CN101199848B - Drug compound for Ca channel retarder/diuretic/ folate coupling and function - Google Patents

Drug compound for Ca channel retarder/diuretic/ folate coupling and function Download PDF

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CN101199848B
CN101199848B CN2007101657773A CN200710165777A CN101199848B CN 101199848 B CN101199848 B CN 101199848B CN 2007101657773 A CN2007101657773 A CN 2007101657773A CN 200710165777 A CN200710165777 A CN 200710165777A CN 101199848 B CN101199848 B CN 101199848B
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hydrochlorothiazide
group
folic acid
diuretic
dosage
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CN101199848A (en
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徐希平
陈光亮
王琳琳
刘海鹏
李莉
吕红霞
胡容峰
段炎炎
孔飞
程芳
甘亚丽
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ANHUI BIOLOGICAL MEDICAL INSTITUTE
Shenzhen Ausa Pharmaceutical Co ltd
Shenzhen Ausa Pharmed Co ltd
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ANHUI BIOLOGICAL MEDICAL SCIENCE INST
AUSA PHARMED Ltd
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Abstract

The invention relates to a drug combination of applying jointly calcium channel blocker/diuretic/folacin and the purpose. The combination includes: officinal dose of calcium channel blocker, officinal dose of diuretic, officinal does of folic acid compound and pharmacy-acceptable carrier. The invention provides the purpose of the combination in preparing the medicine used for preventing, treating or delaying hypertension, target organ damage caused by hypertension or hypertension-related diseases; the invention also provides the purpose of the drug combination in preparing the medicine used for reducing the danger of cardiovascular and cerebrovascular events caused by hypertension, in particular for reducing the incidence of cerebral apoplexy. The implementation of the invention, which provides the patient with the drug combination, can improve the curative effect, increase the compliance of the patient, convenience the drug administration and reduce the medical expenses.

Description

The medical composition and its use that calcium channel blocker/diuretic/folate coupling is used
Technical field
The present invention relates to the medical composition and its use of calcium channel blocker/diuretic/folic acid Combined application, belong to pharmaceutical field.
Background technology
As one of healthy commonly encountered diseases of harm humans, 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 prevention and control guide are recommended is respectively: diuretic, beta-adrenoceptor antagonists, calcium channel blocker, angiotensin converting enzyme inhibitor, angiotensin ii receptor antagonist, the composite antihypertensive preparation of the fixed dosage of perhaps 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 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; It is the treatment necessary to hypertension that the effective blood volume that diuretic causes reduces, and possibly 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 these two types of medicines.
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 to the research of common cardiovascular poor risk hyperpietic cardiovascular primary prevention clinically, 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), and 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 angiotensin converting enzyme inhibitor in case of necessity that hyperpietic with cardiovascular disease poor risk adopts with the calcium channel blocker; Its curative effect is superior to the atenolol to be the basis or to add the curative effect with thiazide diuretic, and this advantage is especially early stage remarkable when up to standard at patient treatment.It is thus clear that 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-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 above-mentioned deficiency of the compound hypertension medicine existence that contains diuretic, provide a kind of at the compound hypertension medicine that is superior to 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 realizing above-mentioned purpose, the present invention adopts following technical scheme:
A kind of pharmaceutical composition comprises:
(1) the single depressor of pharmaceutical dosage;
(2) diuretic of pharmaceutical dosage;
(3) folacin compound of pharmaceutical dosage;
(4) acceptable carrier on the pharmaceutics.
Above-mentioned single depressor is selected from a kind of in beta-adrenoceptor antagonists, calcium channel blocker, angiotensin converting enzyme inhibitor, angiotensin ii receptor antagonist or the diuretic; Preferred calcium channel blocker.
Above-mentioned " pharmaceutical dosage " is meant " Chinese hypertension prevention and control guide (2005) " and " The Seventh Report of theJoint National Committee on Prevention; Detection; Evaluation; And Treatment of High BloodPressure (JNC-7) " in the RD 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 calcium channel blocker is selected from a kind of in amlodipine, felodipine, nisoldipine, lercanidipine, lacidipine, nicardipine or the nitrendipine, and dosage is 2.5～90mg.
Above-mentioned diuretic is selected from a kind of in hydrochlorothiazide, indapamide, eplerenone or the spironolactone, and dosage is 2.5～50mg.The compound hypertension medicine that contains diuretic of above-mentioned pharmaceutical dosage, its specific category and dosage see the following form, but are not limited to the following table scope.
The compound hypertension medicine that contains diuretic share type Share dosage ratio, mg *
Calcium channel blocker and diuretic Amlodipine/hydrochlorothiazide (5/12.5,10/12.5,10/25)
Felodipine/hydrochlorothiazide (5/12.5,10/12.5,20/25)
Nisoldipine/hydrochlorothiazide (10/12.5,20/12.5,40/25)
Lacidipine/hydrochlorothiazide (4/12.5,6/12.5,6/25)
Lercanidipine/hydrochlorothiazide (10/12.5,20/12.5,20/25)
Beta-blocker and diuretic Atenolol/hydrochlorothiazide (50/25,100/25)
Bisoprolol/hydrochlorothiazide (2.5/6.25,5/6.25,10/6.25)
Propranolol/hydrochlorothiazide (40/25,80/25)
Metoprolol/hydrochlorothiazide (50/25,100/25)
Nadolol/hydrochlorothiazide (40/12.5,80/25)
Timolol/hydrochlorothiazide (10/25)
Central action medicine and diuretic Methyldopa/hydrochlorothiazide (250/15,250/25,500/30,500/50)
Reserpine/hydrochlorothiazide (0.125/25,0.125/50)
Diuretic and diuretic Amiloride/hydrochlorothiazide (5/50)
Spironolactone/hydrochlorothiazide (25/25,50/50)
Triamterene/hydrochlorothiazide (37.5/25,50/25,75/50)
* can obtain the compound medicine of various fixed dosage.The dosage of every kind of medicine is mg
In addition, the above-mentioned compound hypertension medicine that contains diuretic can also be selected from a kind of in homemade FUFANG JIANGYA PIAN (serpasil-apreroline-hydrochlorothiazide), FUFANG LUOBUMA PIAN (guanethidine-hydralazine-hydrochlorothiazide), precious chrysanthemum (clonidine-hydrochlorothiazide) and the normal medicine hypertension pill (clonidine-hydrochlorothiazide-hydralazine).
