CN107737108A - A kind of combination of oral medication for treating Pathogenesis of Post-infarction Ventricular Remodeling - Google Patents
A kind of combination of oral medication for treating Pathogenesis of Post-infarction Ventricular Remodeling Download PDFInfo
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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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
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Abstract
The invention belongs to field of medicaments, more particularly to a kind of combination of oral medication for treating Pathogenesis of Post-infarction Ventricular Remodeling.The combination of oral medication of the treatment Pathogenesis of Post-infarction Ventricular Remodeling is by pharmaceutically acceptable pharmaceutic adjuvant and Atorvastatin, disulfiram, neoquipenyl, roller is smooth is made；The wherein smooth weight part ratio of Atorvastatin, disulfiram, neoquipenyl, roller is：The parts by weight of Atorvastatin 53~97, the parts by weight of disulfiram 8~14, the parts by weight of neoquipenyl 5~11, smooth 3~7 parts by weight of roller.Composition middle roller is smooth to suppress the Cardiovascular Toxicity effect of disulfiram, neoquipenyl, and eliminates disulfiram and drug effect offseting phenomenon when neoquipenyl is used in combination.The smooth prescription of Atorvastatin, disulfiram, neoquipenyl, roller has Ventricular Remodeling effect and security after good anti-infarction.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of oral pharmaceutical compositions for treating Pathogenesis of Post-infarction Ventricular Remodeling
Thing.
Background technology
Pathogenesis of Post-infarction Ventricular Remodeling refers to changing for the structure and form of ventricular infarctions area and non-infarcted region after myocardial infarction
Become.Its typical performance is ventricle decompensation plumpness；Ventricular weight, volume increase and morphologic change, can cause ventricular pump blood
Hypofunction, and develop into heart failure.The fundamental mechanism for causing heart failure occurrence and development is Ventricular Remodeling.The symptom is
Change after the continuation after myocardial infarction, progressive, its order of severity decides Cardiac Function of Patients situation and prognosis.Along with
The raising of the myocardial infarction incidence of disease, Pathogenesis of Post-infarction Ventricular Remodeling, which also turns into, influences patient's heart function threat public's life security
One of Main Cardiovascular Disease.In past 10 years, due to the rapid progress of coronary heart disease treatment, the death of myocardial infarction
Rate have dropped close to 30%；But the death rate of heart failure is still higher, heart failure admission rate only accounts for same period cardiovascular disease
20%, but the death rate accounts for 40%.
Definite pathogenesis on Pathogenesis of Post-infarction Ventricular Remodeling it is not immediately clear.Current viewpoint thinks, is immunized
Mechanism may take part in the occurrence and development of Pathogenesis of Post-infarction Ventricular Remodeling.At present in patients with heart failure of coronary heart disease serum
In detect anti-myosin heavy chain antibody, and the anti-myosin heavy chain antibody positive patient death rate, wall motion weaken journey
Degree and aneurysm formation rate are all remarkably higher than negative antibody group, show that autoimmune response may be with Pathogenesis of Post-infarction Ventricular Remodeling
It is relevant（Liao Yuhua, the amynologic mechanism medical science of the new viewpoint of Ching Cheong's Ventricular Remodelings --- Pathogenesis of Post-infarction Ventricular Remodeling are ground
Study carefully magazine, 2004,33 (10):6-8.）.The high expression of Pro-inflammatory mediator can be accompanied by after myocardial infarction, including
TNF-α, IL-1, IL-6 etc., and with Pathogenesis of Post-infarction Ventricular Remodeling positive correlation, illustrate that inflammatory cytokine has also assisted in myocardium stalk
The after death occurrence and development of Ventricular Remodeling.
It is main at present to carry out early stage Reperfu- sion, angiotensins using to patient after myocardial infarction to prevent Ventricular Remodeling
The treatment such as converting enzyme inhibitor and beta-blocker is to reduce infarct size, improve revascularization, to mitigate Ventricular Remodeling, the heart
Room remodeling process still can not be effectively blocked and reverse.One is had been achieved with present in terms of the treatment of Pathogenesis of Post-infarction Ventricular Remodeling
Fixed achievement in research.
