CN104173334B - A kind of pharmaceutical composition of antiplatelet aggregation - Google Patents
A kind of pharmaceutical composition of antiplatelet aggregation Download PDFInfo
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- CN104173334B CN104173334B CN201410349954.3A CN201410349954A CN104173334B CN 104173334 B CN104173334 B CN 104173334B CN 201410349954 A CN201410349954 A CN 201410349954A CN 104173334 B CN104173334 B CN 104173334B
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- coumarin
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Abstract
The present invention provides a kind of pharmaceutical composition of antiplatelet aggregation, is made up of cinnamic acid, P-coumaric acid and coumarin, the molar concentration rate of wherein cinnamic acid, P-coumaric acid and coumarin is followed successively by (1 9):(1‑9):(4‑36).Test result indicate that, the inhibitory action that cinnamic acid, P-coumaric acid, coumarin are used in combination the platelet aggregation to ADP induction is used alone the inhibitory action to the platelet aggregation that ADP induces apparently higher than coumarin.
Description
Technical field
The invention belongs to drug world is and in particular to a kind of pharmaceutical composition of antiplatelet aggregation.
Background technology
Under physiological statuss, in intac vascular system, platelet does not activate, assembles, and has protection endothelium thin
Born of the same parents, the function that the cardiovascular disease such as atherosclerosis is formed.Platelet aggregation has in normal coagulation mechanism
Pivotal role, but then can form thrombosis when it occurs abnormal deformation, adhesion, assembles.For example when platelet is subject to coagulate
After the stimulations of agonist such as hemase (THR), it is activated, assembles, form thrombosis, lead to sending out of cardiovascular event
Raw.In cerebral ischemia re-pouring, the signaling molecule such as oxygen-derived free radicals can activate inflammatory cytokine, causes chemotactic factor
Release, adhesion molecule raises, and then leads to hematoblastic adhesiveness and aggregation to strengthen.Long-term psychentonia, Jiao
Worry, hypertension etc. can cause the degeneration of blood vessel wall, atherosclerosiss etc., make vessel endothelium and induced endothelial, cause blood little
The activation of plate.
ADP is present on hematoblastic dense granule, is released after platelet activation, can activate surrounding loop blood
In platelet, make platelet aggregation accelerate [document Gachet C.Regulati on of platelet functions by P2
receptors[J].Annu RevPharmacol Toxico,2006,46:277-300.].ADP induced platelet aggregation has calcium
Dependency, platelet plasma membrane exists 3 kinds of adp receptors, P2Y1, P2Y12 and P2X1.ADP and its receptor
After P2Y1 combines, P2Y1 receptor activates phospholipase C with Gq albumen coupling, leads to intracellular Ca2+Interior stream, cell
Interior Ca2+Concentration causes hematoblastic deformation and assembles after raising.Hematoblastic aggreation is divided into biphase：Blood vessel wall is damaged
Platelet adhesion reaction after wound, injury tissue or erythrocyte release ADP, cause platelet aggregation, are the first gathering phase.
ADP concentration now is relatively low, depolymerization quickly after gathering；Then platelet is activated, and itself starts to discharge ADP,
Now ADP concentration raises, and starts the second gathering phase, and this process platelet aggregation is slow, but irreversible,
Ultimately result in the formation of thrombosis and the generation of cardiovascular event.
Antiplatelet drug can suppress hematoblastic adhesion and assemble, and prevent thrombosiss, antiplatelet aggregation is to control
Treat one of important channels of cardiovascular and cerebrovascular disease such as coronary heart disease, atherosclerosiss, myocardial infarction.
Coumarinses are more effective oral anticoagulation things, research display, Coumarinses medicine can anticoagulant because
Son plays the effect of anticoagulant in the synthesis of liver.A lot of Chinese medicines have good anticoagulation, such as Radix Peucedani, Ramulus Cinnamomi etc.,
Their main component includes Coumarinses.Common Coumarinses medicine has dicoumarol (dicoumarol), Hua Fa
Woods (warfarin, tromexan ethyl acetate) and acenocoumarol (acenocoumarol, acenocoumarol).Warfarin is because of it
Absorb in gastrointestinal tract and be once widely used in clinic soon, but cause the danger of bleeding to start to be gradually backed out due to existing
Market.
