CN109966298A - Tolvaptan is preparing the application in blood lipid-lowering medicine - Google Patents
Tolvaptan is preparing the application in blood lipid-lowering medicine Download PDFInfo
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- CN109966298A CN109966298A CN201910388124.4A CN201910388124A CN109966298A CN 109966298 A CN109966298 A CN 109966298A CN 201910388124 A CN201910388124 A CN 201910388124A CN 109966298 A CN109966298 A CN 109966298A
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- tolvaptan
- cholesterol
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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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Abstract
The invention discloses tolvaptans to prepare the application in blood lipid-lowering medicine.The present invention has found that tolvaptan can play a role in terms of reducing blood lipid, belong to old medicine and newly use in studying norcholesterol.Present invention demonstrates that tolvaptan 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 tolvaptan has important application value and meaning in terms of reducing blood lipid.
Description
Technical field
The invention belongs to medicinal application fields, are specifically related to new opplication of the old medicine tolvaptan 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.It is clinical at present generally to use Statins cholesterol-lowering drug.But the effect of statins
Mechanism is the enzyme HMG CoA (HMG-CoA) by the Reverse transcriptase Biosynthesis of cholesterol process initial stage
Reductase 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.
Tolvaptan (English name: Tolvaptan), structure are such as the drugs for treating hyponatremia, it is shown in (I)
The active antagonist of vasopressing (antidiuretic hormone [ADH]) 2 receptors.It can be dense by increasing sodium ion in blood plasma
Degree, the ability of enhancing kidney processing water, helps extra moisture to be discharged from urine.Tolvaptan can also be treated due to ADH simultaneously
It secretes improper caused blood volume to increase, and the problems such as the raising of the blood volume as caused by cirrhosis and congestive heart failure.
(I), tolvaptan (Tolvaptan), CAS:150683-30-0
In the past few years, existing clinical test, which demonstrates tolvaptan, can treat polycystic kidney disease.Polycystic kidney disease is
A kind of autosomal dominant disorder, which is polycystic kindey intracellular loops adenosine phosphate (cAMP) accumulation, and passes through stimulation cyst fluid point
It secretes and promotes cysts grown with lining cell hyperplasia.And tolvaptan can inhibit cAMP generation and build up so that it is aobvious to treat autosome
Property polycystic kidney disease (ADPKD).But tolvaptan treatment polycystic kidney disease long-term effectiveness still have it is to be determined.
Report is studied disclosed in lipid aspects without any can reduce about tolvaptan so far.
Summary of the invention
Based on the above issues, the present invention provides a kind of new applications of tolvaptan --- the application in terms of reducing blood lipid.
The present invention has found that tolvaptan can play a role in terms of reducing blood lipid, belong to old medicine and newly use in studying norcholesterol.
The technical solution adopted by the present invention is that: tolvaptan is applied alone as effective component or combines with other blood lipid-lowering medicines
Preparing the application in blood lipid-lowering medicine.
Further, tolvaptan is by inhibiting DHCR24 activity to reduce cellular cholesterol content.
Further, tolvaptan is by inhibiting the synthesis of cholesterol to reduce the content of intracellular cholesteryl.
Further, in cellular level, the adding consistency of tolvaptan is 1~80 μM.Further, in cellular water
Flat, the adding consistency of tolvaptan is 1 μM.
Further, in mouse animal experiment level, the adding consistency of tolvaptan is preferably 1mg/kg.
The beneficial effects of the present invention are:
1, the present invention has found that tolvaptan can reduce cholesterol level in studying norcholesterol, in terms of reducing blood lipid
It plays a role.Therefore, tolvaptan can be used as the active drug of reducing blood lipid, for treating hyperlipemia, belongs to old medicine and newly uses,
The drug has important application value and meaning in terms of reducing blood lipid.When concrete application, can directly using tolvaptan as
Therapeutic agent is for treating hyperlipidemia.
2, present invention demonstrates that, tolvaptan 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 tolvaptan applies valence with important in terms of reducing blood lipid
Value and meaning.
3, the present invention is newly used by old medicine, has done drug study to the function of norcholesterol, is researched and developed for new drug for lowering cholesterol
Experiment basis is provided, Lowering cholesterol effect and prevention cholesterol level mostly bring disease are met.