Pathogenesis of Post-infarction Ventricular Remodeling can be reversed in studies have shown that bone marrow cell transplantation（Height is even as bone marrow cell transplantations are inverse
Turn the progress Navy General Hospital journals .2014,17 of Pathogenesis of Post-infarction Ventricular Remodeling（1）：31-36.）.Granular leukocyte colony
Stimulating factor can stimulate the cell factor of a variety of stem cells in marrow to produce, and its security has obtained clinical test tentative confirmation.
But final conclusion there is no to the effect of Pathogenesis of Post-infarction Ventricular Remodeling（Yun Ji examples summarize, Li Yuming examine and revise granular leukocyte colonies stimulate because
Son treatment Pathogenesis of Post-infarction Ventricular Remodeling progress angiocardiologies progress .2008,29（3）:441-444.）.Animal
Experiment display, drug for hypertension Losartan have certain inhibitory action to Pathogenesis of Post-infarction Ventricular Remodeling, are possibly used for the heart
The treatment of flesh remodeling（Cui Zhenyu, Han Suxia, Feng Lei, Dong Xiaoguang, Guo Liping, often building plum Losartans influences rat myocardial infarction model
The Mechanism Study China circulation magazine of Ventricular Remodeling afterwards, 2014,29（8）：629-633.）.In zoopery, Chinese medicine leads to the heart
Network Ultramicro-powder, red stilbene protect heart side also to having certain inhibitory action to Pathogenesis of Post-infarction Ventricular Remodeling（You Minsheng, Wen Jinkun,
The influence of Han Mei Tongxinluo Superfine Powder on Rats Pathogenesis of Post-infarction Ventricular Remodeling and its pathology and myocardial mitochondria ultra microstructure
Aged in China magazine .2009,29（6）：661-664.）.
As fully visible, it is unclear for the mechanism of Pathogenesis of Post-infarction Ventricular Remodeling at present, clinically also lack of targeted
Medicine.
The content of the invention
For above-mentioned prior art, it is an object of the invention to provide a kind of mouth for treating treatment Pathogenesis of Post-infarction Ventricular Remodeling
Medication compositions.To achieve the above object, the technical solution adopted by the present invention is as follows：
A kind of combination of oral medication for treating Pathogenesis of Post-infarction Ventricular Remodeling, containing pharmaceutically acceptable pharmaceutic adjuvant and
Atorvastatin.
Preferably, the combination of oral medication of the treatment Pathogenesis of Post-infarction Ventricular Remodeling is by pharmaceutically acceptable medicine
With auxiliary material and Atorvastatin, disulfiram, neoquipenyl, roller are smooth is made；The treatment Pathogenesis of Post-infarction Ventricular Remodeling
The smooth weight part ratio of Atorvastatin, disulfiram, neoquipenyl, roller is in combination of oral medication：Atorvastatin 53
~97 parts by weight, the parts by weight of disulfiram 8~14, the parts by weight of neoquipenyl 5~11, smooth 3~7 parts by weight of roller.
Preferably, it is described treatment Pathogenesis of Post-infarction Ventricular Remodeling combination of oral medication in Atorvastatin, disulfiram,
The smooth weight part ratio of neoquipenyl, roller is：The parts by weight of Atorvastatin 61, the parts by weight of disulfiram 11, the weight of neoquipenyl 7
Part, smooth 5 parts by weight of roller.
Preferably, it is described treatment Pathogenesis of Post-infarction Ventricular Remodeling combination of oral medication in Atorvastatin, disulfiram,
The smooth weight part ratio of neoquipenyl, roller is：The parts by weight of Atorvastatin 75, the parts by weight of disulfiram 9, the weight of neoquipenyl 6
Part, smooth 4 parts by weight of roller.
Preferably, it is described treatment Pathogenesis of Post-infarction Ventricular Remodeling combination of oral medication in Atorvastatin, disulfiram,
The smooth weight part ratio of neoquipenyl, roller is：The parts by weight of Atorvastatin 83, the parts by weight of disulfiram 12, the weight of neoquipenyl 9
Part, smooth 6 parts by weight of roller.
Preferably, it is described treatment Pathogenesis of Post-infarction Ventricular Remodeling combination of oral medication in Atorvastatin, disulfiram,
The smooth weight part ratio of neoquipenyl, roller is：The parts by weight of Atorvastatin 95, the parts by weight of disulfiram 13, the weight of neoquipenyl 10
Measure part, smooth 6 parts by weight of roller.
