CN110237070A - Irbesartan is preparing the application in blood lipid-lowering medicine - Google Patents
Irbesartan is preparing the application in blood lipid-lowering medicine Download PDFInfo
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Abstract
The invention discloses Irbesartans (Irbesartan) to prepare the application in blood lipid-lowering medicine.The present inventor has found that Irbesartan can play a role in terms of reducing blood lipid in studying cholesterol-lowering drug, belongs to old medicine and newly uses.Present invention demonstrates that Irbesartan can not only reduce cholesterol in cellular level, additionally it is possible to play significant lipid-lowering effect in the mouse high blood lipid model of zoopery.Therefore Irbesartan has important application value and meaning in terms of reducing blood lipid.
Description
Technical field
The present invention relates to medicinal application fields, and in particular to Irbesartan is preparing the application in blood lipid-lowering medicine.
Background technique
Cholesterol is the indispensable important substance of human tissue cell, but cholesterol level is excessively high can induce generation disease
Disease, especially cardiovascular disease.The Statins cholesterol-lowering drug that clinic generally uses at present.But the work of statins
With the enzyme HMG CoA (HMG- that mechanism is by the Reverse transcriptase Biosynthesis of cholesterol process initial stage
CoA) reductase inhibitor is realized.However take statins for a long time, there are many side effects.
Hyperlipidemic conditions show as Blood Cholesterol, low-density lipoprotein sterol, triglyceride levels and are higher than normal value,
And high-density lipoprotein sterol is lower than normal value, these factors are that the important risk of atherosclerosis and cardiovascular disease is commented
Estimate factor.Therefore, norcholesterol is always the essential therapeutic arsenals of this kind of diseases.
Low-density lipoprotein (Low Density Lipoprotein, LDL) be an independent hyperlipidemia assessment risk because
Element, LDL is by the cholesterol transport in liver or enteron aisle to tissue.Since LDL contains high-caliber cholesterol, when in blood plasma
It when LDL level increases, may be accumulated in arterial wall, coronary artery disease and heart disease risk is caused to increase.Therefore LDL
It is considered as " harmful cholesterol ".
At the same time, screening is carried out for " old medicine " and be subject to " new to use ", can also greatly improve the efficiency of exploitation." old medicine
It is new to use " refer to the New indication of marketed drug or the exploitation of new purposes.The research and development of completely new drug generally from the project of establishment to
Listing needs more than 10 years time, and cost is also high, and success rate is less than 10%." old medicine is newly used " can then greatly reduce research and development
Risk.Safety and pharmacokinetic data due to " old medicine " is perfect, and safety just has very big guarantee.It is new to develop it
Purposes can substantially reduce the R&D cycle, reduce research and development cost, save human and material resources.Thus old medicine is newly with as current new drug development
In maximally efficient, the most efficiently one of means.
Based on above-mentioned, the present invention by the method for old medicine newly carry out cholesterol-lowering drug computer virtual screening and
Cell and animal it is horizontal carried out drug study, new drug for lowering cholesterol can be researched and developed and experiment basis is provided, to meet drop gallbladder
Sterol effect and prevention cholesterol level mostly bring disease.
Irbesartan (English name: Irbesartan), structure such as shown in (I), are clinically mainly used for treating primary
The treatment of hypertension and the diabetes B nephrosis of complicated hypertension, so far without finding any related Irbesartan energy
Enough reduce the report of lipid aspects.
Summary of the invention
The present invention provides a kind of new applications of Irbesartan --- the application in drop hyperlipidemia.It is new to belong to old medicine
With the drug has important application value and meaning in terms of reducing blood lipid.
The present invention is achieved by the following technical solutions: Irbesartan is applied alone or drops blood in preparation with other drugs combination
Application in terms of rouge drug.
Preferably, above-mentioned application, which is characterized in that Irbesartan is applied alone or closes with other drugs combination in preparation treatment
And the application in the hyperlipemia drug of hypertension.
Preferably, above-mentioned application, Irbesartan are preparing the application in cholesterol lowering drug object.
Preferably, above-mentioned application, Irbesartan are the enzyme inhibitors of 24- dehydrocholesterol reductase DHCR24.
Preferably, above-mentioned application, in cellular level, the dosage of Irbesartan is 1~80 μM.
Preferably, above-mentioned application, in cellular level, the dosage of Irbesartan is 5 μM.
