthracycline antibiotics and officinal salt thereof and pharmaceutically acceptable auxiliary material combination are prepared into the disease that various conventional preparation is used for the treatment of neovascular glaucoma by the present invention, and these preparations comprise: common flour injection, long-acting sustained-release injection.Preferably, described long-acting sustained-release injection can be nano particle preparations, microball preparation, aqueogel or Liposomal formulation.Preferably, described aqueogel is temperature-sensitive hydrogel preparation.Described anthracycline antibiotics is 0.5-2000 μ g/kg for the eye drops dosage of human body, preferred 1-1500 μ g/kg, more preferably 3-1000 μ g/kg.
When nanoparticle, microsphere, the aqueogel described in preparing, the pharmaceutically acceptable adjuvant adopted comprises macromolecular material, described macromolecular material is selected from: one or more in condensing model, polyoxyalkylene, polyamide, polyester, polyacrylic resin, polyethers or polysaccharide, or the copolymer between the different monomers being selected from described several macromolecular material.Preferably, described macromolecular material is selected from condensing model, polyvinyl alcohol, Polyethylene Glycol, condensing model-ethylene glycol copolymer, NIPA-acrylic copolymer, polybutylcyanoacrylate, polylactic acid, octadecane diacid acid anhydride-glycol copolymer, PLGA, polylactic-co-glycolic acid-ethylene glycol copolymer, PGA, Acetic acid, hydroxy-, bimol. cyclic ester lactide-ethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide triblock copolymer, polyether sulfone, gelatin, poly(hydrobutyl ester), poloxamer, collagen protein, Fibrinogen, albumin, cellulose, glucosan, alginate, dextran, hyaluronic acid, one or more in polypeptide or chitosan etc.
When the Liposomal formulation described in preparing, the pharmaceutically acceptable adjuvant of employing comprises phospholipid that is natural or that synthesize, lipoid or its combination.
Said medicine preparation can be prepared by method disclosed in prior art, and the method recorded in the embodiment of the present invention also can be adopted to prepare.
At present, anthracycline antibiotics is usually used in treatment leukemia and antitumor.Less people is had to use it for treatment proliferative retinopathy.The present inventor has carried out the research of new indication to anthracycline antibiotics, and delightedly find it with after the form eye drops of the durative action preparation such as nanometer or microsphere, anthracycline antibiotics has good effect to treatment neovascular glaucoma, and can not produce anthracycline antibiotics very easily to the multiple side effect that eye produces.Research finds that anthracycline long-acting slow-release preparation not only intervenes the adjusting and controlling growth of iris neovascularization simultaneously, and have extraordinary therapeutical effect to neovascular glaucoma, have more targeting, it has long action time, toxic and side effects is little, can significantly improve the advantages such as bioavailability.At the model of action of this target slow-release administration, medicine can continuous action for a long time, the larger eye pair that significantly reducing anthracycline originally has does use, makes it to play new eye treatment effect, can treat neovascular glaucoma.
Detailed description of the invention
Specific embodiment is described in further detail the present invention below, but the present invention not only limits to following examples.In following embodiment, method therefor is conventional method if no special instructions, test material used, if no special instructions, is the purchase of routine biochemistry reagent suppliers and obtains.
Preparation embodiment is as follows:
Embodiment 1
1. get 300mg PLGA (PLGA) to join in 1ml dichloromethane and be prepared into solution;
2. 50mg aclarubicin is joined in solution obtained 1., ultrasonic mixing;
3. with syringe, the solution in 2. is slowly injected in the Oleum Gossypii semen containing 0.05% egg yolk ovum Oletum Trogopterori, after 1000r/min stirs 20min, reduces rotating speed and continue to stir 4h to 200r/min;
4. to step 3. in add 20ml petroleum ether, the centrifugal 5min of 8000r/min after 30min;
5. microsphere is collected, petroleum ether and volatilizing.
