CN106913570A - A kind of application of composition containing 3-methyl-1-phenyl-2-pyrazolin-5-one in cerebrovascular disease - Google Patents
A kind of application of composition containing 3-methyl-1-phenyl-2-pyrazolin-5-one in cerebrovascular disease Download PDFInfo
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- 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
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- 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
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- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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- A—HUMAN NECESSITIES
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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- A61K36/88—Liliopsida (monocotyledons)
- A61K36/902—Sparganiaceae (Bur-reed family)
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Abstract
This explanation is related to a kind of composition containing 3-methyl-1-phenyl-2-pyrazolin-5-one or its pharmaceutically acceptable salt and SsnB or its pharmaceutically acceptable salt, the application in cerebrovascular disease, particularly ischemic cerebrovascular disease.
Description
Technical field
The invention belongs to pharmaceutical field, it is related to 3-methyl-1-phenyl-2-pyrazolin-5-one and SsnB composition
Application in cerebrovascular disease, particularly ischemic cerebrovascular disease.
Background technology
Cranial vascular disease（cerebrovascular disease, CVD）Refer to caused by various cerebrovascular diseases
Brain lesionses, can be divided into ACVD by its Development process（Apoplexy）With two kinds of chronic cerebrovascular disease.Acute cerebrovascular
Disease is including transient ischemic attack, cerebral thrombosis, cerebral embolism, hypertensive encephalopathy, cerebral hemorrhage and subarachnoid hemorrhage etc.；
Chronic cerebrovascular disease includes cerebral arteriovenous malformation, dull-witted cerebrovascular characteristic of disease, cerebral artery robber's blood syndrome, Parkinson's disease etc..Ischemic
Property cerebral apoplexy（Stroke）It refer to the feeding artery due to brain（Arteria carotis and vertebral artery）Narrow or inaccessible, cerebral blood supply insufficiency causes
Brain tissue necrosis general name.Cerebral ischemia includes four types, and a point ratio is transient ischemic attack（TIA）, reversible nerve
Dysfunction（RIND）, advancing stroke（SIE）Complete stroke（CS）.TIA exists without cerebral infarction, and RIND, SIE and CS have
Different degrees of cerebral infarction is present.
Cerebral ischemia/reperfusion injury pathology is complicated, and wherein free radical and inflammatory reaction plays an important role.Exempt from congenital
In epidemic disease reaction and the acquired immune response, TLRs（Toll-like Receptors）, including TLR1-9 member, it is capable of identify that outer
The pathogen-associated molecular pattern of source property（Pathogen-associated molecular patterns, PAMPs）And endogenous
, related molecular pattern stress be damaged（Damage-associated molecular patterns, DAMPs）.With other
TLRs member compares, and TLR2 and TLR4 plays prior effect in cerebral reperfusion injury（Neurological
Research, 2010, 32(2)123–126; Neuroscience2013, 238, 87–96）.
3-methyl-1-phenyl-2-pyrazolin-5-one（Edaravone, edaravone）As a kind of freedom of novel potent
Base scavenger, can be with scavenging hydroxyl（·OH）, nitric oxide free radical（NO·）, Peroxynitrite ion（ONOO-）
（Chem Pharm Bull 2004,52(2):186-91；Redox Rep. 2002, 7(4): 219-22；J
PharmacolExpTher. 2007, 322 (1): 274-81）, suppress cellular superoxideization and damage, as a kind of effective god
Through first protective agent（Free radical scavenger）With distribution it is wide, half-life period is disconnected, safety, low toxin, is clinical ischemic brain
The effective first-line treatment medicine of palsy（Chinese acute ischemic cerebral apoplexy diagnosis and treatment guide (2010 editions)）.
