CN105395547A - Applications of Leuconodine B in preparing drugs used for treating ischemic brain injuries - Google Patents
Applications of Leuconodine B in preparing drugs used for treating ischemic brain injuries Download PDFInfo
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- CN105395547A CN105395547A CN201510956929.6A CN201510956929A CN105395547A CN 105395547 A CN105395547 A CN 105395547A CN 201510956929 A CN201510956929 A CN 201510956929A CN 105395547 A CN105395547 A CN 105395547A
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- leuconodineb
- ischemic brain
- brain injury
- leuconodine
- compound
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- 0 CCCN[C@@](*C(C1)([C@@](CC)(C2C)[C@@]2C#IC)O)(C2(CC)*CCC2)NC1O Chemical compound CCCN[C@@](*C(C1)([C@@](CC)(C2C)[C@@]2C#IC)O)(C2(CC)*CCC2)NC1O 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses applications of Leuconodine B in preparing drugs used for treating ischemic brain injuries, and belongs to the technical field of drug new application. Leuconodine B possesses curative effects on ischemic brain injuries; the development and application prospect is promising; the applications are disclosed for the first time; and the curative activity of Leuconodine B on ischemic brain injuries is high.
Description
Technical field
The present invention relates to the novelty teabag of compound L euconodineB, particularly relate to the application of LeuconodineB in preparation treatment ischemic brain injury medicine.
Background technology
The present inventor is found by a large amount of experiments, and LeuconodineB has the pharmacological action of ischemia resisting brain injury, anti-cerebral ischemia/reperfusion injury, has the medical usage of prevention or treatment ischemic brain injury.
The compound L euconodineB that the present invention relates to is one and delivers (AtsushiUmehara in 2014, etal., TotalSynthesesofLeuconoxine, LeuconodineB, andMelodinineEbyOxidativeCyclicAminalFormationandDiaster eoselectiveRing-ClosingMetathesis.Org.Lett.2014, 16, noval chemical compound 2526-2529.), this compound has brand-new framework types (AtsushiUmehara, etal., TotalSynthesesofLeuconoxine, LeuconodineB, andMelodinineEbyOxidativeCyclicAminalFormationandDiaster eoselectiveRing-ClosingMetathesis.Org.Lett.2014, 16, 2526-2529.), the purposes of the LeuconodineB that the present invention relates in preparation treatment ischemic brain injury medicine belongs to first public.
Summary of the invention
The object of the invention is to not find that it has the present situation of the report for the treatment of ischemic brain injury according in existing LeuconodineB research, provide the application of LeuconodineB in preparation treatment ischemic brain injury medicine.
Described compound L euconodineB structure is as shown in formula I:
The application of described LeuconodineB in treatment ischemic brain injury medicine, LeuconodineB reduces cerebral ischemia tissues following MCAO in rats edema, reduces Infarction volume, improves SOD active, reduces MDA content.
One treats ischemic brain injury medicine, and be that active component interpolation adjuvant is prepared from by LeuconodineB, preparation method, for getting 5 g of compound LeuconodineB, adds 195 grams, dextrin, and mixing, Conventional compression makes 1000.
One treats ischemic brain injury medicine, and be that active component adds adjuvant and is prepared from by LeuconodineB, preparation method, for getting 5 g of compound LeuconodineB, adds starch 195 grams, and mixing, encapsulatedly makes 1000.
The purposes of the LeuconodineB that the present invention relates in preparation treatment ischemic brain injury medicine belongs to first public, because framework types belongs to brand-new framework types, and its effect for ischemic brain injury is strong, possess outstanding substantive distinguishing features, be used for the treatment of ischemic brain injury simultaneously and obviously there is significant progress.
The present inventor demonstrates by the experiment in detailed description of the invention the effect that LeuconodineB has treatment or prevention ischemic brain injury.
Detailed description of the invention
The preparation method of compound L euconodineB involved in the present invention is see document (AtsushiUmehara, etal., TotalSynthesesofLeuconoxine, LeuconodineB, andMelodinineEbyOxidativeCyclicAminalFormationandDiaster eoselectiveRing-ClosingMetathesis.Org.Lett.2014,16,2526-2529.)
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Embodiment 1: the preparation of compound L euconodineB tablet involved in the present invention:
Get 5 g of compound LeuconodineB and add 195 grams, dextrin, mixing, Conventional compression makes 1000.
Embodiment 2: the preparation of compound L euconodineB capsule involved in the present invention:
Get 5 g of compound LeuconodineB and add starch 195 grams, mixing, encapsulatedly makes 1000.
Its pharmaceutically active is further illustrated below by pharmacodynamic experiment.
The impact that experimental example 1:LeuconodineB damages focal cerebral ischemia in rats
(1) material is implemented: SD rat, male and female dual-purpose, body weight 190 ~ 210g, Nanjing Medical University's Experimental Animal Center.Positive control drug: taponin, pharmaceutical Co. Ltd of Kang Enbei group produces, every sheet composition containing ginkgo folic acid extract 40mg.