Preferably, above-mentioned application, in mouse animal experiment level, the dosage of Irbesartan is 6mg/kg.
The beneficial effects of the present invention are:
1. the present inventor has found that Irbesartan is solid for 24- dehydrogenation gallbladder in the drug screening early period research of oneself
The enzyme inhibitor of alcohol reductase DHCR24, thus speculate that it can play a role as novel blood lipid-lowering medicine.In the present invention, benefit
It is proved with liver cell experiment and hyperlipidemia animal model experiment, Irbesartan can be reduced in cellular level and animal level
The content of various blood lipids in cellular cholesterol and hyperlipidemia model mouse, thus play the effect of reducing blood lipid.Therefore, Irbesartan can be with
Effective medicine as reducing blood lipid.When concrete application, directly it can be used to treat hyperlipidemia for Irbesartan as therapeutic agent, especially
It is the treatment of the hyperlipemia of complicated hypertension.
2. present invention demonstrates that Irbesartan can not only reduce cholesterol in cellular level, additionally it is possible in zoopery
Significant lipid-lowering effect is played in mouse high blood lipid model.Therefore Irbesartan applies valence with important in terms of reducing blood lipid
Value and meaning.
Detailed description of the invention
Figure 1A is that cellular level Irbesartan adding consistency determines.
Figure 1B is 0.6mg/ml cholesterol standards map, appearance time 34min.
Fig. 1 C is 0.6mg/ml desmosterol standard items map, appearance time 24min.
Fig. 1 D is the map of desmosterol Yu cholesterol standards mixed liquor (1:1), respectively desmosterol appearance time
24min, cholesterol appearance time 34min.
Fig. 1 E is solvent control dehydrated alcohol map.
Fig. 1 F is the standard curve and equation of linear regression of cholesterol standards and desmosterol, and wherein desmosterol is
Desmosterol；Cholesterol is cholesterol.
Fig. 1 G is that per unit quantity intracellular cholesteryl content after Irbesartan drug is added in high performance liquid chromatography detection
Column diagram；Wherein, content (UD, undetectable) n=3, nean ± SD, * * *: p of per unit quantity intracellular cholesteryl <
0.001vs.S(+)。
Fig. 2A is the cholesterol dyeing that cellular cholesterol fluorescence colour (Filipin method) examines Irbesartan norcholesterol
Fluorogram.Filipin (Filipin) is cholesterol fluorescent dye, and the power of fluorescence intensity represents cholesterol levels height.
Fig. 2 B is the cholesterol dyeing that cellular cholesterol fluorescence colour (Filipin method) examines Irbesartan norcholesterol
Fluorescence gray value analysis chart；Wherein, Filipin dye gray value ratio significance analysis n=30mean ± SD, * * *: P <
0.001vs.S(+),###:P<0.001vs.S(-)。
Fig. 3 A is that Irbesartan reduces total cholesterol level in C57BL/6J hyperlipemia model mice serum；Wherein, n=
12,mean±SD,*:p<0.05vs.HFD.ND (Normal Diet) is normal diet group；HFD (High Fat Diet) is height
Rouge diet control group；HFD+SM (Simvastatin) is Simvastatin positive controls；HFD+IRB (Irbesartan) is strategic point
Bei Shatan group.
Fig. 3 B is that Irbesartan reduces C57BL/6J hyperlipemia model mice Triglycerides in Serum level；Wherein, n=
12,mean±SD,*:p<0.05vs.HFD.ND (Normal Diet) is normal diet group；HFD (High Fat Diet) is height
Rouge diet control group；HFD+SM (Simvastatin) is Simvastatin positive controls；HFD+IRB (Irbesartan) is strategic point
Bei Shatan group.
Fig. 3 C is the low-density lipoprotein sterol levels that Irbesartan reduces C57BL/6J hyperlipemia model mice；Its
In, n=12, mean ± SD, *: p < 0.01vs.HFD of *.ND (Normal Diet) is normal diet group；HFD(High Fat
It Diet) is high fat diet control group；HFD+SM (Simvastatin) is Simvastatin positive controls；HFD+IRB
It (Irbesartan) is Irbesartan group.
Fig. 3 D is that Irbesartan increases C57BL/6J hyperlipemia model mice serum middle-high density lipoprotein sterol levels；
Wherein, n=12, mean ± SD, *: p < 0.05vs.HFD.ND (Normal Diet) is normal diet group；HFD(High Fat
It Diet) is high fat diet control group；HFD+SM (Simvastatin) is Simvastatin positive controls；HFD+IRB
It (Irbesartan) is Irbesartan group.