But the interaction between Coumarinses medicine yet there are no and studies have reported that.
Content of the invention
An object of the present invention is to provide a kind of pharmaceutical composition of antiplatelet aggregation.
Pharmaceutical composition provided by the present invention is made up of cinnamic acid, P-coumaric acid and coumarin, wherein cinnamic acid, right
The molar concentration rate of coumaric acid and coumarin is followed successively by (1-9):(1-9):(4-36), preferably (3-9):(1-7):
(28-36).
Specifically described cinnamic acid and the molar concentration rate of P-coumaric acid and coumarin are followed successively by 3:7:36,6:4:32,
9:1:28,2:8:24,5:5:20,8:2:16,1:9:12,4:6:8 or 7:3:4.
It is also another object of the present invention to provide the application of described pharmaceutical composition.
The application of pharmaceutical composition provided by the present invention is its application in preparing medicament for resisting platelet aggregation.
The medicine of the antiplatelet aggregation made for active component with aforementioned pharmaceutical compositions falls within the protection model of the present invention
Enclose.
By by aforementioned pharmaceutical compositions, preparing after directly preparing or add pharmaceutically acceptable adjuvant, can be made into
Any pharmaceutically acceptable dosage form.Include taking oral formulations as a example：Capsule, tablet, granule, powder, ball
Agent, drop pill, sustained-release preparation, oral liquid, mixture and syrup；Include taking external preparation as a example：Ointment,
Suppository, patch, medicated wine, tincture, gel, liniment, aerosol, spray and liniment.Above-mentioned various dosage form
Medicine all can according to pharmaceutical field conventional method prepare.
Test result indicate that, cinnamic acid, P-coumaric acid and coumarin are used in combination the platelet aggregation to ADP induction
Inhibitory action is used alone the inhibitory action of the platelet aggregation to ADP induction apparently higher than coumarin.
Brief description
Fig. 1 is the impact to the platelet aggregation that ADP induces for the cinnamic acid.
Fig. 2 is the impact to the platelet aggregation that ADP induces for the P-coumaric acid.
Fig. 3 is impact (the * p to the platelet aggregation that ADP induces for the coumarin<0.05, * * p<0.01).
When Fig. 4 is cinnamic acid, P-coumaric acid, coumarin are used in combination and coumarin is used alone, blood is induced to ADP
The impact of platelet aggregation.
Specific embodiment
Below by specific embodiment, the present invention will be described, but the invention is not limited in this.
Experimental technique used in following embodiments if no special instructions, is conventional method；Institute in following embodiments
Reagent, biomaterial etc., if no special instructions, all commercially obtain.
Embodiment 1, the preparation of the pharmaceutical composition of antiplatelet aggregation
The molar concentration rate of each component according to table 1 weighs cinnamic acid, P-coumaric acid and coumarin, mixing, obtains
To pharmaceutical composition.
The molar concentration rate of each component of table 1
The experiment of embodiment 2, the pharmaceutical composition inhibitory action to the platelet aggregation that ADP induces
1st, the preparation of anticoagulant buffer B uffer A
By sodium chloride 130mmol/L, sodium citrate 10mmol/L, sodium bicarbonate 9mmol/L, glucose 6
Mmol/L, magnesium chloride 0.9mmol/L, potassium dihydrogen phosphate 0.81mmol/L, trishydroxymethylaminomethane 10mmol/L
Mixing, prepared anticoagulant buffer B uffer A.
2nd, the preparation of medicinal composition solution
A, the pharmaceutical composition of test number 1 is added Buffer A and be configured to the medicine that coumarin molar concentration is 720 μM
Compositions solution 1；
B, the pharmaceutical composition of test number 2 is added Buffer A and be configured to the medicine that coumarin molar concentration is 640 μM
Compositions solution 2；
C, the pharmaceutical composition of test number 3 is added Buffer A and be configured to the medicine that coumarin molar concentration is 560 μM
Compositions solution 3；
D, the pharmaceutical composition of test number 4 is added Buffer A and be configured to the medicine that coumarin molar concentration is 480 μM
Compositions solution 4；
E, the pharmaceutical composition of test number 5 is added Buffer A and be configured to the medicine that coumarin molar concentration is 400 μM
Compositions solution 5；
F, the pharmaceutical composition of test number 6 is added Buffer A and be configured to the medicine that coumarin molar concentration is 320 μM
Compositions solution 6；
G, the pharmaceutical composition of test number 7 is added Buffer A and be configured to the medicine that coumarin molar concentration is 240 μM
Compositions solution 7；
H, the pharmaceutical composition of test number 8 is added Buffer A and be configured to the medicine that coumarin molar concentration is 160 μM
Compositions solution 8；
I, the pharmaceutical composition of test number 9 is added Buffer A and be configured to the medicine that coumarin molar concentration is 80 μM
Composition solution 9.
