CN101229374A - Medicine compounds containing isosorbide mononitrate for treating high blood pressure - Google Patents
Medicine compounds containing isosorbide mononitrate for treating high blood pressure Download PDFInfo
- Publication number
- CN101229374A CN101229374A CNA200810006975XA CN200810006975A CN101229374A CN 101229374 A CN101229374 A CN 101229374A CN A200810006975X A CNA200810006975X A CN A200810006975XA CN 200810006975 A CN200810006975 A CN 200810006975A CN 101229374 A CN101229374 A CN 101229374A
- Authority
- CN
- China
- Prior art keywords
- isosorbide mononitrate
- group
- patient
- pressure
- hypertension
- 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.)
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- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
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- 206010042957 Systolic hypertension Diseases 0.000 description 1
- 206010046607 Urine abnormality Diseases 0.000 description 1
- 229960002122 acebutolol Drugs 0.000 description 1
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940077927 altace Drugs 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000002376 aorta thoracic Anatomy 0.000 description 1
- 210000001765 aortic valve Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229950001730 budralazine Drugs 0.000 description 1
- DQGFCLJXYFXXIJ-LFIBNONCSA-N budralazine Chemical compound C1=CC=C2C(N/N=C(C)/C=C(C)C)=NN=CC2=C1 DQGFCLJXYFXXIJ-LFIBNONCSA-N 0.000 description 1
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- 230000007213 cerebrovascular event Effects 0.000 description 1
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- 230000001276 controlling effect Effects 0.000 description 1
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- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 229960002877 dihydralazine Drugs 0.000 description 1
- VQKLRVZQQYVIJW-UHFFFAOYSA-N dihydralazine Chemical compound C1=CC=C2C(NN)=NN=C(NN)C2=C1 VQKLRVZQQYVIJW-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
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- 229960002474 hydralazine Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical group O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 229960004427 isradipine Drugs 0.000 description 1
- FPCCSQOGAWCVBH-UHFFFAOYSA-N ketanserin Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCN2C(C3=CC=CC=C3NC2=O)=O)CC1 FPCCSQOGAWCVBH-UHFFFAOYSA-N 0.000 description 1
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- 230000002503 metabolic effect Effects 0.000 description 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 1
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- 229960004255 nadolol Drugs 0.000 description 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 description 1
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- 229960001999 phentolamine Drugs 0.000 description 1
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- 239000001103 potassium chloride Substances 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention provides a medical composite which consists of isosorbide mononitrate and angiotensin converting enzyme inhibitor. Experimental results reveal that isosorbide mononitrate and angiotensin converting enzyme inhibitor can achieve quite good synergistic effect on reducing blood pressure and preventing hypertension complications. The medical composite provided by the invention can effectively prevent the organ from being damaged by hypertension and improve the long-term survival rate of hypertension sufferers.
Description
Technical field
The application is that the application number submitted on November 23rd, 2005 is 200510125589.9, denomination of invention is divided an application for the patent application of " being used for the treatment of the hypertensive pharmaceutical composition that contains isosorbide mononitrate ".
The invention belongs to medical technology, relate to the new pharmaceutical composition that is used for the senile hypertension treatment.
