CN107174578A - A kind of pharmaceutical composition for treating hyperlipidemia - Google Patents
A kind of pharmaceutical composition for treating hyperlipidemia Download PDFInfo
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- CN107174578A CN107174578A CN201710151123.9A CN201710151123A CN107174578A CN 107174578 A CN107174578 A CN 107174578A CN 201710151123 A CN201710151123 A CN 201710151123A CN 107174578 A CN107174578 A CN 107174578A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to pharmaceutical technology field, and in particular to a kind of pharmaceutical composition for treating hyperlipidemia.The useful effect composition of the pharmaceutical composition has having structure：Wherein, R1, R2, R3, R4 are identical or different group.In addition, the pharmaceutical composition is also containing one or more pharmaceutically acceptable carriers.Found using after medicine of the present invention; medicine of the present invention can effectively slow down and reduce the speed and degree of hyperlipidemia patient hepatic steatosis; there are certain treatment and restitution to hyperlipidemia patient; taking, after a period of time hyperlipidemia patient serum lipids can change to normalization horizontal direction; and TG and HDL can recover to normal level, and then reduce the risk of coronary heart disease.
Description
Technical field
The present invention relates to field of medicaments, specifically, the present invention relates to a kind of pharmaceutical composition for treating hyperlipidemia.
Background technology
Hyperlipidemia is the increased a kind of symptom of lipoprotein abnormalities in blood, and it is with some diseases such as artery sclerosis and cardiac muscle
Infraction is closely related, therefore its treatment is considered as particularly significant.The main component of blood lipoprotein is cholesterol and triglycerides,
In many cases, the blood cholesterol levels of hyperlipemic patients not only increase, and are accompanied by the increase of triglycerides.The present invention
From the medicine of existing a variety for the treatment of hyperlipidemias, the new medicine of the treatment hyperlipidemia of effective and safe is developed.
The content of the invention
It is an object of the invention to provide a kind of pharmaceutical composition for treating hyperlipidemia.
In order to realize the purpose of the present invention, the present invention provides a kind of pharmaceutical composition for treating hyperlipidemia, the medicine
Composition is made up of active drug composition and other pharmaceutically acceptable auxiliary elements.
Preferably, the active drug composition has formula：
Wherein R1, R2, R3, R4 are identical or different group.
Preferably, R1, R2, R3, R4 can arbitrarily be selected from halogen, alkyl, alkoxy, hydroxyl, hydrogen.
Preferably, R1, which independently is hydroxyl, R2 and independently is methyl, R3 and independently is methoxyl group, R4, independently is methyl.
It is highly preferred that other described pharmaceutically acceptable auxiliary elements can be selected from one or more pharmaceutically acceptable
Carrier, diluent, excipient.
It is highly preferred that described pharmaceutical composition can be any regular dosage form pharmaceutically, such as capsule or particle
Agent or powder agent or pill.
The present invention also provides purposes of the compound in the medicine for preparing treatment hyperlipidemia, and the compound has following
Structure：
Wherein R1, R2, R3, R4 are identical or different group.
Preferably, R1, R2, R3, R4 can arbitrarily be selected from halogen, alkyl, alkoxy, hydroxyl, hydrogen.
Preferably, R1, which independently is hydroxyl, R2 and independently is methyl, R3 and independently is methoxyl group, R4, independently is methyl.
Found using after medicine of the present invention, medicine of the present invention can effectively slow down and reduce hyperlipidemia patient liver fat
The speed and degree of denaturation, have certain treatment and restitution to hyperlipidemia patient, high fat can be made by taking after a period of time
Mass formed by blood stasis patients serum lipid changes to normalization horizontal direction, and TG and HDL can recover to normal level, and then reduces hat
The risk of worry.
Brief description of the drawings
Fig. 1 be various dose drug therapy hyperlipidemia ratses liver section effect of the present invention (HE, × 20).
Fig. 2 is shadow of the various dose medicine of the present invention to ACCl, HSL protein expression in hyperlipidemia ratses liver organization
Ring.
A. normal group；B. model group；C. Lovastatin group；D. medicine high dose group of the present invention；E. agent in medicine of the present invention
Amount group；F medicine low dose groups of the present invention.
