[go: up one dir, main page]

CN101176788B - Pharmaceutical composition for ACE restrainer/uretica/folic acid, and uses thereof - Google Patents

Pharmaceutical composition for ACE restrainer/uretica/folic acid, and uses thereof Download PDF

Info

Publication number
CN101176788B
CN101176788B CN2007101657788A CN200710165778A CN101176788B CN 101176788 B CN101176788 B CN 101176788B CN 2007101657788 A CN2007101657788 A CN 2007101657788A CN 200710165778 A CN200710165778 A CN 200710165778A CN 101176788 B CN101176788 B CN 101176788B
Authority
CN
China
Prior art keywords
group
hypertension
folic acid
hydrochlorothiazide
dosage
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN2007101657788A
Other languages
Chinese (zh)
Other versions
CN101176788A (en
Inventor
陈光亮
王琳琳
吕红霞
胡容峰
段炎炎
李莉
刘海鹏
段玉光
曹康
徐希平
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ANHUI BIOLOGICAL MEDICAL INSTITUTE
Shenzhen Ausa Pharmaceutical Co ltd
Shenzhen Ausa Pharmed Co ltd
Original Assignee
ANHUI BIOLOGICAL MEDICAL SCIENCE INST
AUSA PHARMED Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ANHUI BIOLOGICAL MEDICAL SCIENCE INST, AUSA PHARMED Ltd filed Critical ANHUI BIOLOGICAL MEDICAL SCIENCE INST
Priority to CN2007101657788A priority Critical patent/CN101176788B/en
Publication of CN101176788A publication Critical patent/CN101176788A/en
Application granted granted Critical
Publication of CN101176788B publication Critical patent/CN101176788B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to a drug composition combined applying the inhibitor of the angiotensin converting enzyme, the diuretic and the folic acid and the use of the drug composition, which comprises the inhibitor of the blood vessel medicinal angiotensin converting enzyme in medicinal purposes dosage, the medicinal purposes dosage diuretic, the medicinal purposes dosage folic acid compound and the acceptable carrier in the pharmaceutics. The invention supplies the use in the preparation of the drugs used for preventing, curing or postponing the hypertension, the target organ damage or the relative disease of the hypertension, and also supplies the use in the preparation of the fatalness drugs used for reducing the cardio-cerebrovascular event caused by the hypertension. The invention has the advantages of providing the patients with the drug composition, enhancing the curative effect, increasing the patient compliance and reducing the medical service cost.