Preferably, the formulation of the combination of oral medication of above-mentioned treatment Pathogenesis of Post-infarction Ventricular Remodeling is granule；It is described
Treat the combination of oral medication of Pathogenesis of Post-infarction Ventricular Remodeling human body be administered daily dosage be calculated as 0.4 with disulfiram~
0.8mg/kg body weight.
Preferably, the pharmaceutic adjuvant of above-mentioned granule is by lactose, microcrystalline cellulose, PVPP, magnesium stearate, poly- dimension
Ketone K30 and water composition.
Preferably, the dosage of lactose is 1.8~2.3 times of Atorvastatin weight in above-mentioned granule；Microcrystalline cellulose
Dosage be 1.0~1.3 times of Atorvastatin weight；The dosage of PVPP for Atorvastatin weight 0.11~
0.14 times；The dosage of magnesium stearate is 0.010~0.014 times of Atorvastatin weight；The dosage of PVP K30 is cut down for atropic
0.16~0.19 times of statin weight；The dosage of water is 32.1~32.8 times of PVP K30 weight.
Preferably, the dosage of lactose is 2.2 times of Atorvastatin weight in above-mentioned granule；Microcrystalline cellulose dosage is
1.2 times of Atorvastatin weight；The dosage of PVPP is 0.13 times of Atorvastatin weight；The dosage of magnesium stearate
For 0.012 times of Atorvastatin weight；The dosage of PVP K30 is 0.18 times of Atorvastatin weight；The dosage of water is
32.5 times of PVP K30 weight.
Wherein Atorvastatin, the entitled Atorvastatin of English.
Disulfiram, the entitled Disulfiram of English, No. CAS is 97-77-8, and the medicine, which has gone through to list, is used for abstinence from alcohol.It is double
Sulphur logical sequence is commercially available.
Neoquipenyl, the entitled Primaquine of English, No. CAS is 90-34-6, belongs to oxidative drug, the medicine is criticized
Standard lists the treatment for malaria.Neoquipenyl is commercially available.
Roller is smooth, and the entitled Rolapitant of English, No. CAS is 552292-08-7, and the medicine has gone through listing for pressing down
Slightly vomitted caused by cancer chemotherapeutic drug processed.
Lactose is 4-O- β-D- galactopyranosyls glycosyl-D-Glucose monohydrate, belongs to common medicinal supplementary material, as filling
Agent and flavouring etc., its standard are shown in Chinese Pharmacopoeia version four in 2015.
Microcrystalline cellulose, for alpha-cellulose made from the fiber pulp of cellulosic plant, partly solved in the presence of inorganic acid
It is poly-, purify and obtain.Belong to common medicinal supplementary material, as filler and disintegrant etc., its standard is shown in Chinese Pharmacopoeia version four in 2015
Portion.
PVPP, it is the synthesizing cross-linked homopolymer not soluble in water of N-ethene -2-Pyrrolidone, belongs to common medicine
With auxiliary material, as disintegrant and filler etc., its standard is shown in Chinese Pharmacopoeia version four in 2015.
PVP K30, vinylpyrrolidone monomer is generated under elevated pressure for pyrrolidones and ethene, in catalyst action
It is lower to polymerize obtained 1 vinyl 2 pyrrolidone homopolymer, belong to common medicinal supplementary material, as binder and cosolvent etc.,
Its standard is shown in Chinese Pharmacopoeia version four in 2015.
It was found by the inventors of the present invention that Ventricular Remodeling acts on after Atorvastatin has certain anti-infarction；Double sulphur
Ventricular Remodeling acts on after logical sequence and neoquipenyl also have weaker anti-infarction, two when disulfiram and neoquipenyl are used in combination
There is obvious offseting phenomenon in person's drug effect, and Cardiovascular Toxicity be present during the exclusive use of disulfiram, neoquipenyl.Roller is smooth not
Ventricular Remodeling acts on after seeing anti-infarction, but can suppress the Cardiovascular Toxicity effect of disulfiram, neoquipenyl, and eliminates double sulphur
Drug effect offseting phenomenon when logical sequence and neoquipenyl are used in combination, improve ventricle weight after the anti-infarction of disulfiram and neoquipenyl
Modeling acts on, and plays Synergy and attenuation effect.The smooth prescription of Atorvastatin, disulfiram, neoquipenyl, roller has good resist
Pathogenesis of Post-infarction Ventricular Remodeling acts on and security.