Embodiment
In order that those of ordinary skill in the art are better understood from the therapeutic effect and mechanism of medicine of the present invention, below in conjunction with
Embodiment is described in detail.
The sign of the medicine of the present invention of experimental example 1
1H-NMR(CDCl3)δ:7.90 (1H, dd, J=8.6,2.3Hz), 7.83-7.80 (1H, m), 7.48 (1H, t, J=
8.2Hz), 7.13-7.06 (2H, m), 6.92 (1H, d, J=8.6Hz), 5.35 (2H, s), 3.94 (3H, s), 3.60 (3H, s),
2.02(3H,s)。
The effect of the drug therapy hyperlipidemia of the present invention of experimental example 2
Body weight 180g~200g healthy adult male SD rat is raised in air-conditioning animal feeding room with room group's cage, freely
Feeding, free water.20 DEG C of ± 2 DEG C of humidity 45%-60% of room temperature.Basal feed is formulated：Corn 35%, wheat bran 25%, dregs of beans
25%th, the yeast 2% of fish meal 8%., bone meal 2%, whey powder 1%, salt 0.5%, rape oil 0.5%, mineral additive 0.1%, compound
Vitamin 0.03%, methionine 0.13%, lysine 0.07%, cod-liver oil 0.05%.High lipid food is formulated：Basal feed
78.8%th, lard 10%, yolk powder 10%, cholesterol 1%, cholate 0.2%.
Experimental rat group is designed
All rats all feed basal feed, and free choice feeding, drinking-water are fed 1 week, to adapt to environment and feed mode.1
According to T-CHOL TC basic value levels after week, rat is randomly divided into 6 groups respectively, every group of 10 rats are specifically divided into：Normally
Control group, hyperlipidemia model group, Lovastatin group, medicine high dose group of the present invention, medicine middle dose group of the present invention, medicine of the present invention
Low dose group.The 7d laundering period sets up the phase after terminating into hyperlipidemia model：Normal group feeds basal feed and distilled water, remaining
Each group feeds high lipid food and distilled water, co-cultures 45d, rat is had hyperlipidemia.
Drug treatment：After 45d, the daily oral disposable gavage amount of the basic, normal, high dosage group of medicine of the present invention is respectively 0.5,
1.0th, the medicine of 2.0mg/kg embodiments 1, Normal group and hyperlipidemia model group gavage equivalent distilled water.Lovastatin 1.0mg/kg
It is used as the given low of positive controls rat.45d is administered.
It is prepared by test serum
Fasting 12h before blood sampling, etherization, eye socket blood sampling.Collect blood sample room temperature to place after 1h, in 2000~2500r/
15min is centrifuged on min low speed centrifuges, suctioning out upper serum 0.5ml with pipettor is sub-packed in centrifuge tube, to be measured.
The measure of blood lipids index in rat blood serum：Analyzed using full automatic biochemical apparatus.
The preparation of liver and adipose tissue to be measured
The preparation of liver, epididymis and mesenteric adipose tissues：Etherization during off-test, the experiment of main artery sacrificed by exsanguination
Rat, dissection, the liver organization, mesenteric adipose tissues, epididymal adipose for winning rat is put into rapidly freezing in liquid nitrogen
Afterwards, -80 DEG C save backup.
The preparation of hepatic pathology section：Rat is taken off into cervical vertebra to put to death, dissection, won after fresh liver tissue weighs, from maximum
Liver organization is taken at blde pitch edge 5mm, and is fixed in 10% formalin.
The measure of index
The measure of lipid metaboli key enzyme activity：Hormone-sensitive lipase (HSL), fatty acid synthetase (FAS), acetyl are auxiliary
Enzyme A carboxylases (ACC) determination of activity uses the ELISA detection kit of RD companies of the U.S.
Hepatic pathology changes：By the liver organization fixed dehydration, FFPE, section, HE (hematoxylin eosin staining)
Dyeing, micro- sem observation.
