CN106860444A - 3,4,7 trihydroxy-isoflavones or 3 methoxyl group Dais are preparing the application of suppression inflammation and brain ischemia medicament - Google Patents
3,4,7 trihydroxy-isoflavones or 3 methoxyl group Dais are preparing the application of suppression inflammation and brain ischemia medicament Download PDFInfo
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- CN106860444A CN106860444A CN201710070891.1A CN201710070891A CN106860444A CN 106860444 A CN106860444 A CN 106860444A CN 201710070891 A CN201710070891 A CN 201710070891A CN 106860444 A CN106860444 A CN 106860444A
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- isoflavones
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
Abstract
The application in suppressing inflammation and brain ischemia medicament is being prepared the invention provides 3,4,7 trihydroxy-isoflavones or 3 methoxyl group Dais.3,4,7 trihydroxy-isoflavone or 3 methoxyl group Dai people can significantly inhibit macrophage IL 6, the secretion of TNF α of LPS inductions；While 3,4,7 trihydroxy-isoflavone gavages have to the brain damage in Cerebral Ischemia-reperfusion in Mice model significantly inhibits effect.Bleeding test result indicate that：Compared with the clopidogrel of Isodose, 3,4,7 trihydroxy-isoflavones and 3 methoxyl group Dais will not substantially increase the mouse tail bleeding time, and the clopidogrel administration group of the same concentration of control group has obviously hemorrhagic activity, this explanation is the present invention provide 3, the application that 4,7 trihydroxy-isoflavones or 3 methoxyl group Dais are concentrated in suppression platelet aggregation, the application of the medicine can reduce bleeding risk, using safety, expand clinical and medical usage.
Description
Technical field
The invention belongs to biomedical sector, and in particular to 3,4,7- trihydroxy-isoflavones or 3- methoxyl groups Dai are in system
The standby application for suppressing inflammation and brain ischemia medicament.
Background technology
Inflammation is the defense reaction that occurs to damage factor of biological tissue of vascular system, be body for stimulate one
Defense reaction is planted, red, swollen, hot, pain is shown as.The reason for any factor that can cause tissue damage can all turn into inflammation, can
It is summarized as following a few classes：Biological factors are including bacterium, virus, Richettsia, mycoplasma, fungi, conveyor screw and parasite etc.
It is the most common reason of inflammation；Physics sex factor, including high temperature, low temperature, radioactive substance and ultraviolet etc. and mechanical damage；Change
Learning sex factor includes xenobiotics such as strong acid, highly basic and turpentine oil, mustard gas；In addition with foreign matter, slough
Can cause inflammation with allergy.
It is disorderly that serious inflammatory reaction also results in blood coagulation system.It is this disorderly including procoagulant activity enhancing, anticoagulating active
Lower suppressed with fibrinolytic system etc., the microvascular thrombosis that show as now are formed or promote disseminated intravascular coagulation to occur, send out more
Exhibition.Fibrin ferment and other clotting factor in blood coagulation system can also mediate a series of inflammatory reaction.The master of acute cerebral ischemia
It is cerebral vessels embolism to want the cause of disease, and this is to cause thrombosis due to forming thrombus in the cerebrovascular, in turn results in blood vessel infarct.Brain lacks
Inflammatory reaction after blood is closely related with subsequent brain damage after cerebral ischemia, is with leukocyte infiltration, micro- blood in cerebral microvascular
Liquid and inflammatory factor accumulation are the acute inflammatory process of mark in pipe dysfunction and local brain tissue.It is now recognized that inflammation because
Son can directly or indirectly participate in the activation and infiltration of inflammatory cell, and encephaledema is played an important role.Such as macrophage
Interleukins (IL) and TNF (TNF) of generation etc. can strengthen infiltration and other inflammatory factors of leucocyte
Release, aggravates local inflammation reaction and acute cerebral ischemia type brain damage is formed.In view of inflammation and acute cerebral ischemia type brain damage are deposited
In the vicious circle network mutually promoted, then can simultaneously for the medicine of blood coagulation system and inflammation will play more persistently and
The effect of effective anti-acute cerebral ischemia type brain damage.