The calcium channel blocker of above-mentioned pharmaceutical dosage is amlodipine 2.5～10mg; The diuretic of above-mentioned pharmaceutical dosage is hydrochlorothiazide 12.5～25mg; Above-mentioned folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and dosage is 0.2～1.6mg.
The calcium channel blocker of above-mentioned pharmaceutical dosage is felodipine 2.5～20mg; The diuretic of above-mentioned pharmaceutical dosage is hydrochlorothiazide 12.5～25mg; Above-mentioned folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and dosage is 0.2～1.6mg.
The calcium channel blocker of above-mentioned pharmaceutical dosage is nisoldipine 10～40mg; The diuretic of above-mentioned pharmaceutical dosage is indapamide 2.5～5mg; Above-mentioned folacin compound is folic acid, calcium folinate or levoleucovorin calcium, and dosage is 0.2～1.6mg.
The calcium channel blocker of above-mentioned pharmaceutical dosage is lercanidipine 10～20mg; The diuretic of above-mentioned pharmaceutical dosage is hydrochlorothiazide 12.5～25mg; Above-mentioned 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 to 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, tube chamber narrows down, and the VPV 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, 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 calcium channel blocker/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 calcium channel blocker/diuretic bigeminy compound hypertension medicine, also is better than list and uses folacin compound, and difference has statistical significance.
Distinguish this, the invention provides pharmaceutical composition that the folacin compound of calcium channel blocker/diuretic and the pharmaceutical dosage of above-mentioned pharmaceutical dosage forms is used for preventing, treating or delay hypertensive medicine in preparation purposes; The present invention provides this pharmaceutical composition to be used for preventing, treat or delay the purposes of the medicine of the target organ damage that hypertension causes in preparation; 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 calcium channel blocker/diuretic and folacin compound are share; It is dangerous collaboratively to reduce the cardiovascular and cerebrovascular vessel incident; And effect is better than only uses calcium channel blocker/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 dangerous medicine of cardiovascular and cerebrovascular vessel incident 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.; Said pharmaceutically acceptable carrier includes excipient and the accessory drugs that helps reactive compound is mixed with pharmaceutical formulation when processing common oral preparation; Compositions like 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 calcium channel blocker/diuretic, and second medicine is 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 contains calcium channel blocker and diuretic respectively with second medicine, contains folacin compound in the 3rd medicine.In this medicine box two or three independently medicine can concomitant dosings, also can be in a kind of pharmaceutical preparation or in the different drug 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, the cardiovascular and cerebrovascular vessel incident that collaborative reduction hypertension causes is dangerous.Therefore, the invention provides pharmaceutical composition that the folacin compound of calcium channel blocker/diuretic and the pharmaceutical dosage of above-mentioned 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 the purposes of aforementioned pharmaceutical compositions in the medicine of the cardiovascular and cerebrovascular vessel incident danger that preparation causes with reduction hypertension.Through 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.
Below in conjunction with the specific embodiment the present invention is further specified, the experiment support of pharmacological action sees the following specific embodiment for details.
The specific embodiment
Embodiment 1 amlodipine/hydrochlorothiazide+folic acid is to the blood pressure lowering and the target organ protection function of two kidneys, one folder Hypertensive Rats
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, amlodipine/hydrochlorothiazide (0.5+1.25mg/kg) group, amlodipine/hydrochlorothiazide+folic acid (0.5+1.25+0.04mg/kg) group, amlodipine/hydrochlorothiazide+folic acid (0.5+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; According to body weight adjustment dose, continuous 26 weeks.Observation index:
(1) measure before the administration respectively and different time blood pressure (179 type blood pressure determination appearance, American I ITC Life ScienceInc.) calculating blood pressure lowering amplitude (systolic pressure before the=administration-administration after-contraction is pressed) after the administration; 26 weekends, get blood and survey by the test kit description, measure blood plasma nitric oxide (NO), Endothelin (ET) level.
(2) 26 weekends of renal function, collect urine, survey 24h UCr, urine protein, 24h urine α 1 microglobulin; Get blood, measure serum creatinine, blood urea nitrogen (BUN), calculate creatinine clearance rate (Ccr).
(3) the heavy index in left chamber is got rat heart, cleans with the pre-cooling normal saline, separates left ventricle (comprising interventricular septum), claims that the left heart is heavy, the heavy index (left ventricle mg/ body weight g) of counting chamber.
(4) 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).
(5) the conventional section of cardiac muscular tissue, Sirius is red-picric acid dyeing, measures 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 arteriolar surrounding area and tube chamber area in the cross section wall for each BIAO and BEN, gets its average.
Statistical analysis: measurement data is expression with
Figure S2007101657773D00051
, relatively adopts the t check between two groups.
The result: compare with normal rats, the model group rat blood pressure significantly raises; With model group relatively, folic acid group rat blood pressure makes moderate progress, amlodipine/hydrochlorothiazide group and amlodipine/hydrochlorothiazide+folic acid (0.04,0.08mg/kg) group rat serum all significantly reduces; But compare with amlodipine/hydrochlorothiazide group, the blood pressure lowering amplitude of amlodipine/hydrochlorothiazide+folic acid group rat does not have significant difference.
Compare with normal rats; Model group rat plasma NO level reduces; The ET level raises, and compares with model group, and folic acid group, amlodipine/hydrochlorothiazide group rat plasma NO raise, ET reduces; Amlodipine/hydrochlorothiazide+folic acid (0.04,0.08mg/kg) group rat plasma NO further raises, and ET further reduces.Show: significant inner skin cell function appears in renal hypertensive rat to be reduced, and amlodipine/hydrochlorothiazide, folic acid have protective effect to the rat aorta inner skin cell function, and the protective effect that both share endotheliocyte significantly strengthens.See table 1.
