CN102512433A - Application of digitoflavone-7-O-beta-D-glucuronide in fundus disease treatment - Google Patents
Application of digitoflavone-7-O-beta-D-glucuronide in fundus disease treatment Download PDFInfo
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- CN102512433A CN102512433A CN2011103525351A CN201110352535A CN102512433A CN 102512433 A CN102512433 A CN 102512433A CN 2011103525351 A CN2011103525351 A CN 2011103525351A CN 201110352535 A CN201110352535 A CN 201110352535A CN 102512433 A CN102512433 A CN 102512433A
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- glucuronide
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- digitoflavone
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- retinopathy
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Abstract
The invention relates to application of digitoflavone-7-O-beta-D-glucuronide in fundus disease treatment, which is characterized in that digitoflavone-7-O-beta-D-glucuronide can be used as a main active component for preparing a medicine treating the pathological change of the fundus. One kind of or a plurality of kinds of natural or synthetic active components with a synergic or auxiliary action with the digitoflavone-7-O-beta-D-glucuronide can be added for preparing a medicine treating fundus diseases. The digitoflavone-7-O-beta-D-glucuronide is used for treating the diabetic pathological change of the retina, the senile pathological change of yellow spots, retinal vein obstruction, and the like, and has an obvious curative effect.
Description
Technical field
The present invention relates to the medical usage that luteolin-7-O-β-the D-glucuronide is new, be specifically related to the application of luteolin-7-O-β-D-glucuronide in preparation treatment retinopathy medicine, belong to the Chinese medicine and pharmacy technical field.
Background technology
Retinopathy has comprised the eye pathological changes that retina, choroid, optic nerve and Vitrea inflammation, tumor, the pathological changes of all kinds of blood vessels, various degenerative disease and multisystem disease cause, and is not only of a great variety, and bigger to the visual function infringement.So retinopathy receives various countries scholar's attention always, and done number of research projects in different fields.Fundus oculi disease at present common and that have a strong impact on visual function has diabetic renal papillary necrosis, treating senile maculopathy, the retinal vein occlusion etc., and the clinical research of these diseases has obtained bigger progress.
1. age-related macular degeneration aging macular degeneration, AMD)
AMD is one of oculopathy of grievous injury old people visual function.Investigation shows that the prevalence of AMD is about 4.9%～8.4%, and with advancing age, sickness rate also increases significantly, and the age can reach 40% in prevalence more than 70 years old.The cause of disease of AMD is unclear yet, but research shows that smoker's sickness rate is apparently higher than the non smoker; Environment, diet and inherited genetic factors also are the causes of disease of significant.It is relevant that the pathogenesis of AMD maybe be old and feeble with the sclerosis of chronic photodamaged, gene mutation, macular area CC and infringement, retinal pigment epithelium, subclinical inflammation and various angiogenesis factor increase factors such as (like VEGFs etc.).At present, the performance according to the optical fundus is divided into atrophic type and exudative type with AMD.Through epidemiological study, confirm suitably to take generation and development that antioxidant and zinc agent can delay AMD.In treatment, a kind of definite method is not still arranged at present.
2. the retinal vein occlusion (retinal vein occlusion.RVO)
RVO is a kind of common optical fundus blood vessel property disease, comprise central retinal vein occlusion (central retinal vein occlusion, CRVO) with the branch retinal vein obstruction (branch retinal vein occlusion, BRVO).The main concurrent vitreous hemorrhage that causes in macular edema and retinal neovascularization of RVO patient's vision infringement and neovascular glaucoma occurs.
Though occurred the new therapy of many treatment CRVO in recent years; Wherein there is couple irrigated CRVO to use laser and causes choroidal artery and retinal vein to coincide,, reduce perfusion property CRVO and be transformed into non-perfusion CRVO incidence rate to improve the vein obstruction blood circulation; Alleviate macular edema, promote vision.Dynamic and static vein sheath otomy treatment BRVO was also arranged in recent years and used the successful report of optic nerve sclerotic ring otomy treatment irrigated CRVOR; But these operations have certain complication; The skill of equipment that need be more valuable and skilled retina operation on vitreous; To add in case of necessity with laser retina light and coagulate,, confirm that these surgical effect still need further randomized clinical control study so only carry out selectively at present in bigger hospital.
