CN104667283B - A kind of compound medicine combination for treating dyslipidemia and atherosclerosis - Google Patents
A kind of compound medicine combination for treating dyslipidemia and atherosclerosis Download PDFInfo
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Abstract
The present invention relates to field of medicaments, the medical usage of the compound medicament composition combined more particularly to 5 hydroxytryptamine, 2 receptor antagonist Sarpogrelate and 5 hydroxytryptamine synthetic inhibitors, i.e., compound medicine of the invention combination can be used for treatment dyslipidemia and prevention and treatment atherosclerosis.Compound medicament composition of the present invention has the function that collaboration improves dyslipidemia.Available for treatment and the relevant disease of dyslipidemia, particularly atherosclerosis.
Description
Technical field
The present invention relates to field of medicaments, and in particular to 2 receptor antagonist Sarpogrelate of serotonin and serotonin synthesis
The compound medicament composition of inhibitor combination, compound medicine of the invention combination can be used for treatment dyslipidemia and prevention and treatment
Atherosclerosis.
Background technology
Major lipids form in blood includes triglycerides (Triglyceride, TG), high-density lipoprotein cholesterol
(High density lipoprotein cholesterol, HDL-C), low density lipoprotein cholesterol (Low density
Lipoprotein cholesterol, LDL-C) and C-VLDL (Very low density
lipoprotein cholesterol,VLDL-C).Dyslipidemia, is also hyperlipidemia, blood fat disorder, refers to that a variety of causes draws
The pathology that blood TG, LDL-C, VLDL-C concentration rise (based on TG, LDL-C rise performance) risen or HDL-C concentration decline
Performance, can also show as the rise of TG, LDL-C isoconcentration at the same time and HDL-C concentration declines.Wherein TG, LDL-C, VLDL-C are " no
Alright " lipid, and LDL-C is mainly converted by VLDL-C and formed, their haemoconcentration rise can directly result in Atherosclerosis
Change (Atherosclerosis, AS), and AS cardiovascular and cerebrovascular diseases thus occur；And HDL-C is a kind of " good " lipoprotein,
Its clinical value is can to drive reverse cholesterol transport -- AS spots cholesterol in the block is transferred to liver etc. and is excreted,
It haemoconcentration rise, at the same time " bad " lipid concentration reduce, show as T-CHOL (Total cholesterol,
TC=HDL-C+LDL-C+VLDL-C) ratio with HDL-C reduces, and can prevent and treat AS.
Lipidosis is the basis that AS is formed on arterial wall.Early stage is formed in AS, monocyte is by endothelial gap, inside
Macrophage is divided under film, it is macrophage-mediated to penetrate into intravascular subcutaneous LDL-C generations oxidative modification, form oxidized form
LDL-C (ox-LDL-C), further swallows a large amount of ox-LDL-C by A types scavenger receptor, causes lipid within endothelial cells to be accumulated, shape
Into foam cells.Foam cells is accumulated to form fatty streaks or even Lipid Plaque, that is, initially forms AS.The development of AS is in foam
On the basis of cell accumulation increase, patch increase, it is also possible to while there is calcium deposition, thrombosis etc..It is now recognized that body
Eliminating AS is completed by reverse cholesterol transport：AS spots cholesterol in the block can be replaced out by forming HDL-C, HDL-
C is conveyed into liver through blood, then is converted into bile acid in liver or is directly discharged by bile from enteron aisle, consolidates so as to complete courage
The counter transport process of alcohol and the elimination to AS patches.Therefore, the rise of blood LDL-C, VLDL-C concentration is to induce the main original of AS
Cause；And elevating blood HDL-C concentration can eliminate AS patches by promoting reverse cholesterol transport, so as to prevent and treat AS.
Many reasons can cause dyslipidemia.It is life style, such as high heat of long-term hyperphagia, food rich in fat, thermophilic
Poor eating habits such as wine and to lack physical exertion, stress, life irregular etc., it is considered to be it is important the reason for, and certain
A little secondary factors, cause blood fat as diabetes, nephrotic syndrome, and inherent cause are considered to interact with life style
It is abnormal.Clinical observation and zoopery have proven to：Blood " good " lipoprotein concentration reduces, the rise of " bad " lipoprotein concentration is
Cause the direct risk factors of AS, so that the cardiovascular and cerebrovascular diseases such as coronary heart disease, cerebral thrombus occur.Improve dyslipidemia, reduce blood
Liquid TG, LDL-C, VLDL-C are horizontal, improve HDL-C levels, are prevention and treatment AS, the important means of cardio-cerebrovascular diseases.
