CN106562944A - Applications of FTY720 in preparation of drugs for prevention or treatment of ischemic stroke - Google Patents
Applications of FTY720 in preparation of drugs for prevention or treatment of ischemic stroke Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
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Abstract
The present invention discloses applications of FTY720 (represented by a formula 1) in preparation of drugs for prevention or treatment of ischemic stroke, wherein the FTY720 can significantly reduce the mortality of ischemic stroke and can be used for preparation of drugs for prevention or treatment of ischemic stroke. The formula 1 is defined in the specification.
Description
Technical field
The present invention relates to biomedicine field, and in particular to a kind of FTY720 is preparing prevention or treating scarce
Application in the medicine of courageous and upright apoplexy.
Background technology
FTY720 is that phenyl ring and hydroxyl alkane are introduced on the hydrocarbon chain of the Thermophilic Bacteria myriocin in Cordyceps
Base and the derivant (structure is shown in formula 1) that synthesizes, chemical entitled 2- amino-[2- (4- octyl phenyls) ethyl] -1,
Ammediol hydrochlorate, molecular formula is C19H33NO2HCl, relative molecular mass is 343.94, readily soluble
In water and ethanol, clinically as a kind of neotype immunosuppressant, multiple sclerosis are currently used primarily in
Treatment.
The blood supply of brain from Internal Carotid System and Vertebro-basilar System, internal carotid artery and substrate
The branch of tremulous pulse forms identical at brain bottom, constitutes basilar artary ring.When the heart contracts, the side of blood flow one
Face is up by branch's internal carotid artery of aorta, and the substrate on the other hand being synthesized by both sides vertebral artery is moved
Arteries and veins, together each branch supplies corresponding brain area before, during and after the brain on Jing basilar artaries ring.And ischemia
Property apoplexy when occurring, supply each branch vessel of corresponding brain area due to thrombus obstruction, reduce and even block
Blood flow, finally causes cerebral hypoxia ischemia to change, and causes the apoptosis/necrosis of neuron.At present with regard to ischemic
The treatment of apoplexy, is mainly treated using Thrombolytic Drugs such as tissue plasminogen activators；And the latter
It is the only approved medicine for treating cerebral infarction of FDA Food and Drug Administration.Therefore urgently
Acquisition can increase the medicine of ischemic brain area hemoperfusion and be used for the treatment of cerebral infarction.
The content of the invention
The technical problem to be solved is for lacking the medicine that can increase ischemic brain area hemoperfusion
Thing is used for the present situation of the treatment of cerebral infarction, there is provided a kind of FTY720 is preparing prevention or treating scarce
Application in the medicine of courageous and upright apoplexy.
The present inventor can be reduced after cerebral ischemia through studying and testing discovery, FTY720 repeatedly
Mortality rate, effectively treatment ischemic cerebrovascular, and the receipts of periphery aortal smooth muscle can be strengthened
Contracting, while the contraction of basilar artary vascular smooth muscle can be suppressed.Based on the research work of inventor,
The present invention provides following technical schemes.
One of technical scheme that the present invention is provided is：There is provided a kind of FTY720 as shown in Equation 1 preparing
Application in the medicine of prevention or treatment cerebral infarction,
Cerebral infarction of the present invention is the conventional cerebral infarction in this area, it is preferred that root
According to acute cerebral infarction Oxfordshire's Community Stroke plan (Oxfordshire Community Stroke Project,
OCSP) typing, it is each relative to the arteriae cerebri of supply cerebral blood flow based on thrombosiss or bolt block thromboembolism
The relative position of branch, by acute ischemic cerebral apoplexy four classes are divided into：Circulation cerebral infarction, part before completely
Front circulation cerebral infarction, Posterior circle cerebral infarction or cerebral infarction.
It is preferred that described FTY720 is used as single-activity composition, or lack with other preventions or treatment
The medicine of courageous and upright apoplexy is collectively as active component.