3rd, the preparation of platelet suspension
SD rat injects 10% chloral hydrate (0.35ml/100g) anesthesia, cuts off integumentary musculature, finds out ventral aorta
And an ilium left side, the right tremulous pulse of ilium.Clamp the right tremulous pulse of ilium with bulldog clamp, in advance by the syringe of 10ml anticoagulant citric acid Portugal
Grape sugar (ACD) rinse (ACD accounts for whole blood 15%), at abdominal aortic bifurcation, centripetal end punctures and takes blood.Blood is taken to join
After flat, room temperature centrifugation, 210 × g, 12min, take supernatant, that is, be rich in hematoblastic blood plasma (PRP).Recentrifuge (800 × g,
10min, room temperature), supernatant discarded, white precipitate is resuspended with Buffer A, and adjustment density is about 5 × 108Individual/ml, obtains
To platelet suspension.
4th, the inhibitory action to the platelet aggregation of ADP induction
After being assembled due to platelet, the turbidity of platelet suspension system, that is, light absorption value (OD value) can decline, because
This characterizes hematoblastic gathering situation (i.e. turbidimetry) with the change of OD value.
Blank control group：Addition platelet suspension 100 μ l to 96 hole elisa Plates, addition Buffer A 50 μ L, 37 DEG C
Constant-temperature incubation 10min, continuous vibration, detects the OD of sample at 405nm using Spectra Max M5 microplate reader
Value.After incubation terminates, every hole adds Buffer A 50 μ L, is immediately placed in microplate reader, and setting microplate reader temperature is 37 DEG C,
Every 45 seconds readings, intermission continuous vibration, until OD value no longer changes, detects 30min altogether.
Negative control group (i.e. ADP group)：Add platelet suspension 100 μ l to 96 hole elisa Plates, add Buffer
A 50 μ L, 37 DEG C of constant-temperature incubation 10min, continuous vibration, detects 405nm using Spectra Max M5 microplate reader
The OD value of place's sample.After incubation terminates, every hole adds chloride containing calcium (CaCl2, final concentration of 3mmol/L) swash
Dynamic agent (25 μm of ol/L ADP) 50 μ L, are immediately placed in microplate reader, and setting microplate reader temperature is 37 DEG C, every 45 seconds
Reading, intermission continuous vibration, until OD value no longer changes.
Positive controls：Add platelet suspension 100 μ l to 96 hole elisa Plates, add that 10 μm of ol/L are double phonetic to be reached
Not (DI) 50 μ L, 37 DEG C of constant-temperature incubation 10min, continuous vibration, using the detection of Spectra Max M5 microplate reader
The OD value of sample at 405nm.After incubation terminates, every hole adds chloride containing calcium (CaCl2, final concentration of 3mmol/L)
Agonist 50 μ L (25 μm of ol/L ADP), be immediately placed in microplate reader, setting microplate reader temperature be 37 DEG C, often
45 seconds readings, intermission continuous vibration, until OD value no longer changes.
Experimental group：Add platelet suspension 100 μ l to 96 hole elisa Plates, then be separately added into 50 μ L steps 1 and prepare
Medicinal composition solution 1-9,37 DEG C of constant-temperature incubation 10min, continuous vibration, using Spectra Max M5 enzyme mark
Instrument detects the OD value of sample at 405nm.After incubation terminates, every hole adds chloride containing calcium (CaCl2, final concentration of
Agonist (25 μm of ol/L ADP) 50 μ L 3mmol/L), are immediately placed in microplate reader, and setting microplate reader temperature is
37 DEG C, every 45 seconds readings, intermission continuous vibration, until OD value no longer changes.
The computing formula of platelet aggregation rate is：Hematoblastic aggregation rate AA=(OD0-ODmin)/OD0× 100%,
Wherein, OD0Represent and add the first OD value detecting after ADP, ODminRepresent minimum in detection process
OD value.