The key agents of clinical treatment dyslipidemia have Statins, fibrates, nicotinic acid class, cholic acid chelating agent, cholesterol absorption inhibitor
And n-3 polyunsaturated fatty acid classes etc., also the medicine of dyslipidemia is treated not over periphery serotonin system is acted on.
Serotonin (5-hydroxy tryptamine, 5-HT) be also thrombocytin, is that one kind is present in periphery and maincenter
Small-molecule substance, the physiological function of 5-HT is complicated, does not understand fully completely so far.
The synthesis of I .5-HT in two steps, the first step：Tryptophan is in tryptophan hydroxylase (tryptophan
Hydroxylase, TPH) catalysis under be changed into 5-hydroxyryptophan (TPH can be divided into two hypotypes：TPH1 and TPH2, TPH1 are deposited
It is periphery, TPH2 is present in maincenter)；Second step：5-hydroxyryptophan is in aromatic amino acid decarboxylase (aromatic
Aminoacid decarboxylase, AADC) catalysis under be changed into 5-HT.Therefore, can be respectively by suppressing TPH or AADC
Realize the suppression to 5-HT synthesis.
Fenclonine (parachlorophenylalanine or p-chlorophenylalanine, pCPA), not
Name:DL-4- chlorophenylalanines, DL- fenclonines etc., molecular formula：C9H10ClNO2, it is TPH inhibitor, no clinical practice
Report.
Carbidopa (Cabidoba, CDP), molecular formula：C10H14N2O4。
Benserazide (Benserazide, BSA), alias：Trihydroxy seryl hydrazine, Benseraside, Benseraside, benserazide,
Molecular formula：C10H15N3O5。
CDP and BSA is AADC inhibitor, is clinically used for the auxiliary treatment of Parkinson's disease, their collective effect is special
Point is periphery decarboxylase inhibitors, is not easily accessible maincenter, only suppresses periphery levodopa and is converted into dopamine, makes left-handed in circulation
The increase of DOPA content, also can inhibit 5-hydroxyryptophan and is converted into 5-HT, the cell of synthesis 5-HT is produced 5-HT and reduces.CDP and
BSA is also reported without the research for improving dyslipidemia.
II .5-HT acceptor 5-HT acceptors (5-HT receptor, 5-HTR) are present on cell membrane, belong to membrane receptor, 5-
HT receptor subtypes are complicated, it has now been found that with the presence of 7 big receptoroids, i.e. 5-HT1-7R, 5-HT1,4,5R is mainly distributed on maincenter, 5-
HT2,3,6,7R is mainly distributed on periphery.This 7 receptoroid is broken into further several hypotypes again.5-HT2R can be divided into 5-
HT2AR、5-HT2BR and 5-HT2CR.That periphery and maincenter are distributed is 5-HT2A,2BR, 5-HT2CR is primarily present in nervous centralis
5-HT is distributed with system, liver, skeletal muscle, visceral adipose tissue2A,2BR.With selective exclusion 5-HT2The medicine of R is few,
Know that Sarpogrelate belongs to selective 5-HT2R antagonists.
Sarpogrelate (Sarpogrelate, SAR) is a species specificity 5-HT2R blocking agents, molecular formula：C24H31NO6.Face
In bed application, SAR can inhibit by the platelet aggregation of 5-HT enhancings and suppression vasoconstrictor effects etc., be clinically used for improving chronic
The all symptoms of the ischemic such as ulcer, pain and creeping chill caused by arterial occlusive disease.Clinic has SAR to treat diabetic complication
The report of arterial obliterans of lower extremity.
The content of the invention
Combined the invention discloses a kind of 2 receptor antagonist Sarpogrelate of serotonin and serotonin synthetic inhibitor
Compound medicament composition form, said composition form have the function that collaboration improves dyslipidemia.It is different with blood fat available for treating
Normal relevant disease, particularly atherosclerosis.This composition is reducing the same of blood TG, LDL-C, VLDL-C level
When, HDL-C levels can be greatly improved, TC/HDL-C ratios are greatly reduced, therefore with the work of prevention and treatment atherosclerosis
With.