The prevention is the conventional prevention in this area, preferably refers to there is possible cause cerebral infarction
During risk factor, the probability of cerebral infarction generation is prevented or reduced after use.The treatment is this
The conventional treatment in field, preferably refers to the further development for preventing cerebral ischemia, mitigates cerebral lesion.
Technical scheme that the present invention is provided two is：A kind of FTY720 as shown in Equation 1 is preparing prevention
Or the application in the medicine for the treatment of cerebral ischemia,
It is preferred that described FTY720 is used as single-activity composition, or prevent or treat brain with other
The medicine of ischemia is collectively as active component.
Technical scheme that the present invention is provided three is：A kind of FTY720 as shown in Equation 1 is preparing prevention
Or the application in treatment periphery aortic diastolic and the medicine of basilar artary contraction,
It is preferred that described FTY720 is used as single-activity composition, or it is outer with other preventions or treatment
The medicine that all aortic diastolics or basilar artary shrink is collectively as active component.
Technical scheme that the present invention is provided four is：A kind of drug regimen of ischemia resisting apoplexy is provided
Thing, its active component includes FTY720 as shown in Equation 1 and other preventions or treats cerebral infarction
Medicine,
Described other preventions or the medicine for the treatment of cerebral infarction are the conventional medicine in this area, preferably
Ground is one or more in butyphthalide, Edaravone and XUESAITONG.
It is preferred that described pharmaceutical composition also includes one or more pharmaceutical carrier.Described medicinal load
Body is this area conventional pharmaceutical carrier, and described pharmaceutical carrier can be any appropriate physiology or pharmacy
Upper acceptable excipient substance.Described excipient substance is the conventional excipient substance in this area, is preferably wrapped
Include pharmaceutically acceptable excipient, filler or diluent etc..
More preferably, described pharmaceutical composition includes 0.01～99.99% FTY720 and 0.01～99.99%
Pharmaceutical carrier, the percentage ratio is the mass percent for accounting for described pharmaceutical composition.
Pharmaceutical composition of the present invention is the conventional various dosage forms in this area, preferably solid, half
The form of solid or liquid, can be aqueous solution, non-aqueous solution or suspension, more preferably tablet, glue
Capsule, granule, injection or infusion agent etc..The route of administration of described pharmaceutical composition is preferably injected
Administration or oral administration.The drug administration by injection preferably include intravenous injection, intramuscular injection, lumbar injection,
The approach such as intradermal injection or subcutaneous injection.
Age and disease of using dosage of the described pharmaceutical composition of the present invention in treatment according to patient
Depending on feelings.Administration number of times is once a day or for several times.
On the basis of common sense in the field is met, above-mentioned each optimum condition, can combination in any, obtain final product this
Bright each preferred embodiments.
Agents useful for same of the present invention and raw material are commercially available.
The present invention positive effect be：FTY720 can significantly increase periphery aortal smooth muscle
Shrink, i.e., strengthen high concentration potassium or Methoxamine with can significantly causing endothelium dependent/non-dependent is drawn
The contraction of the thoracic aortic smooth muscle for rising, the level for making ERK phosphorylations rises；Also, FTY720 energy
Enough significantly inhibit the contraction of basilar artary vascular smooth muscle；Additionally, FTY720 can significantly reduce brain
The mortality rate of mice after ischemia, so as to be used for treating and preventing cerebral infarction.With FTY720 as work
Property composition medicine can be used for treat and prevent cerebral infarction.
Description of the drawings
Fig. 1 is mouse Nerve neurological deficit score.Wherein, FTY0.2 refers to that the dosage of FTY720 is
0.2mg/kg, FTY1.0 refer to that the dosage of FTY720 is 1.0mg/kg, and model group is injection 1.0mL/kg
The matched group of normal saline.
Fig. 2 is mortality rate in mice 7 days, survival rate statistics.Wherein, FTY1.0 refers to the agent of FTY720
Measure as 1.0mg/kg, model group is to inject the matched group of 1.0mL/kg normal saline.