Description

The medical composition and its use that ACE inhibitor/diuretic/folate coupling is used
Technical field
The present invention relates to the medical composition and its use of Angiotensin-Converting (ACE) inhibitor/diuretic/folic acid use in conjunction, belong to pharmaceutical field.
Background technology
As one of commonly encountered diseases of harm humans health, essential hypertension is to cause serious cardiovascular and cerebrovascular disease such as myocardial infarction, apoplexy, and the main cause of kidney disease etc.Treating hypertensive main purpose is to reduce cardiovascular diseases's death and invalid total danger to greatest extent, medicine brings high blood pressure down and can reduce the M ﹠ M of cardiovascular complication effectively, prevents the generation and the development of apoplexy, coronary heart disease, heart failure and kidney disease.The line antihypertensive drug that WHO and China hypertension therapeutic guide are recommended is respectively: diuretic, beta-adrenoceptor antagonists, calcium channel blocker, ACE inhibitor, angiotensin ii receptor antagonist, the perhaps composite antihypertensive preparation of the fixed dosage of being made up of said medicine.Most hyperpietics need two or more antihypertensive drug to reach the controlling blood pressure target, and two kinds of medicines can be write out a prescription separately or are the compound preparation of fixed dosage.International extensive clinical trial proof drug combination has it to need and is worth, and the dosage of every kind of medicine is little, and the therapeutical effect of medicine should have collaborative or summation action at least, and its ill effect can be cancelled out each other or not overlapping at least or addition.
In the hypertension drug combination of U.S.'s hypertension prevention, detection, assessment and the treatment whole nation the 7th report (JNC-7), ESC/European hypertension association (ESC/ESH) of joint committee and the recommendation of Chinese hypertension prevention and control guide, having used diuretic in the drug combination compatibility more than half, wherein mainly is thiazide diuretic hydrochlorothiazide (Hydrochlorothiazide).
Since half a century, people are to the use of diuretic setback comparatively.From the fifties, diuretic just is applied to clinical as common antihypertensive.Thiazide diuretic was promptly classified as a line depressor by World Health Organization (WHO) in 1978, often was applied to treat light, moderate hypertension separately.But clinical practice finds that the life-time service thiazide diuretic can cause low blood sodium, hypokalemia and low blood chlorine, and impaired glucose tolerance takes place about 30% patient.Owing to suppress carbonic anhydrase, reduce H in addition +Secretion makes NH 3Discharge and reduce, cause that blood ammonia raises.The hydrochlorothiazide life-time service can influence the activity of lipase, and triglyceride catabolism is reduced, and triglyceride raises, and causes fat metabolic disturbance, or causes that slight cholesterol increases.Therefore, along with the appearance of novel antihypertensive medicines such as calcium channel blocker, angiotensin-convertion enzyme inhibitor, the clinical use amount of diuretic significantly reduces.
Yet over past ten years, people rediscover with low dose of diuretic as basic antihypertensive drugs, can significantly reduce the prevalence and the mortality rate of senile hypertension patient's cardiovascular disease; Low dose of diuretic was compared with former dosage, the similar and adverse reaction reduction of antihypertensive effect; The effective blood volume minimizing that diuretic causes is the treatment to hypertension necessity, may be the basis of other antihypertensive drugs treatments; So begin to pay attention to the use of diuretic again.And think that diuretic and beta receptor antagonist are present unique clear and definite medicines that can significantly reduce cardiovascular disease (especially to the gerontal patient) prevalence and fatality rate.If there is not the use contraindication, there is not the strong indication of using other antihypertensive drugs, should first-selected this two classes medicine.
The result of ASCOT (Anglo-Scandinavian CardiocOutcomes Trial) is announced in the academic conference of European cardiology association (ESC) in 2005, and the object of study of ASCOT is 19257 routine hypertension (therapist blood pressure 〉=160/100mmHg not; The patient of curer blood pressure 〉=140/90mmHg), have other 3 or above cardiovascular risk factors at least, and the coronary heart disease that nothing is clarified a diagnosis, ASCOT can be used as the research at common clinically cardiovascular poor risk hyperpietic cardiovascular primary prevention, and main terminal point is non-lethal myocardial infarction (MI) or mortality coronary heart disease (CHD).Result: with atenolol or coupling diuretic (beta receptor blocker and thiazide diuretic compatibility) contrast, amlodipine (or coupling perindopril) group general mortality rate decline 11% (P=0.0247), cardiovascular death reduces by 24% (P=0.001), apoplexy reduces by 23% (P=0.0003), coronary event reduces by 16% (P＜0.01), and the kainogenesis diabetes reduce by 30% (P＜0.01).Therefore, it is that the basis adds the therapeutic scheme with ACE inhibitor in case of necessity that hyperpietic with cardiovascular disease poor risk adopts with the calcium channel blocker, its curative effect is better than based on atenolol or adds curative effect with thiazide diuretic, and this advantage is especially early stage remarkable when up to standard at patient treatment.As seen, beta receptor blocker coupling thiazide diuretic no longer is all hyperpietics' a first-line treatment medicine.
ASCOT research causes that people examine the status of diuretic in hypertension therapeutic again closely, uses the pros and cons of thiazide diuretic all very outstanding.Among the U.S. hypertension prevention and control guide JNC-7, strengthened the critical role of thiazide diuretic, in 6 stiffness of the nape indications, had 4 (heart failure, coronary heart disease are high-risk, diabetes and the recurrence of prevention of brain apoplexy) to show thiazide diuretic as resisting hypertension first-line treatment medicine; And from cost one benefit angle analysis, thiazide diuretic is classified the antihypertensive drug of worth selection as.How also confessed by people the untoward reaction of thiazide diuretic is simultaneously.How can further improve diuretic or to contain the target organ protection function of the compound hypertension medicine of diuretic the hyperpietic; the risk of the cardiovascular and cerebrovascular vessel incident that reduction hypertension causes; reduce diuretic or contain the untoward reaction of the compound hypertension medicine of diuretic; on no matter still being social meaning, all be the problem that is worth research or solves from clinical meaning.
Summary of the invention
The objective of the invention is to overcome the compound hypertension medicine above shortcomings that contain diuretic, provide a kind of at the compound hypertension medicine that is better than containing diuretic aspect target-organ protection and the reduction cardiovascular and cerebrovascular vessel incident danger, and the pharmaceutical composition that side effect does not increase.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition comprises:
(1) angiotensin converting enzyme inhibitor of pharmaceutical dosage;
(2) diuretic of pharmaceutical dosage;
(3) folacin compound of pharmaceutical dosage;
(4) acceptable carrier on the pharmaceutics.
Above-mentioned " pharmaceutical dosage " is meant referring to " Chinese hypertension prevention and control guide (2005) " and " The Seventh Reportof the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of HighBlood Pressure (JNC-7) " in the recommended dose of corresponding various concrete depressor, or the dosage range of each package insert regulation.
The folacin compound of above-mentioned pharmaceutical dosage is folic acid, calcium folinate or levoleucovorin calcium, and dosage is 0.2～1.6mg, preferred 0.4～1.0mg.
Above-mentioned ACE inhibitor is selected from a kind of in enalapril, lisinopril, perindopril, imidapril, benazepril, ramipril, captopril, moexipril, quinapril, trandolapril, cilazapril or the fosinopril, and dosage is 2.5～40mg.
Above-mentioned diuretic is selected from a kind of in hydrochlorothiazide, indapamide, eplerenone or the spironolactone, and dosage is 2.5～50mg.
The ACE inhibitor of above-mentioned pharmaceutical dosage and diuretic, its specific category and dosage see the following form, but are not limited to the following table scope.
Share type Share dosage ratio, mg *
ACE inhibitor and diuretic Benazepril/hydrochlorothiazide (5/6.25,10/12.5,20/12.5,20/25)
Captopril/hydrochlorothiazide (25/15,25/25,50/15,50/25)
Enalapril/hydrochlorothiazide (5/12.5,10/25)
Lisinopril/hydrochlorothiazide (10/12.5,20/12.5,20/25)
Moexipril/hydrochlorothiazide (7.5/12.5,15/25)
Quinapril/hydrochlorothiazide (10/12.5,20/12.5,20/25)
Imidapril/hydrochlorothiazide (5/12.5,10/12.5,10/25)
Trandolapril/hydrochlorothiazide (1/12.5,2/12.5,2/25)
Perindopril/hydrochlorothiazide (4/12.5,8/12.5,8/25)
Cilazapril/hydrochlorothiazide (2.5/12.5,5/12.5,5/25)
Fosinopril/hydrochlorothiazide (10/12.5,20/12.5,20/25)
Ramipril/hydrochlorothiazide (2.5/12.5,5/12.5,5/25)
* can obtain the compound medicine of various fixed dosage.The dosage of every kind of medicine is mg
The ACE inhibitor of above-mentioned pharmaceutical dosage is enalapril 5～40mg; The diuretic of pharmaceutical dosage is hydrochlorothiazide 12.5～25mg; Folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and dosage is 0.2～1.6mg.
The ACE inhibitor of above-mentioned pharmaceutical dosage is lisinopril 5～40mg; The diuretic of pharmaceutical dosage is hydrochlorothiazide 12.5～25mg; Folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and dosage is 0.2～1.6mg.
The ACE inhibitor of above-mentioned pharmaceutical dosage is perindopril 2～8mg; The diuretic of pharmaceutical dosage is hydrochlorothiazide 12.5～25mg; Folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and dosage is 0.2～1.6mg.
The ACE inhibitor of above-mentioned pharmaceutical dosage is imidapril 5～10mg; The diuretic of pharmaceutical dosage is indapamide 2.5～5mg; Folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and dosage is 0.2～1.6mg.
The ACE inhibitor of above-mentioned pharmaceutical dosage is benazepril 5～20mg; The diuretic of pharmaceutical dosage is spironolactone 25～50mg; Folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and dosage is 0.2～1.6mg.
We use in the research process of medicine of the present invention to hypertension therapeutic, emphatically at target-organ protection and the dangerous aspect of reduction cardiovascular and cerebrovascular vessel incident.This be because: if hypertension do not control effectively, continue several Nian Houke and cause the tiny arteriosclerosis of whole body, become stiff and lack flexibility, tube chamber narrows down, and the blood flow rate that is delivered to tissue slows down, and causes important organs such as the heart, brain, kidney, eye to damage.The target organ damage that hypertension causes comprises left ventricular hypertrophy, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, renal failure, retinal arteriosclerosis or hypertension retinopathy.When above-mentioned these target organ damages still can not give effective control, then develop into more serious consequence, be the generation of cardiovascular and cerebrovascular vessel incident, the cardiovascular and cerebrovascular vessel incident comprises angina pectoris, myocardial infarction, heart failure, cerebral infarction or cerebral hemorrhage, and wherein cerebral infarction and cerebral hemorrhage are referred to as apoplexy.Therefore, treatment hypertensive patient's main purpose is to reduce the death of cardiovascular and cerebrovascular disease and invalid total danger to greatest extent, and it is the core of hypertension therapeutic that blood pressure lowering and target-organ protection develop simultaneously.
Discover that pharmaceutical composition provided by the invention not only has hypotensive effect and also has target organ protection function.When ACE inhibitor/diuretic and folacin compound are share; can also work in coordination with the intensifier target organ protection; and its protective effect is better than only uses ACE inhibitor/diuretic bigeminy compound hypertension medicine, also is better than list and uses folacin compound, and difference has statistical significance.