Fig. 4 is the immuning tissue that Irbesartan improves the liver organization lipid vacuolation of C57BL/6J hyperlipemia model mice
Change result.ND (Normal Diet) is normal diet group；HFD (High Fat Diet) is high fat diet control group；HFD+SM
It (Simvastatin) is Simvastatin positive controls；HFD+IRB (Irbesartan) is Irbesartan group.
Fig. 5 A is no substrate desmosterol but cholesterol biosynthesis reaction system when containing compounds such as coenzyme NAD prothetic group FAD
HPLC detection figure.
Fig. 5 B is that cholesterol biosynthesis reaction system HPLC is detected when having the compounds such as substrate desmosterol+coenzyme NAD prothetic group FAD
Figure.
Fig. 5 C is that have the cholesterol biosynthesis of the compounds such as substrate desmosterol+enzyme (DHCR24)+coenzyme NAD prothetic group FAD to react
The HPLC of system detects figure.
Fig. 5 D is the HPLC inspection of cholesterol biosynthesis reaction system after 200nM Irbesartan is added in the reaction system of Fig. 5 C
Mapping.
Fig. 5 E is the HPLC inspection of cholesterol biosynthesis reaction system after 500nM Irbesartan is added in the reaction system of Fig. 5 C
Mapping.
Fig. 5 F is the HPLC of cholesterol biosynthesis reaction system after 1000nM Irbesartan is added in the reaction system of Fig. 5 C
Detection figure.
Fig. 5 G is the HPLC of cholesterol biosynthesis reaction system after 2000nM Irbesartan is added in the reaction system of Fig. 5 C
Detection figure.
Fig. 5 H is Irbesartan Lowering cholesterol effect IC50 curve graph
Specific embodiment
1 high performance liquid chromatography of embodiment detects cellular level Irbesartan Lowering cholesterol effect
(1) HepG2 cell adding consistency determines
HepG2 cell, is separately added into 1 μM, and 5 μM, 10 μM, 20 μM, 40 μM, 80 μM of Irbesartan, after processing for 24 hours,
Microscopically observation group of cells growing state, final 5 μM of adding consistency for determining Irbesartan.As shown in Figure 1A.
From Figure 1A, it can be seen that with the increase of drug concentration, the quantity of cell is reduced, and physiological status changes.When
When Irbesartan drug concentration is 1 μM, cell growth state is best.Therefore cellular level of the present invention, the dosing of Irbesartan are dense
Preferably 1 μM of degree.
(2) efficient liquid phase condition determines
Using C18 as stationary phase, methanol (chromatographic grade) is used as mobile phase, sets flow velocity as 1.0ml/min, Detection wavelength is
210nm.Detectable concentration is 0.6mg/mL cholesterol standards sample and concentration is 0.6mg/mL desmosterol standard items sample, and gallbladder is solid
The mixed liquor sample of alcohol standard sample and desmosterol standard items 1:1 in mass ratio and with dehydrated alcohol (chromatographic grade) for Vehicle controls
Group.From Figure 1B to Fig. 1 shown in E, the chromatographic peak retention time of cholesterol standards is 34 minutes, the chromatographic peak of desmosterol standard items
Retention time is 24 minutes, and cholesterol standard sample is consistent respectively therewith with the appearance time of desmosterol standard items mixed liquor, because
And it can be detected with above-mentioned condition.
(3) Specification Curve of Increasing
Methanol is mobile phase, makes the standard curve of cholesterol and desmosterol.3mg cholesterol and chain steroid are accurately weighed respectively
Alcohol standard items dilute simultaneously constant volume 0.3mg/ml, 0.4mg/ml, 0.6mg/ml, 0.8mg/ml with dehydrated alcohol (chromatographic grade) respectively,
The standard solution of 1.0mg/ml.By above-mentioned high-efficient liquid phase chromatogram condition measurement (using C18 as stationary phase, methanol (chromatographic grade) conduct
Mobile phase sets flow velocity as 1.0ml/min, Detection wavelength 210nm), applied sample amount is 20 μ L, and same concentration in triplicate, is surveyed
Each peak area out.