The preferred fenclonine of serotonin synthetic inhibitor, carbidopa or the benserazide.
The weight ratio of Sarpogrelate and serotonin synthetic inhibitor preferably 9:1~1:7.
The weight ratio of Sarpogrelate and fenclonine is more preferably 7:1~1:5.Further preferred 2:1.
The weight ratio of Sarpogrelate and carbidopa is more preferably 9:1~1:5.Further preferred 2:1.
The weight ratio of Sarpogrelate and benserazide is more preferably 6:1~1:7.Further preferred 1:1.
We have found under study for action：
I, feeds in high-fat and high-cholesterol diet (high lipid food) and establishes in lipid of mice exception animal model, uses SAR+
PCPA, SAR+CDP, SAR+BSA form different compounds by the different weight proportion of two kinds of medicines and model are treated.As a result
Show, dyslipidemia caused by high lipid food is substantially reversed, and is shown as：Serum TG, the horizontal obvious reduction of LDL-C, VLDL-C,
And HDL-C levels are significantly raised, TC/HDL-C ratios are obviously reduced.Also, tri- kinds of SAR+pCPA, SAR+CDP, SAR+BSA is multiple
Side shows obvious synergistic effect, drug combination can be significantly improved by the certain weight proportion of medicine to treatment dyslipidemia
Curative effect of medication.Rise effect especially to HDL-C is particularly evident, and the horizontal normal control that is even above of administration group Serum HDL-C moves
Thing.
II, establishes the animal mould of rat fat exception glucocorticoid medicine-dexamethasone (DEX) is subcutaneously injected
In type, model is treated with SAR+pCPA, SAR+CDP, SAR+BSA compound, it is different can equally to improve blood fat caused by Dex
Often, experimental result causes dyslipidemia model result similar to high lipid food, also shows as the serum of three kinds of compound medicine treatment groups
The horizontal obvious reduction of TG, LDL-C, VLDL-C, and HDL-C levels are significantly raised, TC/HDL-C ratios reduce, and show obvious
Synergistic effect.In two dyslipidemia models, the drug weight ratio that SAR+pCPA compounds produce synergistic effect curative effect is：9:1~
1:5；SAR+CDP compounds produce synergistic effect curative effect drug weight ratio be：7:1~1:5；SAR+BSA compounds produce collaboration and make
It is with the drug weight ratio of curative effect：6:1~1:7.In experiment, SAR+pCPA weight ratios are 2:1st, SAR+CDP weight ratios are 2:1、
SAR+BSA weight ratios are 1:1 compound is best to the therapeutic effect of dyslipidemia, prompts the combination of these three compounds close or is exactly
Optimal compound combining form.
In conclusion with Sarpogrelate and serotonin synthetic inhibitor such as fenclonine or carbidopa or benzyl silk
Hydrazine forms compound in the range of certain weight ratio, has obvious synergistic effect to improving dyslipidemia, available for dyslipidemia
Treatment.Especially, the compound medicine treatment of three kinds of forms is found in experiment is reducing the same of blood TG, LDL-C, VLDL-C concentration
When, it can make that blood HDL-C levels are increased to the degree apparently higher than intact animal blood level, TC/HDL-C ratios are narrowed down to and connect
The level of nearly intact animal, prompts that there are preventive and therapeutic action to atherosclerosis caused by dyslipidemia.
The compound medicament composition of the present invention is prepared into suitable Clinical practice by adding pharmaceutically acceptable carrier
Formulation, such as tablet, capsule, liquid preparation.The pharmaceutically acceptable carrier such as disintegrant, diluent, adhesive, lubrication
Agent etc..
The elaboration of further pharmacodynamic experiment result is done to the compound medicament composition of the present invention below by embodiment.
Embodiment
Embodiment 1
Medicine feeds high lipid food the therapeutic effect for causing lipid of mice Exception Model
Compare SAR and pCPA, CDP, BSA administering drug combinations, and be each administered alone to feed high lipid food and cause rat fat
The therapeutic effect of Exception Model, so as to verify the cooperative effect that SAR treats dyslipidemia with pCPA, CDP, BSA administering drug combinations.