Table 1 amlodipine/hydrochlorothiazide+folic acid gastric infusion, continuous 26 weeks are to the influence of two kidneys, one folder hypertensive rat blood pressure, serum NO level, ET level
Group Dosage (mg/kg) Quantity (n) Blood pressure lowering amplitude (mmHg) NO(mmol/L) ET(pg/ml)
Normal group - 19 -2.8±3.5 101.1±15.6 166.3±43.8
Model group - 18 -12.2±7.2 ** 52.7±11.0 ** 361.8±100.8 **
Amlodipine/hydrochlorothiazide+folic acid 0.5+1.25+0.04 17 ?34.7±8.5 ▲▲ 80.1±13.1 ▲★ 221.2±47.4 ▲▲★
Amlodipine/hydrochlorothiazide+folic acid 0.5+1.25+0.08 19 38.0±10.4 ▲▲ 84.0±15.6 ▲▲★ 212.3±58.6 ▲▲★
Amlodipine/hydrochlorothiazide 0.5 20 30.8±9.2 ▲▲ 68.1±11.9 ▲▲ 269.6±61.9 ▲▲
Folic acid 0.08 18 -9.6±3.4 67.6±15.6 ▲ 286.3±64.4
Compare with normal group, *P＜0.01; Compare with model group, ▲P＜0.05, ▲ ▲P＜0.01;
Compare with amlodipine/hydrochlorothiazide group, ★P＜0.05
Compare with normal rats; Model group rat urine 24h α 1-microglobulin, urine protein significantly raise, and Ccr obviously reduces, and BUN does not have obvious rising; Compare with model group; Amlodipine/hydrochlorothiazide group, amlodipine/hydrochlorothiazide+folic acid (0.04,0.08mg/kg) group rat urine 24h α 1-microglobulin, urine protein reduce, and Ccr raises, and the folic acid list is used does not have obvious influence to the renal hypertensive rat renal function.Amlodipine/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 amlodipine/hydrochlorothiazide group significant difference is arranged relatively.Show that early stage renal function injury appears in renal hypertensive rat; Amlodipine/hydrochlorothiazide has protective effect to the renal function injury of renal hypertensive rat; Folic acid and amlodipine/hydrochlorothiazide share, and the protecting renal function effect of renal hypertensive rat is significantly strengthened.See table 2.
Table 2 amlodipine/hydrochlorothiazide+26 weeks of folic acid successive administration are urinated α to renal hypertensive rat 1The influence of-microglobulin, urine protein, serum creatinine clearance rate, blood urea nitrogen
Figure S2007101657773D00062
Group Dosage (mg/kg) Quantity (n) 24hα 1-microglobulin (μ g) Urine protein (mg) Ccr(ml/min) BUN(mmol/L)
Normal group - 19 17.4±5.8 3.3±2.2 0.235±0.06 8.67±1.34
Model group - 18 62.9±12.6 ** 19.3±4.1 ** 0.112+0.03 ** 9.17±2.45
Amlodipine/hydrochlorothiazide+folic acid 0.5+1.25+0.04 17 40.0±8.2 ▲▲★ 11.2±3.8 ▲▲★ 0.190±0.04 ▲▲★ 8.28±2.10
Amlodipine/hydrochlorothiazide+folic acid 0.5+1.25+0.08 19 36.8±9.0 ▲▲★ 12.0±3.3 ▲▲ 0.186±0.04 ▲▲★ 8.23±1.26
Amlodipine/hydrochlorothiazide 0.5 20 48.5±12.9 ▲▲ 14.4±3.7 ▲▲ 0.156±0.03 ▲▲ 8.13±1.16
Folic acid 0.08 18 57.8±10.6 20.6±7.8 0.116±0.03 8.36±0.98
Compare with normal group, *P＜0.01; Compare with model group, ▲ ▲P＜0.01;
Compare with amlodipine/hydrochlorothiazide group, ★P＜0.05
Normal group compares, and the heavy index of model group rat left chamber obviously increases; Amlodipine/hydrochlorothiazide group, the heavy index in amlodipine/hydrochlorothiazide+folic acid group rat chamber all significantly reduce, and relatively there were significant differences with model group; But amlodipine/hydrochlorothiazide+folic acid group and amlodipine/hydrochlorothiazide group is no significant difference relatively.Show: the myocardium of left ventricle plumpness appears in the hypertension group rat.Amlodipine/hydrochlorothiazide, amlodipine/hydrochlorothiazide+folic acid group leader phase administration can prevent rat heart muscle plump, and it is close with amlodipine/hydrochlorothiazide group that the drug combination group is improved the effect of left ventricular hypertrophy.See table 3
Remodeling ventricle is hypertensive important pathological change, mainly shows as myocardial cell propagation, hypertrophy and interstitial fibrosis, and hydroxyproline is that collagen fiber institute is peculiar, and its content can reflect fibrosis.Compare with normal group, hypertension group rat heart muscle collagen content significantly raises.Compare with model group, amlodipine/hydrochlorothiazide group rat heart muscle collagen content significantly reduces, and amlodipine/hydrochlorothiazide+folic acid group rat heart muscle collagen content further reduces, and with amlodipine/hydrochlorothiazide group significant difference is arranged relatively.See table 3.
The influence
Figure S2007101657773D00071
that table 3 amlodipine/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 - 19 ?750.8±113.2 1.66±0.31 ?2.39±0.23
Model group - 18 ?1001.3±155.8 ** 2.37±0.31 ** ?3.47±0.37 **
Amlodipine/hydrochlorothiazide+folic acid 0.5+1.25+0.04 17 ?843.6±136.7 ▲▲ 1.91±0.34 ▲▲ ?2.70±0.21 ▲▲★
Amlodipine/hydrochlorothiazide+folic acid 0.5+1.25+0.08 19 ?856.7±107.3 ▲▲ 1.86±0.32 ▲▲ ?2.64±0.32 ▲▲★
Amlodipine/hydrochlorothiazide 0.5 20 ?895.8±106.6 ▲▲ 1.95±0.28 ▲▲ ?2.96±0.26 ▲▲
Folic acid 0.08 18 ?995.2±148.4 2.14±0.29 ?3.40±0.37
Compare with normal group, *P＜0.01; Compare with model group, ▲ ▲P＜0.01; Compare with amlodipine/hydrochlorothiazide group, ★P＜0.05
Table 4 amlodipine/hydrochlorothiazide+26 weeks of folic acid successive administration are to the influence of area of collagen (PVCA) around renal hypertensive rat myocardial collagen fraction by volume (CVF) and the myocardial vascular
Group Dosage (mg/kg) Quantity (n) CVF(％) PVCA(％)
Normal group - 19 0.98±0.16 0.86±0.13
Model group - 18 3.22±0.42 ** 2.25±0.33 **
Amlodipine/hydrochlorothiazide+folic acid 0.5+1.25+0.04 17 2.56±0.23 ▲▲★ 1.39±0.33 ▲▲★★
Amlodipine/hydrochlorothiazide+folic acid 0.5+1.25+0.08 19 2.51±0.33 ▲▲★ 1.54±0.21 ▲▲★★
Amlodipine/hydrochlorothiazide 0.5 20 2.83±0.26 ▲▲ 1.80±0.22 ▲▲
Folic acid 0.08 18 3.10±0.45 1.95±0.29 ▲
Compare with normal group, *P＜0.01; Compare with model group, ▲P＜0.05, ▲ ▲P＜0.01;
Compare with amlodipine/hydrochlorothiazide group, ★P＜0.05, ★ ★P＜0.01
With normal rats relatively, fibrosis index PVCA all significantly increases around model group rat heart muscle interstitial fibrosis index CVF, the myocardial vascular, shows that myocardium interstitial fibrosis participated in the pathological process of renal hypertensive rat cardiac remodeling.Compare with model group, amlodipine/hydrochlorothiazide group rat heart muscle CVF, PVCA all significantly reduce, and amlodipine/hydrochlorothiazide+folic acid group rat heart muscle CVF, PVCA further reduce, and with amlodipine/hydrochlorothiazide group significant difference are arranged relatively.See table 4.