Embodiment
The present invention is further explained with reference to embodiment.It should be appreciated that following examples are only used for solving
The present invention is released, rather than is limited the scope of the invention.
Embodiment 1 treats granule and its preparation of Pathogenesis of Post-infarction Ventricular Remodeling
Preparation method：
A：Take Atorvastatin, disulfiram, neoquipenyl, roller are smooth to cross 100 mesh sieves respectively, be well mixed.
B：Take lactose, microcrystalline cellulose, PVPP to cross 100 mesh sieves respectively, be well mixed.The wherein use of lactose
Measure as 2.2 times of Atorvastatin weight；Microcrystalline cellulose dosage is 1.2 times of Atorvastatin weight；The poly- dimension of crosslinking
The dosage of ketone is 0.13 times of Atorvastatin weight.
C：Powder obtained by step A and step B is well mixed.
D：Take PVP K30 to add water to stir evenly, liquid dispersion system is made.Wherein the dosage of PVP K30 is that atropic cuts down him
0.18 times of spit of fland weight；The dosage of water is 32.5 times of PVP K30 weight.
E ：Liquid dispersion system obtained by step D is added into powder obtained by step C, pelletizes, dries, dry particl crosses 20 mesh sieves.
F：Magnesium stearate is added into dry particle obtained by step E, is well mixed, crushed 50 mesh sieves point after tabletting again
Dress.Wherein the dosage of magnesium stearate is 0.012 times of Atorvastatin weight.
Embodiment 2 treats granule and its preparation of Pathogenesis of Post-infarction Ventricular Remodeling
Preparation method：
A：Take Atorvastatin, disulfiram, neoquipenyl, roller are smooth to cross 100 mesh sieves respectively, be well mixed.
B：Take lactose, microcrystalline cellulose, PVPP to cross 100 mesh sieves respectively, be well mixed.The wherein use of lactose
Measure as 2.2 times of Atorvastatin weight；Microcrystalline cellulose dosage is 1.2 times of Atorvastatin weight；The poly- dimension of crosslinking
The dosage of ketone is 0.13 times of Atorvastatin weight.
C：Powder obtained by step A and step B is well mixed.
D：Take PVP K30 to add water to stir evenly, liquid dispersion system is made.Wherein the dosage of PVP K30 is that atropic cuts down him
0.18 times of spit of fland weight；The dosage of water is 32.5 times of PVP K30 weight.
E ：Liquid dispersion system obtained by step D is added into powder obtained by step C, pelletizes, dries, dry particl crosses 20 mesh sieves.
F：Magnesium stearate is added into dry particle obtained by step E, is well mixed, crushed 50 mesh sieves point after tabletting again
Dress.Wherein the dosage of magnesium stearate is 0.012 times of Atorvastatin weight.
Embodiment 3 treats granule and its preparation of Pathogenesis of Post-infarction Ventricular Remodeling
Preparation method：
A：Take Atorvastatin, disulfiram, neoquipenyl, roller are smooth to cross 100 mesh sieves respectively, be well mixed.
B：Take lactose, microcrystalline cellulose, PVPP to cross 100 mesh sieves respectively, be well mixed.The wherein use of lactose
Measure as 2.2 times of Atorvastatin weight；Microcrystalline cellulose dosage is 1.2 times of Atorvastatin weight；The poly- dimension of crosslinking
The dosage of ketone is 0.13 times of Atorvastatin weight.
C：Powder obtained by step A and step B is well mixed.
D：Take PVP K30 to add water to stir evenly, liquid dispersion system is made.Wherein the dosage of PVP K30 is that atropic cuts down him
0.18 times of spit of fland weight；The dosage of water is 32.5 times of PVP K30 weight.
E ：Liquid dispersion system obtained by step D is added into powder obtained by step C, pelletizes, dries, dry particl crosses 20 mesh sieves.
F：Magnesium stearate is added into dry particle obtained by step E, is well mixed, crushed 50 mesh sieves point after tabletting again
Dress.Wherein the dosage of magnesium stearate is 0.012 times of Atorvastatin weight.