Background technology
The theoretical new development of hypertension drug treatment
In the treatment to the hyperpietic, whether the long-term survival rate of paying attention to the patient is significantly improved, and is a much progress of hypertension therapeutic theory in recent years.Thought in the past that diastolic pressure (DBP) was the index preferably of decision hypertension seriousness, the target of Drug therapy also is that DBP is reduced to less than 90,85 or 80mmHg.Systolic pressure (SBP) also reduces simultaneously, but the degree that reduces is less than DBP, so PP can not drop to normally.Although the result shows Drug therapy DBP is reduced to normally, cardiovascular (CV) is dangerous further not to be improved.The epidemiological study of nearly decades shows that systolic pressure is the better prediction index of CV danger, and pulse pressure (PP) broadening is CV risk factor independently.The PP of broadening may be the strongest prediction index of determining to take place the maximum hyperpietic of myocardial infarction danger, even shows also that the hyperpietic who receives treatment PP has prognostic value.It is to determine the most strong prediction index of myocardial infarction danger takes place that pulse pressure has been realized, and this has great importance on the hypertension clinical therapeutics, is the much progress to hypertension therapeutic understanding.This also can explain for many years in clinical hypertension therapeutic, and blood pressure has obtained effective control and hyperpietic's long-term mortality rate does not improve, even the large sample clinical investigation that has shows that mortality rate descends to some extent.Three clinical trials promptings of EWPHE, syst-Eur, syst-China when systolic pressure constant during at 160mmHg, diastolic pressure low more (≤75mmHg) (the cardiovascular event incidence rate in the period of＞95mmHg) the patient two increases 12% than diastolic pressure height.Hyperpietic's mortality rate that this explanation pulse pressure is big more is high more.A senile hypertension survival analysis research prompting of announcing in the recent period, systolic pressure＜130mmHg, diastolic pressure is minimum at hyperpietic's mortality rate of 80～85mmHg, and systolic pressure＞160mmHg, this group patient death rate of diastolic pressure＜70mmHg is the highest.Mean arterial pressure and diastolic pressure and mortality rate are uncorrelated, and systolic pressure and pulse pressure are the strong predictor of mortality rate.
Simple property systolic hypertension patient's arterial elasticity and compliance significantly descend, and arteriogram and echo speed are accelerated, and echo falls into the systole of heart, and it also is the key factor that causes cardiovascular event that the moment blood pressure when arteriogram and echo meet increases.
Clinical now present situation to hypertension therapeutic
In hyperpietic's crowd, diastolic pressure (DBP) control easily (≤90mmHg), systolic pressure (SBP) control difficult (≤140mmHg).In traditional hypertension therapeutic method, diastolic pressure as an important controlling of blood pressure target, be it seems it is incorrect now, be the fresh target of hypertension therapeutic to the control of systolic pressure and pulse pressure, be new breakthrough to the hypertension therapeutic theory.Yet in present clinical treatment, still there is not the ideal medicine that systolic pressure and pulse pressure are had very good effect.For a lot of hyperpietics, diastolic pressure is easy to control often, and systolic pressure can not be well controlled.For these hyperpietics, the result of traditional antihypertensive therapy is that diastolic pressure has obtained effective control, and systolic pressure still maintains higher level, and pulse pressure increases, and has increased patient's mortality risk relatively.
Therefore, traditional hypertension and treating cardiovascular disease have been subjected to challenge, have actively carried out both at home and abroad at the clinical research that can improve arterial elasticity and compliance medicine.Seek a kind of ideal medicament that meets present hypertension therapeutic theory, can either reduce and effectively reduce blood pressure, prevent that long-term blood pressure from increasing the various complication that may cause, can effectively prevent the generation of cardiovascular events such as myocardial infarction again, effectively reduce mortality rate, meet nearly 100,000,000 hyperpietics' of China interests.
Nitrate esters medicines such as isosorbide mononitrate are mainly used in the treatment of myocardial ischemia disease in clinical, pharmaceutical research is in the past thought, the antianginal mechanism of nitrate esters medicine mainly is expansion small artery and venule, thereby reduce the preload and the afterload of heart, it can strengthen atherosis aortic elasticity discovered in recent years, make that aortic compliance is effectively recovered, pulse pressure difference reduces.In youngster, echo arrives aorta behind aortic valve closing, does not influence SBP so only influence DBP, helps to increase Coronary Perfusion Pressure.In the stiff patient of central artery (hyperpietic or old people), pulse wave velocity enlarges markedly, and makes echo fall into the systole of heart, and left ventricle and aortic systolic pressure are raise, and aortic diastolic pressure reduces.When old and feeble, the hardenability of central artery increases, and reflection coefficient raises.Clinical research shows that isosorbide mononitrate can make the enhancing coefficient of arteriogram and echo descend 50%, and systolic pressure is had significant reduction effect.This may be one of antianginal mechanism of nitrate esters medicine.