Fig. 3 A cause situation (the * P of thoracic aortic smooth muscle contraction for potassium<0.05, * * P<0.01).Its
In, the matched group of saline pointed injection 1.0mL/kg normal saline.
Fig. 3 B cause situation (the * P of thoracic aortic smooth muscle contraction for Methoxamine<0.05,
**P<0.01).Wherein, the matched group of saline pointed injection 1.0mL/kg normal saline, Phe is benzene oxygen kidney
The English of upper parathyrine is write a Chinese character in simplified form.
Fig. 4 is FTY720 in dose-effect relationship (the * P of ERK phosphorylations<0.05).Wherein, saline refers to note
Penetrate the matched group of 1.0ml/kg normal saline；FTY1 refers to that the dosage of FTY720 is 1mg/kg；FTY5
The dosage for referring to FTY720 is 5.0mg/kg；P.S. the brain of the positive control as western blot test is referred to
Tissue sample, it contains the tri- kinds of albumen of ERK, p38 and Akt for having detected.
Fig. 5 A are the feelings that ERK inhibitor PD98059 suppresses the thoracic aortic smooth muscle that potassium causes to shrink
Condition (* P<0.05, * * P<0.01).Wherein, DMSO refers to the vehicle control group of PD98059.
Fig. 5 B are that ERK inhibitor PD98059 suppresses the thoracic aorta that Methoxamine causes to smooth
Situation (the * P that flesh shrinks<0.05, * * P<0.01).Wherein, DMSO refers to the Vehicle controls of PD98059
Group, Phe writes a Chinese character in simplified form for the English of Methoxamine.
Fig. 6 A go to deposit the situation (P that the thoracic aortic smooth muscle caused with potassium shrinks for endothelium>0.05).
Fig. 6 B go to deposit situation about shrinking with the thoracic aortic smooth muscle of Methoxamine for endothelium
(P>0.05).Wherein, Phe writes a Chinese character in simplified form for the English of Methoxamine.
Fig. 7 causes situation (the * P of basilar artary smooth muscle contraction for potassium<0.05, * * P<0.01).Its
In, the matched group of saline pointed injection 1.0mL/kg normal saline.
Fig. 8 is that ERK inhibitor PD98059 suppresses potassium to cause the situation of basilar artary smooth muscle contraction.
Wherein, DMSO refers to vehicle control group (the * P of PD98059<0.05, * * P<0.01).
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but is not therefore limited the present invention to
Among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to normal
Rule method and condition, or select according to catalogue.
FTY720 used is purchased from Selleck Chemicals companies of the U.S., lot number in embodiment：S5002.
Instrument and equipment used is purchased from following manufacturer in embodiment：PGL precision balances, weigh purchased from Ai Demu
Device (Wuhan) company limited；Sartorius BS 110S electronic balances, purchased from Beijing Sai Duolisi balances
Company limited；LH586-1 type thermostatic water bath, purchased from music theory machinery plant of Shanghai City section；JZJ01H type fleshes
Meat tonotransducer, purchased from Chengdu Instruement Factory；The chamber organ bath's system of SQG4 types four, purchased from Chengdu instrument
Device factory；Physiological signal collection processing system being led RM6240BD types, purchased from Chengdu Instruement Factory more；MPA
Multiple tracks bio signal analysis system, purchased from Shanghai Alcott bio tech ltd；ALC-M from
Body histoorgan experimental system, purchased from Shanghai Alcott bio tech ltd.
Improvement results of the FTY720 of embodiment 1 to cerebral infarction
Mice used is Kunming mouse, male, every 18-20g of body weight；Purchased from the western pul in Shanghai-must
Triumphant laboratory animal company limited, production licence number：SCXK (Shanghai) 2013-0016；Using licence
Number：SYXK (Shanghai) 2013-0058；Grade：SPF levels；Raise in positive pressure purification ventilation Animal House,
23 ± 2 DEG C of room temperature, humidity 40～70%, artificial lighting's simulation day-night change, ad lib and drinking-water.