2.1 experimental method
(1) animal is handled
180 male ICR mouses are randomly divided into 18 groups (every group 10)：Control group, dyslipidemia model group, dyslipidemia
Model SAR treatment groups, dyslipidemia model SAR+pCPA compound treatment groups (SAR:PCPA presses 4 kinds of different weight proportioning again
Side), dyslipidemia model pCPA treatment groups, dyslipidemia model SAR+CDP compound treatment groups (SAR:CDP is matched somebody with somebody by different weight
4 kinds of compounds of ratio), dyslipidemia MODEL C DP treatment groups, dyslipidemia model SAR+BSA compound treatment groups (SAR:BSA is not by
With 4 kinds of compounds of weight proportion), dyslipidemia Model B SA treatment groups.Animal cage keeps room temperature 24 ± 2 in common mouse cage
DEG C, illumination control ensure that 12h is bright, dark condition, light water is fed.In addition to control group is fed with normal diet, each group animal is used first
High lipid food (fatty 23% in high lipid food, cholesterol 2.6%, protein 17.5%), which is fed, to be established dyslipidemia in 8 weeks and moves
Thing model；Animal is divided at random again after blood lipid detection confirms to have formed high TG, LDL-C mass formed by blood stasis (compared with the control group)
For 17 groups, every group 10, give relative medicine respectively；It is taken twice daily (morning and afternoon respectively once), successive administration 4 weeks.Administration
Period, in addition to control group is fed with normal diet, each group is still fed with high lipid food.Last time be administered after the fasting of each group animal (no
Prohibit water) 12 it is small when after, animal break end after anesthesia takes blood, centrifugation acquisition serum.
In experiment, four kinds of compounds that SAR+pCPA compounds are matched by different weight are：
SAR+pCPA-1—SAR:PCPA=1:5； SAR+pCPA-2—SAR:PCPA=1:2；
SAR+pCPA-3—SAR:PCPA=2:1； SAR+pCPA-4—SAR:PCPA=7:1.
In experiment, four kinds of compounds that SAR+CDP compounds are matched by different weight are：
SAR+CDP-1—SAR:CDP=1:5； SAR+CDP-2—SAR:CDP=1:2；
SAR+CDP-3—SAR:CDP=2:1； SAR+CDP-4—SAR:CDP=9:1.
In experiment, four kinds of compounds that SAR+BSA compounds are matched by different weight are：
SAR+BSA-1—SAR:BSA=1:7； SAR+BSA-2—SAR:BSA=1:3；
SAR+BSA-3—SAR:BSA=1:1； SAR+BSA-4—SAR:BSA=6:1.
(2) dosage
0.5% sodium carboxymethylcellulose (CMC-Na) solution 0.20ml/10g weight of control group-oral administration (p.o.)/
It is secondary；
Dyslipidemia model group-p.o.0.5%CMC-Na 0.20ml/10g weight/time；
Dyslipidemia model drug treatment group-p.o. each group medicines, all administration group dosages are all homogeneously：
25.0mg/kg/ times.
Each medicine is suspended with 0.5%CMC-Na, and concentration is identical to be：Volume is administered in 1.25mg/ml, each group medicine p.o.
0.20ml/10g weight/time；It is taken twice daily, morning and afternoon is respectively administered once.
2.2 experimental index detection methods
Kit, spectrophotometry serum TG, HDL-C, LDL-C and VLDL-C concentration.
2.3 experimental result
Student-t is detected between all statistical data detection groups, p<0.05 indicates obvious significant difference, p<
0.01 indicates clearly significant difference.In table data with means standard deviation () represent, N=10；$p<
0.05,$$p<0.01 compared with the control group；*p<0.05,**p<0.01 compared with dyslipidemia model group；#p<0.05,##p<
0.01 compound group is compared with SAR folk prescription groups；&p<0.05,&&p<0.01 compound group is compared with pCPC or CDP or BSA folk prescription groups.
