CN107737108B - 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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- 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
- A61K31/40—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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- 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
- A61K31/47—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：53~97 parts by weight of Atorvastatin, 8~14 parts by weight of disulfiram, 5~11 parts by weight of neoquipenyl, smooth 3~7 parts by weight of roller.Composition middle roller is smooth to can inhibit 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 safety 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
Object.
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 increases and morphologic change, can cause ventricular pump blood
Hypofunction, and develop into heart failure.The fundamental mechanism for leading to heart failure occurrence and development is Ventricular Remodeling.The symptom is
Change after duration, the progressive after myocardial infarction, its severity decides Cardiac Function of Patients situation and prognosis.Along with
The raising of myocardial infarction incidence, Pathogenesis of Post-infarction Ventricular Remodeling, which also becomes, 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 is had dropped close to 30%；However 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 about 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 related（Liao Yuhua, the amynologic mechanism medicine 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 at 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 generate, and safety has obtained clinical test tentative confirmation.
But final conclusion there is no to the effect of Pathogenesis of Post-infarction Ventricular Remodeling（Yun Ji summary, Li Yuming examine and revise granular leukocyte colonies stimulation 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 inhibiting effect 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 cycle 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 inhibiting effect 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.）.
To sum up, it is unclear for the mechanism of Pathogenesis of Post-infarction Ventricular Remodeling at present, clinically also it is lack of pertinence
Medicine.
Invention content
For the above-mentioned prior art, the object of the present invention is to provide a kind of mouths 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 medicinal auxiliary
Material 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, 8~14 parts by weight of disulfiram, 5~11 parts by weight of neoquipenyl, 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：61 parts by weight of Atorvastatin, 11 parts by weight of disulfiram, 7 weight of neoquipenyl
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：75 parts by weight of Atorvastatin, 9 parts by weight of disulfiram, 6 weight of neoquipenyl
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：83 parts by weight of Atorvastatin, 12 parts by weight of disulfiram, 9 weight of neoquipenyl
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：95 parts by weight of Atorvastatin, 13 parts by weight of disulfiram, 10 weight of neoquipenyl
Measure part, smooth 6 parts by weight of roller.
Preferably, the dosage form 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 weight.
Preferably, the pharmaceutic adjuvant of above-mentioned granule is by lactose, microcrystalline cellulose, crospovidone, 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 crospovidone 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 crospovidone is 0.13 times of Atorvastatin weight；The dosage of magnesium stearate
0.012 times for 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, which has gone through listing 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, which is criticized
Quasi- listing is used for the treatment of malaria.Neoquipenyl is commercially available.
Roller is smooth, and the entitled Rolapitant of English, No. CAS is 552292-08-7, which has gone through listing for pressing down
It is 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 corrigent etc., standard are shown in Chinese Pharmacopoeia version four in 2015.
Microcrystalline cellulose for alpha-cellulose made from the fiber pulp of cellulosic plant, partly solves under the action of inorganic acid
It is poly-, it purifies and obtains.Belong to common medicinal supplementary material, as filler and disintegrant etc., standard is shown in Chinese Pharmacopoeia version four in 2015
Portion.
Crospovidone is the synthesizing cross-linked homopolymer not soluble in water of N-ethylene -2-Pyrrolidone, belongs to common medicine
With auxiliary material, as disintegrant and filler etc., standard is shown in Chinese Pharmacopoeia version four in 2015.
PVP K30 generates vinylpyrrolidone monomer, in catalyst action under elevated pressure for pyrrolidones and ethylene
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 Atorvastatin has Ventricular Remodeling effect after certain anti-infarction；Double sulphur
Logical sequence and neoquipenyl also have Ventricular Remodeling effect after weaker anti-infarction, two when disulfiram and neoquipenyl are used in combination
Person's drug effect is there are apparent offseting phenomenon, and there are Cardiovascular Toxicities during the exclusive use of disulfiram, neoquipenyl.Roller is smooth not
Ventricular Remodeling acts on after seeing anti-infarction, but can inhibit the Cardiovascular Toxicity effect of disulfiram, neoquipenyl, and eliminate double sulphur
Drug effect offseting phenomenon when logical sequence and neoquipenyl are used in combination improves 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 anti-
Pathogenesis of Post-infarction Ventricular Remodeling acts on and safety.
Specific embodiment
The present invention is further explained with reference to embodiment.It should be understood that following embodiment is only used for solving
It releases the present invention rather than limits the scope of the invention.
Embodiment 1 treats granule and its preparation of Pathogenesis of Post-infarction Ventricular Remodeling
Preparation method：
A：It takes Atorvastatin, disulfiram, neoquipenyl, roller are smooth to sieve with 100 mesh sieve respectively, is uniformly mixed.
B：Lactose, microcrystalline cellulose, crospovidone is taken to sieve with 100 mesh sieve respectively, is uniformly mixed.The wherein use of lactose
Measure 2.2 times for Atorvastatin weight；Microcrystalline cellulose dosage is 1.2 times of Atorvastatin weight；Crosslinking
The dosage of povidone is 0.13 times of Atorvastatin weight.