Therefore, the invention provides pharmaceutical composition that the folacin compound of the ACE inhibitor/diuretic of above-mentioned pharmaceutical dosage and pharmaceutical dosage forms is used for preventing, treating or delay hypertensive medicine in preparation purposes; The invention provides this pharmaceutical composition is used for preventing, treat or delay the medicine of the target organ damage that hypertension causes in preparation purposes, the target organ damage that hypertension causes comprises left ventricular hypertrophy, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, renal failure, retinal arteriosclerosis or hypertension retinopathy.
Further, in experiment, we find, when ACE inhibitor/diuretic and folacin compound are share, can collaboratively reduce cardiovascular and cerebrovascular vessel incident danger, and effect is better than only uses ACE inhibitor/diuretic bigeminy compound hypertension medicine, also is better than list and uses folacin compound, and difference has statistical significance.
And then the present invention also provides this pharmaceutical composition to be used for reducing the purposes of the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension causes in preparation; Wherein reduce cardiovascular and cerebrovascular vessel incident danger and be meant the incidence rate that reduces angina pectoris, myocardial infarction, heart failure, cerebral infarction or cerebral hemorrhage, reduce the incidence rate that cardiovascular and cerebrovascular vessel incident danger also refers to reduce apoplexy.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, comprise conventional tablet, capsule, granule etc., described pharmaceutically acceptable carrier includes excipient and the accessory drugs that helps reactive compound is mixed with pharmaceutical formulation when making oral formulations, compositions as one or more materials of starch, microcrystalline Cellulose, inorganic salts, sucrose, dextrin, lactose, Icing Sugar, glucose, sodium chloride, cysteine, citric acid and sodium sulfite etc. belongs to this area general knowledge.
The dosage form of this pharmaceutical composition include but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, single chamber controlled release tablet, two chambers controlled release tablet, pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, contain micropill or small pieces capsule, contain the dosage forms such as pH dependent form capsule, granule, oral liquid, membrane or patch of micropill or small pieces, wherein preferred tablet, capsule or granule.
According to the present invention, pharmaceutical composition also can be meant the medicine box that contains two or three independent medicines.When " pharmaceutical composition " was meant the medicine box that contains two independent medicines, above-mentioned " Combined drug box " was a kind of case type container, the drug regimen of built-in multiple dosage form, and take description, " Combined drug box " more is applicable to personalized medicine; First medicine is for containing ACE inhibitor/diuretic, and second medicine is for containing folacin compound.When " pharmaceutical composition " was meant the medicine box that contains three independent medicines, above-mentioned " Combined drug box " was a kind of case type container, the drug regimen of built-in multiple dosage form, and take description; First and second medicine contain ACE inhibitor and diuretic respectively, contain folacin compound in the 3rd medicine.In this medicine box two or three independently medicine can concomitant dosing, also can be in a kind of pharmaceutical preparation or in different pharmaceutical preparation sequential administration.
The invention has the beneficial effects as follows: pharmaceutical composition provided by the invention has obvious synergism, and its synergism is to work in coordination with and reduces the target organ damage that hypertension causes, works in coordination with and reduces the cardiovascular and cerebrovascular vessel incident danger that hypertension causes.Therefore, the invention provides pharmaceutical composition that the folacin compound of the ACE inhibitor/diuretic of above-mentioned pharmaceutical dosage and pharmaceutical dosage forms is used for preventing, treat or delays the medicine of hypertension, target organ damage that hypertension causes or hypertension relevant disease in preparation purposes; Further, the invention provides aforementioned pharmaceutical compositions is used for reducing the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension causes in preparation purposes.By enforcement of the present invention, the pharmaceutical composition that offers this special-purpose of patient can improve patient's compliance, and the patient is taken medicine conveniently, reduces medical expense, has better market prospect.
The present invention will be further described below in conjunction with the specific embodiment, and the experiment support of pharmacological action sees the following specific embodiment for details.
The specific embodiment
Embodiment 1: lisinopril/hydrochlorothiazide+folic acid is to the protective effect of apoplexy susceptible type spontaneous hypertensive rat (SHRsp) target organ damage
10～12 age in week SHRsp respectively available from Shanghai City hypertension institute, Fuwai Hospital's Experimental Animal Center, raise in room temperature (23 ± 2) ℃ relative humidity (50 ± 10) %, each 12h of illumination light and shade, the standard feed of freely ingesting.Measure blood pressure before the test, according to blood pressure values, SHRsp is divided into model group, lisinopril/hydrochlorothiazide (1mg/kg+1.25mg/kg) group, lisinopril/hydrochlorothiazide+folic acid (1mg/kg+1.25mg/kg+0.04mg/kg) group, and other establishes the WKY matched group, 30 every group.Gastric infusion is weighed weekly once every day 1 time, adjusts dose, continuous 20 weeks according to body weight.Observation index:
(1) observes animal diet followed, survival condition and behavioral activity every day, write down each treated animal cerebral seizure number and reach duration of seizure first.
(2) all rats of pathological observation are all got cerebral tissue, and cerebral hemorrhage, cerebral infarction or Combination apoplexy are observed in section, HE dyeing, calculate and respectively organize the rat brain stroke incidence.
(3) row aorta intubate behind the rat anesthesia, the perfusion of 2.5% glutaraldehyde is fixing, and broken end is got brain, separates skull base arterial ring and intraparenchymatous small artery of brain and arteriole, and 2.5% glutaraldehyde is fixed, embedding, section, Toluidine blue staining.Computer pathology image analysis system is measured media thickness, the lumen diameter footpath of blood vessel, calculates the ratio of media thickness/lumen diameter, and 10 blood vessels are surveyed in every section.
The result: in the phase, the model group rat amounts to, and 12 of apoplexy take place at experimental observation, and histopathology is observed, and amounts to 24 of apoplexy, 12 of its midbrains hemorrhage, 9 of cerebral infarctions, 3 of Combination apoplexy take place.Apoplexy kitchen range and all visible on every side small artery hyaline degeneration or fibrinoid necrosis, tube wall thickens, and all oozings of blood are managed in visible microthrombusis in the luminal stenosis, the tube chamber that has.Lisinopril/hydrochlorothiazide group, lisinopril/hydrochlorothiazide+folic acid group rat brain stroke incidence all significantly reduce, and duration of seizure postpones.Lisinopril/hydrochlorothiazide+folic acid group apoplexy incidence rate further reduces, and sees Table 1.
Table 1 lisinopril/hydrochlorothiazide+20 weeks of folic acid successive administration are to the influence of apoplexy susceptible type spontaneous hypertensive rat apoplexy
Group Dosage (mg/kg) Number of animals Apoplexy generation number (incidence rate) Duration of seizure (my god, with the on-test Time Calculation) first Histopathology is observed number (incidence rate) is taken place
Normal group - 29 0(0％) 1(3.4％)
Model group - 28 12(42.9％) 37、56、 60、73、80、94、94、107、115、123、135、135(92±32) 24(85.7％) **
Lisinopril+hydrochlorothiazide 1+1.25 ?27 6(22.2％) 74、74、88、126、126(97.6±26.5) 10(37.0％) ▲▲
Lisinopril+hydrochlorothiazide+folic acid 1+1.25+ 0.04 29 4(13.8％) ▲ 98、130、138(122±21) 6(20.7％) ▲▲
Compare with normal group, *P＜0.01; Compare with model group, ▲P＜0.05; ▲ ▲P＜0.01
Cerebrovascular that hypertension causes changes, and shows as mainly that the tube wall middle level thickens, the inner membrance vitreous degeneration, endotheli ocytosis, and blood vessel wall thickness/tube chamber ratio reduces.Compare with normal rats, model group rat brain tunica media of artery thickness increases, and lumen diameter reduces, and media thickness/lumen diameter is than increasing.Compare with hypertension group, lisinopril/hydrochlorothiazide group rat brain tunica media of artery thickness, media thickness/lumen diameter are than reducing, lisinopril/hydrochlorothiazide+folic acid group cerebral arteries media thickness, media thickness/lumen diameter relatively have significant difference than further reducing with lisinopril/hydrochlorothiazide group.See Table 2.
Table 2 lisinopril/hydrochlorothiazide+20 weeks of folic acid successive administration are to the arteriocerebral influence of apoplexy susceptible type spontaneous hypertensive rat
Figure S2007101657788D00061
Group Dosage (mg/kg) Number of animals Media thickness (μ m) Lumen diameter (μ m) Media thickness/lumen diameter (%)
Normal group - 29 ?12.3±3.1 103.9±17.0 12.4±3.0
Model group - 28 ?50.4±8.2 ** 90.7±10.7 ** 56.6±7.9 **
Lisinopril+hydrochlorothiazide 1+1.25 27 ?36.8±5.6 ▲▲ 100.5±12.5 ▲▲ 36.8±9.3 ▲▲
Lisinopril+hydrochlorothiazide+folic acid 1+1.25+ 0.04 29 ?32.6±4.7 ▲▲ 112.3±16.5 ▲▲ 27.9±6.5 ▲▲★★
Compare with normal group, *P＜0.01; Compare with model group, ▲ ▲P＜0.01; Compare with lisinopril/hydrochlorothiazide group, ★ ★P＜0.01
Embodiment 2: enalapril/hydrochlorothiazide+folic acid is to the protective effect of apoplexy susceptible type spontaneous hypertensive rat (SHRsp) target organ damage
Employing SHRsp in 10～12 age in week according to blood pressure values, is divided into model group, enalapril/hydrochlorothiazide (1+1.25mg/kg) group, enalapril/hydrochlorothiazide+folic acid (1+1.25+0.08mg/kg) group with SHRsp, and other establishes the WKY matched group, 30 every group.Gastric infusion, every day 1 time, continuous 20 weeks.
Observe animal diet followed, survival condition and behavioral activity every day, write down each treated animal cerebral seizure number.Row aorta intubate behind the rat anesthesia, the perfusion of 2.5% glutaraldehyde is fixing, and broken end is got brain, separates skull base arterial ring and intraparenchymatous small artery of brain and arteriole, and 2.5% glutaraldehyde is fixed, embedding, section, Toluidine blue staining.Computer pathology image analysis system is measured media thickness, the lumen diameter footpath of blood vessel, calculates the ratio of media thickness/lumen diameter, and 10 blood vessels are surveyed in every section.The desirable rat that gets pathological tissue of all surviving animals and dead back is all got cerebral tissue, and cerebral hemorrhage, cerebral infarction or Combination apoplexy are observed in section, HE dyeing, calculate and respectively organize the rat brain stroke incidence.
The result:
(1) in the overview experimentation, obvious lethargy appears after the model group rat apoplexy, drowsiness, hair is fluffy, withered or come off, tarnish, weight loss, active movement obviously reduces, be slow in action, limbs are in various degree paralysis, and with symptoms such as tic, diarrhoea, urinary incontinence, eyeball are hemorrhage, the person of being in a bad way is dead in a few hours simultaneously for the morbidity of part rat.Most of animal nerve functional impairment of treatment group is slight than model group, and the mental status obviously is better than model group, and autonomic activities increases, and initiatively looks for food, drinks water, and weight loss is not obvious, and hair is also glossy along sliding than model group.