Diabetic renal papillary necrosis (diabetic retinopathy, DR)
DR is the complication of the main blinding of diabetes.Nineteen ninety-five, China had 2 000 ten thousand diabeticss approximately, had reached 3 000 ten thousand to 2002.The prevalence of DR is along with the growth of diabetic duration increases, and the investigation of being in hospital of China shows that the prevalence of diabetics DR has reached 15%～25%, and visible China DR prevalence is higher, should cause that we enough pay attention to.
But aspect experimentation, still lack the maturation method that causes the animal retinopathy.The model of Cavia porcellus ischemic retinopathy and the model of rabbit conjunctive bulbi microcirculation disturbance have been set up in this research; Inquire into prevention and the therapeutical effect of luteolin-7-O-β-D-glucuronide, for the clinical treatment retinopathy of luteolin-7-O-β-D-glucuronide provides experimental basis to retinopathy and retinopathy.
The luteolin that the present invention relates to-7-O-β-D-glucuronide be the feverfew Herba Ixeritis Sonchifoliae (another name: the flavone compound that extracts Herba Ixeritis Sonchifoliae), structure is following:
Molecular formula: C
21H
18O
12Molecular weight: 462
Summary of the invention
The purpose of this invention is to provide the purposes of luteolin-7-O-β-D-glucuronide aspect preparation treatment retinopathy medicine.
Another object of the present invention provides with the medicine of luteolin-7-O-β-D-glucuronide as main active preparation treatment retinopathy.
Innovation advantage of the present invention is following several respects:
1. set up the retinopathy animal model
According to patients such as some hypertension, nephropathy, severe infections clinically; Can form fundus oculi disease because of circulatory disturbance such as optical fundus blood vessel spasm, thromboembolisms; We cause homonymy eyes retina central artery blood supply insufficiency at ligation one side common carotid artery method on probation, and hypoxic-ischemic forms retinopathy.Experiment sees that this method can make the P wave-amplitude of Cavia porcellus ligation common carotid artery branch hole VER significantly reduce, and the N wave-amplitude also reduces, and the hide Shi Junyou prolongation of P ripple and N ripple proves to form obvious retinopathy, can be used for studying the influence of medicine to retinopathy.
2. luteolin-7-O-β-D-glucuronide has the obvious treatment effect to retinopathy
At ligation Cavia porcellus one side common carotid artery and with after luteolin-7-O-β-D-glucuronide is treated a week, measure Cavia porcellus ligation branch hole VER.As a result, saline control group P wave-amplitude significantly reduces, and prolongs when hiding; Luteolin-7-O-β-D-glucuronide group P wave-amplitude do not reduce or the reduction degree less, prolong when hiding less or shorten.Proof luteolin-7-O-β-D-glucuronide has the obvious treatment effect to retinopathy.
3. the research of therapeutical effect mechanism
According to the reason that causes the Cavia porcellus retinopathy is to make the Zinn's artery blood supply insufficiency, and the therapeutical effect that can know luteolin-7-O-β-D-glucuronide is with to improve the optical fundus Circulation relevant; The result proves from the rabbit fundus photography, the luteolin-7-O-β-expansible optical fundus of D-glucuronide arteries; From rabbit conjunctive bulbi microcirculation experiment proof; Luteolin-7-O-β-D-glucuronide can obviously improve the systemic microcirculation obstacle that is caused by high molecular dextran; See that the conjunctive bulbi microvascular blood flow velocity obviously increases; Therefore the blood cell aggregation extent has improvement, can think luteolin-7-O-β-D-glucuronide to the therapeutical effect and this medicine blood vessel dilating, blood flow increasing of Cavia porcellus retinopathy, and increase side Zhi Xunhuan is with to improve the optical fundus microcirculation relevant.