(1) SAR+pCPA compounds feed high lipid food the therapeutic effect result of study for causing hyperlipidemia
It the results are shown in Table 1.High lipid food, which is fed, to be caused in dyslipidemia model, and animal blood serum TG, LDL-C, VLDL-C concentration is bright
Aobvious rise, and HDL-C concentration substantially reduces, TC/HDL-C ratios significantly increase, and prompts obvious dyslipidemia and generation occur
Atherosclerosis risk symptom.With the SAR of identical dosage, tetra- kinds of compounds of pCPA, SAR+pCPA：SAR+pCPA-1、
SAR+pCPA-2, SAR+pCPA-3, SAR+pCPA-4 treat dyslipidemia, can substantially reduce serum TG, LDL-C and
VLDL-C is horizontal and raises HDL-C levels, reduces TC/HDL-C ratios；Compound SAR+pCPA-2, SAR+pCPA-3 treatment are equal
Show its reduce that TG, LDL-C, VLDL-C are horizontal and rise HDL-C is horizontal, reduce TC/HDL-C positive effects and be better than SAR or
PCPA is used individually, and prompts to produce obvious cooperative effect (note：Compound group is to wait dosage administration with folk prescription group, as long as therefore multiple
Side's group curative effect is better than folk prescription group and has indicated that cooperative effect).Especially it is noted that two compound group treatments make Serum HDL-C water
It is flat be increased to the degree apparently higher than control group, TC/HDL-C ratios are substantially reduced, especially SAR+pCPA-3 treatments make TC/HDL-
C ratios narrow down to horizontal close to control group, this prevention and treatment for atherosclerosis caused by dyslipidemia may have
Special meaning；The improvement dyslipidemia effect of compound SAR+pCPA-1, SAR+pCPA-4 treatment is better than or mono- equal to pCPA and SAT
Solely treatment.As a result prompt, SAR and pCPA forms a certain proportion of compound, to dyslipidemia caused by treatment high lipid food nursing
There are obvious synergistic effect, by weight ratio, SAR:The proportion of pCPA is：7:1~1:5, with SAR in this experiment:pCPA
=2:1 compound (SAR+pCPA-3) curative effect is best.
Table 1SAR+pCPA compound medicines feed mouse high lipid food the influence for causing dyslipidemia model
Note：Each administration group dosage is identical, is 25.0mg/kg. times, and twice a day, morning and afternoon is respectively once
TC (T-CHOL)=HDL-C+LDL-C+VLDL-C
$:P<0.05,$$:P<0.01, compared with the control group； *:P<0.05,**:P<0.01, compared with model group；
#:P<0.05,##:P<0.01, compared with SAR groups； &:P<0.05,&&:P<0.01, compared with pCPA groups
(2) SAR+CDP compounds feed high lipid food the therapeutic effect result of study for causing hyperlipidemia
It the results are shown in Table 2.With the CDP of identical dosage, tetra- kinds of compounds of SAR+CDP：SAR+CDP-1、SAR+CDP-2、SAR
+ CDP-3, SAR+CDP-4, which feed high lipid food, causes dyslipidemia to treat, and can substantially drop serum TG, LDL-C, VLDL-
C is horizontal, and raises HDL-C levels, reduces TC/HDL-C ratios；Compound SAR+CDP-2, SAR+CDP-3 treatment display change
Kind dyslipidemia curative effect is used individually significantly better than SAR or CDP, prompts to produce obvious cooperative effect (note：Compound group and folk prescription
Group for wait dosage administration, as long as therefore compound group curative effect be better than folk prescription group and indicated that cooperative effect), display that two compound groups
Treatment makes Serum HDL-C level be increased to the degree apparently higher than control group, TC/HDL-C ratios are substantially reduced, SAR+CDP-3
Treatment group's TC/HDL-C ratios are close to control group；Compound SAR+CDP-1, SAR+CDP-4 therapeutic effect be better than or equal to CDP,
SAR is used individually.As a result prompt, SAR and CDP forms a certain proportion of compound, to blood fat caused by treatment high lipid food nursing
Exception has obvious synergistic effect, by weight ratio, SAR:The proportion of CDP is：9:1~1:5, with SAR in this experiment:
CDP=2:1 compound (SAR+CDP-3) curative effect is best.