(2) apoplexy incidence rate normal group has 1 apoplexy takes place, 1 improper unexpected death of administration in 30 rats of model group, 14 apoplexy takes place, except that 3 animals, other 27 animals have all carried out the histopathology observation, and totally 22 have only apoplexy that 10 of its midbrains hemorrhage take place, 6 of cerebral infarctions, 6 of Combination apoplexy.Apoplexy kitchen range and all visible on every side small artery hyaline degeneration or fibrinoid necrosis, tube wall thickens, and all oozings of blood are managed in visible microthrombusis in the luminal stenosis, the tube chamber that has.Enalapril/30 rats of hydrochlorothiazide group have 9 apoplexy takes place; Histopathology is observed totally 15 and is had only apoplexy to take place, and relatively there were significant differences (P＜0.05) with model group.In enalapril/hydrochlorothiazide+30 rats of folic acid group, there are 5 apoplexy takes place; Histopathology observation 29 has been merely hit 7 apoplexy has been taken place, and has significance (P＜0.05) with the model group comparing difference, compares with enalapril/hydrochlorothiazide group, and enalapril/hydrochlorothiazide+folic acid group rat brain stroke incidence further reduces.See Table 3.
Table 3 enalapril/hydrochlorothiazide+20 weeks of folic acid successive administration are to the influence of SHRsp rat brain apoplexy
Group Dosage (mg/kg) Apoplexy generation number/actual observation number Histopathology is observed apoplexy generation number/actual observation number
The matched group model group **Enalapril/hydrochlorothiazide enalapril/hydrochlorothiazide+folic acid - - 1+1.25 1+1.25 +0.08 0/30 14/29 ** 9/30 5/30 ▲▲ 1/30 22/27 ** 15/30 ▲ 7/29 ▲▲★
x 2Check is compared with normal group, *P＜0.01; Compare with model group, ▲P＜0.05, ▲ ▲P＜0.05
Compare with enalapril/hydrochlorothiazide group, ★P＜0.05
(3) influence the cerebrovascular that hypertension causes and change the SHRsp rat is arteriocerebral, show as mainly that the tube wall middle level thickens, the inner membrance vitreous degeneration, endotheli ocytosis, blood vessel wall thickness/tube chamber ratio reduces.Compare with normal rats, model group rat brain tunica media of artery thickness increases, and lumen diameter reduces, and media thickness/lumen diameter is than increasing.Compare with model group, enalapril/hydrochlorothiazide group rat brain tunica media of artery thickness, media thickness/lumen diameter are than reducing, enalapril/hydrochlorothiazide+folic acid group cerebral arteries media thickness, media thickness/lumen diameter relatively have significant difference than further reducing with enalapril/hydrochlorothiazide group.See Table 4.
Table 4 enalapril/hydrochlorothiazide+20 weeks of folic acid successive administration are to the arteriocerebral influence of apoplexy susceptible type spontaneous hypertensive rat
Figure S2007101657788D00071
Group Dosage (mg/kg) Number of animals Media thickness (μ m) Lumen diameter (μ m) Media thickness/lumen diameter (%)
Matched group model group enalapril/hydrochlorothiazide enalapril/hydrochlorothiazide+folic acid --1+1.25?1+1.25+0.08 28 25 26 27 ?19.3±4.0?55.4±8.5 **?42.8±7.1 ▲▲ 35.6±6.3 ▲▲★★ 104.3±18.576.5±9.7 **84.3±13.2 ▲▲?85.1±14.6 ▲▲ 18.8±4.1 73.1±11.1 ** 51.6±7.3 ▲▲ 41.5±6.8 ▲▲★★
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲ ▲P＜0.01; Compare with enalapril/hydrochlorothiazide group, ★ ★P＜0.01
Embodiment 3: perindopril/hydrochlorothiazide+folic acid is to the blood pressure lowering of renal hypertensive rat and the protective effect of target organ damage
With the narrow Wistar rat of 0.2mm silver brain clip left renal artery, it is hypertension animal model that the back rat blood pressure rising of 8～10 weeks surpasses 140mmHg above.According to the rat blood pressure level, Hypertensive Rats is divided into model group, perindopril/hydrochlorothiazide (0.4+1.25mg/kg) group, perindopril/hydrochlorothiazide+folic acid (0.4+1.25+0.04mg/kg) group, perindopril/hydrochlorothiazide+folic acid (0.4+1.25+0.08mg/kg) group, folic acid (0.08mg/kg) group at random, other establishes the normal control group, every group 20, gastric infusion, is weighed weekly once at every day 1 time, adjust dose, continuous 26 weeks according to body weight.Observation index:
(1) measures before the administration and different time blood pressure after the administration, calculate blood pressure lowering amplitude (systolic pressure before the=administration-administration after-contraction is pressed).
(2) 26 weekends of inner skin cell function, get blood and measure blood plasma nitric oxide (NO), Endothelin (ET) level by the test kit description.
(3) 26 weekends of renal function, collect urine, survey 24h urine creatine, urine protein, 24h urine α 1 microglobulin; Get blood, measure serum creatinine, blood urea nitrogen (BUN), serum calculates creatinine clearance rate (Ccr).
(4) after the administration of hemodynamics last 1 hour, 20% urethane (1g/kg ip) anesthesia, it is fixing to face upward the position, separate right carotid, insert one and be full of the heparin-saline conduit,, connect the RM6240BD type and lead the physiological signal acquisition processing system more by pressure transducer to left ventricle, stablize 10min, 3 hours left chamber peak pressure meansigma methodss (LVSP) behind the record medicine, left chamber end diastolic pressure (LVEDP), the maximum rate of change in left chamber (± dp/dtmax).
(5) behind the heavy assessment of indices cardiac function in left chamber, get rat heart, clean, separate left ventricle (comprising interventricular septum), weigh, calculate the heavy index (left ventricle mg/ body weight g) in left chamber with pre-cold saline.
(6) after myocardium hydroxyproline determination rat is put to death, get the left chamber about 50mg of cardiac muscular tissue, adopt the Bergman method to measure hydroxyproline content, and calculate collagen content.Collagen content=8.2 * hydroxyproline content (mg/g).
Statistical analysis: measurement data is used
Figure S2007101657788D00081
The t check is relatively adopted in expression between two groups.
The result: compare with normal rats, hypertension group rat systolic pressure significantly raises; Compare with hypertension group, folic acid group rat systolic pressure makes moderate progress, perindopril/hydrochlorothiazide group and perindopril/hydrochlorothiazide+folic acid (0.04,0.08mg/kg) group rat systolic pressure all significantly reduces, but with perindopril/hydrochlorothiazide group relatively, perindopril/hydrochlorothiazide+folic acid (0.04,0.08mg/kg) group blood pressure lowering amplitude does not have significant difference.
Compare with normal rats, hypertension group rat plasma NO level reduces, the ET level raises, compare with hypertension group, folic acid group, perindopril/hydrochlorothiazide group rat plasma NO raise, ET reduces, perindopril/hydrochlorothiazide+folic acid (0.04,0.08mg/kg) group rat plasma NO further raises, and ET further reduces, and relatively there were significant differences with perindopril/hydrochlorothiazide group.Show: significant blood vessel inner skin cell function appears in renal hypertensive rat to be reduced, and perindopril/hydrochlorothiazide, folic acid have protective effect to the rat aorta inner skin cell function, and both share Vascular Endothelial is significantly strengthened.See Table 5.
Table 5 perindopril/hydrochlorothiazide+folic acid gastric infusion, continuous 26 weeks are to the influence of renal hypertensive rat blood pressure, serum NO level, ET level
Figure S2007101657788D00082
Group Dosage (mg/kg) Quantity (n) Blood pressure lowering amplitude (mmHg) NO(mmol/L) ET(pg/ml)
Normal group - 18 -5.3±4.6 84.2±18.5 124.6±23.9
Hypertension - 16 -20.1±8.1 ** 44.3±10.2 ** 190.5±41.8 **
Perindopril/hydrochlorothiazide+folic acid 0.4+1.25 +0.04 16 28.3±7.4 ▲▲ 70.6±13.6 ▲▲★ 138.44±22.6 ▲▲★
Perindopril/hydrochlorothiazide+folic acid 0.4+1.25 +0.08 17 34.0±10.4 ▲▲ 68.6±10.3 ▲▲★ 140.6±18.1 ▲▲★
Perindopril/hydrochlorothiazide 0.4+1.25 17 26.6±6.5 ▲▲ 58.5±8.5 ▲▲ 160.2±20.8 ▲
Folic acid 0.08 16 -12.4±4.9 ▲ 54.7±9.2 ▲ 168.3±38.9
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲P＜0.05, ▲ ▲P＜0.01: compare with perindopril/hydrochlorothiazide group, ★P＜0.05
Compare with normal rats, hypertension group rat urine 24h α 1-microglobulin, urine protein, BUN significantly raise, and Ccr obviously reduces.With hypertension group relatively, perindopril/hydrochlorothiazide group, perindopril/hydrochlorothiazide+folic acid (0.04,0.08mg/kg) group rat urine 24h α 1-microglobulin, urine protein reduce, Ccr raises.The folic acid list is used does not have obvious influence to the renal hypertensive rat renal function.Perindopril/hydrochlorothiazide+folic acid (0.04,0.08mg/kg) group rat urine 24h α 1-microglobulin, urine protein further reduce, and Ccr further raises, and with perindopril/hydrochlorothiazide group significant difference is arranged relatively.Show that early stage renal function injury appears in renal hypertensive rat; perindopril/hydrochlorothiazide has protective effect to the renal function injury of renal hypertensive rat; folic acid and perindopril/hydrochlorothiazide share, and the protecting renal function effect of renal hypertensive rat is significantly strengthened.See Table 6.
Table 6 perindopril/hydrochlorothiazide+26 weeks of folic acid successive administration are to the influence of renal hypertensive rat urine α 1-microglobulin, urine protein, blood inosine clearance rate, blood urea nitrogen
Figure S2007101657788D00091
Group Dosage (mg/kg) Quantity (n) 24hα 1-microglobulin (μ g/d) Urine protein (mg/d) Ccr(ml/min) BUN(mmol/L)
Normal group - 18 3.2±2.4 2.3±0.8 0.35±0.10 7.14±1.32
Hypertension - 16 25.7±6.1 ** 9.3±3.1 ** 0.12±0.03 ** 10.20±3.05 **
Perindopril/hydrochlorothiazide+folic acid 0.4+1.25 +0.04 16 15.0±2.6 ▲▲★ 5.6±1.1 ▲▲★ 0.22±0.04 ▲▲★ 8.25±2.12
Perindopril/hydrochlorothiazide+folic acid 0.4+1.25 +0.08 17 14.8±3.2 ▲▲★ 5.3±1.4 ▲▲★★ 0.24±0.04 ▲▲★★ 8.10±1.62
Perindopril/hydrochlorothiazide 0.4+1.25 17 18.5±4.1 ▲▲ 6.9±1.6 ▲▲ 0.19±0.03 ▲▲ 7.97±1.60
Folic acid 0.08 16 21.8±3.9 7.8±1.8 0.30±0.04 8.67±1.96
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲P＜0.05, ▲ ▲P＜0.01;
Compare with perindopril/hydrochlorothiazide group, ★P＜0.05, ★ ★P＜0.01
Compare with normal group, the heavy index of hypertension group rat left chamber obviously increases; With hypertension group relatively, the folic acid list uses that the heavy and heavy index in chamber does not have obvious influence, perindopril/hydrochlorothiazide group, all significantly reductions of the heavy index in perindopril/hydrochlorothiazide+folic acid group rat chamber to the renal hypertensive rat left side heart; Compare perindopril/hydrochlorothiazide+folic acid group no significant difference with perindopril/hydrochlorothiazide group.Show: the myocardium of left ventricle plumpness appears in the hypertension group rat.Perindopril/hydrochlorothiazide, perindopril/hydrochlorothiazide+folic acid group leader phase administration can prevent the rat heart muscle plumpness, and it is stronger that the drug combination group is improved the effect of left ventricular hypertrophy.
Remodeling ventricle is hypertensive important pathological change, mainly shows as myocardial cell propagation, hypertrophy and interstitial fibrosis, and hydroxyproline is peculiar by collagen fiber, and its content can reflect fibrosis.Compare with normal group, hypertension group rat heart muscle collagen content significantly raises.Compare with hypertension group, perindopril/hydrochlorothiazide group rat heart muscle collagen content significantly reduces, and perindopril/hydrochlorothiazide+folic acid group rat heart muscle collagen content further reduces, and with perindopril/hydrochlorothiazide group significant difference is arranged relatively.See Table 7.
Compare with normal rats, hypertension group rat LVSP, LVEDP significantly raise, and ± dp/dtmax descends.Compare with hypertension group, perindopril/hydrochlorothiazide group, perindopril/hydrochlorothiazide+folic acid group rat LVSP, LVEDP significantly reduce, and ± dp/dtmax raises.The folic acid list is used does not have obvious influence to the renal hypertensive rat hemodynamics.Perindopril/hydrochlorothiazide+folic acid (0.04,0.08mg/kg) group rat LVSP, LVEDP further reduce, and ± dp/dtmax further raises, and relatively there were significant differences with perindopril/hydrochlorothiazide group.Show that renal hypertensive rat cardiac preload, afterload increase; heart contraction, diastolic dysfunction; perindopril/hydrochlorothiazide has protective effect to the cardiac function infringement of renal hypertensive rat; folic acid and perindopril/hydrochlorothiazide share, and the cardiac function protective effect of renal hypertensive rat is significantly strengthened.See Table 8.
The influence that table 7 perindopril/hydrochlorothiazide+26 weeks of folic acid successive administration are heavy to the renal hypertensive rat left ventricle, the chamber weighs index, myocardial collagen protein content