The present invention is following as the method for preparing of main active preparation treatment retinopathy medicine with chicoric acid:
Test drug and reagent:
(1) receive the reagent thing: purity is the luteolin-7-O-β-D-glucuronide more than 98%.
(2) high molecular dextran: Sweden's product weight average molecular weight is 500,000 dextran, processes 10% solution with sterile saline, supplies the moulding of animal microcirculation disturbance to use.
(3) pentobarbital sodium: Serva import packing, Shanghai chemical reagent purchasing and supply station chemical reagent work.
Experimental animal: 200 of SD rats, male and female are regardless of, body weight 250-300g.
Statistical procedures: experimental data is represented with mean ± standard deviation
; Adopt SPSSl3.0 statistics software data processing; One factor analysis of variance (Oneway-ANOVA) carries out significance test, and P＜0.05 is for there being statistical significance.
Test method:
The vision brainstem evoked potential is measured; Cavia porcellus is with the anesthesia of lumbar injection 35mg/kg pentobarbital sodium, and in the positive middle part of head parietal bone near the frontal bone end, hair is shaved by left mastoid process portion and right mastoid process portion; Link to each other with positive pole, negative pole and the ground wire of brain disk electrode respectively, Cavia porcellus is put in the screen darkroom.Began test in back 20 minutes in anesthesia; Promptly in a branch hole 40cm place (opposite side covers light); With MS-2PS type photic stimulator (stimulus intervals 0.5 second) eye is carried out photostimulation; The potential change that produces is through brain electricity disk electrode input bioelectrode amplifier, through wave filter (15Hz-1000Hz) and main twt amplifier input computer, with x-y monitor record visual evoked potential.
With the mensuration of method to the conjunctive bulbi microcirculation blood flow velocity, (800w 200v) puts into the circular lampshade of iron sheet system with high voltage mercury lamp; Lampshade tiltedly below is made a call to a diameter 1.5cm aperture, inserts a leaded light teat glass, leaded light test tube mouth diameter 1.5cm; Down be tapered; The pipe bottom blowing becomes little spheroidal, fills with distilled water in the pipe, and whole test tube is coated with the prepared Chinese ink shading except that roundlet ball bottom.Light makes light source become cold light source through the water of test tube, reaches optically focused through the little ball in test tube bottom, makes light gather into the circular light spot of the about 3mm of diameter.This light is projected on the rabbit conjunctive bulbi with miter angle, amplify 100 times, observe conjunctive bulbi microvascular blood flow velocity and erythrocyte and assemble situation with simple microscope.Regulate the oscillography scanning speed, make with VPV synchronously, scope sweep this moment speed is microvascular blood flow velocity.
Following experiment has shown the pharmacological action of luteolin of the present invention-7-O-β-D-glucuronide to retinopathy; Select akin animal model or test method for use; Medicine of the present invention is used for prevention and treatment retinopathy effect is studied, for its effectiveness is made science appraisal.
Experiment and result
Experimental example 1
Luteolin-7-O-β-D-glucuronide is to the therapeutical effect of retinopathy
(1) mensuration of Cavia porcellus visual evoked potential (VER) under the normal condition
40 of the Cavia porcelluss of body weight 200-400g are measured VER as stated above, and except that 8 animals do not occur the obvious waveform, all the other 32 obvious P ripple (positive phase wave) and N ripple (negative phase wave) all occur.
P ripple and N wave-amplitude differ bigger between the different animals, the fluctuation between 4-34 μ v, between the different animals P ripple and N ripple the appearance hide the time, differ less relatively.But same animal via different time is measured among its VER the P ripple with N wave-amplitude size be close when hiding, and is comparatively stable.64 eye VER of 32 Cavia porcelluss normal value is measured the result list in table 1.From table, see P ripple, the N wave-amplitude of Cavia porcellus two branch hole VER and very approaching when hiding, the P wave-amplitude is all greater than the N wave-amplitude.