C：Powder obtained by step A and step B is uniformly mixed.
D：It takes PVP K30 that water is added to stir evenly, liquid dispersion system is made.Wherein the dosage of PVP K30 cuts down him for atropic
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 in into powder obtained by step C, is pelletized, dry, dry particl crosses 20 mesh sieve.
F：Magnesium stearate is added in into dry particle obtained by step E, is uniformly mixed, crushed the screening of 50 mesh 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：It takes Atorvastatin, disulfiram, neoquipenyl, roller are smooth to sieve with 100 mesh sieve respectively, is uniformly mixed.
B：Lactose, microcrystalline cellulose, crospovidone is taken to sieve with 100 mesh sieve respectively, is uniformly mixed.The wherein use of lactose
Measure 2.2 times for Atorvastatin weight；Microcrystalline cellulose dosage is 1.2 times of Atorvastatin weight；Crosslinking
The dosage of povidone is 0.13 times of Atorvastatin weight.
C：Powder obtained by step A and step B is uniformly mixed.
D：It takes PVP K30 that water is added to stir evenly, liquid dispersion system is made.Wherein the dosage of PVP K30 cuts down him for atropic
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 in into powder obtained by step C, is pelletized, dry, dry particl crosses 20 mesh sieve.
F：Magnesium stearate is added in into dry particle obtained by step E, is uniformly mixed, crushed the screening of 50 mesh 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：It takes Atorvastatin, disulfiram, neoquipenyl, roller are smooth to sieve with 100 mesh sieve respectively, is uniformly mixed.
B：Lactose, microcrystalline cellulose, crospovidone is taken to sieve with 100 mesh sieve respectively, is uniformly mixed.The wherein use of lactose
Measure 2.2 times for Atorvastatin weight；Microcrystalline cellulose dosage is 1.2 times of Atorvastatin weight；Crosslinking
The dosage of povidone is 0.13 times of Atorvastatin weight.
C：Powder obtained by step A and step B is uniformly mixed.
D：It takes PVP K30 that water is added to stir evenly, liquid dispersion system is made.Wherein the dosage of PVP K30 cuts down him for atropic
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 in into powder obtained by step C, is pelletized, dry, dry particl crosses 20 mesh sieve.
F：Magnesium stearate is added in into dry particle obtained by step E, is uniformly mixed, crushed the screening of 50 mesh 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：It takes Atorvastatin, disulfiram, neoquipenyl, roller are smooth to sieve with 100 mesh sieve respectively, is uniformly mixed.
B：Lactose, microcrystalline cellulose, crospovidone is taken to sieve with 100 mesh sieve respectively, is uniformly mixed.The wherein use of lactose
Measure 2.2 times for Atorvastatin weight；Microcrystalline cellulose dosage is 1.2 times of Atorvastatin weight；Crosslinking
The dosage of povidone is 0.13 times of Atorvastatin weight.
C：Powder obtained by step A and step B is uniformly mixed.
D：It takes PVP K30 that water is added to stir evenly, liquid dispersion system is made.Wherein the dosage of PVP K30 cuts down him for atropic
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 in into powder obtained by step C, is pelletized, dry, dry particl crosses 20 mesh sieve.
F：Magnesium stearate is added in into dry particle obtained by step E, is uniformly mixed, crushed the screening of 50 mesh 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 5 pharmaceutical composition of embodiment
SPF grades of male SD rats, 260~350g of weight are carried by Beijing Vital River Experimental Animals Technology Co., Ltd.
For.Rat is quarantined 7 after buying, free water, feeds the Rat Standard daily ration-type feed of U.S.'s NIH41 standards（Purchased from Henan
Tian Chi experimental animals feed corporation,Ltd）.
Quarantine terminates, and the rat Patients Under Ketamine Anesthesia for taking quarantine qualified, 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 records 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
Wave is broadening to be increased, and the ST sections of back of a bow raise 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.500,000 IU/kg of penicillin 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, gives to be administered daily 1 time altogether
Medicine approach be gastric infusion, free water during administration, feed U.S.'s NIH41 standards Rat Standard daily ration-type feed（It is purchased from
Henan Tian Chi experimental animals feed corporation,Ltd）.
I.e. first group is model group；Second to the 5th group be experimental drug group, prescription respectively with of embodiment 1 to 4
Raw material prescription proportioning is identical in granula；6th to the 13rd group is drugs compared group, wherein the 6th to the 9th group is respectively atropic
The smooth one-component control group of statin, disulfiram, neoquipenyl, roller is cut down, the tenth group is disulfiram+neoquipenyl two-component pair
According to 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 for roller it is smooth+three component control group of disulfiram+neoquipenyl.