Now for hypertensive treatment, single medicine often can not be obtained ideal curative effect, usually with two or more depressor use in conjunction, can obtain efficacy of antihypertensive treatment preferably clinically, but still can't overcome when mean arterial pressure reduces the phenomenon that makes the pulse pressure increase.
Summary of the invention
The forward position that nitrate esters medicine antianginal study on mechanism is closelyed follow by our Lunan Pharmacy Co. Ltd, according to the recent clinical trial and the latest notion of hypertension therapeutic, we are in conjunction with the curative effect characteristics of existing antihypertensive drug, creatively propose the glad health of southern Shandong and other antihypertensive drug that my company produces are united use, be used for the patient that the invalid intractable systolic pressure of traditional clinically antihypertensive therapy raises, after perhaps using vasodilation, the patient that reflex tachycardia is comparatively serious, large sample clinical trial through has for many years obtained the good clinical curative effect.Nitrate esters medicines such as isosorbide mononitrate are compared with existing antihypertensive drug, has unique mechanism of action, be mainly used in antianginal treatment clinically, we find in clinical trial, isosorbide mononitrate and nearly all Altace Ramipril use in conjunction, existing cooperative effect aspect the reduction systolic pressure, wherein with calcium ion antagonist, the renin angiotensin aldosterone system antagonist, vasodilation, during antihypertensive drug use in conjunction such as adrenoceptor blocker, effect is ideal, at synergitic reduction systolic pressure; Alleviate the untoward reaction that antihypertensive drugs causes; Effectively increase hyperpietic's aspects such as survival rate, obtained beyond thought effect.Wherein tool meaningfully their use in conjunction is the most obvious to the reduction of hyperpietic's systolic pressure, effectively reduced pulse pressure difference, greatly reduce the risk of the various cardiovascular events of hyperpietic, this may have great significance to patient's long-term survival rate.Therefore, the combination antihypertensive that contains isosorbide mononitrate provided by the present invention, antihypertensive therapy mistaken ideas have clinically been broken through for a long time, the promptly simple blood pressure lowering target of pursuing, especially to the reduction effect of diastolic pressure, and ignored hypertensive patient's long-term survival rate, make hypertension therapeutic has been lost its most basic meaning.The advantage of the present composition is embodied in following several aspect:
One, isosorbide mononitrate and calcium ion antagonist, angiotensin-convertion enzyme inhibitor, angiotensin ii receptor antagonist, vasodilation, adrenoceptor blocker etc. have good concertedness hypotensive effect, have curative effect preferably for common clinically obstinate hypertension.
Two, compositions of the present invention is compared with traditional antihypertensive drug, to the significantly reduced while of mean arterial pressure, systolic pressure and pulse pressure difference is also had reduction effect preferably, has overcome the pulse pressure increase after a lot of hyperpietics use conventional medicament.
Three, compositions of the present invention has been avoided hyperpietic's reflex tachycardia when effectively bringing high blood pressure down, and sympathetic activity raises, the generation of untoward reaction such as edema.
Four, life-time service compositions of the present invention has wholesome effect to hyperpietic's long-term survival rate, and patient's prognosis is produced active influence, and this also is the clinical treatment problem that has meaning most solved by the invention.In a word, the antihypertensive composition that the present invention contains isosorbide mononitrate has revolutionary meaning for hypertensive treatment, and the obtained long term clinical results of compositions of the present invention is unprecedented on the hypertension therapeutic history.