Table 2SAR+CDP compound medicines feed mouse high lipid food the influence for causing dyslipidemia model
Note：Each administration group dosage is identical, is 25.0mg/kg. times, and twice a day, morning and afternoon is respectively once
TC (T-CHOL)=HDL-C+LDL-C+VLDL-C
$:P<0.05,$$:P<0.01, compared with the control group； *:P<0.05,**:P<0.01, compared with model group；
#:P<0.05,##:P<0.01, compared with SAR groups； &:P<0.05,&&:P<0.01, compared with CDP groups
(3) SAR+BSA compounds feed high lipid food the therapeutic effect result of study for causing dyslipidemia
It the results are shown in Table 3.With the BSA of identical dosage, tetra- kinds of compounds of SAR+BSA：SAR+BSA-1、SAR+BSA-2、SAR
+ BSA-3, SAR+BSA-4, which feed high lipid food, causes dyslipidemia to treat, and can substantially drop serum TG, LDL-C, VLDL-
C is horizontal, and raises HDL-C levels, reduces TC/HDL-C ratios；Compound SAR+BSA-2, SAR+BSA-3 treatment display change
Kind dyslipidemia curative effect is used individually significantly better than SAR or BSA, is produced obvious cooperative effect, is displayed that two compound groups are controlled
Treatment makes that Serum HDL-C level is increased to the degree apparently higher than control group, TC/HDL-C ratios are substantially reduced, and SAR+BSA-3 is controlled
Treatment group TC/HDL-C ratios are close to control group；Compound SAR+BSA-1, SAR+BSA-4 therapeutic effect is better than or equal to BSA, SAR
Monotherapy.As a result prompt, SAR and BSA forms a certain proportion of compound, to dyslipidemia caused by treatment high lipid food nursing
There are obvious synergistic effect, by weight ratio, SAR:The proportion of BSA is：6:1~1:7, with SAR in this experiment:BSA=
1:1 compound (SAR+BSA-3) curative effect is best.
Table 3SAR+BSA compound medicines feed mouse high lipid food the influence for causing dyslipidemia model
Note：Each administration group dosage is identical, is 25.0mg/kg. times, and twice a day, morning and afternoon is respectively once
TC (T-CHOL)=HDL-C+LDL-C+VLDL-C
$:P<0.05,$$:P<0.01, compared with the control group； *:P<0.05,**:P<0.01, compared with model group；
#:P<0.05,##:P<0.01, compared with SAR groups； &:P<0.05,&&:P<0.01, compared with BSA groups
Embodiment 2
Medicine causes DEX the therapeutic effect of rat fat Exception Model
Compare SAR and pCPA, CDP, BSA administering drug combinations, and be each administered alone and rat fat Exception Model is caused to DEX
Therapeutic effect (long-term nervous or chronic stress the situation of simulation people), so as to verify that SAR joins with pCPA, CDP, BSA again
Close cooperative effect of the administration to dyslipidemia treatment.
3.1 experimental method
(1) animal is handled
144 male SD rats are randomly divided into 18 groups (every group 8)：Control group, model group, model SAR treatment groups, model
SAR+pCPA compound treatment groups (SAR:PCPA presses 4 kinds of compounds of different weight proportioning), model pCPA treatment groups, model SAR+
CDP compound treatment groups (SAR:CDP presses 4 kinds of compounds of different weight proportioning), MODEL C DP treatment groups, model SAR+BSA compounds are controlled
Treatment group (SAR:BSA presses 4 kinds of compounds of different weight proportioning), Model B SA treatment groups.Animal cage keeps room in common mouse cage
24 ± 2 DEG C of temperature, illumination control guarantee 12h are bright, dark condition, and light water is fed.In addition to control group, each group animal is first with subcutaneous note
Penetrate DEX modelings in 10 days；Again will be dynamic after blood lipid detection confirms to have formed high TG, LDL-C mass formed by blood stasis (compared with the control group)
Thing is randomly divided into 17 groups, every group 8, gives relative medicine, successive administration 10 days respectively.During administration, in addition to control group, each group
Still model is consolidated with hypodermic injection DEX.After when each group animal fasting (can't help water) 12 is small after last time is administered, animal is through fiber crops
Abdominal aortic blood, centrifugation obtain serum after liquor-saturated.
In experiment, four kinds of compounds that tri- kinds of compound forms of SAR+pCPA, SAR+CDP, SAR+BSA are matched by different weight are matched somebody with somebody
5 the same as embodiment 1.
(2) dosage
Control group-hypodermic injection (s.c.) physiological saline 0.50ml/kg/ times, and 0.5% carboxylic first of oral administration (p.o.)