Suppression ratio=(AA to platelet aggregation for the pharmaceutical compositionADP group-AAExperimental group)/AAADP group× 100%, wherein,
AAADP groupRepresent the hematoblastic aggregation rate of ADP group, AAExperimental groupRepresent the hematoblastic aggregation rate of experimental group.
This pharmaceutical composition is shown in Table 2 to the inhibitory action of the platelet aggregation that ADP induces.
Table 2 cinnamic acid, P-coumaric acid and coumarin combine the effect (n=3) of suppression ADP induced platelet aggregation
Note：To each molar concentration rate composition pharmaceutical composition parallel do three experiments, average.
As shown in Table 2, in this pharmaceutical composition, the molar concentration rate of described cinnamic acid and P-coumaric acid and coumarin according to
Secondary is 3:7:36, when the molar concentration of coumarin is 180 μM, this pharmaceutical composition reaches to platelet suppression ratio
53.57 ± 4.23%.
Comparative example 1, carry out the experiment of the inhibitory action to the platelet aggregation that ADP induces for the cinnamic acid with reference to embodiment 2.
Fig. 1 is the impact to the platelet aggregation that ADP induces for the cinnamic acid.
As shown in Figure 1, the platelet aggregation that cinnamic acid induces to ADP does not have inhibitory action.
Comparative example 2, carry out the experiment of the inhibitory action to the platelet aggregation that ADP induces for the P-coumaric acid with reference to embodiment 2.
Fig. 2 is the impact to the platelet aggregation that ADP induces for the P-coumaric acid.
As shown in Figure 2, the platelet aggregation that P-coumaric acid induces to ADP does not have inhibitory action.
Comparative example 3, carry out the experiment of the inhibitory action to the platelet aggregation that ADP induces for the coumarin with reference to embodiment 2.
Fig. 3 is impact (the * p to the platelet aggregation that ADP induces for the coumarin<0.05, * * p<0.01).
From the figure 3, it may be seen that the platelet aggregation that coumarin induces to ADP has inhibitory action.
The inhibitory action that coumarin is used alone to the platelet aggregation of ADP induction is shown in Table 3.
Table 3 coumarin suppresses the effect (n=3) of ADP induced platelet aggregation
Note：Parallel to the coumarin of same molar concentration do three experiments, average.
As shown in Table 3, when the molar concentration of coumarin is 200 μM, the suppression ratio of its platelet aggregation to ADP induction
For 22.79 ± 2.7%.
Contrasted with the experimental result in table 2, when cinnamic acid in this pharmaceutical composition, P-coumaric acid, the rubbing of coumarin
Your concentration ratio is 5:5:20, when the molar concentration of coumarin is 100 μM, the platelet aggregation that pharmaceutical composition induces to ADP
The suppression ratio of collection is 34.56 ± 8.60%, and when coumarin is used alone, when the molar concentration of coumarin is 100 μM, fragrant
Legumin is only 14.84 ± 5.68%, therefore, cinnamic acid, P-coumaric acid to the suppression ratio of the platelet aggregation that ADP induces
With coumarin be used in combination to ADP induction platelet aggregation inhibitory action be used alone apparently higher than coumarin right
The inhibitory action of the platelet aggregation of ADP induction.
When Fig. 4 is cinnamic acid, P-coumaric acid, coumarin are used in combination and coumarin is used alone, blood is induced to ADP
The impact of platelet aggregation.
As shown in Figure 4, cinnamic acid, P-coumaric acid, coumarin are used in combination the suppression to the platelet aggregation that ADP induces
Effect is used alone the inhibitory action of the platelet aggregation to ADP induction apparently higher than coumarin.
Claims (3)
1. a kind of pharmaceutical composition, is made up of cinnamic acid, P-coumaric acid and coumarin, wherein cinnamic acid, to perfume (or spice)
The molar concentration rate of bean acid and coumarin is followed successively by (1-9):(1-9):(4-36).
2. application in preparing medicament for resisting platelet aggregation for the pharmaceutical composition described in claim 1.
3. a kind of medicine of antiplatelet aggregation, its active component is the pharmaceutical composition described in claim 1.
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