Embodiment 2: felodipine/hydrochlorothiazide+calcium folinate is to the target organ protection function of two kidneys, one folder Hypertensive Rats
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 at random model group, felodipine/hydrochlorothiazide (1+1.25mg/kg) group, felodipine/hydrochlorothiazide+calcium folinate (in folinic acid) (1+1.25+0.05mg/kg) are organized, felodipine/hydrochlorothiazide+calcium folinate (in folinic acid) (1+1.25+0.10mg/kg) is organized, calcium folinate (in folinic acid) (0.10mg/kg) is organized; Other establishes the normal control group; Every group 20, gastric infusion, continuous 26 weeks.At 26 weekends, get hematometry serum levels of nitric oxide (NO), Endothelin (ET), level; Collect urine, measure 24h urine α 1Microglobulin, UCr (Scr); Get rat heart and measure the heavy index in the heavy and left chamber of the left heart; Measure myocardium hydroxyproline content, calculate collagen content; Cardiac muscular tissue's conventional cross section section, cross-sectional area, major diameter and the minor axis of measurement myocardial cell; 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 in the kidney are measured in the section of Mesenteric artery secondary branch, calculate media thickness/internal diameter ratio.
The result: with hypertension group relatively, calcium folinate group, felodipine/hydrochlorothiazide group rat plasma NO raise, ET reduces, felodipine/hydrochlorothiazide+calcium folinate (0.05,0.10mg/kg) group rat plasma NO further raises, ET further reduces.With hypertension group relatively, felodipine/hydrochlorothiazide group, felodipine/hydrochlorothiazide+calcium folinate (0.05,0.10mg/kg) group rat urine 24h α 1-microglobulin, urine protein reduce, and Ccr raises, and the calcium folinate list is used does not have obvious influence to the renal hypertensive rat renal function; With felodipine/hydrochlorothiazide group relatively, felodipine/hydrochlorothiazide+calcium folinate (0.05,0.10mg/kg) group rat urine 24h α 1-microglobulin, urine protein further reduce, and Ccr further raises.Compare with hypertension group; Felodipine/hydrochlorothiazide group, a felodipine/hydrochlorothiazide+calcium folinate group rat left side heart cross-sectional area, major diameter and minor axis heavy, that the chamber weighs index, myocardial collagen protein content, CVF, PVCA, myocardial cell all significantly reduce; Compare with felodipine/hydrochlorothiazide group, the above-mentioned myocardium relevant parameter of felodipine/hydrochlorothiazide+calcium folinate group rat further reduces.Compare with hypertension group; Felodipine/hydrochlorothiazide group rat mesenteric artery media thickness, middle film/internal diameter are than reducing; Felodipine/hydrochlorothiazide+calcium folinate group rat mesenteric artery media thickness, middle film/internal diameter relatively have significant difference than further reducing with felodipine/hydrochlorothiazide group.The above results shows that felodipine/hydrochlorothiazide, calcium folinate have protective effect to Hypertensive Rats inner skin cell function, renal function, myocardial structural, and both share protective effect is significantly strengthened.
Embodiment 3: nisoldipine/indapamide+folic acid is to the protective effect of spontaneous hypertensive rat (SHR) blood pressure lowering and target organ damage
The SHR rat; Body weight 160～190g; Be equally divided into 5 groups according to blood pressure level; Every group 20, be respectively model group, nisoldipine/indapamide (2+0.25mg/kg) group, nisoldipine/indapamide+folic acid (2+0.25+0.04mg/kg) group, nisoldipine/indapamide+folic acid (2+0.25+0.08mg/kg) group, folic acid (0.08mg/kg) group, other gets 20 normal rats as matched group.Wait capacity 0.5%CMC solution, weigh weekly once, according to body weight adjustment dose, 20 weeks of successive administration.Observation index:
(1) blood pressure is measured before the administration respectively and different time Mus tail systolic pressure, relatively blood pressure difference between each group after the administration.
(2) renal function is collected the 24h urine, with the turbidimetry for Determination urine protein, put the method for exempting from and measure 24h urine α 1 microglobulin, measures UCr according to the test kit description, gets the hematometry serum creatinine, calculating creatinine clearance rate (Ccr).
(3) 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).
(4) the conventional section of myocardial collagen tissue test cardiac muscular tissue, Sirius is red-picric acid dyeing, measures 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 arteriolar surrounding area and tube chamber area in the cross section wall for each BIAO and BEN, gets its average.
(5) after the histological observation of Mesenteric artery is put to death rat, get superior mesenteric artery second-order branching 5mm (, second piece superior mesenteric artery branched second-order branching in the middle of 5mm reciprocal) from ileocecus; Put in 10% neutral formalin and fix, conventional dehydration, embedding, slice thick 5 μ m; HE dyeing, every tremulous pulse is cut 5 cross sections, and om observation is carried out in the cross section section of selection standard; Utilize 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, calculate media thickness/lumen diameter ratio.