We are according to the result of preceding clinical trial phase, physicochemical property with various antihypertensive drug, from numerous pharmaceutically useful adjuvants, selected starch, low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl emthylcellulose 4000 (HPMC--4M), HPMC--15M, microcrystalline Cellulose, polyvinylpyrrolidone (PVP), micropowder silica gel, magnesium stearate, lactose, carboxymethyl starch sodium, pregelatinized Starch, Rikemal B 200, glyceryl monostearate, Pulvis Talci, ethyl cellulose (EC), stearic acid, Polyethylene Glycol-6000, mannitol, crospolyvinylpyrrolidone, sodium carboxymethyl cellulose (CMC-Na), polyvinyl alcohol (PVA), hexadecanol, octadecanol, cross-linking sodium carboxymethyl cellulose, sodium alginate or ethylene-vinyl acetate copolymer etc., with isosorbide mononitrate and nitrendipine, nifedipine, nicardipine, nisoldipine, felodipine, amlodipine, Isradipine, captopril, enalapril, benazepril, perindopril, lisinopril, fosinopril, trandolapril, ramipril, cilazapril, losartan, valsartan, Irb, eprosartan, Candesartan, olmesartan medoxomil, telmisartan, pinacidil, minoxidil, hydralazine, dihydralazine, cadralazine, budralazine, ketanserin, Propranolol, timolol, nadolol, sotalol, atenolol, oxprenolol, metoprolol, betaxolol, acebutolol, carvedilol, antihypertensive drug such as phentolamine are prepared into the compound preparation that the patient is convenient to take for a long time, and carried out preliminary animal experiment, obtained ideal effect.
The specific embodiment
Below be 1000 recipe quantity.
Embodiment 1
Isosorbide mononitrate nitrendipine sustained-release sheet
Prescription A
Isosorbide mononitrate 15g
Starch 50g
L--HPC 20g
10% starch slurry is an amount of
Magnesium stearate 1g
Prescription B
Nitrendipine 15g
HPMC--4M 20g
HPMC--15M 30g
Microcrystalline Cellulose 20g
PVP 8g
Micropowder silica gel 35g
The 8%PVPk30 ethanol solution is an amount of
Magnesium stearate 2g
Preparation technology:
Isosorbide mononitrate and starch, L-HPC among the A crosses 100 mesh sieves respectively with prescription, and mixing, add 10% starch slurry and granulate in right amount, oven dry below 50 ℃, 18 mesh sieve granulate add the magnesium stearate mixing; 100 mesh sieves are crossed in nitrendipine among the prescription B, HPMC--4M, HPMC--15M, microcrystalline Cellulose, PVP, micropowder silica gel respectively, mixing, add the 8%PVPk30 ethanol solution and granulate in right amount, oven dry, granulate, add the magnesium stearate mixing, the compacting double-layer tablet promptly.
Embodiment 2
Isosorbide mononitrate captopril sheet
Isosorbide mononitrate 10g
Captopril 50g
Starch 60g
Microcrystalline Cellulose 100g
L-HPC 30g
10% starch slurry is an amount of
Magnesium stearate 2g
Preparation technology:
Isosorbide mononitrate, captopril, starch, microcrystalline Cellulose and L-HPC in the prescription are crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 50 ℃, 18 mesh sieve granulate add the magnesium stearate mixing of recipe quantity, and tabletting is promptly.
Embodiment 3
The isosorbide mononitrate Nifedipine sustained release tablets
Prescription A
Isosorbide mononitrate 20g
Starch 100g
Carboxymethyl starch sodium 10g
10% starch slurry is an amount of
Magnesium stearate 1g
Prescription B
Nifedipine 15g
Hexadecanol 10g
Glyceryl monostearate 20g
Microcrystalline Cellulose 40g
The 8%PVPk30 ethanol solution is an amount of
Magnesium stearate 2g
Preparation technology:
Isosorbide mononitrate and starch, the carboxymethyl starch sodium of prescription among the A crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 50 ℃, 18 mesh sieve granulate add the magnesium stearate mixing; Nifedipine, hexadecanol, glyceryl monostearate, the microcrystalline Cellulose of prescription among the B crossed 100 mesh sieves respectively, mixing, add the 8%PVPk30 ethanol solution and granulate in right amount, oven dry, granulate adds the magnesium stearate mixing, and the compacting double-layer tablet is promptly.