Edaravone
Rhizoma scirpi（Sparganium stoloniferum）It is perennial swampweed sheet, its rhizome is applied in traditional Chinese medicine
Treatment inflammation disease（Pharmacology and Clinics of Chinese Materia Medica 2008,14,7-10）.Qiaoli Liang et al. are carried from rhizoma scirpi
Take, separate and identify a kind of monomer --- SsnB（Sparstolonin B, SsnB）.In mouse macrophage,
SsnB can suppress LPS（TLR4 parts）, Pam3CSK4（TLR1/2 parts）And Fsl-1（TLR2/6 parts）Induction inflammatory factor table
Reach, and to poly（I:C）（TLR3 parts）And ODN1668（TLR9 parts）The inflammatory factor of induction does not have inhibitory action.Enter one
Step research shows that SsnB can reduce the combination of TLR2 and TLR4 and MyD88, so as to suppress the activation of NF- κ B（J Biol
Chem 2011, 286:26470–26479）, and Mouse endotoxin can be protected to suffer a shock（Cytokine 2015, 75:302–
309）.SsnB can suppress VSMC（VSMCs）Propagation, migration, inflammatory reaction and lipid are produced, and prompting may be used
In anti-atherogenic lesions treatment（Vascul Pharmacol 2015, 67-69:59–66；The A of patent CN 101899054）.
Henry R. Bateman et al. have found that SsnB can suppress Angiogensis and blocking cell cycle, it may be possible to by lowering
CCNE2 and CDC6 and by G1/S check points prevent process and play a role（PLoS ONE 2013, 8:e70500）.In addition,
Ambrish Kumar et al. have found that SsnB can also block the growth cycle of N-myc amplifications or the tumour cell not expanded（G2-M
Phase）, increase the ROS in 3-D cultured cells and produce the intracellular GSH levels that reduce, and inducing cell apoptosis（PLoS ONE 2014,
9:e96343）.Additionally, SsnB can protect cardiac muscle cell's inflammation damnification that Ischemia Reperfusion is induced（Exp Biol Med
(Maywood) 2014, 239:376–384；Cardiovasc Drugs Ther2014, 28:433–439）, and blocking
HIV is transcribed（Virol J 2015, 12:108）.
SsnB.
The content of the invention
It is an object of the present invention to provide a kind of pharmaceutical composition, including 3-methyl-1-phenyl-2-pyrazolin-5-one or its
Pharmaceutically acceptable salt and SsnB.
Aforementioned pharmaceutical compositions, it is characterised in that weight compares 3-methyl-1-phenyl-2-pyrazolin-5-one：Rhizoma scirpi lactone
9：1~1：9, preferred weight ratio 9：1~1：4, preferred weight ratio is 4：1~1：4, preferred weight ratio is 4：1~1：2.
Drug regimen of the invention can apply to prepare cerebrovascular medicine.Wherein, the preferred ischemic brain of cerebrovascular disease
Angiosis, further excellent effect cerebral arterial thrombosis.
The beneficial effects of the invention are as follows：Both 3-methyl-1-phenyl-2-pyrazolin-5-one and SsnB compatibility,
According to animal drug effect result of the test, for cerebrovascular disease, both increase the effect of drug effect with having concertedness.
Specific embodiment
Following embodiments illustrate the present invention, are not considered as limitation of the present invention.Referred in embodiment according to
Da Lafeng is 3-methyl-1-phenyl-2-pyrazolin-5-one.
Protective effect of the Edaravone of embodiment 1 with SsnB composition to focal cerebral reperfusion injury is ground
Study carefully
1 material and method
1.1 experimental animals
Sprague-Dawley（SD）Rat, male, cleaning grade, body weight 270-290g.
1.2 tested medicines
Edaravone raw material medicine
SsnB bulk drug
1.3 experimental techniques
1.3.1 focal cerebral ischemia fills the preparation of model again
Middle cerebral artery occlusion is prepared using internal carotid line brush（Middle cerebral artery occlusion,
MCAO）Cerebral ischemia re-pouring model.7% chloral hydrate of animal（6 ml/kg）After anesthesia, operating table is fixed in prone position
On, skin of sterilizing, neck midsection separates right carotid, external carotid artery, internal carotid, gently peels off vagus nerve,
External carotid artery is ligatured and cut, internal carotid is followed forward, arteria pterygopalatina is ligatured.Folder closes arteria carotis communis proximal part, from external carotid artery
The distal end of ligature make a kerf, insertion external diameter is the nylon wire of 0.285 mm, enters arteria carotis communis bifurcated into moving in neck
Arteries and veins, untill being then inserted into light resistance slowly（From the mm of crotch about 20）, all blood supplies of arteria cerebri media are blocked, it is right
After side cerebral ischemia 2.0h, nylon wire is gently extracted, recovering blood supply carries out Reperfu- sion, skin suture, sterilization.