Base sodium cellulosate (CMC-Na) solution 5.0ml/kg/ times；
Model group-s.c.DEX 0.75mg/kg/ times, and p.o.CMC-Na 5.0ml/kg/ times at the same time；
Model drug treatment group-s.c.DEX 0.75mg/kg/ times, and p.o. each groups medicine at the same time, all administration groups are given
Pharmaceutical quantities are all homogeneously：30.0mg/kg/ times.
Each medicine is suspended with 0.5%CMC-Na, and concentration is identical to be：6.0mg/ml；Volume is administered in DEX s.c.
0.50ml/kg/ times, each group medicine p.o. administration volumes are 5.0ml/kg/ times；It is taken twice daily, morning and afternoon is respectively administered once.
3.2 experimental result
Each index detection method, statistical procedures are the same as embodiment 1.
(1) SAR+pCPA compounds cause DEX the therapeutic effect result of study of dyslipidemia
It the results are shown in Table 4.DEX is caused in dyslipidemia model, and animal blood serum TG, LDL-C, VLDL-C concentration is significantly raised,
HDL-C concentration substantially reduces, the increase of TC/HDL-C ratios.With the SAR of identical dosage, tetra- kinds of compounds of pCPA, SAR+pCPA：
SAR+pCPA-1, SAR+pCPA-2, SAR+pCPA-3, SAR+pCPA-4 cause dyslipidemia model to treat DEX, can be bright
Aobvious to reduce serum TG, LDL-C, VLDL-C level, rise HDL-C is horizontal, reduces TC/HDL-C ratios, prompts to be respectively provided with significantly
Improve dyslipidemia curative effect；Compound SAR+pCPA-2, SAR+pCPA-3 treatment show that it reduces serum TG, LDL-C, VLDL-C
Horizontal and rise HDL-C horizontal forces are used individually significantly better than SAR or pCPA, produce obvious cooperative effect.Also, two
It is close or even small that compound treatment group makes Serum HDL-C level be increased to the degree apparently higher than control group, TC/HDL-C ratios
In control group；The improvement dyslipidemia curative effect of compound SAR+pCPA-1, SAR+pCPA-4 treatment is better than or mono- equal to pCPA and SAR
Solely treatment.As a result prompt, SAR and pCPA forms a certain proportion of compound, causes dyslipidemia to have obvious collaboration to make treatment DEX
With, by weight ratio, SAR:The proportion of pCPA is：7:1~1:5, with SAR in this experiment:PCPA=2:1 compound (SAR+
PCPA-3) curative effect is best.
Table 4SAR+pCPA compound medicines cause rat DEX the influence of hyperlipemia model
Note：Each administration group dosage is identical, is 30.0mg/kg. times, and twice a day, morning and afternoon is respectively once
TC (T-CHOL)=HDL-C+LDL-C+VLDL-C
$:P<0.05,$$:P<0.01, compared with the control group； *:P<0.05,**:P<0.01, compared with model group；
#:P<0.05,##:P<0.01, compared with SAR groups； &:P<0.05,&&:P<0.01, compared with pCPA groups
(2) SAR+CDP compounds cause DEX the therapeutic effect result of study of hyperlipidemia
It the results are shown in Table 5.With the CDP of identical dosage, tetra- kinds of compounds of SAR+CDP：SAR+CDP-1、SAR+CDP-2、SAR
+ CDP-3, SAR+CDP-4 cause dyslipidemia to treat DEX, can substantially drop serum TG, LDL-C, VLDL-C level, and
And rise HDL-C is horizontal, reduces TC/HDL-C ratios；Compound SAR+CDP-2, SAR+CDP-3 treatment show that improvement blood fat is different
Normal curative effect is used individually significantly better than SAR or CDP, is produced obvious cooperative effect, is displayed that two compound treatment groups make serum
HDL-C levels are increased to the degree apparently higher than control group, TC/HDL-C ratios close to even less than control group；Compound SAR+
CDP-1, SAR+CDP-4 therapeutic effect are better than or are used individually equal to CDP, SAR.As a result prompt, the certain ratio of SAR and CDP compositions
The compound of example, has obvious synergistic effect, by weight ratio, SAR to dyslipidemia caused by treatment DEX:The proportion of CDP
For：9:1~1:5, with SAR in this experiment:CDP=2:1 compound (SAR+CDP-3) curative effect is best.