As a result respectively chromatographic peak area (A) is in a linear relationship with its with desmosterol concentration (C) for cholesterol.Such as Fig. 1 F institute
Show, using cholesterol or desmosterol concentration as abscissa, standard curve made of being drawn using chromatographic peak area as ordinate is returned
Equation is respectively are as follows: cholesterol y=4001.6x+408.06, R2=0.955, range of linearity 0.4-1.0mg/ml；Desmosterol y=
2345.9x+91.599, R2=0.9969, range of linearity 0.4-1.0mg/ml.
(4) in cell cholesterol level measurement result
The content that cholesterol in different groups of cells is measured using the method for efficient liquid phase (HPLC) ultraviolet detection, is as a result sent out
It is existing, by Irbesartan treated HepG2 cell, and it is provided with one group of positive controls U18666A (known DHCR24
Noncompetitive inhibitor) cell in, intracellular cholesteryl content falls below undetectable very with high performance liquid chromatography
Low degree.As shown in Figure 1 G.As a result it proves that Irbesartan has and inhibits DHCR24 activity, to reduce liver cell cholesterol
The effect of content.
2 cellular cholesterol fluorescence colour of embodiment (Filipin method) examines Irbesartan Lowering cholesterol effect
By in the good HepG2 cell inoculation to cell climbing sheet of growth conditions, Irbesartan is added in cell, is received afterwards for 24 hours
Collect cell, Filipin fluorescent dyeing, with fluorescence microscope fluorescence intensity.Specifically: control group S (+) is cultivated completely
Base, S (-) is without blood nonreactive, positive controls U18666A and Irbesartan group (IRB).Filipin fluorescent dyeing is carried out,
With fluorescence microscope blue-fluorescence intensity, with blue-fluorescence labeled cholesterol, with laser confocal microscope shooting result,
By Fig. 2A it can be seen that, the fluorescence at the boundary cell membrane of cell is stronger, illustrates that the cholesterol level on cell membrane is very high.This
At most it is consistent with the content of generally accepted intracellular cholesteryl with cholesterol on cell membrane.Compared with S (+) and S (-) group, sun
The fluorescence intensity of property control group U18666A and Irbesartan group (IRB) obviously weakens, and illustrates synthesis of the Irbesartan to cholesterol
Inhibiting effect is played, to inhibit the content of intracellular cholesteryl.
Gray value analysis is carried out to each group fluorescent image using Image-J, as a result as shown in Figure 2 B.It can be seen that with S
(+) and S (-) group is compared, and positive controls U18666A and Irbesartan group (IRB) have the variation of extremely significant property, and cholesterol contains
Amount is substantially reduced, and illustrates that Irbesartan has the effect of norcholesterol.
The blood lipid level of 3 Irbesartan of embodiment reduction hyperlipidemia model mouse C57BL/6J mouse
48 C57BL/6J male mices are randomly assigned into 4 groups (n=12), respectively normal diet group, high fat diet pair
According to group, Simvastatin positive controls and Irbesartan group.The normal raising of normal diet group mouse feeding, excess-three group mouse are raised
High lipid food, Simvastatin positive controls (20mg/kg) and Irbesartan group (6mg/kg) while daily gastric infusion are fed, is held
Continuous surrounding.Period replaces drinking water daily, weighs weekly and records weight.After testing four weeks, etherization mouse orbit takes blood,
Mouse is put to death simultaneously, acquires mouse liver and is weighed.The blood of acquisition and 4 DEG C of refrigerators place 30min, and 4 DEG C, 3000rpm/min
It is centrifuged 15min, upper serum is shifted into new EP pipe, is measured TC, TG, LDL-C, HDL-C in blood lipid.Serum Nanjing
Build up kit detection cholesterol in serum, triglycerides, low-density lipoprotein and hdl level variation.As a result such as
Fig. 3 A- Fig. 3 D.ND (Normal diet) is expressed as the mouse of normal diet group, HFD (High-fat/cholesterol
Diet high fat diet control group mouse) is indicated, SM (Simvastatin) is Simvastatin positive controls mouse, IRB
It (Irbesartan) is Irbesartan group mouse.
Fig. 3 A is that Irbesartan reduces total cholesterol level in C57BL/6J hyperlipemia model mice serum, is by Fig. 3 A
It is found that total cholesterol level is aobvious in the mice serum high in fat of Irbesartan stomach-filling processing compared with high fat diet control group mouse
Work property is lowered.