Embodiment 2
1. get 200mg PLGA to join in 1ml tetrahydrofuran solution and be prepared into solution;
2. add in 0.2ml glycerol by 50mg mitoxantrone, join in 1. obtained solution after mixing, homogenizer obtains colostrum after stirring 1min;
3. joined in 2% polyvinyl alcohol (PVA) solution of 12ml, 1000r/min adds 120ml again 0.5%PVA solution after stirring 5min obtains emulsion;
4. after reducing rotating speed to 200r/min continuation stirring 4h, the centrifugal 5min of 8000r/min;
5. microsphere is collected, distilled water wash postlyophilization.
Embodiment 3
1. get 100mg PSA-PEG to join in 1ml dichloromethane solution and be prepared into solution;
2. 50mg aclarubicin is joined in solution obtained 1., ultrasonic mixing;
3. 2. obtained solution is joined in 15ml 1%PVA solution;
4. after reducing rotating speed to 200r/min continuation stirring 4h, the centrifugal 5min of 8000r/min;
5. collect microsphere, collect after distilled water wash.
Embodiment 4
1. get 160mg condensing model-ethylene glycol copolymer (PSA-PEG) to join in 2ml dimethyl sulfoxide and dichloromethane (8: 2) and be prepared into organic facies;
2. 40mg doxorubicin is joined 1., after mixing, be positioned in 1% polyvinyl alcohol ultrasonic;
3. will 2. in solution be placed in poly-vinyl alcohol solution and stir;
4. remove organic solvent 3., collected by centrifugation, obtains nanoparticle solution.
Embodiment 5
1. daunorubicin and polylactic-co-glycolic acid-ethylene glycol copolymer (PLGA-PEG) 800mg 3ml dichloromethane and 1ml DMF being acted in 30 DEG C of water-baths makes it dissolve and high-speed stirred;
2. joining in 1. containing 1% polyvinyl alcohol to 100ml, fully mix;
3. stirring at room temperature volatilization 2h, obtains nanoparticle solution;
4. at 4 DEG C, gained nanoparticle after centrifugal 20min, is collected;
5. will 4. in gains distilled water wash three times and be drug-carrying nanometer particle.
Embodiment 6
1. get 300mg condensing model (PSA) to join in 3ml dichloromethane and be prepared into organic facies;
2. 40mg idarubicin is joined in organic facies obtained 1.;
3. getting propylene glycol block polyether and Tween 80 (1: 1), to make containing emulsifying agent be the aqueous solution of 4%, and add macrodex wherein, regulates solution PH to be 8;
4. nanometer sedimentation is used obtained organic facies to be dropped in 3. obtained aqueous phase;
5. stir removing organic solvent, obtain nanoparticle solution, collected by centrifugation.
Embodiment 7
1. 0.01molL is used
-1sodium hydroxide solution as solvent;
2. get 1. solvent 10ml and add 100 μ l hydroxypropyl emthylcelluloses, stir and make it even;
3. add 50 μ l carbomer 934s in the solution 2. obtained to step, stir and make its mix homogeneously;
4. add 40mgPSA-PEG in the solution 3. obtained to step, stir and make its mix homogeneously;
5. in above-mentioned solution, 1mg aclarubicin is added;
6. take 1.8g poloxamer188 to join in 4. obtained solution, under magnetic agitation, make it be uniformly dispersed, 4 DEG C of conditions place more than 24 hours, make gel fully swelling, are uniformly dispersed and obtain clear and bright solution, both obtain aclarubicin hydrogel.
Embodiment 8
1. 0.01molL is used
-1sodium hydroxide solution as solvent;
2. get 1. solvent 10ml and add 80 μ l hydroxypropyl emthylcelluloses, stir and make it even;
3. add 50 μ l sodium alginates in the solution 2. obtained to step, stir and make its mix homogeneously;
4. add 40mgPSA-PEG in the solution 3. obtained to step, stir and make its mix homogeneously;
5. in above-mentioned solution, 1mg mitoxantrone is added;
6. take 1.8g poloxamer188 to join in 4. obtained solution, under magnetic agitation, make it be uniformly dispersed, 4 DEG C of conditions place more than 24 hours, make gel fully swelling, are uniformly dispersed and obtain clear and bright solution, both obtain mitoxantrone hydrogel.