Lumbar injection chloral hydrate anesthesia mice, separates a bilateral common carotid artery and inserts customization nylon wire, causes
Focal cerebral ischemia, skin suture after ligation builds arterial thrombosiss model in mouse brain.According to animal
Neuroethology performance carry out Neuroscore：0 point：Behavior is without exception；1 point：Left fore is not
Can be fully extended；2 points；Lift tail, body to the left side bends；3 points：Body inclines askew to the left side；4
Point：Spontaneous can not walk；5 points：Animal dead.Animal occurs above-mentioned 1 and assigns to 5 points of corresponding behaviors
It is abnormal, that is, judge arterial thrombosiss model construction success in mouse brain.
Mice in constructed model is grouped at random, wherein, the mice quantity of model group is 41；
The mice quantity of FTY720 groups (FTY1.01.0mg/kg) is 32；FTY720 group (FTY0.2
Mice quantity 0.2mg/kg) is 29.Three groups of mices of the above distinguish an intravenous injection 10.0mL/kg life
Reason saline, 1.0mg/kg FTY720 and 2.0mg/kg FTY720.Wherein, the part in model group is little
Some animals (19) in Mus (21) and FTY720 groups (FTY1.01.0mg/kg), due to
Need to carry out 7 days neuroethologys and mortality statisticses, continue intravenous injection 1.0mg/kg once a day
FTY720。
Neuroscore is carried out again by above-mentioned neuroethology performance to above-mentioned three groups of mices, and
Count mortality rate in 7 days.As a result as shown in Fig. 1～2 and table 1-1,1-2 and 2.
24h mouse Nerves neurological deficit score result (mean value ± standard error) after table 1-1 ischemias
| Group | Quantity | Scoring |
| Model group | 41 | 2.34±0.09 |
| FTY720 groups (FTY0.20.2mg/kg) | 29 | 2.48±0.14 |
| FTY720 groups (FTY1.01.0mg/kg) | 32 | 2.13±0.09 |
7 days mouse Nerve neurological deficit score results (mean value ± standard error) after table 1-2 ischemias
Mortality rate, survival rate statistics in 2 mice of table 7 days
| Group | Mortality rate (%) | Survival rate (%) |
| Model group | 57 | 43 |
| FTY720 groups (FTY1.01.0mg/kg) | 42 | 58 |
The experimental data of embodiment 1 is represented using mean ± standard error, entered using SigmaStat softwares
Row statistical disposition, data analysiss adopt one factor analysis of variance, compare between group using SNK check analyses,
With P<0.05 is with statistical significance.
As a result illustrate, in mouse brain in arterial thrombosiss model, vein gives FTY720 and do not observe
To its improvement result to neurological deficit score.But, survival rate in 7 days after structure model is counted,
It was found that FTY720 can reduce mortality rate [the FTY720 groups (FTY1.01.0mg/kg) of animal：42%th,
Model group：57%；P<0.05], percentage survival [FTY720 groups (FTY1.01.0mg/kg) are improved：
58%th, model group：43%；P<0.05].
Impacts of the FTY720 of embodiment 2 to periphery arteries (aorta) tension variation
A, rat used be adult male SD rats, 30, body weight 230.0g～280.0g；It is purchased from
Western pul-Bi Kai laboratory animals the company limited in Shanghai, laboratory animal production licence number：SCXK (Shanghai)
2008-0016, laboratory animal uses credit number：SYXK (Shanghai) 2009-0068；All rats exist
SPF level toy barrier system (23.0 ± 1.0 DEG C of room temperature, humidity 50.0～70.0%, artificial lighting's mould
Intend day-night change, ad lib with drinking-water) adaptability raise 1 week after start experiment.