Fat metabolism key enzyme albumen expression quantity is determined：Using HSL Antibody (1:500), FASn Antibody (1:
600), Rabbit anti ACCl Polyclonal antibody (1:1000), alpha Tubulin Antibody (1:
10000), β-Actin Antibody (1:10000).Using BCA kit measurement protein concentrations, using SDS-PAGE electrophoresis,
During hybridization, primary antibody is diluted with PBS or confining liquid：HSL Antibody(1:500), FASn Antibody (1:600),
Rabbit anti ACCl Polyclonal antibody(1:1000),alpha Tubulin Antibody(1:1000),
2-3h or 4 DEG C is shaken in 37 DEG C to shake overnight.Film is washed with the PBS containing 1%Tween-20 three times, each 10min.Add with PBS or
It is the corresponding secondary antibody of confining liquid dilution：HRP-Goat Anti-Rabbit IgG(1:10000), stay overnight for 4 DEG C.Again with containing 1%
Tween-20 PBS washes film three times, each 10min.By the colour developing of ECL colour reagent boxes specification, it is fixed.
Data statistic analysis
Data with " mean+SD ', represent, all data first carry out Grubbs inspections, to exclude human error；
Qualified data are examined through G, using SPSS 16.0, significance analysis is carried out with duncan's method.
Influence of the various dose medicine of the present invention to hyperlipidemia ratses serum lipids
As can be seen that different group rat fat index TC, TG, LDL, HDL do not have conspicuousness in the laundering period from following table
Difference, feeding high lipid food is after 45 days, compared with feeding the Normal group of basal feed, and the group of other feeding high lipid foods is big
Blood lipids index TC, TG, LDL of mouse are all remarkably higher than Normal group (p<0.05), HDL indexs are then substantially less than Normal group
(p<0.05), illustrate that hyperlipidemia model is successfully established.
(it see the table below) in terms of the pharmaceutical intervention result of the present invention of 45 days, medicine high dose group rat blood serum index of the present invention
TC, TG, LDL are substantially less than hyperlipidemia model group (p<0.01), HDL is significantly higher than hyperlipidemia model group (p<, and TG and HDL 0.01)
There was no significant difference with Normal group.Serum Indexes TC, TG, LDL, HDL of Lovastatin group (positive control) and high fat mould
Type group has significant difference, and there was no significant difference with Normal group.Though the lipid-lowering effect of medicine high dose group of the present invention is not
And Lovastatin, but also demonstrate effect of the medicine high dose group of the present invention with stronger regulation blood lipid metabolism.
In medicine of the present invention, low dose group rat blood serum index TC, LDL, HDL and the electrodeless significant difference of hyperlipidemia model group,
But in medicine of the present invention, low dose group improve HDL contents levels.Result of the test shows, high dose medicament adjusting of the present invention
The effect of blood lipid metabolism be better than in, low dosage medicine of the present invention.
Influence of the various dose medicine of the present invention to hyperlipidemia ratses liver
Under normal circumstances, except fat is extracellular, other cells typically lose fat drips under light microscopic, if in these cytoplasms
There are fat drips or fat drips to increase, then referred to as steatosis, abbreviation fat becomes.From Fig. 1 a, Normal group liver tissue slices
Show liver blood sinus substantially, liver cell is arranged radially around central vein, and liver cell is hexagonal, and kytoplasm is abundant in content,
Cell circumference understands；Fig. 1 b show occur significant quantities of fat drop vacuole in liver cell, be dispersed in whole endochylema, part has been merged
Into big vacuole, whole endochylema position is occupied, nucleus is extruded to one side, it is similar to fat cell, and liver cell circumference is fuzzy
Unclear, cell diffuses swelling, liver cell arrangement disorder, the light dye of endochylema, loose.Illustrate that hyperlipidemia model rat liver fat cell becomes
Property is serious.From the point of view of Fig. 1 d (medicine high dose group of the present invention), liver organization structure is normal, there are no steatosis and its
Its pathological change；And go out in Fig. 1 e (medicine middle dose group of the present invention), figure if (medicine low dose group of the present invention) displays, liver cell
The small fat drop vacuole that existing quantity is not waited, but hepatic cell cords arrangement compared with Fig. 1 a, there is slight fat still in substantially radial
Denaturation, but compared with Fig. 1 b, lesser extent.From the point of view of liver section result, high dose medicine of the present invention effectively can slow down and drop
The speed and degree of low hyperlipidemia ratses hepatic steatosis.