Embodiment 4
The isosorbide mononitrate enalapril tablet
Isosorbide mononitrate 15g
Enalapril 10g
Lactose 20g
Microcrystalline Cellulose 30g
Crospolyvinylpyrrolidone 5g
10% starch slurry is an amount of
Magnesium stearate 1g
Preparation technology:
Isosorbide mononitrate, enalapril, lactose, microcrystalline Cellulose and crospolyvinylpyrrolidone in the prescription are crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 60 ℃, 18 mesh sieve granulate, add the magnesium stearate mixing of recipe quantity, tabletting promptly.
Embodiment 5
Isosorbide mononitrate spectinomycin hydrochloride slow releasing tablet
Prescription A
Isosorbide mononitrate 15g
Starch 100g
Carboxymethyl starch sodium 10g
The 8%PVPk30 alcoholic solution is an amount of
Magnesium stearate 1g
Prescription B
Spectinomycin hydrochloride 100g
Octadecanol 10g
Rikemal B 200 20g
Microcrystalline Cellulose 40g
3% ethyl cellulose ethanol solution is an amount of
Magnesium stearate 2g
Preparation technology:
Isosorbide mononitrate and starch, the carboxymethyl starch sodium of prescription among the A crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 60 ℃, 18 mesh sieve granulate add the magnesium stearate mixing; Spectinomycin hydrochloride, octadecanol, Rikemal B 200, the microcrystalline Cellulose of prescription among the B crossed 100 mesh sieves respectively, mixing, add 5% ethyl cellulose ethanol solution and granulate in right amount, oven dry, granulate adds the magnesium stearate mixing, and the compacting double-layer tablet is promptly.
Embodiment 6
Isosorbide mononitrate carvedilol slow releasing tablet
Prescription A
Isosorbide mononitrate 20g
Microcrystalline Cellulose 100g
Henan gelling starch 10g
10% starch slurry is an amount of
Pulvis Talci 1g
Prescription B
Carvedilol 20g
Ethyl cellulose 8g
Glyceryl monostearate 20g
Microcrystalline Cellulose 40g
PVP 8g
The 8%PVPk30 ethanol solution is an amount of
Magnesium stearate 2g
Preparation technology:
Isosorbide mononitrate and microcrystalline Cellulose, the Henan gelling starch of prescription among the A crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 50 ℃, 18 mesh sieve granulate add the magnesium stearate mixing; Carvedilol, ethyl cellulose, glyceryl monostearate, microcrystalline Cellulose, PVP among the B crosses 100 mesh sieves respectively with prescription, and mixing, add the 8%PVPk30 ethanol solution and granulate in right amount, oven dry, granulate adds the magnesium stearate mixing, and the compacting double-layer tablet is promptly.
Embodiment 7
Isosorbide mononitrate losartan capsule
Isosorbide mononitrate 15g
Losartan 20g
Lactose 20g
Microcrystalline Cellulose 30g
Carboxymethyl starch sodium 5g
10% starch slurry is an amount of
Preparation technology:
Isosorbide mononitrate, losartan, lactose, microcrystalline Cellulose and carboxymethyl starch sodium in the prescription are crossed 100 mesh sieves respectively, mixing, add 10% starch slurry and granulate in right amount, oven dry below 60 ℃, 18 mesh sieve granulate, capsule charge gets final product.
Embodiment 8
Isosorbide mononitrate, lisinopril and pinacidil slow releasing capsule
Prescription A
Isosorbide mononitrate 15g
Lisinopril 5g
Celphere 200g
Sodium carboxymethyl cellulose 10g
Carboxymethyl starch sodium 40g
The 7%PVP alcoholic solution is an amount of
Preparation technology:
Isosorbide mononitrate, lisinopril are crossed 160 mesh sieves, and sodium carboxymethyl cellulose, carboxymethyl starch sodium are crossed 100 mesh sieves, and recipe quantity takes by weighing, and be miscible in the 7%PVP alcoholic solution (solvent is a 60-70% ethanol).Drive the granulating and coating machine, go into wind pressure 0.5bar, CYL (inlet air air door pressure) 3bar, CAP1 (atomizing pressure) 0.8bar pours celphere into, pelletize.Blanking velocity 4rpm, the pump 12% of wriggling, rotary speed 145rpm, 50 ℃ of oven dry.