(μ is when hiding (ms) v) for P ripple and N wave-amplitude among the table 1. normal guinea pig VER
(2) retinopathy animal model replication
Get the Cavia porcellus of body weight 250-400g, after surveying its normal vision and bringing out current potential (VER), slightly anaesthetize with low dose of pentobarbital sodium, cervical incision is peeled off a side common carotid artery, and two pass ligation common carotid artery is sewed up the incision, and measures VER after the week again, and the result sees table 2.Because ligation one side common carotid artery, branch hole Zinn's artery blood supply insufficiency causes with the branch hole retinopathy optical fundus hypoxic-ischemic.The result sees table 2-5.
The variation (P wave-amplitude) of all visual evoked potentials behind the table 2 ligation Cavia porcellus one side common carotid artery
The variation (when the P ripple is hidden) of all visual evoked potentials behind the table 3 ligation Cavia porcellus one side common carotid artery
The variation (N wave-amplitude) of all visual evoked potentials behind the table 4 ligation Cavia porcellus one side common carotid artery
The variation (when the N ripple is hidden) of all visual evoked potentials behind the table 5 ligation Cavia porcellus one side common carotid artery
The result shows; Ligation is Carotid obviously to be reduced with P wave-amplitude among the branch hole VER, reduces to 6.09, significant difference (P＜0.05) by 12.87; The N ripple reduces to 6.6 by 8.14; Certain prolongation is also all arranged when P ripple and N ripple are hidden, show with ligation one side common carotid artery method and can cause with the branch hole retinopathy, wherein the most responsive with the reaction of P ripple among the VER.
(3) luteolin-7-O-β-D-glucuronide is to the therapeutical effect of Cavia porcellus retinopathy
30 of the male and female Cavia porcelluss of body weight 250-400g behind the mensuration VER, are chosen tangible 24 of waveform; Do not have animal ligation one side common carotid artery, divide three groups at random, difference intraperitoneal injection of saline 2ml/kg every day; Receive reagent thing 4mg/kg, after company annotates seven, measure Cavia porcellus VER; Comparative drug is to the influence of P wave-amplitude among the Cavia porcellus ligation common carotid artery branch hole VER when hiding, and the result sees table 6,7.
Behind the table 6 ligation one side common carotid artery injecting normal saline after seven days with the variation of branch hole VER
Inject the variation with branch hole VER after seven days of luteolin-7-O-β-D-glucuronide behind the table 7 ligation one side common carotid artery
The P wave-amplitude obviously reduces among the common carotid artery of the normal saline group Cavia porcellus ligation as a result branch hole VER, with normal saline group comparing difference remarkable (P＜0.05).Show that luteolin-7-O-β-D-glucuronide can obviously treat the ischemic retinopathy that ligation carotid artery causes.
Experimental example 2
Luteolin-7-O-β-D-glucuronide is to the effect on rabbit optical fundus
9 of the rabbit of body weight 1.85-2.8kg, male and female have concurrently.Take two fundus photograph before the experiment; Intravenous injection receives reagent thing 4mg/kg then; Inject and took two fundus photographs by similarity condition in back 15 minutes, be administered once later every day, took two fundus photographs on the 7th day again; Egative film is washed into the photo of 2.7 times of diameters of amplification, measure the optical fundus tremulous pulse and begin outside 8mm artery diameter from mastoid process.The relatively variation of blood vessel diameter before and after the administration.The result sees table 8.
Table 8 luteolin-7-O-β-D-glucuronide is to the dilating effect of rabbit optical fundus tremulous pulse
The result shows, increase all arranged with seven days optical fundus artery diameters before than administration in 15 minutes after the administration, than before the administration between the increase 8.3-3.8%, shows that luteolin-7-O-β-D-glucuronide has certain dilating effect to optical fundus blood vessel.