Influence of the various dose medicine of the present invention to hyperlipidemia ratses lipid-metabolism key enzyme activity
From following table as can be seen that medicine high dose group of the present invention, medicine middle dose group of the present invention, Lovastatin group and height
Not notable (the p of HSL enzyme activity sex differernce in fat model group rats liver organization>0.05), but they be significantly higher than Normal group,
Medicine middle dose group of the present invention and medicine low dose group (p of the present invention<0.05), agent in Normal group, medicine of the present invention
Not notable (the p of the HSL enzyme activity sex differernce of amount group and medicine low dose group of the present invention>0.05).Medicine high dose group of the present invention
HSL enzymatic activitys improve 13.2% compared with hyperlipidemia model group.In terms of entire change, the HSL activity in liver organization is improved and failed to understand
Aobvious, this is consistent with the change of liver organization HSL protein expressions.In terms of the HSL activity changes in epididymis tissue, medicine of the present invention
The active poles of the HSL of high dose group and Lovastatin group are significantly higher than hyperlipidemia model group (p<0.01) it is, electrodeless with Normal group
Significant difference, and medicine middle dose group of the present invention and medicine low dose group of the present invention and hyperlipidemia model group also electrodeless significant difference.
Illustrate the HSL enzymatic activitys that medicine high dose of the present invention is favorably improved in hyperlipidemia ratses epididymis tissue.From mesentery tissue
In HSL activity changes see, medicine high dose group of the present invention, medicine middle dose group of the present invention, medicine low dose group of the present invention with
And the active poles of HSL of Lovastatin group are significantly higher than hyperlipidemia model group and Normal group (p<0.01).Illustrate medicine of the present invention
Thing can improve the enzymatic activity of HSL in hyperlipidemia ratses mesentery tissue as Lovastatin.
Following table shows that acetyl-CoA carboxylase (ACC) activity of medicine high dose group of the present invention extremely shows in liver organization
Write and be less than hyperlipidemia model group, medicine middle dose group of the present invention, medicine low dose group of the present invention and Normal group (p<0.01),
And electrodeless significant difference between other groups.In epididymis tissue, the active poles of medicine high dose group ACC of the present invention are substantially less than other groups
Not (p<0.01), hyperlipidemia model group is then significantly higher than other groups (p<0.01).In mesentery tissue, medicine high dose of the present invention
Group ACC activity is also substantially less than other groups (P in pole<0.01) medicine low dose group of the present invention is also significantly lower than hyperlipidemia model group (p
<0.01), but it is significantly higher than Normal group (p<0.01).Therefore, high dose medicine of the present invention contributes to suppression hyperlipidemia big
Mouse adipose tissue activity of acetyl coenzyme A carboxylase (p<0.01), this and ACC1 protein expression variation tendencies are consistent.
From following table it is also seen that medicine of the present invention helps to suppress hyperlipidemia ratses liver organization FAS activity (p<
, and medicine middle dose group of the present invention and medicine low dose group inhibition of the present invention are significantly higher than other groups (p 0.05)<
0.05).But in epididymis tissue, high dose medicine of the present invention and Lovastatin significantly inhibit FAS enzymatic activitys (p<0.01),
And the FAS enzyme activity of hyperlipidemia model group is significantly higher than Normal group (p<0.01), medicine middle dose group of the present invention and medicine of the present invention
There was no significant difference with hyperlipidemia model group by the FAS of thing low dose group.In mesentery tissue, medicine each group of the present invention cuts down him with Lip river
The FAS activity of spit of fland group is without significant difference (p>, but substantially less than hyperlipidemia model group (p 0.05)<0.05).On the whole, high dose
Medicine of the present invention can significantly suppress FAS enzymatic activitys in hyperlipidemia ratses adipose tissue.