Statistical analysis: measurement data is expression with
Figure S2007101657773D00091
, relatively adopts the t check between two groups.
The result:
(1) to the 20th weekend that influenced of SHR rat blood pressure, compare with normal rats, the model group rat blood pressure significantly raises; With model group relatively, folic acid group rat blood pressure makes moderate progress, nisoldipine/indapamide group, nisoldipine/indapamide+folic acid (0.04,0.08mg/kg) group rat systolic pressure all significantly reduces; But compare with nisoldipine/indapamide group, nisoldipine/indapamide+folic acid group rat blood pressure does not have significant difference.See table 5.
Table 5 nisoldipine/indapamide+folic acid is to the influence
Figure S2007101657773D00092
of SHR rat blood pressure (mmHg)
Group Dosage (mg/kg) Blood pressure (n) before the administration 8 all blood pressures (n) 16 all blood pressures (n) 20 all blood pressures (n)
Normal group - 109.6±12.7(20) 124.7±14.1(20) 118.9±±16.9(20) 130.1±15.8(19)
Model group - 172.3±16.5 **(20) 180.8±18.4 **(18) 190.3±±23.1 **(18) 203.1±26.2 **(16)
Nisoldipine/indapamide+folic acid 2+0.25+0.04 173.1±15.1(20) 143.9±19.6 ▲▲(19) 138.2±14.8 ▲▲(18) 143.9±18.8 ▲▲(18)
2+0.25+0.08 170.8±20.2(20) 144.2±16.6 ▲▲(20) 142.1±19.5 ▲▲(19) 146.6±17.5 ▲▲(17)
Nisoldipine/indapamide 2+0.25 172.3±18.7(20) 146.1±20.2 ▲▲(20) 148.3±14.8 ▲▲(18) 152.1±20.1 ▲▲(17)
Folic acid 0.08 173.2±17.4(20) 179.1±21.3(19) 182.4±25.2(18) 190.8±27.1(18)
Compare with normal group, *P＜0.01; Compare with model group, ▲ ▲P＜0.01
(2) influence and the normal rats to SHR kidney of rats function compares, and model group rat urine 24h α 1-microglobulin, urine protein significantly raise, and Ccr obviously reduces.Compare with model group, nisoldipine/indapamide group rat urine 24h α 1-microglobulin, urine protein significantly reduce, and Ccr significantly raises.Compare with nisoldipine/indapamide group, nisoldipine/indapamide+folic acid group rat Ccr further raises, and 24h α 1-microglobulin, urine protein further reduce.Show that nisoldipine/indapamide has protective effect to the early stage renal function injury that the SHR rat occurs, share, the protecting renal function effect of SHR rat is significantly strengthened with folic acid.See table 6.
(3) influence and the normal rats to area of collagen (PVCA) around SHR rat heart muscle collagen content and myocardial collagen fraction by volume (CVF) and the myocardial vascular compares; Model group rat heart muscle collagen content; Fibrosis index PVCA all significantly increases around cardiac muscle interstitial fibrosis index CVF, the myocardial vascular, shows that myocardium interstitial fibrosis participated in the pathological process of Hypertensive Rats cardiac remodeling.Compare with model group, nisoldipine/indapamide group rat heart muscle collagen content, myocardium CVF, PVCA all significantly reduce.Nisoldipine/indapamide+folic acid group rat heart muscle collagen content and myocardium CVF, PVCA further reduce, and with nisoldipine/indapamide group significant difference are arranged relatively.Show that nisoldipine/indapamide and folic acid share, the Hypertensive Rats myocardium protecting action is strengthened.See table 7.
Table 6 nisoldipine/indapamide+folic acid is to the influence of SHR kidney of rats function
Group Dosage (mg/kg) N Urine protein (mg/24h) 24hα 1-microglobulin (μ g) Ccr(ml/min)
Normal group - 19 1.55±0.31 10.8±3.1 0.542±0.133
Model group - 16 6.89±2.01 ** 54.3±13.8 ** 0.201±0.032 **
Nisoldipine/indapamide+folic acid 2+0.25 +0.04 18 3.91±0.88 ▲▲★ 35.9±8.7 ▲▲ 0.313±0.041 ▲▲
2+0.25+ 0.08 17 3.70±0.93 ▲▲★ 32.3±6.1 ▲▲★ 0.348±0.061 ▲▲★
Nisoldipine/indapamide 2+0.25 17 5.02±1.35 ▲▲ 40.9±9.5 ▲▲ 0.289±0.037 ▲▲
Folic acid 0.08 18 6.23±1.36 49.4±15.3 0.228±0.026
Compare with normal group, *P＜0.01; Compare with model group, ▲ ▲P＜0.01; Compare with nisoldipine/indapamide group, ★P＜0.05
Table 7 nisoldipine/indapamide+folic acid is to the influence
Figure S2007101657773D00102
of area of collagen (PVCA) around SHR rat heart muscle collagen content, myocardial collagen fraction by volume (CVF) and the myocardial vascular
Group Dosage (mg/kg) N Collagen protein (mg/g) CVF(％) PVCA(％)
Normal group ?- 19 1.24±0.32 3.12±0.78 0.64±0.22
Model group ?- 16 5.23±1.41 ** 7.04±1.23 ** 3.43±0.64 **
Nisoldipine/indapamide+folic acid ?2+0.25 ?+0.04 18 4.02±0.64 ▲▲ 4.98±0.63 ▲▲★ 2.28±0.43 ▲▲★★
?2+0.25+ ?0.08 17 3.43±0.66 ▲▲★ 4.74±0.86 ▲▲★ 2.34±0.32 ▲▲★
Nisoldipine/indapamide ?2+0.25 17 4.16±0.81 ▲ 5.73±0.96 ▲▲ 2.82±0.52 ▲▲
Folic acid ?0.08 18 5.26±1.12 6.12±1.03 3.12±0.36
Compare with normal group, *P＜0.01; Compare with model group, ▲P＜0.05, ▲ ▲P＜0.01;
Compare with nisoldipine/indapamide group, ★P＜0.05, ★ ★P＜0.05
(4) influence and the normal rats to the SHR rat mesenteric artery compares, and model group rat mesenteric artery media thickness increases, and internal diameter reduces, and middle film/internal diameter is than increasing.Compare with model group; Nisoldipine/indapamide group rat mesenteric artery media thickness, middle film/internal diameter are than reducing; Nisoldipine/indapamide+further, the middle film of folic acid group rat mesenteric artery media thickness/internal diameter relatively has significant difference than further reducing with nisoldipine/indapamide group.See table 8.