Embodiment 4 treats granule and its preparation of Pathogenesis of Post-infarction Ventricular Remodeling
Preparation method：
A：Take Atorvastatin, disulfiram, neoquipenyl, roller are smooth to cross 100 mesh sieves respectively, be well mixed.
B：Take lactose, microcrystalline cellulose, PVPP to cross 100 mesh sieves respectively, be well mixed.The wherein use of lactose
Measure as 2.2 times of Atorvastatin weight；Microcrystalline cellulose dosage is 1.2 times of Atorvastatin weight；The poly- dimension of crosslinking
The dosage of ketone is 0.13 times of Atorvastatin weight.
C：Powder obtained by step A and step B is well mixed.
D：Take PVP K30 to add water to stir evenly, liquid dispersion system is made.Wherein the dosage of PVP K30 is that atropic cuts down him
0.18 times of spit of fland weight；The dosage of water is 32.5 times of PVP K30 weight.
E ：Liquid dispersion system obtained by step D is added into powder obtained by step C, pelletizes, dries, dry particl crosses 20 mesh sieves.
F：Magnesium stearate is added into dry particle obtained by step E, is well mixed, crushed 50 mesh sieves point after tabletting again
Dress.Wherein the dosage of magnesium stearate is 0.012 times of Atorvastatin weight.
Ventricular Remodeling pharmacodynamic experiment after the anti-infarction of the pharmaceutical composition of embodiment 5
SPF level male SD rats, 260~350g of body weight, are provided by Beijing Vital River Experimental Animals Technology Co., Ltd..Greatly
Mouse is quarantined 7 after buying, free water, feeds the Rat Standard daily ration-type feed of U.S.'s NIH41 standards（Speeded reality purchased from Henan day
Test animal feed Co., Ltd）.
Quarantine terminates, and takes qualified rat Patients Under Ketamine Anesthesia of quarantining, and dorsal position is fixed.Direct oral cavity promoting the circulation of qi cannula, connects
Toy lung ventilator (60~70 times/min of respiratory rate).Four limbs are subcutaneously inserted electrode connection BL-420S biological function experiments
System, persistently record electrocardiogram.Operative region shaving sterilizes, and spreads sterile list, chest, left auricle of heart bottom right edge are opened in left side 2,3 intercostals
With suture with needle following coronary artery occlusion descending anterior branch at 1 mm, pulmonary conus left border.Electrocardiogram shows different limb leads QRS
Ripple is broadening to be increased, and the ST sections back of a bow raises 0.2 more than mV upwards.Visually observe ligation after infarcted region lose color, be considered as ligation into
Work(.Chest is closed after ligaturing successfully.The IU/kg of penicillin 500,000 prevention infection is given in daily intramuscular injection in postoperative 3 days.
The rat 78 of survival in postoperative 48 hours is taken, is randomly divided into 13 groups, every group 6.Each group animal administration prescription is seen below
Table.Table middle dosage and volume are the dosage and volume of single-dose.Administration frequency is administered 4 weeks, given to be administered daily 1 time altogether
Medicine approach is gastric infusion, free water during administration, feeds the Rat Standard daily ration-type feed of U.S.'s NIH41 standards（It is purchased from
Henan Tian Chi experimental animals feed corporation,Ltd）.
I.e. first group is model group；Second to the 5th group is Experimental agents group, its prescription granule with embodiment 1 to 4 respectively
Middle raw material prescription proportioning is identical；6th to the 13rd group is drugs compared group, wherein the 6th to the 9th group is respectively that atropic cuts down him
The smooth one-component control group of spit of fland, disulfiram, neoquipenyl, roller, the tenth group is disulfiram+neoquipenyl two-component control
Group, the 11st group and the 12nd group be respectively roller it is smooth+disulfiram, roller be smooth+neoquipenyl two-component
Control group, the 13rd group be roller it is smooth+the component control group of disulfiram+neoquipenyl three.
In above-mentioned each group, the rat of disulfiram is administered daily dosage and is calculated as 2.57~5mg/kg body weight according to body weight, i.e.,
0.9mg/0.35kg~1.3mg/0.26 kg.According to the equivalent dosage of the standard weight of rat and people conversion adult（Rat
Dosage is 6.3 times of human body dose,equivalent）For 0.41~0.79 mg/ kg body weight.