The expression analysis of lipid-metabolism key enzyme albumen
Various dose medicine of the present invention is shown in figure to ACC1 in hyperlipidemia ratses liver organization, the influence of HSL protein expressions
2.Using Image J softwares, band OD value, experimental data destination protein band OD value and internal reference band light are determined
The ratio of density value is represented, as a result see the table below.Western Blot detections find that high dose medicine of the present invention has up-regulation HSL eggs
White expression, the effect for lowering ACC1 protein expressions.
| Group | HSL | ACCl |
| Normally | 1.4965±0.086 | 0.6846±0.187 |
| Model | 0.7386±0.094 | 1.5777±0.264 |
| Lovastatin | 1.4052±0.320 | 0.9544±0.250 |
| High dose | 1.2721±0.336 | 0.9556±0.308 |
| Middle dosage | 1.2754±0.061 | 1.2550±0.245 |
| Low dosage | 0.8224±0.241 | 1.2540±0.171 |
Claims (9)
1. a kind of pharmaceutical composition for treating hyperlipidemia, it is characterised in that described pharmaceutical composition by active drug composition with
And pharmaceutically acceptable other auxiliary elements composition.
2. the pharmaceutical composition for the treatment of hyperlipidemia according to claim 1, it is characterised in that the active drug composition
With formula：
Wherein R1, R2, R3, R4 are identical or different group.
3. the pharmaceutical composition for the treatment of hyperlipidemia according to claim 2, it is characterised in that R1, R2, R3, R4
Arbitrarily to be selected from halogen, alkyl, alkoxy, hydroxyl, hydrogen.
4. it is according to claim 3 treatment hyperlipidemia pharmaceutical composition, it is characterised in that R1 independently be hydroxyl,
R2, which independently is methyl, R3 and independently is methoxyl group, R4, independently is methyl.
5. the pharmaceutical composition for the treatment of hyperlipidemia according to claim 4, it is characterised in that described pharmaceutically acceptable
Other auxiliary elements can be selected from one or more pharmaceutically acceptable carriers, diluent, excipient.
6. the pharmaceutical composition for the treatment of hyperlipidemia according to claim 5, it is characterised in that described pharmaceutical composition can
To be any regular dosage form pharmaceutically, such as capsule or granule or powder agent or pill.
7. purposes of the compound in the medicine for preparing treatment hyperlipidemia, it is characterised in that the compound has following knot
Structure：
Wherein R1, R2, R3, R4 are identical or different group.
8. purposes according to claim 7, it is characterised in that R1, R2, R3, R4 can from halogen, alkyl, alkoxy,
Arbitrarily selected in hydroxyl, hydrogen.
9. purposes according to claim 8, it is characterised in that R1 independently is hydroxyl, R2 and independently is methyl, R3 independences
Ground is methoxyl group, R4 independently is methyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710151123.9A CN107174578A (en) | 2017-03-14 | 2017-03-14 | A kind of pharmaceutical composition for treating hyperlipidemia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710151123.9A CN107174578A (en) | 2017-03-14 | 2017-03-14 | A kind of pharmaceutical composition for treating hyperlipidemia |
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| Publication Number | Publication Date |
|---|---|
| CN107174578A true CN107174578A (en) | 2017-09-19 |
Family
ID=59829967
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710151123.9A Withdrawn CN107174578A (en) | 2017-03-14 | 2017-03-14 | A kind of pharmaceutical composition for treating hyperlipidemia |
Country Status (1)
| Country | Link |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101385719A (en) * | 2007-09-10 | 2009-03-18 | 鲁南制药集团股份有限公司 | Osmotic pump preparation composition for treating hyperlipemia |
| CN105593217A (en) * | 2013-08-29 | 2016-05-18 | 住友化学株式会社 | Tetrazolinone compound and use of same |
-
2017
- 2017-03-14 CN CN201710151123.9A patent/CN107174578A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101385719A (en) * | 2007-09-10 | 2009-03-18 | 鲁南制药集团股份有限公司 | Osmotic pump preparation composition for treating hyperlipemia |
| CN105593217A (en) * | 2013-08-29 | 2016-05-18 | 住友化学株式会社 | Tetrazolinone compound and use of same |
Non-Patent Citations (1)
| Title |
|---|
| 彭春秀等: "普洱茶茶褐素对高脂血症大鼠的治疗作用", 《现代食品科技》 * |
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Application publication date: 20170919 |
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