Table 8 nisoldipine/indapamide+folic acid is to the influence
Figure S2007101657773D00111
of SHR rat mesenteric artery
Group Dosage (mg/kg) N Media thickness (μ m) Vessel diameter (μ m) Wall thickness/internal diameter (%)
Normal group - 19 ?17.6±4.2 158.2±33.8 11.4±3.0
Model group - 16 ?45.1±10.1 ** 117.3±26.5 ** 39.1±6.4 **
Nisoldipine/indapamide+folic acid 2+0.25 +0.04 18 ?33.4±7.3 ▲▲ 143.6±31.2 23.3±3.0 ▲▲★
2+0.25+ 0.08 17 ?31.7±8.1 ▲▲ 150.4±35.6 22.1±4.0 ▲▲★★
Nisoldipine/indapamide 2+0.25 17 ?36.4±7.2 ▲ 135.1±32.5 27.2±4.8 ▲▲
Folic acid 0.08 18 ?40.4±8.6 130.6±25.3 31.8±5.6
Compare with normal group, *P＜0.01; Compare with model group, ▲ ▲P＜0.01;
Compare with nisoldipine/indapamide group, ★P＜0.05, ★ ★P＜0.01
Embodiment 4: lercanidipine/hydrochlorothiazide+folic acid is to the protective effect of apoplexy susceptible type spontaneous hypertensive rat (SHRsp) target organ damage
8～10 the week age SHRsp respectively available from Shanghai City hypertension institute, Fuwai Hospital's Experimental Animal Center; Raising is in room temperature (23 ± 2) ℃; Relative humidity (50 ± 10) %, each 12h of illumination light and shade, the standard feed of freely ingesting; Solid feed is provided by Chinese Academy of Medical Sciences's laboratory animal breeding field, and drinking water is a pure water.Measure blood pressure before the test; According to blood pressure values; SHRsp is divided into model group, lercanidipine/hydrochlorothiazide (1mg/kg+1.25mg/kg) group, lercanidipine/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, according to body weight adjustment dose, continuous 20 weeks.Observation index:
(1) observes animal diet followed, survival and behavioral activity every day, write down each treated animal cerebral seizure number and reach duration of seizure first.
(2) function of nervous system's classification is with reference to function of nervous system's grade scale (Bederson JB of Bederson; Pitts LH, Tsuji M, et al.Ratmiddle cerebral artery occlusion:Evaluation of the model and development a eurologicexamination [J] .Stroke; 1986; 17 (3): 472-476.), be divided into following 5 grades, observe once weekly.
0 grade (normally): impassivity functional impairment symptom.
1 grade (slightly): forelimb is rolled up or flexing, mainly is to receive companion's ancon in persistence wrist flexing or the shoulder to stretch.
2 grades (moderate): the forelimb persistence is rolled up or flexing, receives or inward turning in visible wrist, the whole flexings of elbow, the shoulder.
3 grades (seriously): the persistence limbs are rolled up or flexing, and the anti-persistence of a side limbs thrust body weakens, and does not accompany limbs to draw the circle behavior during autonomic activities.
4 grades (very heavy): bilateral limbs persistence is rolled up or flexing, and the anti-persistence of a side limbs thrust body weakens, and occurs limbs during autonomic activities and draws the circle behavior.
(3) all survival rats anesthesia back row aorta intubate of cerebral arteries and cerebral tissue pathological observation, the perfusion of 2.5% glutaraldehyde is fixing, and broken end is got brain; Separate skull base arterial ring and intraparenchymatous small artery of brain and arteriole; 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, and 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 the morbidity of part rat is simultaneously with symptoms such as tic, diarrhoea, urinary incontinence, eyeball are hemorrhage, and are dead in the person of being in a bad way several hours.Most of animal nerve functional impairment of treatment group is slight than model group, and the mental status obviously is superior to 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) function of nervous system's scoring is compared with normal group; The scoring of model group nervous symptoms significantly increases; Lercanidipine/hydrochlorothiazide group, lercanidipine/hydrochlorothiazide+folic acid group nervous symptoms scoring significantly reduce; Wherein lercanidipine/hydrochlorothiazide+folic acid group further reduces, and with lercanidipine/hydrochlorothiazide group significant difference is arranged relatively.See table 9, table 10.
Table 9 lercanidipine/hydrochlorothiazide+10 weeks of folic acid successive administration are to SHRsp rat brain apoplexy function of nervous system size scale (only)
Group Dosage (mg/kg) Number of animals 0 grade 1 grade 2 grades 3 grades 4 grades
The matched group model group **Lercanidipine/hydrochlorothiazide ▲Lercanidipine/hydrochlorothiazide+folic acid ▲▲★ --1+1.251+1.25?+0.04 29 26 26 28 29 7 11 18 0 3 5 5 0 3 4 2 0 6 3 2 0 7 3 1
Ridit analyzes, compares with normal group, *P＜0.01; Compare with model group, ▲P＜0.05, ▲ ▲P＜0.01;
Compare with lercanidipine/hydrochlorothiazide group, ★P＜0.05
Table 10 lercanidipine/hydrochlorothiazide+20 weeks of folic acid successive administration are to SHRsp rat brain apoplexy function of nervous system size scale (only)
Group Dosage (mg/kg) Number of animals 0 grade 1 grade 2 grades 3 grades 4 grades
The matched group model group **Lercanidipine/hydrochlorothiazide ▲Lercanidipine/hydrochlorothiazide+folic acid ▲▲ --1+1.251+1.25?+0.04 ?29?24?25?26 ?29?7?12?16 ?0?2?3?4 ?0?4?4?3 ?0?6?4?2 ?0?5?2?1
Ridit analyzes, compares with normal group, *P＜0.01; Compare with model group, ▲P＜0.05, ▲ ▲P＜0.01;
(3) the apoplexy incidence rate so this test is standard more than 2 grades and 2 grades with function of nervous system's scoring, is judged the generation of apoplexy because function of nervous system marks 1 grade between normal and apoplexy, and judgement differs greatly, and the influence factor is many.Normal group does not have 1 apoplexy takes place.1 improper unexpected death of administration in 30 rats of model group, 17 apoplexy takes place, and except that 1 animal, other 29 animals have all carried out the histopathology observation, and totally 25 apoplexy takes 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.In lercanidipine/30 rats of hydrochlorothiazide group 1 the improper death of administration is arranged; Have 12 apoplexy takes place, 2 animals fail to obtain pathological tissue, and other 28 animals have all carried out the histopathology observation; Totally 17 apoplexy takes place, and relatively there were significant differences with model group.In lercanidipine/hydrochlorothiazide+30 rats of folic acid group; Have 8 apoplexy takes place, wherein 1 animal fails to obtain pathological tissue, and other 29 animals have all carried out the histopathology observation; Totally 10 apoplexy takes place, and has significance (P＜0.05) with the model group comparing difference; Compare with lercanidipine/hydrochlorothiazide group, lercanidipine/hydrochlorothiazide+folic acid group rat brain stroke incidence further reduces (P＜0.05).See table 11.