Before anesthesia 30 minutes, 16 rats are pressed into body weight hierarchical grouping, be divided in every packet
FTY720 groups and saline group, difference intraperitoneal injection 1.0mg/kg FTY720 and 1.0mL/kg physiology
Saline.Rapid after anesthesia to open thoracic cavity, fetch bit is put relatively-stationary thoracic aorta, prepares the blood of 2cm length
Pipe bar, with Krebs-Henseleit nutritional solutions [composition (mol/L)：KCl 4.7、NaCl 118.3、CaCl2
2.5、MgSO4 1.2、KH2PO4 1.2、NaHCO325.0 and glucose 5.6] rinse to without after bloodstain move
Enter containing 95.0% (v/v) oxygen and 5.0% (v/v) carbon dioxide, the Krebs-Henseleit battalion of saturation
In the culture dish of nutrient solution, ice-water bath.The fatty tissue around thoracic aorta is separated, 2.0～3.0mm is intercepted
4 long thoracic aortic ring bars are fixed as specimen with frog heart clip, and the bath of 10.0cm is fixed in lower end
In groove, upper end connection muscle tone transducer.It is Krebs-Henseleit nutritional solutions in groove, bath constant temperature
37.0 DEG C, and it is passed through the mixed gas of 95.0% (v/v) oxygen and 5.0% (v/v) carbon dioxide.
Specimen preload is adjusted to 1.0g, balances 60min, and one time of nutrition liquid is changed per 15min.Treat its baseline
It is slowly added to along bath wall again shrink derivant (Methoxamine solution or KCl solution) after stable,
The stable 5min after vascular ring shrinks and reaches amplitude peak, adds shrink derivant, repetitive stimulation 5 again
It is secondary, record each maximum collapse tension value.
As a result as shown in Fig. 3 A, 3B and table 3～4, the implication of data is contraction (g) in table 3～4.Table
3～4 result explanation, the potassium and Methoxamine of high concentration can cause the receipts of thoracic aortic smooth muscle
Contracting, and giving FTY720 (1mg/kg) can further enhance this effect.
The Methoxamine of table 3 causes the contraction situation of thoracic aortic smooth muscle
The potassium of table 4 causes the contraction situation of thoracic aortic smooth muscle
B, the activation (i.e. Phosphorylation status) to including the serial kinases such as ERK, p38 and Akt are entered
Row is investigated, and by the method described in step A, builds saline group and FTY720 groups.
Wherein, the dosage of FTY720 is respectively 1.0mg/kg and 5.0mg/kg, and FTY720 is obtained respectively
Group (1.0mg/kg) and FTY720 groups (5.0mg/kg).By the saline group of gained, FTY720 groups
(1.0mg/kg) and FTY720 groups (5.0mg/kg) thoracic aortic ring bar as specimen.Specifically,
Rapid after rat anesthesia to open thoracic cavity, fetch bit is put relatively-stationary thoracic aorta, prepares the blood vessel of 2cm length
Bar, with Krebs-Henseleit nutritional solution (contents mol/L：KCl 4.7、NaCl 118.3、CaCl2 2.5、
MgSO4 1.2、KH2PO4 1.2、NaHCO325.0 and glucose 5.6) rinse to without after bloodstain move into
Krebs-Henseleit nutrition containing 95.0% (v/v) oxygen and the saturation of 5.0% (v/v) carbon dioxide
In the culture dish of liquid, the culture dish is placed in frozen water carries out ice-water bath.Then tissue homogenate is further carried out,
Supernatant is centrifuged and is collected, with Western blot protein level detection is carried out.As a result such as table 5 and Fig. 4 institutes
Show.The result explanation of table 5, after FTY720 is given, the phosphorylation of ERK is significantly increased.And Fig. 4
Result explanation, after FTY720 is given, the phosphorylation degree of ERK is remarkably reinforced, and p38 is not
Phosphorylation is detected, the phosphorylation level of Akt is unaffected.