(2) method and result
1) LeuconodineB is to rat medium-sized artery thrombosis (MCAO) model test
60 rats are divided into six groups at random, i.e. Sham-operated control group, MCAO model group, administration group 3 groups, taponin group (24mg/kg).Gastric infusion before modeling, once-a-day, altogether administration seven times, Sham-operated control group, MCAT model group, gives the drinking water (1ml/100g) of equivalent, and after modeling, gastric infusion once.Rats by intraperitoneal injection 12% chloral hydrate solution (350mg/kg) is anaesthetized, Rat Right lateral position is fixed, a curved incision is made at paropia and external auditory meatus line mid point, be about 115cm, pinch off temporal bone, do a diameter 215mm bone window at cheekbone and temporo squamosum joint near 1mm place, mouth side by dental burr, cleaning residue, exposes middle cerebral artery (between tractus olfactorius and inferior cerebral vein).There is the small pieces quantitative filter paper of 50% ferric chloride solution 10ul to apply suction on this section of middle cerebral artery, after 30min, to take off filter paper, use normal saline flushing local organization, layer-by-layer suture, steam again and raise.Sham operated rats except not dripping except ferric chloride solution, the same model group of all the other operating procedures.The evaluation of MCAO rat symptom and infarction size: in operation different time (6h, 24h), is also improved by methods such as Bederson, is carried out behavior scoring to animal.1. carry Mus tail and leave ground about one chi, observe forelimb flexing situation.As two forelimb symmetry stretches to ground, be designated as 0 point; As perform the operation offside forelimb occur shoulder flexing, time flexing, shoulder inward turning or existing wrist time flexing have inward turning person again, be designated as 1 point.2. animal is placed on level and smooth ground, pushes away both shoulders respectively and move to offside, detect resistance.As bilateral resistance equity and strong person is designated as 0 point; During as promoted to operation offside, resistance descender, is designated as 1 point.3. animal two forelimb is put on a wire netting, observe the muscular tension of two forelimbs.Bilateral muscular tension is reciprocity and strong person is 0 point; Operation offside muscle of anterior limb tension force declines and is designated as 1 point.4. carry Mus tail and leave ground about one chi, animal have ceaselessly to operation offside be rotating, be designated as 1 point; Otherwise be designated as 0 point.According to above scale, full marks are 4 points, and the behavior disorder of the higher animal of mark is more serious.Compare between behavioral value marking value group, t checks.The results are shown in Table 1.After animal via last behavior scoring, broken end gets brain.Remove olfactory bulb, cerebellum and low brain stem, remainder is crown at 4 DEG C is cut into 5.(every 5ml dye liquor is containing 4%TTC1.5ml, 1MK rapidly brain sheet to be placed in TTC dye liquor
2hPO
40.1ml), 37 DEG C of lucifuge temperature incubate 30min, then take out and be placed in 10% formalin and keep in Dark Place.Dyed rear non-ischemic region is rose, and infarct is white.White tissues is carefully dug down and weighs, account for the percentage ratio of right side half brain weight as Range of Cerebral Infarction using blocking tissue's weight.Compare between result group, t checks, and the results are shown in Table 2.
Table 1LeuconodineB is on the impact (n=10) of MCAO rat cerebral infarction scope and nervous symptoms
Note: * p<0.05, * * p<0.01 compared with model group.
Table 2LeuconodineB is on the impact (n=10) of photochemical induction cerebral thrombosis rat cerebral infarction
Note: * p<0.05, * * p<0.01 compared with model group.
Result shows, and change except sham-operation has no dystropy, hemiplegia sample symptom all appears in MCAO model group rats after surgery 6h, 24h.The rat of administration group and taponin group after surgery its nervous symptoms of 6h, 24h all has improvement (P<0.01, P<0.05) in various degree.Postoperative 24h, except sham operated rats has no cerebral tissue abnormal change, model group is compared has significant difference (P<0.01, P<0.05).LeuconodineB can alleviate focus of infarct, and result demonstrates certain dose-effect relationship.
Experimental example 2:LeuconodineB is on the impact of focal cerebral ischemia in rats/reperfusion injury
(1) experiment material: SD rat, male and female dual-purpose, body weight 190 ~ 210g.MDA, SOD, protein quantification (Coomassie brilliant blue) test kit (Bioengineering Research Institute is built up in Nanjing).