Table 11 lercanidipine/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 **Lercanidipine/hydrochlorothiazide lercanidipine/hydrochlorothiazide+folic acid ?-?-?1+1.25 1+1.25+0.04 ?0/30 ?17/29 ** ?12/29 8/30 ▲ 0/30 25/29 ** 17/28 ▲ 10/29 ▲▲★
x 2Check is compared with normal group, *P＜0.01; Compare with model group, ▲P＜0.05, ▲ ▲P＜0.01
Compare with lercanidipine/hydrochlorothiazide group, ★P＜0.05
(4) arteriocerebral influence of SHRsp rat and normal rats are compared, SHRsp group rat brain tunica media of artery thickness increases, and lumen diameter reduces, and media thickness/lumen diameter is than increasing.Compare with the SHRsp group; Lercanidipine/hydrochlorothiazide group rat brain tunica media of artery thickness, media thickness/lumen diameter are than reducing; Lercanidipine/hydrochlorothiazide+folic acid group cerebral arteries media thickness, media thickness/lumen diameter relatively have significant difference than further reducing with lercanidipine/hydrochlorothiazide group.See table 12.
Table 12 lercanidipine/hydrochlorothiazide+20 weeks of folic acid successive administration are to the arteriocerebral influence of apoplexy susceptible type spontaneous hypertensive rat
Figure S2007101657773D00131
Group Dosage (mg/kg) Number of animals Media thickness (μ m) Lumen diameter (μ m) Media thickness/lumen diameter (%)
Matched group - 28 ?35.9±8.3 ?158.2±31.9 23.3±3.6
Model group ** - 23 ?68.1±20.1 ** ?96.6±18.2 ** 71.2±8.4 **
Lercanidipine/hydrochlorothiazide 1+1.25 24 ?52.6±15.4 ?124.2±26.4 ▲▲ 42.4±5.8 ▲▲
Lercanidipine/hydrochlorothiazide+folic acid 1+1.25+0.04 26 ?46.7±13.9 ▲▲ ?138.6±20.8 ▲▲ 33.2±6.1 ▲▲★★
Compare with normal group, *P＜0.01; Compare with hypertension group, ▲ ▲P＜0.01;
Compare with lercanidipine/hydrochlorothiazide group, ★P＜0.05, ★ ★P＜0.01
The preparation of embodiment 5 amlodipine 5mg/ hydrochlorothiazide 12.5mg/ folic acid 0.2mg sheets
Prescription
Amlodipine Besylate Tablet (in amlodipine) 5.0g
Hydrochlorothiazide 12.5g
Folic acid 0.2g
Starch 30.0g
Microcrystalline Cellulose 60.0g
Carboxymethyl starch sodium 15.0g
Pool Luo Samu F68 1.0g
Water is an amount of
Magnesium stearate is an amount of
Process 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 subsequent use; Accurate amlodipine, hydrochlorothiazide, lactose, cross-linking sodium carboxymethyl cellulose and the microcrystalline Cellulose of claiming the to decide recipe quantity mixing that sieves, subsequent use; Equivalent increases progressively good amlodipine, lactose, cross-linking sodium carboxymethyl cellulose and the microcrystalline Cellulose of adding premix after getting the folic acid of recipe quantity and mooring the abundant mix homogeneously of Luo Samu F68, adds entry and makes soft material in right amount, and 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 6 amlodipine 5mg/ hydrochlorothiazide 12.5mg/ folic acid 0.4mg sheets
Prescription
Amlodipine Besylate Tablet (in amlodipine) 5.0g
Hydrochlorothiazide 12.5g
Folic acid 0.4g
Lactose 30.0g
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
Process 1000
Preparation technology: with embodiment 5.
The preparation of embodiment 7 amlodipine 5mg/ hydrochlorothiazide 12.5mg/ folic acid 0.8mg sheets
Prescription
Amlodipine Besylate Tablet (in amlodipine) 5.0g
Hydrochlorothiazide 12.5g
Folic acid 0.8g
Lactose 50.0g
Microcrystalline Cellulose 80.0g
Carboxymethyl starch sodium 20.0g
Sodium lauryl sulphate 5.0g
Water is an amount of
Magnesium stearate is an amount of
Process 1000
Preparation technology: with embodiment 5.
The capsular preparation of embodiment 8 felodipine 10mg/ hydrochlorothiazide 12.5mg/ calcium folinate 0.5mg
Prescription:
Felodipine 10g
Hydrochlorothiazide 12.5g
Calcium folinate (by folinic acid) 0.5g
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
Process 1000
Preparation technology: with felodipine 10g, hydrochlorothiazide 25g, calcium folinate (by folinic acid) 0.5g, microcrystalline Cellulose 20g, starch 40g, the carboxymethyl starch sodium 20g back mix homogeneously of pulverizing, sieve; Process behind the soft material with 5% an amount of polyvidone k-30 aqueous solution granulate, dry, granulate; Add the micropowder silica gel mix homogeneously, promptly get by encapsulated 1000 of conventional method.
The capsular preparation of embodiment 9 felodipine 10mg/ hydrochlorothiazide 12.5mg/ calcium folinate 1.0mg
Prescription:
Felodipine 10g
Hydrochlorothiazide 12.5g
Calcium folinate (by folinic acid) 1.0g
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
Process 1000
Preparation technology: with embodiment 8.