Clinically mainly there is anti-freezing for preventing and treating inflammation and the medicine of acute cerebral ischemia type brain injury disease at present
Blood class medicine, but common anti-inflammatory drugs such as aspirin, clopidogrel etc. often produce drug effect weaken, stomach stimulate and
Granulocyte such as reduces at the side effect, in addition, the medicine such as aspirin, clopidogrel can also cause the bleeding risk to increase, this serious shadow
Ring the life and health of Clinical practice and patient.
The content of the invention
In view of this, it is an object of the invention to provide 3, prepared by 4,7- trihydroxy-isoflavones or 3- methoxyl groups Dai
Suppress the application of inflammation and brain ischemia medicament, the application of the medicine can reduce bleeding risk, using safety, expand it is clinical and
Medical usage.
In order to realize foregoing invention purpose, the present invention provides following technical scheme：
The invention provides 3,4,7- trihydroxy-isoflavones or 3- methoxyl groups Dai in the medicine for preparing prevention of inflammation
Application, described 3, the structural formula of 4,7- trihydroxy-isoflavones as shown in formula I, the structural formula such as formula of the 3- methoxyl groups Dai
Shown in II：
Preferably, the inflammation is caused by lipopolysaccharide-induced macrophage inflammatory factor.
Preferably, the formulation of the medicine is oral agents.
Preferably, described 3,4,7- trihydroxy-isoflavones according to different weight patient pill burden >=100 μm ol/kg.
Preferably, the 3- methoxyl groups Dai according to different weight patient pill burden >=100 μm ol/kg.
Lack in preparation prevention and/or treatment brain the invention provides 3,4,7- trihydroxy-isoflavones or 3- methoxyl groups Dai
Application in the medicine of blood Reperfu- sion type brain damage；The structural formula of the 3,4,7- trihydroxy-isoflavones and 3- methoxyl group Dais
Structure in applying as claimed in claim 1.
Preferably, the cerebral ischemia re-pouring type brain damage is caused by inflammation.
Preferably, the formulation of the medicine is oral agents.
Preferably, described 3,4,7- trihydroxy-isoflavones according to different weight patient pill burden >=100 μm ol/kg.
Preferably, the 3- methoxyl groups Dai according to different weight patient pill burden >=100 μm ol/kg.
Suppression inflammation and cerebral ischemia are being prepared the invention provides 3,4,7- trihydroxy-isoflavones or 3- methoxyl groups Dai
Application in the medicine of Reperfu- sion type brain damage, described 3, the structural formula of 4,7- trihydroxy-isoflavones as shown in formula I, the 3- first
The structural formula of epoxide Dai is as shown in formula II.The 3,4,7- trihydroxy-isoflavones or 3- methoxyl group Dai people can significantly press down
Macrophage IL-6, the secretion of TNF-α of LPS inductions processed；Simultaneously 3,4,7- trihydroxy-isoflavone gavages to focal cerebral ischemia again
Brain damage in perfusion model has and significantly inhibits effect.Bleeding test result indicate that：Compared with the clopidogrel of Isodose,
3,4,7- trihydroxy-isoflavones and 3- methoxyl groups Dai are not all significantly increased mouse tail hemorrhagic activity, and control group is equally dense
The clopidogrel administration group of degree has obviously hemorrhagic activity, and this explanation is the present invention provide 3,4,7- trihydroxy-isoflavones or 3-
Methoxyl group Dai is preparing the application in controlling inflammation and cerebral ischemia re-pouring type brain damage medicine in advance, the application energy of the medicine
Bleeding risk is enough reduced, using safety, expands clinical and medical usage.