The ERK Phosphorylation status of table 5
| Group | Relative level degree |
| Saline group | 1.00±0.00 |
| FTY720 groups (1.0mg/kg) | 1.99±0.17* |
| FTY720 groups (5.0mg/kg) | 2.23±0.46* |
C, rats by intraperitoneal injection is administered into 1.0mg/kg FTY720, the step of according to described in step A,
After its baseline stability, 10 μM of ERK upstream kinases inhibitor PD98059 of addition (are purchased from Cell
Signaling Technology) to final concentration of 10 μM, then according to the step of described in step A,
Add and shrink derivant, that is, obtain inhibitor group.
Similarly, according to described in step A the step of, after its baseline stability, DMSO is added,
Its final concentration of 0.1% (w/w) is made, then according to the step of described in step A, adding and shrinking induction
Agent, that is, obtain DMSO groups.Each maximum collapse tension value is recorded according to the method described in step A,
As a result as shown in Fig. 5 A, 5B and table 6～7.
The Methoxamine of table 6 causes the contraction situation of thoracic aortic smooth muscle
The potassium of table 7 causes the contraction situation of thoracic aortic smooth muscle
As a result find, giving ERK upstream kinases inhibitor PD98059, can to significantly inhibit FTY720 high
The potentiation of the contraction of the potassium of concentration and the thoracic aortic smooth muscle of Methoxamine induction.
D, by step A, described method, obtain the rat breast master of FTY720 groups (1.0mg/kg)
Tremulous pulse, respectively method as described by Chan et al. remove blood vessel endothelium (Chan S., Choi A., Jones
RL,Lin G.,Mechanisms underlying the vasolaxing effects of butylidenephthalide,
an active constitute of Ligusticum chuanxiong in rat isolated aorta.,2006,
Vol537:111-117), it is destroyed endothelium and does not destroy the thoracic aortic ring bar of endothelium, respectively as broken
Bad endothelium group and endothelium group is not destroyed.Each maximum collapse tension force is recorded according to the method described in step A
Value.As a result as shown in Fig. 6 A, 6B and table 7～8.
The potassium of table 7 causes the contraction situation of thoracic aortic smooth muscle
The Methoxamine of table 8 causes the contraction situation of thoracic aortic smooth muscle
As a result illustrate, after destruction endothelium, FTY720 strengthens the blood vessel of the potassium or Phe induction of high concentration and receives
The function of contracting reaction compares with endothelium group is not destroyed, and has no significance impact.As can be seen here, FTY720
The contraction of periphery aorta, and this effect and vascular smooth muscle ERK can effectively be strengthened
The activation of kinases is relevant.
Wherein, all experimental datas of embodiment 2 using mean ± standard error (mean ± sem) represent,
Statistical disposition is carried out using SigmaStat softwares, p-ERK analyses adopt one factor analysis of variance, blood vessel
Tension analysis adopt replication two-way analysis of variance, compare between group and are analyzed using SNK Test, with
P<0.05 is with statistical significance.
Impact of embodiment 3FTY720 to basilar artary tension variation
A, rabbit used be regular grade male rabbit, 2.0～3.0kg of body weight；Purchased from the dry biology of Shanghai first
Science and Technology Ltd., production licence number：SCXK (Shanghai) 2010-0028, using credit number：SYXK
(Shanghai) 2013-0087；Rearing conditions：16 DEG C～22 DEG C of temperature, humidity：20%～60%, it is natural
Illumination, ad lib, drinking-water.