Embodiment 9
1. take 0.9g phospholipid, 0.3g cholesterol in 50ml small beaker, add dehydrated alcohol 1-2ml, be placed in 65-70 DEG C of water-bath, be stirred to dissolve, rotate this small beaker and make the ethanol of phospholipid film forming on wall of cup, with rubber pipette bulb featheriness wind, ethanol is flung to;
2. doxorubicin solution 30ml is separately got in small beaker, with being placed in 65-70 DEG C of water-bath, insulation, stand-by;
3. get the doxorubicin solution 30ml of preheating, add in the small beaker containing phospholipid and cholesterol ester plasma membrane, 65-70 DEG C of stirred in water bath aquation 10min.Subsequently small beaker is placed on magnetic stirring apparatus, stirring at room temperature 30-60min, mixes and obtain Mycocet.
Effect experimental is as follows:
1, the foundation of animal model and grouping:
Oxygen environment is used to bring out the iris neovascularization of Mus, the C57 mice 200 be just born only is put into hyperbaric oxygen chamber with brood female Mus, the purity oxygen of 100% humidifying is passed into by oxygen feeding tube, during beginning, oxygen influx is adjusted to and per minutely passes into 8 liters, oxygen is made comparatively promptly to be full of whole oxygen cabin, after continuous washing of tanks, when the concentration of oxygen is shown as 75%, reduce the intake of oxygen to 1 liter per minute, maintain oxygen concentration in whole oxygen cabin at (75 ± 5) %, monitor oxygen concentration the oxygen concentration maintained in whole oxygen cabin subsequently at set intervals at zone of reasonableness.Open the cabin every day and once check, change food and water.Oxygen supply is after 1 week; they are taken out from oxygen cabin; be placed in home to raise; by its random packet; be divided into anthracycline antibiotics ordinary preparation medication group respectively (after sodium carboxymethyl cellulose, mannitol hydrotropy doxorubicin; with suspended form injection), embodiment 9 groups (nanometer formulation of embodiment, microball preparation, aqueogel, Liposomal formulation).Model group and do not stand the normal mouse (Normal group) of oxygen environment, 12 groups altogether.
2, animals administer and disposal:
After Animal Model, the first day respectively after Animal Model carries out administration to each group.Treatment group is respectively anthracycline antibiotics ordinary preparation medication group (after sodium carboxymethyl cellulose, mannitol hydrotropy doxorubicin, with suspended form injection), embodiment group (nanometer formulation of embodiment, microball preparation, aqueogel, Liposomal formulation).Except model group and Normal group, other each treatment groups equal intraocular injection 5 μ g medicine or the drug-carrying nanometer particle (microsphere, nanoparticle, hydrogel or liposome) containing 5 μ g medicines.Normal group is the normal Mus not having neovascular glaucoma.The PBS solution of Normal group and the equal intraocular injection 0.1mL of model group.Often organize and be all administered once, within the 14th day, put to death each group of half animal, carry out laboratory observation, terminate treatment after Therapy lasted surrounding, namely within the 28th day, put to death each and organize remaining Mus, carry out laboratory observation.
3, experimental technique:
Respectively at the 14th day and the 28th day, carry out eyeball excise by after sacrifice, the fatty tissue of periphery removed, cornea opening, puts into and organizes fixed bin, and is placed in the DEPC-PBS buffer of 4% paraformaldehyde, and 48h fixed by 4 DEG C of refrigerators.Conventional dehydration, transparent, paraffin embedding, notice during embedding that the placement of eyeball need be sagittal plain, makes section for cornea is to looking nipple direction.Continuous 6 μm of thickness section, HE staining section observes iris neovascularization tube chamber number.The section that HE dyes, every eyeball selects multiple, counts under an optical microscope and often opens the upper iris tissue morphosis of section, get 5mm under the visual field during counting
2new vessels under area counts and averages.