1.3.2 animal packet and administration
Experimental animal is divided into Edaravone group（3 mg/kg）, SsnB（1.5 mg/kg）, in Edaravone and rhizoma scirpi
Ester composition B group and model group, totally 4 groups.After preparing cerebral ischemic model, by the impartial single blind distribution of animal probability to each group.Animal
In intravenously administrable 1 time immediately after Reperfu- sion, model group animal awards isometric physiological saline.Evaluate god within 24 hours after cerebral ischemia
Through defect symptom, animal is then put to death, take brain, dyeed, measure of taking pictures brain infarction area.
1.3.3 the measure of neurologically handicapped symptom score and brain infarction area
Neurologically handicapped symptom assessment is carried out using improvement 5 points of preparation methods of Bederson.Rats after Focal Cerebral Ischemia is evaluated using mono blind method
Neurologically handicapped symptom, i.e., press group echo by experimental design person by animal, and the experimenter that neurologically handicapped symptom is scored is not known
The packet situation of road animal, after scoring terminates, the appraisal result of various marks is submitted designer by scoring person, is taken off by designer
It is blind, obtain the scoring of each every animal of test group.
The measure of cerebral infarction degree, at animal after death, broken end takes brain, and removal olfactory bulb, cerebellum and low brain stem use physiology salt
Water rinses brain surface's bloodstain, sucks remained on surface water mark, and 20 min are placed in -20 DEG C, intersects in sight line immediately after taking-up and puts down
Coronal section is made in face vertically downward, and cuts every 2 mm backward a piece of, brain piece is placed in (37 DEG C are incubated in 2%TTC dye liquors
90min), normal cerebral tissue dyes peony, and ischemic tissue of brain is in then pale asphyxia, with normal saline flushing after, rapidly by brain piece
It is arranged in a row in order from front to back, blots remained on surface water mark, takes pictures.
Photo is processed with image analysis software, and the left corresponding volume of brain and infarct cerebral volume are calculated according to formula, is obtained
Infarct percentage.
Infarction volume calculating method：
V=t (A1+ A2+ A3+ ………+An)
T is slice thickness, and A is infarct size.
%I=100%×(VC-VL)/VC
%I is Infarction volume percentage, and VC is control sides（Left brain hemisphere）Brain volume, VL is infarct side（Right brain hemisphere）Non- infarct
Domain Volume.
2 experimental results
2.1 pairs of influences of neurologically handicapped symptom
The degree of each group animal nerve defect symptom is shown in Table 1, compared with model group, in Edaravone, Edaravone and rhizoma scirpi
Ester composition B can significantly improve rat defect symptom（P=0.021,0.000）, SsnB is alone with certain
Improve the trend of neurologically handicapped symptom（p=0.111）.
According to Edaravone and black three in the equal formula q=E (a+ b) of Nintaus/(Ea+ Eb- Ea × Eb) evaluation compositions
Whether rib lactone B has synergy.E (a+ b) is the effective percentage of combination with medication in formula, and Ea, Eb are respectively A medicines, B prescriptions
The effective percentage of private medicine.It is that two medicines share simple addition, q values if q values are in the range of 0.85~1.15>1.15 is increasing
By force, q values<0.85 represents that two medicines have shared antagonism.Calculated according to above-mentioned formula, q=1.23 illustrates composition group
There is cooperative effect, compound is better than folk prescription between point.
The Edaravone of table 1. and influence of the SsnB polypharmacy to neurologically handicapped symptom
| Group | Number of animals | Neurologically handicapped symptom score |
| Model group | 13 | 2.69± 0.75 |
| Edaravone group | 13 | 1.85 ± 0.99* |
| SsnB group | 11 | 2.18±0.75 |
| Edaravone and SsnB group | 13 | 1.23±0.72*** |
X±SD.Compared with model group, * p<0.05, * * * p<0.001
2.2 pairs of influences of cerebral infarction area
Influence to cerebral infarct size is shown in Table 2, compared with model group, Edaravone, SsnB, Edaravone and black three
Rib lactone composition B can be substantially reduced rat cerebral infarction area（P=0.038,0.038,0.000）.
Calculated according to the equal formula of above-mentioned Nintaus, q=1.25, there is cooperative effect between illustrating composition component, compound is better than single
Side.