Group Dosage (mg/kg) Quantity (n) Left ventricular mass (mg) The heavy index (mg/g) in chamber Myocardial collagen content (mg/g)
Normal group - 18 670.7±88.9 1.63±0.35 1.03±0.33
Hypertension - 16 936.4±136.7 ** 2.55±0.42 ** 1.96±0.43 **
Perindopril/hydrochlorothiazide+folic acid 0.4+1.25 +0.04 16 748.8±106.4 ▲▲ 1.92±0.34 ▲▲ 1.38±0.24 ▲▲★
Perindopril/hydrochlorothiazide+folic acid 0.4+1.25+ 0.08 17 736.3±126.6 ▲▲ 1.85±0.32 ▲▲ 1.42±0.18 ▲▲★
Perindopril/hydrochlorothiazide 0.4 17 799.1±159.1 ▲▲ 2.11±0.39 ▲▲ 1.62±0.22 ▲▲
Folic acid 0.08 16 885.2±218.6 2.30±0.45 1.88±0.41
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲ ▲P＜0.01; Compare with perindopril/hydrochlorothiazide group, ★P＜0.05
Table 8 perindopril/hydrochlorothiazide+26 weeks of folic acid successive administration are to the hemodynamic influence of renal hypertensive rat
Figure S2007101657788D00102
Group Dosage (mg/kg) Quantity (n) ?LVSP?(mmHg) LVEDP (mmHg) +dp/dtmax (mmHg/s×10 3) -dp/dtmax (mmHg/s×10 3)
Normal group - 16 ?129±13 -2±8 12.4±2.5 8.7±1.2
Hypertension - 16 ?188±30 ** 29±14 ** 7.3±2.1 ** 5.0±1.5 **
Perindopril/hydrochlorothiazide+folic acid 0.4+1.25 +0.04 14 ?142±17 ▲▲ -0±6 ▲▲★★ 11.5±2.4 ▲▲★ 7.3±1.4 ▲▲
Perindopril/hydrochlorothiazide+folic acid 0.4+1.25 +0.08 15 ?137±19 ▲▲ 2±5 ▲▲★★ 11.5±2.1 ▲▲★ 7.7±1.3 ▲▲★
Perindopril/hydrochlorothiazide 0.4+1.25 15 ?152±23 ▲▲ 10±3 ▲▲ 9.5±1.9 ▲▲ 6.6±1.1 ▲▲
Folic acid 0.08 16 ?177±26 20±9 8.8±2.2 5.6±1.6
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲ ▲P＜0.01; Compare with perindopril/hydrochlorothiazide group, ★P＜0.05, ★ ★P＜0.01
Embodiment 4: imidapril/indapamide+folic acid is to the protective effect of spontaneous hypertensive rat blood pressure lowering and target organ damage
Spontaneous hypertensive rat (SHR) is respectively available from Shanghai Slac Experimental Animal Co., Ltd. (credit number: SCXK (Shanghai) 2003-0003), Beijing Vital River Experimental Animals Technology Co., Ltd. (credit number: SCXK (capital) 2002-0003), and at this chamber captive breeding, standby.Rat blood pressure raises after 8～10 ages in week, measures 1 week of rat blood pressure (the 1st, 6 day), and the rat of getting blood pressure stabilization is used for experiment.Hypertensive Rats grouping and dosage see Table 7, and other establishes WKY normal control group, 20 every group.Gastric infusion is weighed weekly once every day 1 time, adjusts dose, continuous 26 weeks according to body weight.Observation index:
(1) measure before the administration and different time blood pressure after the administration, calculate blood pressure lowering amplitude=administration before systolic pressure-administration after-contraction press.
(2) 26 weekends of inner skin cell function, get blood by the test kit description, measure serum levels of nitric oxide (NO), Endothelin (ET) level.
(3) renal function is collected urine, in spectrophotometric determination urine protein concentration, calculates the 24h urine albumen amount with sulfosalicylic acid method.Put the method for exempting from and measure 24h urine α 1 microglobulin, measure urine creatine according to the test kit description; Get blood, measure serum creatinine, blood urea nitrogen (BUN), calculate creatinine clearance rate (Ccr).
(4) the heavy and heavy index in chamber of left ventricle is got rat heart, cleans with pre-cold saline, separates left ventricle (comprising interventricular septum), claims left ventricle to weigh, and counting chamber weighs index (left ventricle mg/ body weight g).
(5) after myocardium hydroxyproline determination rat is put to death, get the left chamber about 50mg of cardiac muscular tissue, adopt the Bergman method to measure hydroxyproline content, and calculate collagen content.Collagen content=8.2 * hydroxyproline content (mg/g).
(6) the conventional section of myocardium pathological examination cardiac muscular tissue, Sirius is red-picric acid dyeing, measure myocardial collagen fraction by volume (CVF) and myocardial vascular area of collagen (PVCA) on every side.CVF is the ratio of the area of collagen and the myocardium gross area, and wherein area of collagen does not comprise PVCA, and its average is got in 5 visuals field of stochastic analysis.PVCA measures 4 ratios that are interior arteriolar surrounding area of cross section wall and tube chamber area for each specimen, gets its average.
(7) after the histological observation of Mesenteric artery is put to death rat, get superior mesenteric artery second-order branching 5mm (from the ileocecus inverse, 5mm in the middle of second branched second-order branching of superior mesenteric artery), put in 10% neutral formalin fixing, conventional dehydration, embedding, slice thick 5 μ m, HE dyeing, every tremulous pulse is cut 5 cross sections, om observation is carried out in the cross section section of selection standard, utilizes collecting image of computer system and analytical system to analyze, at the unified microscopically that amplifies 10 * 40 times, measure little tunica media thickness, internal diameter calculates media thickness/lumen diameter (W/L) ratio.
Statistical analysis: measurement data is used
Figure S2007101657788D00111
The t check is relatively adopted in expression between two groups.
The result: compare with normal rats, the hypertension group rat blood pressure significantly raises; With hypertension group relatively, folic acid group rat blood pressure makes moderate progress, imidapril/indapamide group and imidapril/indapamide+folic acid (0.04,0.08mg/kg) group rat blood pressure all significantly reduces; Compare with imidapril/indapamide group, the blood pressure lowering amplitude of imidapril/indapamide+folic acid (0.08mg/kg) group rat systolic pressure has significant difference.
The inner skin cell function imbalance is subjected to extensive concern as the early sign of cardiovascular infringement, and endothelial cell activity mark (nitric oxide and metabolite thereof, Endothelin etc.) research can be used as a kind of straightforward procedure that detects endothelial function.Compare with normal rats, hypertension group rat blood serum NO level significantly reduces, the ET level significantly raises, compare with hypertension group, folic acid group, imidapril/indapamide group rat plasma NO raise, ET reduces, imidapril/indapamide+folic acid (0.04,0.08mg/kg) group rat plasma NO further raises, and ET further reduces, and with imidapril/indapamide group significant difference is arranged relatively.Show: significant blood vessel inner skin cell function infringement appears in spontaneous hypertensive rat, and imidapril/indapamide, folic acid have protective effect to the rat aorta inner skin cell function, and both share protective effect and significantly strengthen.See Table 9.
Twenty-four-hour urine α 1 microglobulin is the label of the early stage proximal convoluted tubule of reflection infringement, and albuminuria is except that as a kind of kidney damage sign, a kind of especially independent hazard factor that promotes the nephropathy progress.Compare with normal group, hypertension group rat urine 24h α 1-microglobulin, urine protein significantly raise, Ccr obviously reduces, BUN raises, compare with hypertension group, imidapril/indapamide group, imidapril/indapamide+folic acid (0.04,0.08mg/kg) group rat urine 24h α 1-microglobulin, urine protein reduce, Ccr raises, BUN reduces, and the folic acid list is used does not have obvious influence to the spontaneous hypertensive rat renal function injury.Imidapril/indapamide+folic acid (0.04,0.08mg/kg) group rat urine 24h α 1-microglobulin, urine protein further reduce, and Ccr further raises, and with imidapril/indapamide group significant difference is arranged relatively.It is early stage to show that spontaneous hypertensive rat occurs.Renal function injury, imidapril/indapamide has protective effect to the renal function injury of spontaneous hypertensive rat, and folic acid and imidapril/indapamide share, and the protecting renal function effect of spontaneous hypertensive rat is significantly strengthened.See Table 10
Continuous 26 weeks of table 9 imidapril/indapamide+folic acid gastric infusion are to the influence of spontaneous hypertensive rat blood pressure, serum NO level, ET
Figure S2007101657788D00121
Group Dosage (mg/kg) Quantity (n) Blood pressure lowering amplitude (mmHg) NO (mmol/L) ET (pg/ml)
Normal group - 17 -3.9±4.1 50.6±10.2 174.6±40.3
Hypertension - 15 -16.9±4.8 ** 20.6±4.3 ** 302.4±51.6 **
Imidapril/indapamide+folic acid 1+0.25+0.04 18 30.0±6.2 ▲▲ 34.4±6.5 ▲▲★★ 185.9±34.7 ▲▲★★
Imidapril/indapamide+folic acid 1+0.25+0.08 16 32.5±8.2 ▲▲★ 32.8±4.6 ▲▲★ 193.2±40.9 ▲▲★
Imidapril/indapamide 1+0.25 17 25.6±5.8 ▲▲ 27.8±5.1 ▲▲ 232.1±30.6 ▲▲
Folic acid 0.08 16 -10.8±4.6 ▲ 25.0±4.9 ▲ 268.7±54.8
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲P＜0.05, ▲ ▲P＜0.01;
Compare with imidapril/indapamide group, ★P＜0.05, ★ ★P＜0.01
Table 10 imidapril/indapamide+26 weeks of folic acid successive administration are urinated α to spontaneous hypertensive rat 1The influence of-microglobulin, urine protein, blood inosine clearance rate, blood urea nitrogen
Figure S2007101657788D00122
Group Dosage (mg/kg) Number of animals Urine protein (mg) 24hα 1-microglobulin (μ g) Ccr (ml/min) BUN(mmol/L)
Normal group - 17 ?1.4±2.1 10.1±3.1 0.654±0.102 5.20±0.84
Hypertension - 15 ?10.5±3.9 ** 48.8±13.2 ** 0.314±0.058 ** 7.53±1.58 **
Imidapril/indapamide+folic acid 1+0.25+0.04 18 ?5.4±1.8 ▲▲★ 29.9±6.2 ▲▲★ 0.426±0.052 ▲▲ 6.67±0.89
Imidapril/indapamide+folic acid 1+0.25+0.08 16 ?5.3±1.5 ▲▲★ 28.3±5.3 ▲▲★★ 0.462±0.032 ▲▲★★ 6.07±0.64 ▲▲
Imidapril/indapamide 1+0.25 17 ?7.3±2.4 ▲ 36.6±8.7 ▲▲ 0.386±0.049 ▲▲ 6.72±0.76 ▲
Folic acid 0.08 16 ?9.2±3.4 40.2±9.1 0.366±0.051 7.35±1.02
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲P＜0.05, ▲ ▲P＜0.01;
Compare with imidapril/indapamide group, ★P＜0.05, ★ ★P＜0.01
Compare with normal group, the hypertension group rat left side heart weighs and the heavy index in chamber obviously increases; The folic acid list uses that the heavy and heavy index in chamber has the trend that alleviates to the spontaneous hypertensive rat left side heart, and imidapril/indapamide group, imidapril/indapamide+folic acid group rat left side heart is heavy and the heavy index in chamber all significantly reduces, and compares with hypertension group that there were significant differences; Compare with imidapril/indapamide group, imidapril/indapamide+folic acid group rat left side heart weighs and the heavy index in chamber further reduces.Show: the myocardium of left ventricle plumpness appears in the hypertension group rat, and imidapril/indapamide group, imidapril/indapamide+folic acid group leader phase administration can prevent the rat heart muscle plumpness, and it is stronger that the drug combination group is improved the effect of left ventricular hypertrophy.See Table 11.
Remodeling ventricle is hypertensive important pathological change, mainly shows as myocardial cell propagation, hypertrophy and interstitial fibrosis, and hydroxyproline is peculiar by collagen fiber, and its content can reflect fibrosis.Compare with normal group, hypertension group rat heart muscle collagen content significantly raises.Compare with hypertension group, imidapril/indapamide group rat heart muscle collagen content significantly reduces, and imidapril/indapamide+folic acid group rat heart muscle collagen content further reduces, and with imidapril/indapamide group significant difference is arranged relatively.See Table 11.
The influence that table 11 imidapril/indapamide+26 weeks of folic acid successive administration are heavy to the spontaneous hypertensive rat left ventricle, the chamber weighs index, myocardial collagen protein content
Figure S2007101657788D00131
Group Dosage (mg/kg) Number of animals Left ventricular mass (mg) The heavy index (mg/g) in chamber Myocardial collagen content (mg/g)
Normal group - 17 820.3±156.2 2.12±0.32 3.18±0.47
Hypertension - 15 1102.4±215.1 ** 3.73±0.44 ** 6.39±1.26 **
Imidapril/indapamide+folic acid 1+0.25+0.04 18 842.6±156.2 ▲▲ 3.03±0.32 ▲▲ 4.75±0.38 ▲▲★
Imidapril/indapamide+folic acid 1+0.25+0.08 16 828.5±127.9 ▲▲ 2.86±0.38 ▲▲ 4.59±0.45 ▲▲★
Imidapril/indapamide 1+0.25 17 867.8±145.6 ▲▲ 3.12±0.43 ▲▲ 5.26±0.73 ▲▲
Folic acid 0.08 16 965.8±167.4 3.33±0.46 6.07±1.18
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲ ▲P＜0.01; Compare with imidapril/indapamide group, ★P＜0.05