After 10 rabbit adaptabilities are raised 2 days, stochastic averagina is divided into saline group and FTY720 groups,
Jing auricular veins give respectively normal saline (1mL/kg) and FTY720 (0.5mg/kg), after 30min
The auricular vein air tube that fans the air is lethal, and basilar artary is taken out rapidly.Under cold light source, by vitro brain
Basilar artery are suspended in pre-cooling perfusate (content mol/L：NaCl 118、KCl 4.7、MgSO4 1.2、
KH2PO4 1.2、NaHCO3 25、CaCl22.5 and glucose 11.1 × 10-3) in, make 4～5mm
Long arterial ring, the steel wire (not damaged arteries inner membrance) for penetrating two a diameter of 0.2mm makes triangle
Ring-type, hangs on and fills 20mL K-HShi nutritional solution (contents mol/L：NaCl 118、KCl 4.7、
MgSO4 1.2、KH2PO4 1.2、NaHCO3 25、CaCl22.5 and glucose 11.1 × 10-3) perseverance
In warm smooth muscle bath, two ends are connected respectively with the hook of tonotransducer and bath bottom, in bath
Persistently pass to the mixed gas of 95.0% (v/v) oxygen and 5.0% (v/v) carbon dioxide, 37 DEG C of constant temperature
Water-bath, 0.6g preloaies are balanced 0.5 hour, and antiotasises connect MPA by muscle tone transducer
Multiple tracks bio signal analysis system is recorded.After Basilar Artery Rings are stable, it is slowly added to along bath wall
Vasoconstrictor agonist (Methoxamine solution or KCl solution), treats that vascular ring shrinkage curve reaches level ground
Shi Zaici add Agonist solutions (administration gradient is followed successively by 10,20,30,40,50,60mmol/L
KCl solution), continued stimuluses 6 times record each maximum shrinkage amplitude value.As a result such as Fig. 7 and Biao
Shown in 9～10, the implication of data is contraction (g) in table 9～10.The result explanation of table 9～10, benzene oxygen
Epinephrine can not cause the significantly contraction of basilar artary ground, and FTY720 can be significantly reduced
(P<0.05、P<0.01) high potassium concentration of 30mmol/L～40mmol/L causes basilar artary to shrink.
The Methoxamine of table 9 causes the contraction situation of basilar artary smooth muscle
The potassium of table 10 causes the contraction situation of basilar artary smooth muscle
B, by step A, described method, obtain family's Medulla Leporis seu Oryctolagi base of FTY720 groups (1.0mg/kg)
Bottom tremulous pulse, after Basilar Artery Rings are stable, addition ERK upstream kinases inhibitor PD98059 (are purchased from
Cell Signaling Technology) to final concentration of 10 μM, then according to the step described in step A
Suddenly, add and shrink derivant, that is, obtain inhibitor group.
Similarly, by the method described in step A, the rabbit of FTY720 groups (1.0mg/kg) is obtained
Basilar artary, after Basilar Artery Rings are stable, adds DMSO to final concentration of 0.1% (w/w),
Then according to the step of described in step A, adding and shrinking derivant, that is, obtain inhibitor group.
Each maximum collapse tension value is recorded according still further to the method described in step A, as a result such as Fig. 8 and Biao
Shown in 11.
The potassium of table 11 causes the contraction situation of basilar artary smooth muscle
Wherein, all experimental datas of embodiment 3 using mean ± standard error (mean ± sem) represent,
Statistical disposition is carried out using SigmaStat softwares, data analysiss adopt replication two-way analysis of variance,
Compare between group and analyzed using SNK Test, with P<0.05 is with statistical significance.
Table 11 result explanation, give ERK upstream kinases inhibitor PD98059 can significantly resist by
The contraction of the internal artery blood vessel (basilar artery) that the decrease that FTY720 is produced is induced high potassium.
The above embodiments illustrate that FTY720 can strengthen the contraction of periphery aortal smooth muscle, i.e., can
Thoracic aorta caused by initiation endothelium dependent/non-dependent ground enhancing high potassium concentration or Methoxamine is smoothed
The contraction of flesh, while raising the level of ERK phosphorylations；Additionally, FTY720 can suppress brain substrate to move
The contraction of arteries and veins vascular smooth muscle, and effectively reduce the mortality rate of mice after cerebral ischemia.In cerebral infarction
Pathogenic process in, due to thrombosiss or embolic infarction, the blood flow for entering brain can be caused to reduce,
And FTY720 is given, and on the one hand can strengthen the contraction of periphery aorta, improve perfusion pressure, the opposing party
Arteriae cerebri blood vessel (basilar artary) is expanded in face simultaneously, is conducive to increasing the hemoperfusion of ischemic brain area,
Improve blood supply.Therefore the characteristics of FTY720 is acted on this distinction of periphery and maincenter be conducive to its
Application in terms of cerebral infarction.