From each group, randomly draw the section of no dyeing, by streptavidin method, Immunohistochemical detection is carried out to VEGF (VEGF).Replace primary antibodie to be negative control with buffer, anti-fluorescein antibody labelling, laser confocal microscope image analysis system is respectively organized vegf protein and is expressed.Operate as follows: 1, paraffin section, conventional dewaxing is to water; 2, distilled water flushing, PBS soaks 5min; 3, drip Normal Goat Serum working solution, incubated at room 20min, then fall serum deprivation; 4, after dripping mice VEGF IgG working solution, 4 DEG C are spent the night; 5, PBS rinses, and then drips appropriate biotin labeling goat anti-mouse two anti-igg working solution, puts into 37 DEG C of water baths subsequently and hatches PBS after 20min and rinse; 6, fluorescein-labelled thing is dripped to it; 7, use glycerol mounting, under laser confocal microscope image analysis system, compare the vegf expression situation of each experimental group.
The pathologic condition of each group iris of Microscopic observation, records and compares simultaneously.
Pharmacodynamic result:
Under each experimental group visual field, the number of new vessels number detects and compares:
The testing result (14 days) of each zoopery group new vessels number:
The testing result (28 days) of each zoopery group new vessels number:
Iris neovascularization modeling success after, by new vessels in each group of iris relatively in can find out: at the 14th day, embodiment group new vessels number comparatively model group had obvious minimizing, and compare with model group, difference has remarkable statistical significance; Simultaneously each embodiment group comparatively anthracycline antibiotics ordinary preparation medication group new vessels number also reduce, have difference.Can find out in two weeks, each embodiment group all shows good result in the disease for the treatment of iris neovascularization, but does not also recover normal completely, and anthracycline antibiotics ordinary preparation group also show curative effect.The 28th day relatively in, can find out that each group of embodiment has very big-difference than model group, wherein section Example group with the new vessels number of normal group closely, difference is little.In treatment group, anthracycline antibiotics ordinary preparation group comparatively embodiment respectively to organize effect slightly poor, can show that each group of embodiment shows better therapeutical effect thus.
Vascular endothelial growth factor expression results contrast:
The expression of results (14 days) of each zoopery group iris tissue section Immunohistochemical detection VEGF:
The expression of results (28 days) of each zoopery group iris tissue section Immunohistochemical detection VEGF:
By each group of iris VEGF relatively in can find out: at the 14th day, each group of embodiment has more the ability suppressing new vessels compared with ordinary preparation group, difference has statistical significance, simultaneously as can be seen from the expression of VEGF also, the difference of each embodiment group and model group has statistical significance, and each group of embodiment shows the situation controlling new vessels.Can find out in two weeks, each embodiment group all shows good result in the disease for the treatment of iris neovascularization, but does not also recover normal completely, and anthracycline antibiotics ordinary preparation group also show curative effect.The 28th day relatively in, can find out that embodiment group has very big-difference than model group, each embodiment group suppresses new vessels preferably.In treatment group, each group of embodiment demonstrates therapeutical effect more better than ordinary preparation group.
Final pathological picture observed result:
The pathological picture display of the 14th day: the new vessels on visible iris surface in the pathological picture of model group.The blood vessel of pathological study new life is blood capillary.The iris neovascularization that embodiment group is a small amount of as seen, be mainly positioned at anterior border layer and Medium Culture, vasodilation is not obvious, the pigment cell having no iris front surface tunica vasculose and fibrovascular membranes and come off.Embodiment group demonstrates and alleviates to some extent than the symptom of model group.The pathological change situation of anthracycline antibiotics ordinary preparation group is between embodiment group and model group.