The preparation of embodiment 10 amlodipine 10mg/ hydrochlorothiazide 25mg/ folic acid 1.6mg sheets
Prescription:
Amlodipine Besylate Tablet (in amlodipine) 10g
Hydrochlorothiazide 25g
Folic acid 1.6g
Microcrystalline Cellulose 45.0g
Lactose 25.0g
Carboxymethyl starch sodium 15.0g
Water is an amount of
Magnesium stearate 0.5g
Process 1000
Preparation technology: amlodipine, hydrochlorothiazide, the folic acid of getting recipe quantity is crossed behind 100 mesh sieves subsequent use by equivalent incremental method mix homogeneously; Other adjuvants are crossed behind 100 mesh sieves 75 ℃ of dryings 2 hours respectively; Press behind the low-substituted hydroxypropyl cellulose, 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, 40～45 ℃ of dryings; Granulate, dried granule add an amount of magnesium stearate mixing, tabletting behind the assay.
The preparation of embodiment 11 Levamlodipine 2.5mg/ hydrochlorothiazide 12.5mg/ levoleucovorin calcium 0.2mg sheets
Prescription:
Left-handed Amlodipine Besylate Tablet (in amlodipine) 2.5g
Hydrochlorothiazide 12.5g
Levoleucovorin calcium (by levo leucovorin) 0.2g
Microcrystalline Cellulose 45.0g
Lactose 25.0g
Carboxymethyl starch sodium 15.0g
Water is an amount of
Magnesium stearate 0.5g
Process 1000
Preparation technology: with embodiment 10.
The capsular preparation of embodiment 12 nisoldipine 20mg/ indapamide 2.5mg/ folic acid 0.4mg
Prescription:
Nisoldipine 20.0g
Indapamide 2.5g
Folic acid 0.4g
Starch 30.0g
Microcrystalline Cellulose 18.0g
Carboxymethyl starch sodium 18.0g
5% polyvidone k-30 aqueous solution is an amount of
Micropowder silica gel is an amount of
Process 1000
Preparation technology: with nisoldipine, indapamide, folic acid, microcrystalline Cellulose, starch, the carboxymethyl starch sodium back mix homogeneously of pulverizing, sieve; Process behind the soft material with 5% an amount of polyvidone k-30 aqueous solution granulate, dry, add the micropowder silica gel mix homogeneously, promptly get by encapsulated 1000 of conventional method.
The capsular preparation of embodiment 13 nisoldipine 20mg/ indapamide 2.5mg/ folic acid 0.8mg
Prescription:
Nisoldipine 20.0g
Indapamide 2.5g
Folic acid 0.8g
Starch 30.0g
Microcrystalline Cellulose 18.0g
Carboxymethyl starch sodium 18.0g
5% polyvidone k-30 aqueous solution is an amount of
Micropowder silica gel is an amount of
Process 1000
Preparation technology: with embodiment 12.
The capsular preparation of embodiment 14 lercanidipine 10mg/ hydrochlorothiazide 12.5mg/ folic acid 0.4mg
Prescription:
Lercanidipine 10.0g
Hydrochlorothiazide 12.5g
Folic acid 0.4g
Starch 30.0g
Microcrystalline Cellulose 18.0g
Carboxymethyl starch sodium 18.0g
5% polyvidone k-30 aqueous solution is an amount of
Micropowder silica gel is an amount of
Process 1000
Preparation technology: with embodiment 12.

Claims (5)

1. pharmaceutical composition comprises:
(1) the single depressor of pharmaceutical dosage;
(2) diuretic of pharmaceutical dosage;
(3) folacin compound of pharmaceutical dosage;
(4) acceptable carrier on the pharmaceutics,
Wherein said single depressor is selected from amlodipine, felodipine, nisoldipine or lercanidipine, and dosage is 2.5～90mg; Wherein said diuretic is selected from hydrochlorothiazide or indapamide, and dosage is 2.5～50mg; Wherein said folacin compound is selected from folic acid or calcium folinate, and dosage is 0.2～1.6mg.
2. according to the pharmaceutical composition described in the claim 1, it is characterized in that the pharmacy dosage form of said pharmaceutical composition is an oral formulations, comprise tablet, capsule or granule.
3. the pharmaceutical composition described in the claim 1 is used for preventing, treating or delay the purposes of hypertensive medicine in preparation.
4. the pharmaceutical composition described in the claim 1 is used for preventing, treat or delay the purposes of the medicine of the target organ damage that hypertension causes in preparation, and said target organ damage is vascular endothelial cell infringement, renal function injury or myocardial structural infringement.
5. be used for reducing the purposes of the dangerous medicine of cardiovascular and cerebrovascular vessel incident that hypertension causes according to the pharmaceutical composition described in the claim 1 in preparation, said cardiovascular and cerebrovascular vessel incident danger is apoplexy.
CN2007101657773A 2006-11-11 2007-11-03 Drug compound for Ca channel retarder/diuretic/ folate coupling and function Active CN101199848B (en)

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CN101897973A (en) * 2009-05-27 2010-12-01 北京奥萨医药研究中心有限公司 Application of pharmaceutical composition containing calcium antagonists and B vitamins to preparing medicines for treating peripheral arterial diseases
CN103599537A (en) * 2013-11-15 2014-02-26 深圳奥萨医药有限公司 Pharmaceutical composition of calcium channel blocker/thiazide diuretic/5-methyltetrahydrofolate
CN110237258A (en) * 2018-03-09 2019-09-17 深圳奥萨制药有限公司 For treating the pharmaceutical composition of hypertension
CN111481554B (en) * 2019-01-29 2022-11-25 深圳奥萨医药有限公司 Tablet containing amlodipine and folic acid and preparation method thereof
CN113616651B (en) * 2020-05-08 2023-12-29 深圳奥萨制药有限公司 Compound antihypertensive pharmaceutical composition and application thereof
WO2022187349A1 (en) * 2021-03-02 2022-09-09 The Regents Of The University Of California Combinatory therapy for preventing, inhibiting, treating, or reducing aneurysms
CN115025057B (en) * 2022-07-20 2023-05-30 江苏亚邦爱普森药业有限公司 Amlodipine besylate folic acid tablet and preparation method thereof

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