The Edaravone of table 2. and influence of the SsnB polypharmacy to cerebral infarction area
| Group | Number of animals | Brain infarction area（%） |
| Model group | 13 | 45.5±10.0 |
| Edaravone group | 13 | 35.6 ± 12.8* |
| SsnB group | 11 | 36.1 ±11.0* |
| Edaravone and SsnB group | 13 | 23.9 ±16.7*** |
X±SD.Compared with model group, * p<0.05, * * * p<0.001.
2 Edaravones of embodiment/SsnB（9:1, 4:1, 2:1, 1:1）Focal cerebral ischemia reperfusion is damaged
The effect of wound
1 material and method
1.1 experimental animals
Sprague-Dawley（SD）Rat, male, cleaning grade, body weight 270-290g.
1.2 tested medicines
Edaravone raw material medicine
SsnB bulk drug
1.3 experimental techniques
Focal cerebral ischemia fills the same embodiment of assay method of the preparation of model, neurologically handicapped symptom score and brain infarction area again
1 1.3。
Experimental animal is divided into four prescription ratio groups（Edaravone/SsnB ratio is respectively 9:1、4:1、2:1、
1:1, the dosage of each group is 4.5 mg/kg）, positive drug Edaravone group（3 mg/kg）And model group, totally 6 groups.Prepare
After cerebral ischemic model, by the impartial single blind distribution of animal probability to each group.Animal is in intravenously administrable 1 time, model immediately after Reperfu- sion
Group animal awards isometric physiological saline.Evaluate neurologically handicapped symptom within 24 hours after cerebral ischemia, then put to death animal, take brain,
Dyeing, measure of taking pictures brain infarction area.
2 experimental results
2.1 pairs of influences of neurologically handicapped symptom
The degree of each group animal nerve defect symptom is shown in Table 3, compared with model group, Edaravone/SsnB ratio 9:1、
4:1、2:1、1:1 and positive drug Edaravone can significantly improve neurologically handicapped symptom（P=0.018,0.000,0.001,
0.038,0.040）.
The Edaravone of table 3. and influence of the SsnB polypharmacy to neurologically handicapped symptom
| Group | Number of animals | Neurologically handicapped symptom score |
| Model group | 10 | 2.90± 0.91 |
| Edaravone group | 9 | 2.05 ± 0.73* |
| Prescription 9:1 group | 9 | 1.94 ±0.63* |
| Prescription 4:1 group | 9 | 1.39 ±0.42*** |
| Prescription 2:1 group | 10 | 1.50±0.74** |
| Prescription 1:1 group | 9 | 2.00±0.83* |
X±SD.Compared with model group, * p<0.05, * * p<0.01, * * * p<0.001.
2.2 pairs of influences of cerebral infarct size
Influence to cerebral infarct size is shown in Table 4, compared with model group, Edaravone/SsnB ratio 9:1、4:1、2:1、
1:1 and positive drug Edaravone can be substantially reduced animal Ischemia Reperfusion cerebral Infarction area（P=0.031,0.002,0.002,
0.014,0.034）.
The Edaravone of table 4 and influence of the SsnB polypharmacy to cerebral infarction area
| Group | Number of animals | Brain infarction area（%） |
| Model group | 10 | 38.2± 13.5 |
| Edaravone group | 9 | 26.3±7.8* |
| Prescription 9:1 group | 9 | 24.5±11.7* |
| Prescription 4:1 group | 9 | 17.8 ±10.4** |
| Prescription 2:1 group | 10 | 18.4±10.4** |
| Prescription 1:1 group | 9 | 23.0±9.9* |
X±SD.Compared with model group, * p<0.05, * * p<0.01
3 Edaravones of embodiment/SsnB（1:1, 1:2, 1:4, 1:9）To focal cerebral reperfusion injury
Effect
1 material and method
1.1 experimental animals
Sprague-Dawley（SD）Rat, male, cleaning grade, body weight 270-290g
1.2 tested medicines
Edaravone raw material medicine
SsnB bulk drug
1.3 experimental techniques
Focal cerebral ischemia fills the same embodiment of assay method of the preparation of model, neurologically handicapped symptom score and brain infarction area again
1 1.3。
Experimental animal is divided into four prescription ratio groups（Edaravone/SsnB ratio is respectively 1:1、1:2、1:4、
1:9, the dosage of each group is 4.5 mg/kg）, positive drug Edaravone group（3 mg/kg）And model group, totally 6 groups.Prepare
After cerebral ischemic model, by the impartial single blind distribution of animal probability to each group.Animal is in intravenously administrable 1 time, model immediately after Reperfu- sion
Group animal awards isometric physiological saline.Evaluate neurologically handicapped symptom within 24 hours after cerebral ischemia, then put to death animal, take brain,
Dyeing, measure of taking pictures brain infarction area.