In above-mentioned each group, the rat of disulfiram is administered daily dosage and is calculated as 2.57~5mg/kg weight according to 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 equivalent dose）For 0.41~0.79 mg/ kg weight.
24 hours after the last administration, 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, the ratio between left heart weight and weight are as Left ventricular massindex (mg/g).
Data are represented with mean+SD, and statistical disposition is carried out using 17. 0 softwares of SPSS.The left heart of each group rat
The comparison among groups of room ponderal index are examined using one-way analysis of variance and Post Hoc.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）Instead with first group without significant difference, it is seen that
Therebetween there are negative functions for drug effect.9th group smooth for roller, and Ventricular Remodeling acts on, but double sulphur after having no anti-infarction
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.
The internal safety research of 6 pharmaceutical composition of embodiment
Regular grade health male Beagle dogs, 6 ~ September age, 8 ~ 10 kilograms of weight, by Beijing dimension tonneau China experimental animal
Technology Co., Ltd. provides.Beagle dogs are quarantined 7 after buying, free water, feed Beagle dog special swelling pellets
(being purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.).
Quarantine terminates, and the Beagle dogs 16 for taking quarantine qualified are randomly divided into 4 groups, every group 4, gavage is given respectively
Drug described in following table.Table middle dosage and volume are the dosage and volume of single-dose.Drug 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 intake, autonomic activities state, stool and urine form, hair color are observed during administration daily；It uses weekly
The big animal physiological signal telemetry systems of DSZF-09（Purchased from Beijing Ruan Long Bioisystech Co., Ltd）Monitor blood pressure, electrocardio, body
The physiological signals such as temperature, breathing.
24 hours after the last administration, put to death each group Beagle dogs, core, liver, spleen, lung, kidney, testis, physiological saline punching
It washes, 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 third group animal.
The above results show disulfiram, neoquipenyl there are certain cardiovascular system toxicity, roller is smooth reduce it is double
Sulphur logical sequence, the cardiovascular system toxicity of neoquipenyl.
Claims (9)
- A kind of 1. combination of oral medication for treating Pathogenesis of Post-infarction Ventricular Remodeling, which is characterized in that the treatment myocardial infarction The combination of oral medication of Ventricular Remodeling is by pharmaceutically acceptable pharmaceutic adjuvant and Atorvastatin, disulfiram, primaquine afterwards Quinoline, roller are smooth to be made；Atorvastatin, double sulphur in the combination of oral medication of the treatment Pathogenesis of Post-infarction Ventricular Remodeling The smooth weight part ratio of logical sequence, neoquipenyl, roller is：53~97 parts by weight of Atorvastatin, 8~14 parts by weight of disulfiram, primary Smooth 3~7 parts by weight of 5~11 parts by weight of ammonia quinoline, roller.
- 2. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 1, which is characterized 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：61 parts by weight of Atorvastatin, 11 parts by weight of disulfiram, 7 parts by weight of neoquipenyl, smooth 5 weight of roller Part.
- 3. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 1, which is characterized 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：75 parts by weight of Atorvastatin, 9 parts by weight of disulfiram, 6 parts by weight of neoquipenyl, smooth 4 weight of roller Part.
- 4. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 1, which is characterized 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：83 parts by weight of Atorvastatin, 12 parts by weight of disulfiram, 9 parts by weight of neoquipenyl, smooth 6 weight of roller Part.
- 5. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 1, which is characterized 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：95 parts by weight of Atorvastatin, 13 parts by weight of disulfiram, 10 parts by weight of neoquipenyl, smooth 6 weight of roller Part.
- 6. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to any one of claims 1 to 5, special Sign is that the dosage form 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.
- 7. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 6, which is characterized in that institute The pharmaceutic adjuvant for stating granule is made of lactose, microcrystalline cellulose, crospovidone, magnesium stearate, PVP K30 and water.
- 8. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 7, which is characterized 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 crospovidone is 0.11~0.14 times of Atorvastatin weight；The use of magnesium stearate Measure 0.010~0.014 times for 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.
- 9. the combination of oral medication for the treatment of Pathogenesis of Post-infarction Ventricular Remodeling according to claim 8, which is characterized in that institute The dosage for stating lactose in granule is 2.2 times of Atorvastatin weight；Microcrystalline cellulose dosage is Atorvastatin weight 1.2 again；The dosage of crospovidone is 0.13 times of Atorvastatin weight；The dosage of magnesium stearate is Atorvastatin weight 0.012 times；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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| US5206264A (en) * | 1991-11-04 | 1993-04-27 | Cypros Pharmaceutical Corporation | Use of disulfiram to prevent cardiovascular damage |
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| GB201020860D0 (en) * | 2010-12-09 | 2011-01-26 | Univ Wolverhampton | Disulfiram formulation and uses thereof |
| CN103301097A (en) * | 2012-03-14 | 2013-09-18 | 上海市肿瘤研究所 | Application of disulfiram in preparing anti-liver cirrhosis or anti-liver fibrosis pharmaceuticals |
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