Experimental example 3
Luteolin-7-O-β-D-glucuronide is to the therapeutical effect of rabbit conjunctive bulbi microcirculation disturbance
12 of rabbit, body weight 1.5-3.0kg, male and female have concurrently.Rabbit abdomen position is fixed, and head is fixed, observes 4-5 the visual field in the eyeball middle part of right eye as stated above apart from the about 2mm of bulbar conjunctiva lower edge place, and the close 2-3 bar blood capillary of thickness is observed in each visual field.The record VPV; Get average and be the preceding normal value of experiment, equal then 10% high molecular dextran normal saline solution 15ml/kg/ day of intravenous drip, annotate 1-2 day; Microvascular blood flow velocity is obviously slowed down; More serious blood cell clustering phenomena occurs, promptly cause microcirculation disturbance, record VPV and blood cell are assembled situation.Rabbit is divided into 2 groups, 6 every group, intravenous drip luteolin-7-O-β-D-glucuronide 4mg/kg and respectively with the capacity normal saline, every day 2-3 time, company annotated 5.Observe the bulbar Conjunctiva Microcirculation situation of about same position every day before administration, the result sees table 9.
Table 9. luteolin-7-O-β-D-glucuronide is to the therapeutical effect of rabbit microcirculation disturbance due to the high molecular dextran
(
*Compare P＜0.05 with the normal saline group)
Find out that by table 9 to behind the high molecular dextran, rabbit conjunctive bulbi microcirculatory vascular VPV obviously slows down, be equivalent to test 1/4 of preceding normal value.The saline group annotates that VPV loses recovery in back 5 days, and administration group VPV slowly increases, returned near 1/2 of normal flow before the experiment in administration 4-6 days, with the saline group relatively, VPV has remarkable recovery (P＜0.05); After giving high molecular dextran; 5-6 or 3-10 the phenomenon that erythrocyte is assembled chaining occur, after receiving the reagent treatment, aggregation extent alleviates; Mostly be 2-3 or 3-5 erythrocyte aggregate chains; But do not eliminate the erythrocyte clustering phenomena, prove that thus the microcirculation disturbance that luteolin-7-O-β-the D-glucuronide causes high molecular dextran has certain therapeutical effect.
Four, experiment conclusion
To sum up; Through this experiment luteolin-7-O-β-D-glucuronide is confirmed that in the research of several respects such as treatment of treatment, the arteriectasia effect of rabbit optical fundus and the rabbit conjunctive bulbi microcirculation disturbance of Cavia porcellus retinopathy luteolin-7-O-β-D-glucuronide has significant prevention and therapeutical effect to retinopathy.
Claims (1)
1. the purposes of luteolin-7-O-β-D-glucuronide is characterized in that: can be the medicine that main active is prepared into the treatment retinopathy with luteolin-7-O-β-D-glucuronide.
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| CN110025625A (en) * | 2019-04-04 | 2019-07-19 | 北京诚毅投资股份有限公司 | Luteolin -7-O- glucoside or luteolin -7-O- glucuronide are in the application for preparing eye injury drug |
| CN114796194A (en) * | 2022-05-27 | 2022-07-29 | 澳门大学 | Application of DA adduct derived from Morus plant in preparation of beta-G inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109876003A (en) * | 2019-04-04 | 2019-06-14 | 中国药科大学 | The pharmacy new opplication of luteolin -7-O- glucoside, luteolin -7-O- glucuronide |
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| JP7281227B2 (en) | 2019-04-04 | 2023-05-25 | ベイジン チェンイー インベストメント カンパニー リミテッド | Use of luteolin-7-O-glucoside or luteolin-7-O-glucuronide in the preparation of medicaments for eye damage |
| CN114796194A (en) * | 2022-05-27 | 2022-07-29 | 澳门大学 | Application of DA adduct derived from Morus plant in preparation of beta-G inhibitor |
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