It should be understood that after the above for having read the present invention, those skilled in the art can be to this
Bright to make various changes or modifications, these equivalent form of values equally fall within the application appended claims and are limited
Scope.
Claims (9)
1. a kind of FTY720 as shown in Equation 1 is preparing prevention or is treating the medicine of cerebral infarction
In application,
2. a kind of FTY720 as shown in Equation 1 prevents or treats answering in the medicine of cerebral ischemia in preparation
With,
3. a kind of FTY720 as shown in Equation 1 is preparing prevention or is treating periphery aortic diastolic and brain
Application in the medicine that basilar artery shrink,
4. the application as described in any one of claims 1 to 3, it is characterised in that described FTY720
As single-activity composition；Or prevent with other or treatment cerebral infarction, cerebral ischemia, periphery master
The medicine that auterial diastole or basilar artary shrink is collectively as active component.
5. a kind of pharmaceutical composition of ischemia resisting apoplexy, it is characterised in that its active component includes
FTY720 as shown in Equation 1 and other preventions or the medicine for the treatment of cerebral infarction,
6. pharmaceutical composition as claimed in claim 5, it is characterised in that described other treatment lacks
The medicine of courageous and upright apoplexy is one or more in butyphthalide, Edaravone and XUESAITONG.
7. pharmaceutical composition as claimed in claim 5, it is characterised in that it also includes a kind of or many
Plant pharmaceutical carrier.
8. pharmaceutical composition as claimed in claim 7, it is characterised in that described pharmaceutical carrier is
Excipient, filler or diluent.
9. pharmaceutical composition as claimed in claim 5, it is characterised in that described pharmaceutical composition
FTY720 and 0.01～99.99% pharmaceutical carrier including 0.01～99.99%, the percentage ratio is to account for
State the mass percent of pharmaceutical composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105640928A (en) * | 2016-02-26 | 2016-06-08 | 南京医科大学 | Application of FTY720 in preparation of medicine for preventing and treating cerebral ischemic stroke |
| EP3677259A1 (en) * | 2019-01-07 | 2020-07-08 | Mosaiques Diagnostics And Therapeutics AG | Use of arachidonyl trifluoromethyl ketone |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104146991A (en) * | 2014-04-04 | 2014-11-19 | 施福东 | Application of fingolimod and analogue thereof in preparing medicines for treating cerebral infarction |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104146991A (en) * | 2014-04-04 | 2014-11-19 | 施福东 | Application of fingolimod and analogue thereof in preparing medicines for treating cerebral infarction |
Non-Patent Citations (3)
| Title |
|---|
| YING FU等: "Impact of an immune modulator fingolimod on acute", 《PNAS》 * |
| 付莹等: "芬戈莫德治疗脑梗死临床概念性研究", 《中华医学会第十七次全国神经病学学术会议论文汇编（下）》 * |
| 刘峻峰: "FTY720(芬戈莫德)治疗缺血性脑卒中动物实验的系统评价", 《中华医学会第十七次全国神经病学学术会议论文汇编（下）》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105640928A (en) * | 2016-02-26 | 2016-06-08 | 南京医科大学 | Application of FTY720 in preparation of medicine for preventing and treating cerebral ischemic stroke |
| EP3677259A1 (en) * | 2019-01-07 | 2020-07-08 | Mosaiques Diagnostics And Therapeutics AG | Use of arachidonyl trifluoromethyl ketone |
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