Fig. 3 B is that Irbesartan reduces C57BL/6J hyperlipemia model mice Triglycerides in Serum level；It is by Fig. 3 B
It is found that compared with high fat diet control group mouse, triglyceride levels in the mice serum high in fat of Irbesartan stomach-filling processing
Show same downward trend.
Fig. 3 C is the low-density lipoprotein sterol levels that Irbesartan reduces C57BL/6J hyperlipemia model mice；By scheming
3C is the low-density lipoprotein in the mice serum high in fat of Irbesartan stomach-filling processing it is found that compared with high fat diet control group mouse
White sterol levels decline.
Fig. 3 D is that Irbesartan increases C57BL/6J hyperlipemia model mice serum middle-high density lipoprotein sterol levels；
It is the mice serum middle-high density high in fat of Irbesartan stomach-filling processing it is found that compared with high fat diet control group mouse by Fig. 3 D
Lipoprotein levels rise.
In conclusion above-mentioned the results show Irbesartan can reduce the synthesis of cholesterol, thus lower height-regulating blood
Total cholesterol, triglycerides, the low-density lipoprotein sterol of rouge disease reduce " the bad factor " that can cause cardiovascular disease, together
When increasing high density lipoprotein sterol, be beneficial to alleviate hyperlipemia, mitigate harm caused by it.
4 Irbesartan stomach-filling C57BL/6J mouse liver HE coloration result of embodiment
After Irbesartan stomach-filling 4 weeks, mouse is put to death in etherization, is collected liver and is weighed.C57BL/6 mouse liver half
It is fixed with 4% paraformaldehyde, paraffin embedding, for making animal tissue sections, the slice of dehydration is put into hematoxylin and is contaminated
Color, distilled water elution, hydrochloride alcohol processing, the dyeing of the Yihong 0.5%-1% solution, 95% ethanol postincubation.Dimethylbenzene transparent processing,
Neutral gum mounting saves.Specifically: normal diet group and high fat diet control group and Simvastatin positive controls and E Bei
4 groups of mouse of Sha Tan group are put to death after raising four weeks, its liver organization is taken to carry out paraffin section, HE dyeing observation mouse liver cell
Pathological change.As a result such as Fig. 4.
As seen from Figure 4, it from left to right respectively indicates normal diet group mouse, high fat diet control group mouse, pungent cut down
Four groups of mouse liver slices of statin positive controls and Irbesartan group.Optical microphotograph sem observation is the results show that and blank control
The normal liver tissue of group is compared, and high fat diet control group mouse liver histological appearance is that lipid is assembled in cell, and liver is thin
Born of the same parents become larger, while lipid intersperses among in endochylema, and nucleus is extruded into edge, show apparent vacuolation, it was demonstrated that high lipid food
Raise mouse modeling success.In the experimental group of hyperlipemia model mouse, compared with Simvastatin positive controls, stomach-filling strategic point shellfish
Sha Tan group mouse liver cell volume becomes smaller, and lipid vacuolation is reduced, and illustrates that Irbesartan can make rouge in mouse liver high in fat
Matter is reduced.
5 high performance liquid chromatography of embodiment (HPLC) detects levels in vitro Irbesartan and inhibits the reduction of 24- dehydrocholesterol
Enzyme is to inhibit the effect of cholesterol biosynthesis
Experiment is divided into three groups, first group, contains cholesterol biosynthesis by the outer cholesterol biosynthesis reaction system of construct such as table 1
Reaction system related substances such as coenzyme, confactor, reducing agent and buffer etc., second group contains cholesterol biosynthesis system correlation
Substance and cholesterol precursor substance, that is, reaction substrate desmosterol, third group, containing cholesterol biosynthesis reaction system related substances,
Substrate desmosterol and catalyzing enzyme 24- dehydrocholesterol reductase (DHCR24).Three groups of experiment reaction systems are placed 37 degree instead
Total lipid extraction is carried out after answering 4 hours, carries out HPLC later, detects the content of cholesterol in reaction system, it is solid to assess gallbladder
Alcohol synthesizes situation.Such as Fig. 5 A- Fig. 5 C, it may be seen that success synthetic cholesterol.Specifically, Fig. 5 A, it is shown that first group
The HPLC test map of reaction system, without apparent sample peak, because not containing cholesterol or desmosterol in the system；And
Fig. 5 B is shown as second group of reaction system, apparent peak occurs in 24 minutes or so times, through the standard items with desmosterol
Map (Fig. 1 C) compares it is found that the peak is the peak of desmosterol；Fig. 5 C shows to be third group reaction system, urges containing DHCR24
In the system for changing enzyme, 24 minutes or so desmosterol peaks disappear after completion of the reaction, the cholesterol peak at 34 minutes or so places, warp occur
Compared with the map (Figure 1B) of the standard items of cholesterol it is found that at 34 minutes occur be cholesterol characteristic peak, it was demonstrated that gallbladder is solid
The building success of the external synthetic reaction system of alcohol.