Compare with normal rats, fibrosis index PVCA all significantly increases around hypertension group rat heart muscle interstitial fibrosis index CVF, the myocardial vascular, and CVF and PVCA raise almost synchronous, show that myocardium interstitial fibrosis has participated in the pathological process of SHR cardiac remodeling.Compare with hypertension group, imidapril/indapamide group rat heart muscle CVF, PVCA all significantly reduces, and imidapril/indapamide+folic acid group rat heart muscle CVF, PVCA further reduces, and with imidapril/indapamide group significant difference arranged relatively.See Table 12.
Table 12 imidapril/indapamide+26 weeks of folic acid successive administration are to the influence of area of collagen (PVCA) around spontaneous hypertensive rat myocardial collagen fraction by volume (CVF) and the myocardial vascular
Group Dosage (mg/kg) Number of animals CVF(％) PVCA(％)
The WKY group - 17 1.11±0.24 0.84±0.17
Hypertension group - 15 3.48±0.60 ** 2.68±0.47 **
Imidapril+draw reaches handkerchief amine+folic acid 1+0.25+0.04 18 2.44±0.36 ▲▲★★ 1.89±0.30 ▲▲
Imidapril+indapamide+folic acid 1+0.25+0.08 16 2.53±0.42 ▲▲★ 1.83±0.24 ▲▲★
Imidapril+indapamide 1+0.25 17 2.94±0.38 ▲▲ 2.17±0.36 ▲▲
Folic acid 0.08 16 3.24±0.36 2.50±0.48
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲ ▲P＜0.01;
Compare with imidapril/indapamide group, ★P＜0.05, ★ ★P＜0.01
The blood vessel that hypertension causes changes, and mainly shows as the fibrosis of blood vessel wall adventitia, and the tube wall middle level thickens (due to being increased by smooth muscle cell proliferation, plumpness and intercellular substance); Inner membrance vitreous degeneration, endotheli ocytosis, above-mentioned variation reduce blood vessel wall thickness/tube chamber ratio, and diastolic function is limited, and the reserve function of arteria coronaria descends.Compare with normal rats, hypertension group rat mesenteric artery media thickness increases, and internal diameter reduces, and middle film/internal diameter is than increasing.Compare with hypertension group, imidapril/indapamide group rat mesenteric artery media thickness and middle film/internal diameter is than all reducing, imidapril/indapamide+folic acid group rat mesenteric artery media thickness and middle film/internal diameter relatively has significant difference than all further reducing with imidapril/indapamide group.See Table 13.
Table 13 imidapril/indapamide+26 weeks of folic acid successive administration are to the influence of spontaneous hypertensive rat Mesenteric artery
Figure S2007101657788D00141
Group Dosage (mg/kg) Number of animals Media thickness (μ m) Vessel diameter (μ m) Media thickness/internal diameter (%)
Normal group - ?17 35.2±7.6 278.6±46.8 13.0±3.2
Hypertension - ?15 54.5±10.5 ** 188.3±28.6 ** 30.6±6.1 **
Imidapril/indapamide+folic acid 1+0.25+ 0.04 ?18 40.2±6.5 ▲▲ 243.8±32.4 ▲▲ 16.2±3.3 ▲▲★★
Imidapril/indapamide+folic acid 1+0.25+ 0.08 ?16 37.7±6.1 ▲▲★ 257.4±26.9 ▲▲ 14.8±2.9 ▲▲★★
Imidapril/indapamide 1+0.25 ?17 44.6±8.3 ▲▲ 220.6±33.9 ▲▲ 20.6±3.9 ▲▲
Folic acid 0.08 ?16 50.6±10.3 205.4±27.2 25.4±5.2
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲ ▲P＜0.01;
Compare with imidapril/indapamide group, ★P＜0.05, ★ ★P＜0.01
Embodiment 5: benazepril/spironolactone+levoleucovorin calcium is to the protective effect of spontaneous hypertensive rat target organ damage
1 week of rat blood pressure is measured in spontaneous hypertensive rat (SHR) rat blood pressure rising after 8～10 ages in week, and the rat of getting blood pressure stabilization is used for experiment.According to blood pressure values, SHR is divided into model group, benazepril/spironolactone (1+4mg/kg) group, benazepril/spironolactone+levoleucovorin calcium (1+4+0.02mg/kg), benazepril/spironolactone+levoleucovorin calcium (1+4+0.04mg/kg) group, levoleucovorin calcium group (0.04mg/kg), other establishes WKY normal control group, every group 20, gastric infusion, every day 1 time, continuous 26 weeks.At 26 weekends, get hematometry serum levels of nitric oxide (NO), Endothelin (ET) level; Collect urine, measure 24h urine α 1 microglobulin, urine creatine, serum creatinine, calculate creatinine clearance rate (Ccr); Get rat heart, measure the heavy and heavy index in chamber of the left heart; Measure hydroxyproline content and calculate collagen content; The conventional section of cardiac muscular tissue, Sirius is red-picric acid dyeing, measure myocardial collagen fraction by volume (CVF) and myocardial vascular area of collagen (PVCA) on every side; Small artery internal diameter, media thickness are measured in the section of Mesenteric artery secondary branch, calculate media thickness/internal diameter ratio.Measurement data is used
Figure S2007101657788D00142
The t check is relatively adopted in expression between two groups.
Result: compare with hypertension group, levoleucovorin calcium group, benazepril/spironolactone group rat plasma NO raise, ET reduces, benazepril/spironolactone (1+4mg/kg)+levoleucovorin calcium (0.02,0.04mg/kg) group rat plasma NO further raises, ET further reduces, and relatively there were significant differences with benazepril/spironolactone group; Compare with hypertension group, benazepril/spironolactone group, benazepril/spironolactone+levoleucovorin calcium (0.02,0.04mg/kg) group rat urine 24h α 1-microglobulin, urine protein reduce, Ccr raises, benazepril/spironolactone+levoleucovorin calcium (0.02,0.04mg/kg) group rat urine 24h α 1-microglobulin, urine protein further reduce, and Ccr further raises; Compare with hypertension group, benazepril/spironolactone group, the left heart of benazepril/spironolactone+levoleucovorin calcium rat weigh, the chamber weighs index, myocardial collagen protein content, CVF, PVCA and all significantly reduces, compare with benazepril/spironolactone group, the above-mentioned myocardium relevant parameter of benazepril/spironolactone+levoleucovorin calcium group rat further reduces; Compare with hypertension group, benazepril/spironolactone group rat mesenteric artery media thickness and middle film/internal diameter is than all reducing, benazepril/spironolactone+levo leucovorin group rat mesenteric artery media thickness and media thickness/internal diameter relatively has significant difference than further all reducing with benazepril/spironolactone group.The above results shows that benazepril/spironolactone, levoleucovorin calcium have protective effect to Hypertensive Rats inner skin cell function, renal function, myocardial structural, and both share protective effect is significantly strengthened.
The preparation of embodiment 6 lisinopril 10mg/ hydrochlorothiazide 12.5mg/ folic acid 1.6mg sheets
Prescription
Lisinopril 10.0g
Hydrochlorothiazide 12.5g
Folic acid 1.6g
Starch 20.0g
Microcrystalline Cellulose 40.0g
Carboxymethyl starch sodium 15.0g
Pool Luo Samu F68 1.0g
Water is an amount of
Magnesium stearate is an amount of
Make 1000
Preparation technology: folic acid is crossed 120 mesh sieves, and other are former, adjuvant is crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively, and are standby; Accurate lisinopril, hydrochlorothiazide, lactose, cross-linking sodium carboxymethyl cellulose and the microcrystalline Cellulose that claims the to decide recipe quantity mixing that sieves, standby; After getting the folic acid and the abundant mix homogeneously of pool Luo Samu F68 of recipe quantity, adopt equivalent to increase progressively mixing with pre-mixed lisinopril, lactose, cross-linking sodium carboxymethyl cellulose and microcrystalline Cellulose, add an amount of water system soft material, 30 mesh sieves are granulated, 60 ℃ of dry 3h, granulate adds an amount of magnesium stearate mixing, tabletting behind the assay, packing
The preparation of embodiment 7 lisinopril 10mg/ hydrochlorothiazide 12.5mg/ folic acid 0.8mg sheets
Prescription
Lisinopril 10.0g
Hydrochlorothiazide 12.5g
Folic acid 0.8g
Lactose 20.0g
Microcrystalline Cellulose 40.0g
Carboxymethyl starch sodium 10.0g
Pool Luo Samu F68 1.0g
Water is an amount of
Magnesium stearate is an amount of
Make 1000
Preparation technology: with embodiment 6.
The preparation of embodiment 8 lisinopril 10mg/ hydrochlorothiazide 12.5mg/ folic acid 0.4mg sheets
Prescription
Lisinopril 10.0g
Hydrochlorothiazide 12.5g
Folic acid 0.4g
Lactose 20.0g
Microcrystalline Cellulose 40.0g
Carboxymethyl starch sodium 20.0g
Sodium lauryl sulphate 5.0g
Water is an amount of
Magnesium stearate is an amount of
Make 1000
Preparation technology: with embodiment 6.
The capsular preparation of embodiment 9 lisinopril 10mg/ hydrochlorothiazide 25mg/ calcium folinate 0.2mg
Prescription:
Lisinopril 10g
Hydrochlorothiazide 25g
Calcium folinate (in folinic acid) 0.2g
Starch 40.0g
Microcrystalline Cellulose 16.0g
Carboxymethyl starch sodium 16.0g
5% polyvidone k-30 aqueous solution is an amount of
Micropowder silica gel is an amount of
Make 1000
Preparation technology: with the lisinopril of recipe quantity, hydrochlorothiazide, calcium folinate, microcrystalline Cellulose, starch, the carboxymethyl starch sodium back mix homogeneously of pulverizing, sieve, make behind the soft material with 5% an amount of polyvidone k-30 aqueous solution granulate, dry, add the micropowder silica gel mix homogeneously, encapsulated according to a conventional method 1000 promptly.
The capsular preparation of embodiment 10 enalapril maleate 10mg/ hydrochlorothiazide 12.5mg/ folic acid 0.4mg
Prescription:
Enalapril maleate (by enalapril) 10g
Hydrochlorothiazide 12.5g
Folic acid 0.4g
Starch 40.0g
Microcrystalline Cellulose 20.0g
Carboxymethyl starch sodium 20.0g
5% polyvidone k-30 aqueous solution is an amount of
Micropowder silica gel is an amount of
Make 1000
Preparation technology: with embodiment 9.
The preparation of embodiment 11 perindopril 4mg/ hydrochlorothiazide 12.5mg/ folic acid 0.4mg sheets
Prescription:
Perindopril 4g
Hydrochlorothiazide 12.5g
Folic acid 0.4g
Microcrystalline Cellulose 45.0g
Lactose 25.0g
Carboxymethyl starch sodium 15.0g
Water is an amount of
Magnesium stearate 0.5g
Make 1000
Preparation technology: perindopril, hydrochlorothiazide, the folic acid of getting recipe quantity is crossed behind 100 mesh sieves standby by equivalent incremental method mix homogeneously; Other adjuvants are crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively; Press behind the lactose, carboxymethyl starch sodium mixing of recipe quantity again and mixed crude drug equivalent incremental method mix homogeneously; Add entry and make soft material in right amount, 24 mesh sieves are granulated, granulate, 40～45 ℃ of dryings; Dried granule adds an amount of magnesium stearate mixing, tabletting behind the assay.
The preparation of embodiment 12 perindopril 4mg/ hydrochlorothiazide 12.5mg/ folic acid 0.8mg sheets
Prescription:
Perindopril 4g
Hydrochlorothiazide 12.5g
Folic acid 0.8g
Microcrystalline Cellulose 45.0g
Lactose 25.0g
Carboxymethyl starch sodium 15.0g
Water is an amount of
Magnesium stearate 0.5g
Make 1000
Preparation technology: with embodiment 11.
The capsular preparation of embodiment 13 imidapril 10mg/ indapamide 2.5mg/ folic acid 0.4mg
Prescription:
Imidapril 10g
Indapamide 2.5g
Folic acid 0.4g
Starch 25.0g
Microcrystalline Cellulose 15.0g
Carboxymethyl starch sodium 15.0g
5% polyvidone k-30 aqueous solution is an amount of
Micropowder silica gel is an amount of
Make 1000
Preparation technology: with the imidapril of recipe quantity, indapamide, folic acid, microcrystalline Cellulose, starch, the carboxymethyl starch sodium back mix homogeneously of pulverizing, sieve, make behind the soft material with 5% an amount of polyvidone k-30 aqueous solution granulate, dry, add the micropowder silica gel mix homogeneously, encapsulated according to a conventional method 1000 promptly.
The capsular preparation of embodiment 14 imidapril 10mg/ indapamide 2.5mg/ folic acid 0.8mg
Prescription:
Imidapril 10g
Indapamide 2.5g
Folic acid 0.8g
Starch 25.0g
Microcrystalline Cellulose 15.0g
Carboxymethyl starch sodium 15.0g
5% polyvidone k-30 aqueous solution is an amount of
Micropowder silica gel is an amount of
Make 1000
Preparation technology: with embodiment 13.
The preparation of embodiment 15 benazepril 10mg/ spironolactone 40mg/ levoleucovorin calcium 0.2mg sheets
Prescription:
Benazepril 10.0g
Spironolactone 40.0g
Levoleucovorin calcium (by levo leucovorin) 0.2g
Microcrystalline Cellulose 35.0g
Lactose 20.0g
Carboxymethyl starch sodium 15.0g
Water is an amount of
Magnesium stearate 0.5g
Make 1000
Preparation technology: with embodiment 11.
The preparation of embodiment 16 benazepril 10mg/ spironolactone 40mg/ levoleucovorin calcium 0.4mg sheets
Prescription:
Benazepril 10.0g
Spironolactone 40.0g
Levoleucovorin calcium (by levo leucovorin) 0.4g
Microcrystalline Cellulose 35.0g
Lactose 20.0g
Carboxymethyl starch sodium 15.0g
Water is an amount of
Magnesium stearate 0.5g
Make 1000
Preparation technology: with embodiment 11.