Brief description of the drawings
Fig. 1 is scorching for the macrophage that 3,4,7- trihydroxy-isoflavones and 3- methoxyl groups Dai in embodiment 1 are induced LPS
Inflammation factor IL-6, TNF-α, the inhibitory action of IFN-γ content；
Fig. 2 is induced LPS for the 3,4,7- trihydroxy-isoflavones and 3- methoxyl groups Dai under various concentrations in embodiment 1
Macrophage inflammatory factor IL-6, the inhibitory action of TNF-α secretion；
The inhibitory action that Fig. 3 is damaged for 3,4,7- trihydroxy-isoflavones gavage in embodiment 2 to Cerebral Ischemia-reperfusion in Mice；
Fig. 4 is the influence of 3,4,7- trihydroxy-isoflavones and clopidogrel to the mouse tail bleeding time in embodiment 3；
Fig. 5 is the influence of 3- methoxyl groups Dai and clopidogrel to the mouse tail bleeding time in embodiment 3.
Specific embodiment
Invention is there is provided 3,4,7- trihydroxy-isoflavones or 3- methoxyl groups Dai in the medicine for preparing prevention of inflammation
Using, described 3, the structural formula of 4,7- trihydroxy-isoflavones as shown in formula I, the structural formula such as formula II of the 3- methoxyl groups Dai
It is shown：
In the present invention, the inflammation is preferably caused by lipopolysaccharide-induced macrophage inflammatory factor.The mechanism of induction is
Interleukins (IL) and TNF (TNF) of macrophage generation etc. can strengthen infiltration and other inflammation of leucocyte
The release of inflammation factor, aggravates local inflammation reaction.
In the present invention, the formulation of the medicine is preferably oral agents.
In the present invention, described 3,4,7- trihydroxy-isoflavones to the patient dosage of different weight preferably >=100 μm of ol/
Kg, more preferably 120 μm ol/kg~300 μm ol/kg, most preferably 200 μm ol/kg, i.e. every kilogram of administration mole of patient >=
100 μm of ol/kg, patient according to different quality determines the mole of medication.The source of the 3,4,7- trihydroxy-isoflavones
It is not particularly limited, using the source of well-known to those skilled in the art 3,4,7- trihydroxy-isoflavones.It is of the invention real
In applying example, described 3,4,7- trihydroxy-isoflavones are purchased from the general Cadence Co., Ltd in Beijing.
In the present invention, the 3- methoxyl groups Dai to the patient dosage of different weight preferably >=100 μm of ol/kg, more
Preferably 120 μm ol/kg~300 μm ol/kg, most preferably 200 μm ol/kg, i.e. every kilogram of administration mole >=100 μ of patient
Mol/kg, patient according to different quality determines the mole of medication.The source of the 3- methoxyl groups Dai is not special
Limitation, using the source of 3- methoxyl groups Dai well-known to those skilled in the art.In the embodiment of the present invention, the 3-
Methoxyl group Dai is purchased from the general Cadence Co., Ltd in Beijing.
Lack in preparation prevention and/or treatment brain the invention provides 3,4,7- trihydroxy-isoflavones or 3- methoxyl groups Dai
Application in the medicine of blood Reperfu- sion type brain damage；The structural formula of the 3,4,7- trihydroxy-isoflavones and 3- methoxyl group Dais
Structure in applying as described.
In the present invention, the cerebral ischemia re-pouring type brain damage is preferably caused by inflammation.Inflammation causes cerebral ischemia re-pouring
It is disorderly that the mechanism of type brain damage is that serious inflammatory reaction also results in blood coagulation system, it is this it is disorderly include procoagulant activity enhancing,
Anticoagulating active lowers and fibrinolytic system is suppressed etc., and the microvascular thrombosis that show as now are formed or promote disseminated intravascular coagulation more
Occur, develop.Fibrin ferment and other clotting factor in blood coagulation system mediate a series of inflammatory reaction.Due to acute cerebral ischemia
Etiological be cerebral vessels embolism, this be due in the cerebrovascular formed thrombus cause thrombosis, in turn result in blood vessel infarct.
Therefore the inflammatory reaction after cerebral ischemia is closely related with subsequent brain damage after cerebral ischemia, is soaked with leucocyte in cerebral microvascular
Profit, microvascular dysfunction and liquid and the acute inflammatory process that inflammatory factor accumulation is mark in local brain tissue.
In the present invention, the formulation of the medicine is preferably oral agents.