The external cholesterol biosynthesis system of table 1
Next Irbesartan is divided into various concentration (0nM, 200nM, 500nM, 1000nM, 2000nM) and is added afterwards by us
Into cholesterol biosynthesis system, various concentration Irbesartan Lowering cholesterol effect is detected, as shown in Fig. 5 C- Fig. 5 G.According to reaction
The content of the product cholesterol generated in system, according to formula:
Calculate the inhibition of Irbesartan when Irbesartan concentration is respectively 0nM, 200nM, 500nM, 1000nM, 2000nM
Rate is respectively 0%, 29%, 35%, 75%, 100%.It can be calculated according to inhibiting rate and different Irbesartan drug concentrations
The effective dose 50 IC of Irbesartan inhibition DHCR24 enzyme50(half maximal inhibitory concentration).Such as
Fig. 5 H is drug concentration-cholesterol biosynthesis inhibition percentage regression curve that Irbesartan inhibits DHCR24 enzymatic activity,
Show that regression equation is Y=-2E-07X2+ 0.0009X+0.0329, R2It is 0.9752.Strategic point is calculated when inhibiting rate is 50%
Bei Shatan norcholesterol IC50Value is 604.08nM.
Claims (7)
1. Irbesartan is applied alone or is combined the application in terms of preparing blood lipid-lowering medicine with other drugs.
2. application according to claim 1, which is characterized in that Irbesartan is applied alone or is combined with other drugs and controls in preparation
Treat the application in the hyperlipemia drug of complicated hypertension.
3. application according to claim 1 or 2, which is characterized in that Irbesartan is in preparing cholesterol lowering drug object
Using.
4. application according to claim 3, which is characterized in that Irbesartan is by inhibiting the synthesis of cholesterol to reduce cell
The content of inner cholesterol.
5. application according to claim 1, which is characterized in that Irbesartan is 1~80 μ in the dosage of cellular level
M。
6. application according to claim 5, which is characterized in that Irbesartan is 5 μM in the dosage of cellular level.
7. application according to claim 1, which is characterized in that in mouse animal experiment level, the dosing of Irbesartan is dense
Degree is 6mg/kg.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1893946A (en) * | 2003-10-24 | 2007-01-10 | 赛诺菲-安万特 | Use of a pyrazole derivative for preparing medicaments for the prevention and the treatment of dyslipidemia and illnesses associated with dyslipidemia and/or obesity |
| CN101590240A (en) * | 2008-05-30 | 2009-12-02 | 北京奥萨医药研究中心有限公司 | The compositions and the purposes that contain Angiotensin, Ta Ting and folic acid |
| CN104602678A (en) * | 2012-08-31 | 2015-05-06 | 韩美药品株式会社 | Pharmaceutical composite capsule formulation comprising irbesartan and HMG-COA reductase inhibitor |
-
2019
- 2019-05-10 CN CN201910387452.2A patent/CN110237070A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1893946A (en) * | 2003-10-24 | 2007-01-10 | 赛诺菲-安万特 | Use of a pyrazole derivative for preparing medicaments for the prevention and the treatment of dyslipidemia and illnesses associated with dyslipidemia and/or obesity |
| CN101590240A (en) * | 2008-05-30 | 2009-12-02 | 北京奥萨医药研究中心有限公司 | The compositions and the purposes that contain Angiotensin, Ta Ting and folic acid |
| CN104602678A (en) * | 2012-08-31 | 2015-05-06 | 韩美药品株式会社 | Pharmaceutical composite capsule formulation comprising irbesartan and HMG-COA reductase inhibitor |
Non-Patent Citations (1)
| Title |
|---|
| JUAN ZHONG等: "Irbesartan ameliorates hyperlipidemia and liver steatosis in type 2 diabetic db/db mice via stimulating PPAR-γ, AMPK /Akt/mTOR signaling and autophagy", 《INTERNATIONAL IMMUNOPHARMACOLOGY》 * |
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Application publication date: 20190917 |