Claims (10)

1. a prevention, treat or delay the pharmaceutical composition of the target organ damage that hypertension or hypertension causes, be grouped into by following one-tenth:
(1) angiotensin converting enzyme inhibitor of pharmaceutical dosage;
(2) diuretic of pharmaceutical dosage;
(3) dosage is folic acid, calcium folinate or the levoleucovorin calcium of 0.2～1.6mg;
(4) acceptable carrier on the pharmaceutics.
2. pharmaceutical composition according to claim 1, it is characterized in that: described angiotensin converting enzyme inhibitor is selected from a kind of in enalapril, lisinopril, perindopril, imidapril, benazepril, ramipril, captopril, moexipril, quinapril, trandolapril, cilazapril or the fosinopril, and dosage is 2.5～40mg.
3. pharmaceutical composition according to claim 1 is characterized in that: described diuretic is selected from a kind of in hydrochlorothiazide, indapamide, eplerenone or the spironolactone, and dosage is 2.5～50mg.
4. according to arbitrary described pharmaceutical composition in the claim 1～3, the pharmacy dosage form that it is characterized in that described pharmaceutical composition is tablet, capsule or granule.
5. arbitrary described pharmaceutical composition is used for preventing, treating or delay the purposes of hypertensive medicine in the claim 1～3 in preparation.
6. arbitrary described pharmaceutical composition is used for preventing, treat or delay the purposes of the medicine of the target organ damage that hypertension causes in the claim 1～3 in preparation.
7. purposes according to claim 6 is characterized in that: described target organ damage is left ventricular hypertrophy, optimum arteriolar nephrosclerosis, pernicious arteriolar nephrosclerosis, renal failure, retinal arteriosclerosis or hypertension retinopathy.
8. be used for reducing the purposes of the medicine of the cardiovascular and cerebrovascular vessel incident danger that hypertension causes in preparation according to arbitrary described pharmaceutical composition in the claim 1～3.
9. purposes as claimed in claim 8 is characterized in that: the cardiovascular and cerebrovascular vessel incident danger that described reduction hypertension causes is meant the incidence rate that reduces angina pectoris, myocardial infarction, heart failure, cerebral infarction or cerebral hemorrhage.
10. purposes as claimed in claim 8 is characterized in that: the cardiovascular and cerebrovascular vessel incident danger that described reduction hypertension causes is meant the incidence rate that reduces apoplexy.
CN2007101657788A 2006-11-11 2007-11-03 Pharmaceutical composition for ACE restrainer/uretica/folic acid, and uses thereof Active CN101176788B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2007101657788A CN101176788B (en) 2006-11-11 2007-11-03 Pharmaceutical composition for ACE restrainer/uretica/folic acid, and uses thereof