Detailed description of the invention
Figure 1A is that cellular level tolvaptan 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 that the map desmosterol appearance time of desmosterol and cholesterol standards mixed liquor (1:1) is 24min, and gallbladder is solid
Alcohol appearance time is 34min.
Fig. 1 E is that dehydrated alcohol figure is general.
Fig. 1 F is the standard curve and equation of linear regression of cholesterol standards Yu desmosterol standard items;Wherein
Desmosterol is desmosterol;Cholesterol is cholesterol.
Fig. 1 G is that per unit quantity intracellular cholesteryl content after tolvaptan 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 tolvaptan 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 tolvaptan norcholesterol
Fluorescence gray value analysis chart;Wherein, filipin dyeing gray value ratio significance analysis n=30mean ± SD, * * *: P <
0.001vs.S(+),###:P<0.001vs.S(-)。
Fig. 3 A is that tolvaptan reduces C57BL/6J hyperlipemia model mice Triglycerides in Serum level;Wherein, n=
12mean ± SD, *: p < 0.05vs.HFD ND (Normal Diet) are normal diet group;HFD (High Fat Diet) is height
Rouge diet group;HFD+SM (Simvastatin) is positive control Simvastatin group;HFD+TOL (Tolvaptan) is tolvaptan
Medicine group.
Fig. 3 B is the low-density lipoprotein sterol levels that tolvaptan reduces C57BL/6J hyperlipemia model mice;Its
In, n=12mean ± SD, *: p < 0.05vs.HFD ND (Normal Diet) are normal diet group;HFD(High Fat
It Diet) is high fat diet group;HFD+SM (Simvastatin) is positive control Simvastatin group;HFD+TOL(Tolvaptan)
For tolvaptan medicine group.
Fig. 3 C is that tolvaptan increases C57BL/6J hyperlipemia model mice serum middle-high density lipoprotein sterol levels;
Wherein, n=12mean ± SD, *: p < 0.05vs.HFD ND (Normal Diet) are normal diet group;HFD(High Fat
It Diet) is high fat diet group;HFD+SM (Simvastatin) is positive control Simvastatin group;HFD+TOL(Tolvaptan)
For tolvaptan medicine group.
Fig. 4 is the immuning tissue that tolvaptan improves the liver organization lipid vacuolation of C57BL/6J hyperlipemia model mice
Change as a result, ND (Normal Diet) is normal diet group;HFD (High Fat Diet) is high fat diet group;HFD+SM
It (Simvastatin) is positive control Simvastatin group;HFD+TOL (Tolvaptan) is tolvaptan medicine group.
Specific embodiment
1 high performance liquid chromatography of embodiment detects cellular level tolvaptan Lowering cholesterol effect
(1) HepG2 cell adding consistency determines
Method: in HepG2 cell, it is separately added into 1 μM, 5 μM, 10 μM, 20 μM, 40 μM, 80 μM of tolvaptan is handled
After for 24 hours, group of cells growing state is observed under the microscope, as a result 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 tolvaptan drug concentration is 1 μM, cell growth state is best.Therefore cellular level of the present invention, the dosing of tolvaptan are dense
Preferably 1 μM of degree.
(2) efficient liquid phase condition determines
C18 is stationary phase, and methanol (chromatographic grade) is used as mobile phase, flow velocity 1.0ml/min, Detection wavelength 210nm.Point
Other cholesterol detection standard sample, desmosterol standard items sample, cholesterol standard sample and desmosterol standard items 1:1 in mass ratio
Mixed liquor sample and dehydrated alcohol (chromatographic grade) vehicle control group.As a result as shown in Figure 1B-Fig. 1 E.
By Figure 1B as it can be seen that the chromatographic peak retention time of cholesterol standards is 34min, by Fig. 1 C as it can be seen that desmosterol standard
The chromatographic peak retention time of product is 24min, by the appearance of Fig. 1 D visible cholesterol standard sample and desmosterol standard items mixed liquor
Time is consistent with Figure 1B and Fig. 1 C respectively, thus available above-mentioned condition is detected.
(3) Specification Curve of Increasing
Method: methanol is mobile phase, makes the standard curve of cholesterol and desmosterol.3mg cholesterol is accurately weighed respectively
With desmosterol standard items, 0.3mg/ml, 0.4mg/ml, 0.6mg/ml are diluted and are settled to dehydrated alcohol (chromatographic grade),
The standard solution of 0.8mg/ml, 1.0mg/ml.(C18 is stationary phase, methanol to the high-efficient liquid phase chromatogram condition determined by above-mentioned (two)
(chromatographic grade) is used as mobile phase, flow velocity 1.0ml/min, Detection wavelength 210nm.) measurement, applied sample amount is 20 μ l, same dense
Degree in triplicate, measures each peak area.