In the present invention, described 3,4,7- trihydroxy-isoflavones to the patient dosage of different weight preferably >=100 μm of ol/
Kg, more preferably 120 μm ol/kg~300 μm ol/kg, most preferably 200 μm ol/kg, i.e. every kilogram of administration mole of patient >=
100 μm of ol/kg, patient according to different quality determines the mole of medication.In the present invention, the 3- methoxyl groups Dai pair
The patient dosage of different weight preferably >=100 μm of ol/kg, more preferably 120 μm ol/kg~300 μm ol/kg, most preferably
200 μm of ol/kg, i.e. every kilogram of patient administration mole >=100 μm ol/kg, patient according to different quality determine medication
Mole.
In the present invention, the oral agents also include the auxiliary material for medically receiving.The auxiliary material includes but is not limited to solvent, throws
Penetrate agent, solubilizer, cosolvent, emulsifying agent, colouring agent, binder, disintegrant, filler, lubricant, wetting agent, osmotic pressure tune
Section agent, stabilizer, glidant, flavouring, preservative, suspending agent, coating material, aromatic, anti-binder, integrated agent, infiltration
Accelerator, pH value regulator, buffer, plasticizer, surfactant, foaming agent, defoamer, thickener, inclusion agents, moisturizing
Agent, absorbent, diluent, flocculant and deflocculant, filter aid, release retarding agent etc..
The present invention also provides the preparation method of the oral agents, including following masses percentage composition component：5~20% work
Property composition, 2~10% disintegrant, 0.2~2% lubricant, 0.1~1.5% glidant and 0~0.5% additive,
Balance of filler mixing, is made oral agents；The active component is 3,4,7- trihydroxy-isoflavones or 3- methoxyl group Dais.
In the present invention, it 3-7 days is a course for the treatment of once a day that the medicine frequency of the oral agents is.
It is prepared by the 3,4,7- trihydroxy-isoflavones and 3- methoxyl groups Dai provided the present invention with reference to embodiment
The application for suppressing inflammation and brain ischemia medicament is described in detail, but they can not be interpreted as to the scope of the present invention
Restriction.
Embodiment 1
The experiment of cellular inflammation factors check is using being incubated at the complete mediums of RPMI 1640 (containing 10%FBS and dual anti-)
Human monocyte cell line THP-1 is completed.THP-1(1×105/ hole) in 200nM concentration phorbol exters (phorbol 12-myristate
13-acetate, PMA) induction under cultivate 2 days, be divided into adherent macrophage, afterwards with without phorbol exters culture medium
Balance 2 days.Inflammatory factor is produced using 100ng/mL Escherichia coli LPSs inducing macrophage, while the 3 of various concentrations are added,
4,7- trihydroxy-isoflavones (3 ', 4 ', 7-Trihydroxyisoflavone) and 3- methoxyl groups Dai (3 '-
Methoxydaidzein) co-incubation 24 hours.Take after cell conditioned medium is diluted to suitable multiple and use cell ELISA
Determine (enzyme-linked immunosorbent assay, ELISA) detection IL-6, TNF-α, the content of IFN-γ.Thrombus
The Inflammatory Factors Contents of mouse are determined using the mice serum of fresh taking-up, are diluted to after suitable multiple also according to following
The flow of ELISA is detected：
A. using preceding, all reagents are fully mixed, it is to avoid produce foam.
B. according to experimental port (blank and standard items) quantity, it is determined that required lath number.Sample (containing standard items) and sky
All do multiple holes in vain.
C. it is loaded：100 μ L/well add the Cytokine standard after dilution to standard sample wells, and 100uL/well adds
Enter sample to sample well, blank well is set, sample and standard items are replaced with Dilution buffer R (1 ×).
Plus detection antibody d.：50 μ L/well add the Biotinylated antibody after dilution.After mixing, envelope is covered
Plate film, 37 degrees Celsius incubate 90 minutes.
E. board-washing：Button goes liquid in hole, 300 μ L/well to add 1 × washing buffer；Hole is discarded after stopping 1min
Interior liquid.It is repeated 4 times, buckles dry on filter paper for the last time.