2 experimental results
2.1 pairs of influences of neurologically handicapped symptom
The degree of each group animal nerve defect symptom is shown in Table 5, compared with model group, Edaravone/SsnB ratio 1:1、
1:2、1:4 and positive drug Edaravone can significantly improve neurologically handicapped symptom（P=0.029,0.001,0.013,0.026）.Group
Compound 1:9 ratios compare with model group, though there are the trend for improving neurologically handicapped symptom, the not up to level of signifiance.
The Edaravone of table 5. and influence of the SsnB polypharmacy to neurologically handicapped symptom
| Group | Number of animals | Neurologically handicapped symptom score |
| Model group | 9 | 2.78± 0.75 |
| Edaravone group | 10 | 1.85 ± 0.88* |
| Prescription 1:1 group | 10 | 1.65 ±1.22* |
| Prescription 1:2 groups | 9 | 1.56±0.53** |
| Prescription 1:4 groups | 10 | 1.60±1.05* |
| Prescription 1:9 groups | 9 | 1.94±1.01 |
X±SD.Compared with model group, * p<0.05, * * p<0.01
2.2 pairs of influences of cerebral infarct size
Influence to cerebral infarct size is shown in Table 6, compared with model group, Edaravone/SsnB ratio 1:1、1:2、1:4、
1:9 and positive drug Edaravone can be substantially reduced animal Ischemia Reperfusion cerebral Infarction area（P=0.016,0.008,0.028,
0.038,0.036）.
The Edaravone of table 6. and influence of the SsnB polypharmacy to cerebral infarction area
| Group | Number of animals | Brain infarction area（%） |
| Model group | 9 | 38.9± 12.0 |
| Edaravone group | 10 | 25.9 ± 12.7* |
| Prescription 1:1 group | 10 | 23.8 ±12.6* |
| Prescription 1:2 groups | 9 | 23.0 ±10.0** |
| Prescription 1:4 groups | 10 | 25.1±12.8* |
| Prescription 1:9 groups | 9 | 27.9±8.4* |
X±SD.Compared with model group, * p<0.05, * * p<0.01.
Claims (7)
1. a kind of application of composition in treatment cerebrovascular disease is prepared, the composition contains 3- methyl isophthalic acids-phenyl -2- pyrazoles
The composition of quinoline -5- ketone or its pharmaceutically acceptable salt and SsnB or its pharmaceutically acceptable salt.
2. any application of composition according to claim 1, it is characterised in that the Edaravone-
The mass ratio of 5- ketone or its pharmaceutically acceptable salt and SsnB or its pharmaceutically acceptable salt is 9：1~1：
9。
3. any application of composition according to claim 1, it is characterised in that the Edaravone-
The mass ratio of 5- ketone or its pharmaceutically acceptable salt and SsnB or its pharmaceutically acceptable salt is 9：1~1：
4。
4. any application of composition according to claim 1, it is characterised in that the Edaravone-
The mass ratio of 5- ketone or its pharmaceutically acceptable salt and SsnB or its pharmaceutically acceptable salt is 4：1~1：
4。
5. any application of composition according to claim 1, it is characterised in that the Edaravone-
The mass ratio of 5- ketone or its pharmaceutically acceptable salt and SsnB or its pharmaceutically acceptable salt is 4：1~1：
2。
6. application according to claim 1, it is characterised in that the cerebrovascular disease is ischemic cerebrovascular disease.
7. application according to claim 6, it is characterised in that the ischemic cerebrovascular disease is cerebral arterial thrombosis.
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|---|---|---|---|---|
| CN114796217A (en) * | 2021-01-29 | 2022-07-29 | 南京宁丹新药技术有限公司 | Application of composition containing cilostazol in cerebrovascular diseases |
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Cited By (1)
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| CN114796217A (en) * | 2021-01-29 | 2022-07-29 | 南京宁丹新药技术有限公司 | Application of composition containing cilostazol in cerebrovascular diseases |
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