24 hours after last dose, rat body weight of weighing, Patients Under Ketamine Anesthesia, heart blood drawing execution.Take out heart, Yu Shengzhu
Artery injects glacial phosphoric acid salt buffer heart perfusion, is drained on filter paper, wipes out bilateral auricle, right ventricular wall, weighs left heart weight
Amount, left heart weight are used for Left ventricular massindex (mg/g) with body weight.
Data are represented with mean+SD, and statistical disposition is carried out using the softwares of SPSS 17. 0.The left heart of each group rat
Compare between the group of room ponderal index using one-way analysis of variance and Post Hoc inspections.P<0. 05, which are considered as difference, has statistics
Learn meaning.
Compared with first group：A p<0.01；B p<0.05.Compared with the 13rd group：C p<0.01, D p<0.05.
As seen from the above table, Left ventricular massindex is notable after the second to eight group and the 11st to 13 group of rat are administered
Less than first group.Wherein the second to five group Left ventricular massindex is minimum.Secondly it is the 6th group and the 13rd group.Seven, the eight, ten
Though the first, 12 groups of substantially less than first group, but still higher of Left ventricular massindex.And the nine, the ten groups of Left ventricular massindex
Without significant difference compared with first group.Illustrate that the prescription of the present invention is better than it to Ventricular Remodeling therapeutic effect after rat myocardial infarction model
The composition of middle one-component and two or three of component.Disulfiram, neoquipenyl are used alone with weaker anti-cardiac muscle stalk
After death Ventricular Remodeling acts on.And the composition of disulfiram+neoquipenyl（Tenth group）On the contrary with first group without significant difference, it is seen that
Therebetween there is negative function in drug effect.9th group is that roller is smooth, and Ventricular Remodeling acts on after having no anti-infarction, but double sulphur
Logical sequence+smooth group of neoquipenyl+roller Left ventricular massindex is substantially less than the tenth group, illustrates that roller is smooth to disulfiram+primaquine
The composition of quinoline has synergistic effect beyond expectation.
Safety research inside the pharmaceutical composition of embodiment 6
The male Beagle dogs of regular grade health, in 6 ~ September age, 8 ~ 10 kilograms of body weight, tonneau China experimental animal technology is tieed up by Beijing
Co., Ltd provides.Beagle dogs are quarantined 7 after buying, free water, the pellet (purchase of feeding Beagle dog special swellings
From Beijing Vital River Experimental Animals Technology Co., Ltd.).
Quarantine terminates, and takes qualified Beagle dogs 16 of quarantining, is randomly divided into 4 groups, every group 4, gavage is given respectively
Medicine described in following table.Table middle dosage and volume are the dosage and volume of single-dose.Medicine is made of physiological saline
It is administered after isometric liquid dispersion system.Administration frequency is administered 4 weeks altogether to be administered daily 1 time.Free water, feeding
Beagle dog special swellings pellet (is purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.).
Animal ingestion water uptake, autonomic activities state, stool and urine form, hair color are observed during administration daily；DSZF- is used weekly
09 big animal physiological signal telemetry system（Purchased from Beijing Ruan Long Bioisystech Co., Ltd）Monitor blood pressure, electrocardio, body temperature, breathing
Deng physiological signal.
24 hours after last dose, put to death each group Beagle dogs, core, liver, spleen, lung, kidney, testis, physiological saline punching
Wash, 4% formalin is fixed, and graded ethanol dehydration, dimethylbenzene is transparent, cuts the paraffin thin slice of 4 μ m thicks, hematoxylin-eosin dye
Color, neutral gum mounting.Histopathologic examination is carried out under Olympus BX51 auto photographing biomicroscopes.
Pathologic finding is showed no exception under first group and the 4th group of animal physiological index and mirror.
2 animals start arrhythmia cordis occur on the 3rd week in administration in second group of animal, separately have 1 pathologic finding to find the heart
Flesh infarct symptom.
2 animal pathologic findings find that vacuolar degeneration, coagulation necrosis occurs in cardiac muscle in 3rd group of animal.