The pathological picture display of the 28th day: visible iris neovascularization in the pathological picture of model group, and in section, anterior border layer new vessels amount is maximum, in iris, four sides, visible vessels chamber is in irregular expansion.Embodiment group is recovered better, show diverse pathologic condition than model group, have no irregular vasodilation, show embodiment under mirror and respectively organize rare iris neovascularization, the closely pathologic condition of normal group, each group of embodiment shows good therapeutic effect.The new vessels situation comparison model group of ordinary preparation group also has difference, demonstrates good curative effect.
Draw thus, each group of embodiment demonstrates extraordinary therapeutic effect than model group, all can treat neovascular glaucoma disease.Each group of embodiment also has significant difference than current therapies group, and each group of embodiment has better effect than ordinary preparation treatment group.
Obviously, the above embodiment of the present invention is only for example of the present invention is clearly described, and is not the restriction to embodiments of the present invention.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here cannot give exhaustive to all embodiments.Every belong to technical scheme of the present invention the apparent change of extending out or variation be still in the row of protection scope of the present invention.
Claims (8)
1.
anthracycline antibiotics and the purposes of officinal salt in preparation treatment neovascular glaucoma medicine thereof,it is characterized in that, described anthracycline antibiotics is doxorubicin, table doxorubicin, pyrans doxorubicin, mitoxantrone, daunorubicin, idarubicin, aclarubicin or carminomycin, and described anthracycline antibiotics directly carries out eye drops.
2. purposes according to claim 1, is characterized in that, described medicine is prepared by described anthracycline antibiotics and officinal salt thereof and pharmaceutically acceptable adjuvant.
3. purposes according to claim 2, is characterized in that, described medicine is common flour injection or long-acting sustained-release injection, and wherein, described long-acting sustained-release injection is nano particle preparations, microball preparation, aqueogel or Liposomal formulation.
4. purposes according to claim 3, it is characterized in that, the adjuvant adopted time prepared by described nano particle preparations, microball preparation, aqueogel comprises macromolecular material, described macromolecular material is selected from: one or more in condensing model, polyoxyalkylene, polyamide, polyester, polyacrylic resin, polyethers, polyether sulfone, polyphosphazene, starch, collagen, polypeptide or polysaccharide, or the copolymer between the different monomers being selected from described macromolecular material; The adjuvant adopted time prepared by described Liposomal formulation comprises phospholipid that is natural or that synthesize, lipoid or its combination.
5. purposes according to claim 4, it is characterized in that, described macromolecular material is selected from: condensing model, polyvinyl alcohol, Polyethylene Glycol, condensing model-ethylene glycol copolymer, NIPA-acrylic copolymer, polybutylcyanoacrylate, polylactic acid, octadecane diacid acid anhydride-ethylene glycol block copolymer, PLGA, polylactic-co-glycolic acid-ethylene glycol copolymer, PGA, Acetic acid, hydroxy-, bimol. cyclic ester lactide-ethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide triblock copolymer, polyether sulfone, gelatin, poly(hydrobutyl ester), poloxamer, collagen, Fibrinogen, albumin, cellulose, glucosan, alginate, dextran, hyaluronic acid, one or more in polypeptide or chitosan.
6. the purposes according to any one of claim 1-3, is characterized in that, described anthracycline antibiotics is 0.5-2000 μ g/kg for the eye drops dosage of human body.
7. purposes according to claim 6, is characterized in that, described anthracycline antibiotics is 1-1500 μ g/kg for the eye drops dosage of human body.
8. purposes according to claim 6, is characterized in that, described anthracycline antibiotics is 3-1000 μ g/kg for the eye drops dosage of human body.
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| 全反式维甲酸和柔红霉素对NB4和HL-60细胞株VEGF表达及分泌的影响;王晨 等;《中华血液学杂志》;20040331;第25卷(第3期);171-174 * |
| 细胞因子和新生血管性青光眼;徐常钦 等;《吉林医学》;20110630;第32卷(第18期);3783-3784 * |
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