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN200610146631 2006-11-11
CN200610146631.X 2006-11-11
CN2007101657788A CN101176788B (en) 2006-11-11 2007-11-03 Pharmaceutical composition for ACE restrainer/uretica/folic acid, and uses thereof

Publications (2)

Publication Number Publication Date
CN101176788A CN101176788A (en) 2008-05-14
CN101176788B true CN101176788B (en) 2011-06-15

Family

ID=39403308

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2007101657788A Active CN101176788B (en) 2006-11-11 2007-11-03 Pharmaceutical composition for ACE restrainer/uretica/folic acid, and uses thereof

Country Status (1)

Country Link
CN (1) CN101176788B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TN2010000566A1 (en) * 2010-12-03 2012-05-24 Rekik Raouf Folic acid - ramipril combination : cell protective neuroprotective and retinoprotective ophtalmologic drugs
CN103386130A (en) * 2013-06-27 2013-11-13 深圳奥萨医药有限公司 ACE inhibitor/thiazide diuretic/5-methyltetrahydrofolate pharmaceutical composition and applications
WO2022104621A1 (en) * 2020-11-19 2022-05-27 北京睿创康泰医药研究院有限公司 Fixed-dose combination of sglt-2 inhibitor and angiotensin converting enzyme inhibitor, and use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1524522A (en) * 2003-09-15 2004-09-01 启东盖天力药业有限公司 Compound pressure-reduction preparation containing indapamide and angiotensin converzyme inhibitor
CN1679943A (en) * 2002-07-31 2005-10-12 安徽省生物医学研究所 Compound medicine for improving effect of ACEI hypotensor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1679943A (en) * 2002-07-31 2005-10-12 安徽省生物医学研究所 Compound medicine for improving effect of ACEI hypotensor
CN1524522A (en) * 2003-09-15 2004-09-01 启东盖天力药业有限公司 Compound pressure-reduction preparation containing indapamide and angiotensin converzyme inhibitor

Also Published As

Publication number Publication date
CN101176788A (en) 2008-05-14

Similar Documents

Publication Publication Date Title
CN100551442C (en) The medical composition and its use that contains calcium channel blocker and vitamin B group
CN101199848B (en) Drug compound for Ca channel retarder/diuretic/ folate coupling and function
KR20080032616A (en) Complex preparations for the treatment of cardiovascular diseases using the time difference dosing principle
CN101406472A (en) Pharmaceutical composition of atenolol/amlodipine/folacin compound and uses thereof
CN101199847B (en) Drug compound for AT1 receptor antagonist/diuretic/folate coupling and uses thereof
CN106310278A (en) Multi-cascade antihypertensive drug composition containing folic acid
CN101176788B (en) Pharmaceutical composition for ACE restrainer/uretica/folic acid, and uses thereof
CN103386130A (en) ACE inhibitor/thiazide diuretic/5-methyltetrahydrofolate pharmaceutical composition and applications
CN101590052A (en) The medical composition and its use that contains calcium ion antagonist, lipid-lowering statins and nicotinic acid
CN102370965A (en) Pharmaceutical composition containing pharmaceutically acceptable salts of levoamlodipine and pharmaceutically acceptable salts of perindopril
CN102579346A (en) Liposome solid preparation of benazepril/hydrochlorothiazide medicine combination
CN101590239B (en) Pharmaceutical composition containing uretic, statin and folic acid as well as applications thereof
CN1969855B (en) Pharmaceutical composition having target organ protection function and usage thereof
CN101590240B (en) Composition containing angiotensin II receptor antagonist, statin and folic acid and application
CN104224788A (en) Medicinal composition of indapamide and folic acid and application of medicinal composition
CN106310273A (en) Quadruple antihypertensive drug composition
CN101422459A (en) Atenolol/nitrendipine/folic-acid compound medicine combination and use thereof
CN110237258A (en) For treating the pharmaceutical composition of hypertension
CN101590030A (en) The medical composition and its use that contains aliskiren, hydrochlorothiazide and folic acid
CN101590230A (en) The medical composition and its use that contains renin inhibitor, diuretic and folic acid
CN101347434B (en) Medicament composition containing renin inhibitor and acidum folicum compound and uses thereof
CN101590232A (en) The medical composition and its use of angiotensin-convertion enzyme inhibitor, lipid-lowering statins and nicotinic acid
CN102631357B (en) Composite tablet of valsartan and hydrochlorothiazide and preparation method thereof
CN106310272A (en) Triple-hypertensive pharmaceutical composition
CN103861081A (en) Perindopril amlodipine tablet and production process thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: Pharmaceutical composition for ACE restrainer/uretica/folic acid, and uses thereof

Effective date of registration: 20130523

Granted publication date: 20110615

Pledgee: China Everbright Bank Shenzhen Bagualing branch

Pledgor: Anhui Biological Medical Institute|SHENZHEN AUSA PHARMED Co.,Ltd.

Registration number: 2013990000307

PLDC Enforcement, change and cancellation of contracts on pledge of patent right or utility model
PC01 Cancellation of the registration of the contract for pledge of patent right

Date of cancellation: 20160705

Granted publication date: 20110615

Pledgee: China Everbright Bank, Limited by Share Ltd, Shenzhen, Bagualing branch

Pledgor: Anhui Biological Medical Institute|SHENZHEN AUSA PHARMED Co.,Ltd.

Registration number: 2013990000307

PLDC Enforcement, change and cancellation of contracts on pledge of patent right or utility model
PM01 Change of the registration of the contract for pledge of patent right

Change date: 20160705

Registration number: 2013990000307

Pledgee after: China Everbright Bank, Limited by Share Ltd, Shenzhen, Bagualing branch

Pledgee before: China Everbright Bank Shenzhen Bagualing branch

CP02 Change in the address of a patent holder

Address after: Three, No. 16 biological incubator No. 518057, high tech Zone, central high tech Zone, Shenzhen, Guangdong, Nanshan District

Co-patentee after: Anhui Biological Medical Institute

Patentee after: SHENZHEN AUSA PHARMED Co.,Ltd.

Address before: 518057, a bio incubator building in Nanshan District hi tech Zone, Guangdong, Shenzhen 1-301

Co-patentee before: Anhui Biological Medical Institute

Patentee before: SHENZHEN AUSA PHARMED Co.,Ltd.

CP02 Change in the address of a patent holder
TR01 Transfer of patent right

Effective date of registration: 20230726

Address after: 518057 the 1st and 2nd floors of Building 2, phase III of biological incubator, No.16, Gaoxin Zhongyi Road, central high tech Zone, Nanshan District, Shenzhen City, Guangdong Province; the east side of the 1st floor and the 2nd and 3rd floors of building 3

Patentee after: SHENZHEN AUSA PHARMACEUTICAL Co.,Ltd.

Patentee after: SHENZHEN AUSA PHARMED Co.,Ltd.

Patentee after: Anhui Biological Medical Institute

Address before: 518057 Phase III Biological Incubator No. 16, Zhongxin Zhongdao, Nanshan High-tech Zone, Shenzhen City, Guangdong Province

Patentee before: SHENZHEN AUSA PHARMED Co.,Ltd.

Patentee before: Anhui Biological Medical Institute

TR01 Transfer of patent right