F. it is enzyme-added：100 μ L/well add the Streptavidin-HRP after dilution.Cover shrouding film, 37 DEG C of incubations
30min。
G. board-washing：Repeat step 5.
H. develop the color：100 μ L/well add TMB, 37 DEG C between Incubation in dark 5-30 minutes, according to the depth of color in hole
To judge terminating reaction, navy blue is reached.Generally colour developing can reach good effect at 10-20 minutes.
I. terminating reaction：100 μ L/well are rapidly added terminate liquid terminating reaction.
J. read plate：After termination in 10 minutes, with Detection wavelength 450nm readings.
IL-6 in 300 μm of ol/kg 3,4,7- trihydroxy-isoflavones and 3- methoxyl group Dai gavage group mice serums,
TNF-α, IFN-γ Inflammatory Factors Contents are significantly reduced.3,4,7- trihydroxy-isoflavones and 3- methoxyl groups Dai to TNF-α,
The inhibitory action of IFN-γ is better than the clopidogrel (Fig. 1) of same concentration.In the macrophage inflammatory factor secretion of LPS inductions
In experiment, 3,4,7- trihydroxy-isoflavones and 3- methoxyl groups Dai can concentration gradient rely on ground suppress IL-6, TNF-α point
Secrete, and respectively under 3 μM and 10 μM of concentration with control group produce significant difference (Fig. 2).
Embodiment 2
Acute cerebral ischemia in mice re-perfusion model
Mouse operation consent 30min gastric infusions, experimental group gavage concentration is 60mg/kg, and control group is physiological saline, volume
100 μ L, every group 6.Kunming mice (30~35g), after middle deep anaesthesia, neck are anaesthetized using 2% yellow Jackets (80mg/kg)
Median incision successively cuts rat skin and hypodermis, separates nutator, cuts off anterior belly of digastric, and exposure right side neck is total
Artery (CCA), internal carotid (ICA) and external carotid artery (ECA), arteria thyreoidea and arteria pharyngea on ECA are condensed using electric coagulating apparatus
And cut.The distal end of ECA is ligatured, and in its proximal part hanging wire, temporarily folder closes CCA and ICA, ECA is cut, by line bolt from ECA
Stump inserts ICA, ligatures ECA stumps, removes the artery clamp of ICA, and by ICA, inwardly top is slowly advanced.Appropriate adjustment direction, inserts
Enter to line bolt mark (calculating 10mm from CCA crotches), start timing, line bolt is removed after 1h, after observing no active bleeding
Sew up the incision.Whole process is incubated with electric blanket, and temperature is 36~37 DEG C.Animal after revival is put back in cage, makes its freedom
Diet.Anesthetized mice cuts head after 24h, takes out brain tissue, is placed in brain mould (on ice), and 2mm is cut into backward along optic chiasma
Slab, puts it into the phosphate buffer of 2%TTC, dyes 30min in 37 DEG C of incubators, then with 4% paraformaldehyde mistake
Night is fixed and takes pictures.60mg/kg 3,4,7- trihydroxy-isoflavones gastric infusion can effectively mitigate what cerebral ischemia re-pouring was caused
Damage (Fig. 3).
Embodiment 3
The bleeding risk assessment of 3,4,7- trihydroxy-isoflavones and 3- methoxyl group Dais
8 one group of male C57BL/6 (18-20g), test sample and control group are by gastric infusion, and administration 3,6,12 is small
Shi Hou, mouse is placed in homemade special fixator, makes 1mL pipettor gun head of its afterbody through after pruning, and is protected with sterilization
Dangerous blade cuts tail point 5mm, immediately immerses rat-tail in 37 DEG C of physiological saline, with blood flow dwell time as index, observation note
The time of record docking stopped bleeding.