As shown in fig. 1F, respectively chromatographic peak area (A) is in a linear relationship with its with desmosterol concentration (C) for cholesterol.
Using cholesterol or desmosterol concentration as abscissa, standard curve made of being drawn using chromatographic peak area as ordinate.
As shown in fig. 1F, regression equation is respectively are as follows: cholesterol y1=4001.6x+408.06, R2=0.955, range of linearity 0.4-
1.0mg/ml;Desmosterol y2=2345.9x+91.599, R2=0.9969, range of linearity 0.4-1.0mg/ml.
(4) in cell cholesterol level measurement result
The method of efficient liquid phase (HPLC) ultraviolet detection, as a result, it has been found that, HepG2 cell after tolvaptan is handled, with
And it is provided with one group of positive controls U18666A (known DHCR24 noncompetitive inhibitor), intracellular cholesterol level
It falls below with the undetectable very low degree of high performance liquid chromatography.
As shown in Figure 1 G.As a result it proves that tolvaptan has and inhibits DHCR24 activity, to reduce cellular cholesterol content
The effect of.This result also demonstrates tolvaptan and has lowered HepG2 intracellular cholesteryl level.
2 cellular cholesterol fluorescence colour of embodiment (Filipin method) examines tolvaptan Lowering cholesterol effect
By in the good HepG2 cell inoculation to cell climbing sheet of growth conditions, tolvaptan 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 tolvaptan (TOL) group.Filipin fluorescent dyeing is carried out,
It as a result can be seen by Fig. 2A with fluorescence microscope blue-fluorescence intensity with blue-fluorescence labeled cholesterol, be copolymerized for laser
Focusing microscope shooting result figure, the fluorescence at the boundary cell membrane of cell is stronger, illustrates that the cholesterol level on cell membrane is very high.
This is also at most consistent with the content of generally accepted intracellular cholesteryl with cholesterol on cell membrane.With S (+) and S (-) group phase
Than the fluorescence intensity of positive controls U18666A and tolvaptan group obviously weakens, and illustrates synthesis of the tolvaptan 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 tolvaptan group have the variation of extremely significant property, and cholesterol level is bright
It is aobvious to reduce, illustrate that tolvaptan has the effect of norcholesterol.
3 tolvaptan of embodiment reduces C57BL/6J lipid of mice
48 C57BL/6J male mices are randomly assigned into 4 groups (n=12), respectively normal diet controls group, drink high in fat
Eat solvent control group, positive drug Simvastatin control group and tolvaptan medicine group.Normal diet controls group mouse feeds just
Often raising, excess-three group mouse feed high lipid food, Simvastatin control group (20mg/kg) and tolvaptan medicine group (1mg/
Kg) gastric infusion respectively daily simultaneously, continues surrounding.Period replaces drinking water daily, weighs weekly and records weight.Experiment four
Zhou Hou, etherization mouse orbit takes blood, while putting to death mouse, acquires mouse liver and weighs.The blood of acquisition is in 4 DEG C of refrigerators
Place 30min, 4 DEG C, 3000rpm/min be centrifuged 15min, shift upper serum into new EP pipe, be measured TG in blood lipid,
LDL-C and HDL-C.Serum builds up kit detection Triglycerides in Serum, low-density lipoprotein and high density lipoprotein level with Nanjing
White level variation.Specifically: by raising C57BL/6J mouse high lipid food, high blood lipid model is established, tolvaptan fills daily
Stomach handles mouse, and serum is collected after four weeks, and it is solid to detect triglycerides, low-density lipoprotein sterol and high-density lipoprotein in blood
Alcohol index.As a result such as Fig. 3 A- Fig. 3 C.ND (Normal diet) is expressed as the mouse of normal diet controls group, HFD (High-
Fat/cholesterol diet) indicate high fat diet solvent control group mouse, SM (Simvastatin), which is that positive drug is pungent, to be cut down
Statin control group mice, TOL are tolvaptan medicine group mouse.