(2) method and result
1) experimental technique: 120 rats are divided into 5 groups at random, i.e. sham operated rats, model group, 3 administration groups, often organize 25.Except sham operated rats not plug wire, all the other 4 groups of modelings (MCAO).Administration group each dosage group ig every day 1 time, continuous 13d.Preoperative 1hig administration 1 time again.6% chloral hydrate (350mg/kg) intraperitoneal anesthesia, cervical region medisection, is separated right carotid (CCA), external carotid artery (ECA), internal carotid artery (ICA).After ligation common carotid artery proximal part, external carotid artery initiating terminal, one " V " shape osculum is cut at common carotid artery place, (line bolt adopts diameter to be the fishing line of 0.235mm to insert line bolt along common carotid artery, head end burns till spherical, and in marking apart from thread ball 18.5mm place) be inserted to middle cerebral artery branching place through internal carotid artery to intracranial, insertion depth is 18 ~ 20mm, by line ligation together with internal carotid artery.Body temperature (37 ± 015) DEG C is maintained in art.When pouring into, external cable makes pommel be back to ECA, pulls out plug wire, ligation ECA.Sham operated rats is except not plug wire, and all the other steps are the same.After middle cerebral artery thromboembolism, 2h recovers blood confession, and Neurological deficits divides standard processed with reference to ZeaLonga5, postoperatively occurs left fore flexing, and turn-take to the left during walking and be considered as modeling success, then insulation is conventional raises, and draws materials to 24h sacrificed by decapitation.In experimentation, because anesthetic accident, MCAO operative failure, modeling are unsuccessful and dead being all discarded in 24h.
The mensuration of brain water content: after rat modeling 24h, broken end gets brain, weighs both sides half cutaneous horn weight.Be placed in baking oven again, 100 DEG C of baking 24h are to constant weight, and accurate weighing dry weight, calculates water content.Brain water content=(weight in wet base-dry weight)/weight in wet base × 100%.
Cerebral infarct volume measures: broken end gets brain, brain is made continuous 2mm coronal section, totally 5, then brain sheet is put into 2%TTC phosphate buffer 37 DEG C of constant-temperature incubation 30min, and normal cerebral tissue's dye is for red, and infarct is in white dead.Carefully carve the mass percent of getting non-coloured part with blade after filter paper sucks surface liquid, react Infarction volume ratio with this.The detection of brain tissue homogenate SOD vigor, MDA content: right side half brain adds ice normal saline by 1:10 after weighing and makes homogenate, with reference to SOD, MDA test kit description, detects SOD, MDA content in cerebral tissue.Application SPSS13.0forwindows software processes data; Continuous data represents with x ± s, compares employing one factor analysis of variance between each group.
2) result
Brain water content: left brain water content compares not statistically significant between respectively organizing, the right brain water content of model group is apparently higher than each group (P<0.05), higher than sham operated rats (P<0.05), each dosage group of administration group can reduce model brain water content (P<0.05) (table 3).
Table 3LeuconodineB is on the impact (n=8) of brain water content, Infarction volume, SOD, MDA content
* p<0.05, * * p<0.01 compared with model group
Cerebral infarct volume: model group cerebral tissue cerebral infarct volume is higher than each group (P<0.05), and each dosage group of administration group can reduce model cerebral tissue Infarction volume (P<0.05).
Conclusion: LeuconodineB can reduce cerebral ischemia tissues following MCAO in rats edema, reduces Infarction volume, improves SOD active, reduces MDA content, alleviates the infringement of radical reaction to cerebral tissue, have significant protective effect to ischemic tissue of brain.LeuconodineB may be used for preparation treatment ischemic brain injury medicine.
Claims (4)
- The application of 1.LeuconodineB in treatment ischemic brain injury medicine, described compound L euconodineB structure is as shown in formula I:Formula I.
- 2. the application of LeuconodineB in treatment ischemic brain injury medicine as claimed in claim 1, is characterized in that LeuconodineB reduces cerebral ischemia tissues following MCAO in rats edema, reduces Infarction volume, improve SOD active, reduce MDA content.
- 3. a treatment ischemic brain injury medicine, it is characterized in that by LeuconodineB described in claim 1 being that active component interpolation adjuvant is prepared from, preparation method, for getting 5 g of compound LeuconodineB, adds 195 grams, dextrin, mixing, Conventional compression makes 1000.
- 4. a treatment ischemic brain injury medicine, it is characterized in that by LeuconodineB described in claim 1 being that active component interpolation adjuvant is prepared from, preparation method, for getting 5 g of compound LeuconodineB, adds starch 195 grams, mixing, encapsulatedly makes 1000.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510956929.6A CN105395547A (en) | 2015-12-18 | 2015-12-18 | Applications of Leuconodine B in preparing drugs used for treating ischemic brain injuries |
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| CN201510956929.6A CN105395547A (en) | 2015-12-18 | 2015-12-18 | Applications of Leuconodine B in preparing drugs used for treating ischemic brain injuries |
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| Publication Number | Publication Date |
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| CN105395547A true CN105395547A (en) | 2016-03-16 |
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| CN201510956929.6A Pending CN105395547A (en) | 2015-12-18 | 2015-12-18 | Applications of Leuconodine B in preparing drugs used for treating ischemic brain injuries |
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Application publication date: 20160316 |
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