Result is as shown in figure 4, in 80mg/kg dosage, 3,4,7- trihydroxy-isoflavone groups are compared with non-administered group each
Individual time point does not all show obvious hemorrhagic activity, and the clopidogrel administration group of same concentration has obviously bleeding
Activity.Result is as shown in figure 5, in 80mg/kg dosage, 3- methoxyl group Dai groups are compared with non-administered group in Each point in time
Obvious hemorrhagic activity is not all shown, and the clopidogrel administration group of same concentration has obviously hemorrhagic activity.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
- The application of 1.3,4,7- trihydroxy-isoflavones or 3- methoxyl groups Dai in the medicine for suppressing inflammation is prepared, described 3,4, As shown in formula I, the structural formula of the 3- methoxyl groups Dai is as shown in formula II for the structural formula of 7- trihydroxy-isoflavones：
- 2. application according to claim 1, it is characterised in that the inflammation by lipopolysaccharide-induced Macrophage Inflamatory because Son causes.
- 3. application according to claim 1 and 2, it is characterised in that the formulation of the medicine is oral agents.
- 4. application according to claim 3, it is characterised in that described 3,4,7- trihydroxy-isoflavones are according to different weight Patient pill burden >=100 μm ol/kg.
- 5. application according to claim 3, it is characterised in that the 3- methoxyl groups Dai according to different weight patient Dosage >=100 μm ol/kg.
- 6.3,4,7- trihydroxy-isoflavones or 3- methoxyl groups Dai are preparing prevention and/or treatment cerebral ischemia re-pouring type brain damage Application in the medicine of wound；The structural formula of the 3,4,7- trihydroxy-isoflavones and 3- methoxyl group Dais such as claim 1 institute State the structure in application.
- 7. application according to claim 6, it is characterised in that the cerebral ischemia re-pouring type brain damage is caused by inflammation.
- 8. the application according to claim 6 or 7, it is characterised in that the formulation of the medicine is oral agents.
- 9. application according to claim 8, it is characterised in that described 3,4,7- trihydroxy-isoflavones are according to different weight Patient pill burden >=100 μm ol/kg.
- 10. application according to claim 8, it is characterised in that the 3- methoxyl groups Dai according to different weight trouble Person dosage >=100 μm ol/kg.
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| CN201710070891.1A CN106860444A (en) | 2017-02-09 | 2017-02-09 | 3,4,7 trihydroxy-isoflavones or 3 methoxyl group Dais are preparing the application of suppression inflammation and brain ischemia medicament |
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| CN201710070891.1A CN106860444A (en) | 2017-02-09 | 2017-02-09 | 3,4,7 trihydroxy-isoflavones or 3 methoxyl group Dais are preparing the application of suppression inflammation and brain ischemia medicament |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019051548A1 (en) * | 2017-09-15 | 2019-03-21 | Norbio No. 2 Pty Ltd | Treatment of neuro-inflammation |
Citations (2)
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| WO2000066576A1 (en) * | 1999-04-30 | 2000-11-09 | G.J. Consultants Pty Ltd | Isoflavone metabolites |
| CN102209536A (en) * | 2008-11-18 | 2011-10-05 | 株式会社太平洋 | Skin external composition for inhibiting epidermal hyperproliferation and alleviating inflammatory skin diseases containing ortho-dihydroxyisoflavone derivatives |
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2017
- 2017-02-09 CN CN201710070891.1A patent/CN106860444A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000066576A1 (en) * | 1999-04-30 | 2000-11-09 | G.J. Consultants Pty Ltd | Isoflavone metabolites |
| CN102209536A (en) * | 2008-11-18 | 2011-10-05 | 株式会社太平洋 | Skin external composition for inhibiting epidermal hyperproliferation and alleviating inflammatory skin diseases containing ortho-dihydroxyisoflavone derivatives |
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| Title |
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| ZHI-BIN WANG等: "Triterpenoids and Flavonoids from the Leaves of Astragalus membranaceus and Their Inhibitory Effects on Nitric Oxide Production", 《CHEMISTRY AND BIODIVERSITY》 * |
| 宁永成: "《有机化合物结构鉴定与有机波谱学 第2版》", 31 January 2000, 科学出版社 * |
| 王晓良: "《应用分子药理学》", 30 September 2015, 中国协和医科大学出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019051548A1 (en) * | 2017-09-15 | 2019-03-21 | Norbio No. 2 Pty Ltd | Treatment of neuro-inflammation |
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