The above results show, disulfiram, neoquipenyl have certain cardiovascular system toxicity, roller is smooth reduce it is double
Sulphur logical sequence, the cardiovascular system toxicity of neoquipenyl.
Claims (10)
1. a kind of combination of oral medication for treating Pathogenesis of Post-infarction Ventricular Remodeling, it is characterised in that containing can pharmaceutically connect
The pharmaceutic adjuvant and Atorvastatin received.
2. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 1, it is characterised in that institute
The combination of oral medication for stating treatment Pathogenesis of Post-infarction Ventricular Remodeling cuts down him by pharmaceutically acceptable pharmaceutic adjuvant and atropic
Spit of fland, disulfiram, neoquipenyl, roller is smooth is made；In the combination of oral medication of the treatment Pathogenesis of Post-infarction Ventricular Remodeling
The smooth weight part ratio of Atorvastatin, disulfiram, neoquipenyl, roller is：The parts by weight of Atorvastatin 53~97, disulfiram
8~14 parts by weight, the parts by weight of neoquipenyl 5~11, smooth 3~7 parts by weight of roller.
3. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 2, it is characterised in that institute
It is smooth to state Atorvastatin, disulfiram, neoquipenyl, roller in the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling
Weight part ratio be：The parts by weight of Atorvastatin 61, the parts by weight of disulfiram 11, the parts by weight of neoquipenyl 7, smooth 5 weight of roller
Part.
4. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 2, it is characterised in that institute
It is smooth to state Atorvastatin, disulfiram, neoquipenyl, roller in the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling
Weight part ratio be：The parts by weight of Atorvastatin 75, the parts by weight of disulfiram 9, the parts by weight of neoquipenyl 6, smooth 4 weight of roller
Part.
5. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 2, it is characterised in that institute
It is smooth to state Atorvastatin, disulfiram, neoquipenyl, roller in the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling
Weight part ratio be：The parts by weight of Atorvastatin 83, the parts by weight of disulfiram 12, the parts by weight of neoquipenyl 9, smooth 6 weight of roller
Part.
6. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 2, it is characterised in that institute
It is smooth to state Atorvastatin, disulfiram, neoquipenyl, roller in the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling
Weight part ratio be：The parts by weight of Atorvastatin 95, the parts by weight of disulfiram 13, the parts by weight of neoquipenyl 10, smooth 6 weight of roller
Part.
7. the combination of oral medication of the treatment Pathogenesis of Post-infarction Ventricular Remodeling according to any one of claim 2 to 6, it is special
Sign is that the formulation of the combination of oral medication of the treatment Pathogenesis of Post-infarction Ventricular Remodeling is granule；The treatment cardiac muscle
The human body of the combination of oral medication of Ventricular Remodeling is administered daily dosage and is calculated as 0.4~0.8mg/kg bodies with disulfiram after infarct
Weight.
8. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 7, it is characterised in that institute
The pharmaceutic adjuvant for stating granule is made up of lactose, microcrystalline cellulose, PVPP, magnesium stearate, PVP K30 and water.
9. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 8, it is characterised in that institute
The dosage for stating lactose in granule is 1.8~2.3 times of Atorvastatin weight；The dosage of microcrystalline cellulose is Atorvastatin
1.0~1.3 times of weight；The dosage of PVPP is 0.11~0.14 times of Atorvastatin weight；The use of magnesium stearate
Measure as 0.010~0.014 times of Atorvastatin weight；The dosage of PVP K30 for Atorvastatin weight 0.16~
0.19 times；The dosage of water is 32.1~32.8 times of PVP K30 weight.
10. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 9, it is characterised in that
The dosage of lactose is 2.2 times of Atorvastatin weight in the granule；Microcrystalline cellulose dosage is Atorvastatin weight
1.2 times；The dosage of PVPP is 0.13 times of Atorvastatin weight；The dosage of magnesium stearate is Atorvastatin weight
0.012 times of amount；The dosage of PVP K30 is 0.18 times of Atorvastatin weight；The dosage of water is PVP K30 weight
32.5 times.
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| CN112826822A (en) * | 2021-01-13 | 2021-05-25 | 南京医科大学 | Application of ABT-263 combined with angiotensin converting enzyme inhibitor and product thereof |
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| CN107737108B (en) | 2018-06-26 |
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