Fig. 3 A is that tolvaptan reduces C57BL/6J hyperlipemia model mice Triglycerides in Serum (TG) level, by scheming
3A with high fat diet solvent control group mouse it is found that compare, triglyceride levels in tolvaptan medicine group mice serum high in fat
Also same downward trend is showed.
Fig. 3 B is low-density lipoprotein sterol (LDL-C) water that tolvaptan reduces C57BL/6J hyperlipemia model mice
It is flat, by Fig. 3 B it is found that being compared with high fat diet solvent control group mouse, low-density in tolvaptan medicine group mice serum high in fat
The horizontal down-regulation of lipoprotein sterol.
Fig. 3 C is that tolvaptan increases C57BL/6J hyperlipemia model mice serum middle-high density lipoprotein sterol (HDL-
C) horizontal, it is high in tolvaptan medicine group mice serum high in fat by Fig. 3 C it is found that being compared with high fat diet solvent control group mouse
Density lipoprotein levels rise.
The triglycerides of hyperlipemia, low-density lipoprotein can be reduced by demonstrating tolvaptan by Fig. 3 A- Fig. 3 C result
Sterol reduces " the bad factor " that can cause cardiovascular disease, raises simultaneously high-density lipoprotein sterol, be beneficial to alleviate high blood
Rouge disease mitigates harm caused by it.
4 tolvaptan stomach-filling C57BL/6J mouse liver HE coloration result of embodiment
After tolvaptan 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 group (ND) and solvent control group high in fat (HFD) and the Simvastatin positive high in fat are right
It according to 4 groups of mouse of group (HFD+SM) and tolvaptan group high in fat (HFD+TOL), is put to death after raising four weeks, its liver organization is taken to carry out
Paraffin section, the pathological change of HE dyeing observation mouse liver cell.As a result such as Fig. 4.
As seen from Figure 4, from left to right respectively indicate the mouse of normal diet, hyperlipidemia model solvent control group mouse,
Four groups of mouse liver slices of Simvastatin positive controls and tolvaptan group.Optical microphotograph sem observation is the results show that and blank
The normal liver tissue of control group is compared, and mouse liver histological appearance high in fat is that lipid is assembled in cell, and liver cell becomes larger,
Lipid intersperses among in endochylema simultaneously, and nucleus is extruded into edge, shows apparent vacuolation, it was demonstrated that high lipid food raises mouse
Modeling success.In the experimental group of hyperlipemia model mouse, compared with Simvastatin positive controls, stomach-filling tolvaptan group is small
Mouse liver cell volume becomes smaller, and lipid vacuolation is reduced, and illustrates that tolvaptan can be such that lipid in mouse liver high in fat reduces.
Claims (6)
1. tolvaptan, which is applied alone as effective component or combines with other blood lipid-lowering medicines, is preparing the application in blood lipid-lowering medicine.
2. application according to claim 1, which is characterized in that tolvaptan is by inhibiting DHCR24 activity to reduce cell gallbladder
Sterol content.
3. application according to claim 1, which is characterized in that tolvaptan is by inhibiting the synthesis of cholesterol to reduce cell
The content of inner cholesterol.
4. application according to claim 1, which is characterized in that in cellular level, the adding consistency of tolvaptan is 1~80
μM。
5. application according to claim 4, which is characterized in that in cellular level, the adding consistency of tolvaptan is 1 μM.
6. application according to claim 1, which is characterized in that in mouse animal experiment level, the dosing of tolvaptan is dense
Degree is 1mg/kg.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004089416A2 (en) * | 2003-04-11 | 2004-10-21 | Novo Nordisk A/S | Combination of an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and an antihypertensive agent |
US20190076425A1 (en) * | 2017-05-16 | 2019-03-14 | Bow River LLC | Methods of treatment with cyp3a4 substrate drugs |
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2019
- 2019-05-10 CN CN201910388124.4A patent/CN109966298A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004089416A2 (en) * | 2003-04-11 | 2004-10-21 | Novo Nordisk A/S | Combination of an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and an antihypertensive agent |
US20190076425A1 (en) * | 2017-05-16 | 2019-03-14 | Bow River LLC | Methods of treatment with cyp3a4 substrate drugs |
Non-Patent Citations (1)
Title |
---|
TADASHI OKADA等: "Tolvaptan, a selective oral vasopression V2 receptor antagonist, ameliorates podocyte injury in puromycin aminonucleoside nephritic rats", 《CLIN EXP NEPHROL》 * |
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Application publication date: 20190705 |