Table 5SAR+CDP compound medicines cause rat DEX the influence of dyslipidemia model
Note：Each administration group dosage is identical, is 30.0mg/kg. times, and twice a day, morning and afternoon is respectively once
TC (T-CHOL)=HDL-C+LDL-C+VLDL-C
$:P<0.05,$$:P<0.01, compared with the control group； *:P<0.05,**:P<0.01, compared with model group；
#:P<0.05,##:P<0.01, compared with SAR groups； &:P<0.05,&&:P<0.01, compared with CDP groups
(6) SAR+BSA compounds cause DEX the therapeutic effect result of study fruit of hyperlipidemia
It the results are shown in Table 6.With the BSA of identical dosage, tetra- kinds of compounds of SAR+BSA：SAR+BSA-1、SAR+BSA-2、SAR
+ BSA-3, SAR+BSA-4 cause dyslipidemia to treat DEX, can substantially drop serum TG, LDL-C, VLDL-C level, and
And rise HDL-C is horizontal, reduces TC/HDL-C ratios；Compound SAR+BSA-2, SAR+BSA-3 treatment show that improvement blood fat is different
Normal curative effect is used individually significantly better than SAR or BSA, is produced obvious cooperative effect, is displayed that two compound treatment groups make serum
HDL-C levels are increased to the degree apparently higher than control group, TC/HDL-C ratios close to even less than control group；Compound SAR+
BSA-1, SAR+BSA-4 therapeutic effect are better than or are used individually equal to BSA, SAR.As a result prompt, the certain ratio of SAR and BSA compositions
The compound of example, has obvious synergistic effect, by weight ratio, SAR to dyslipidemia caused by treatment DEX:The proportion of BSA
For：6:1~1:7, with SAR in this experiment:BSA=1:1 compound (SAR+BSA-3) curative effect is best.
Table 6SAR+BSA compound medicines cause rat Dex the influence of dyslipidemia model
Note：Each administration group dosage is identical, is 30.0mg/kg. times, and twice a day, morning and afternoon is respectively once
TC (T-CHOL)=HDL-C+LDL-C+VLDL-C
$$:P<0.01, compared with the control group； *:P<0.05,**:P<0.01, compared with model group；
#:P<0.05,##:P<0.01, compared with SAR groups； &:P<0.05,&&:P<0.01, compared with BSA groups
Claims (7)
- It is athero- that 1. the compound medicament composition containing Sarpogrelate and serotonin synthetic inhibitor is used to prepare treatment/prevention of arterial The purposes of the medicine of disease is hardened, wherein serotonin synthetic inhibitor be fenclonine, carbidopa or benserazide, sand The weight ratio of Gray's ester and serotonin synthetic inhibitor is 9:1~1:7.
- 2. the weight ratio of the purposes of claim 1, wherein Sarpogrelate and fenclonine is 7:1~1:5.
- 3. the weight ratio of the purposes of claim 2, wherein Sarpogrelate and fenclonine is 2:1.
- 4. the weight ratio of the purposes of claim 1, wherein Sarpogrelate and carbidopa is 9:1~1:5.
- 5. the weight ratio of the purposes of claim 4, wherein Sarpogrelate and carbidopa is 2:1.
- 6. the weight ratio of the purposes of claim 1, wherein Sarpogrelate and benserazide is 6:1~1:7.
- 7. the weight ratio of the purposes of claim 6, wherein Sarpogrelate and benserazide is 1:1.
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| CN104940180A (en) * | 2015-07-09 | 2015-09-30 | 中国药科大学 | Novel application of benserazide hydrochloride |
| CN105267192A (en) * | 2015-09-29 | 2016-01-27 | 中国药科大学 | New use of benserazide hydrochloride reverse cholesterol transport way |
| US11103499B2 (en) * | 2016-08-26 | 2021-08-31 | EXCIVA (UG) (haftungsbeschränkt) | Compositions and methods thereof |
| CN106177962B (en) * | 2016-09-07 | 2019-04-30 | 中国药科大学 | Pharmaceutical composition containing Sarpogrelate is for treating or preventing fatty liver, liver fibrosis and/or the purposes of hepatic injury |
| CN107929739A (en) * | 2017-11-30 | 2018-04-20 | 中国药科大学 | Pharmaceutical composition containing Sarpogrelate is used for the purposes for treating diabetic nephropathy |
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