Prescription B
(1) contains the preparation of pill core
Pinacidil 80g
Celphere 200g
7%PVP solution (solvent is 90% ethanol) is an amount of
Preparation technology:
Pinacidil is crossed 160 mesh sieves, and recipe quantity takes by weighing, and pours in the hopper.Drive the granulating and coating machine, go into wind pressure 0.5bar, CYL 2bar, CAP1 0.6bar pours celphere into, pelletize.Blanking velocity 4rpm, the pump 12% of wriggling, rotary speed 145rpm, spray 7%PVP solution (solvent is 90% ethanol), 50 ℃ of oven dry.Pelletize finishes.
Contain pill core 500g
Acrylic resin RS100 10g
Acrylic resin RL 100 10g
Polyethylene Glycol-6000 2g
Pulvis Talci 3g
95% ethanol is an amount of
Preparation technology: recipe quantity takes by weighing and contains pill core, pours in the hopper.Drive the granulating and coating machine, go into wind pressure 0.5bar, CYL 3bar, CAP1 0.9bar, 30 ℃ of inlet air temperature, rotary speed 180rpm, the pump 7% of wriggling sprays into the alcoholic solution of acrylic resin RS 100 and acrylic resin RL 100.Coating finishes.
Is to carry out capsule at 1: 1 to fill and get final product with the pastille piller of prescription A and prescription B gained according to weight ratio.
Acrylic resin in the present embodiment can replace with the polyvinyl alcohol or the ethylene-vinyl acetate copolymer of equal number.
Embodiment 9
The glad health of southern Shandong and other antihypertensive drug use in conjunction are to the clinical trial of hypertension therapeutic
Our Lunan Pharmacy Co. Ltd is in domestic top standard in the research and development and the production of the glad health of southern Shandong (isosorbide mononitrate) always, domestic blank has been filled up in the production of crude drug, closely follow the forward position of nitrate esters medicine antianginal study on mechanism in recent years, with the associating of how tame hospital, creatively propose the glad health of southern Shandong and other antihypertensive drug that my company produces are united use, be used for the patient that the invalid intractable systolic pressure of traditional clinically antihypertensive therapy raises, after perhaps using vasodilation, the patient that reflex tachycardia is comparatively serious, large sample clinical trial through has for many years obtained the good clinical curative effect.Nitrate esters medicines such as isosorbide mononitrate are compared with existing antihypertensive drug, has unique mechanism of action, be mainly used in antianginal treatment clinically, we find in clinical trial, antihypertensive drug use in conjunction such as isosorbide mononitrate and calcium ion antagonist, angiotensin-convertion enzyme inhibitor, angiotensin ii receptor antagonist, vasodilation, adrenoceptor blocker are at synergitic reduction systolic pressure; Alleviate the untoward reaction that antihypertensive drugs causes; Effectively increase hyperpietic's aspects such as survival rate, obtained beyond thought effect.Now announce a part of test data wherein as follows.
One, case is selected
Age is the senile hypertension patient between 60-70 year, and tangible other diseases of cardiovascular and cerebrovascular systems history through the not good patient of traditional antihypertensive therapy clinical efficacy, all can not participated in this test.
Two, therapeutic regimen
All patients that participate in this test are divided into two groups at random according to the level and the age level of systolic pressure, test group is before uniting the glad health of use southern Shandong and other antihypertensive drug, use glad 2 weeks and other 2 weeks of antihypertensive drug of health of southern Shandong of same dose respectively, the 5th week was worked preceding two kinds of medicines of uniting use and former same dose; Matched group only uses corresponding antihypertensive drug except that the glad health of southern Shandong, and in order to reach the purpose of effective blood pressure lowering, its using dosage will be higher than test group dosage.
Three, observation index
In test, we have observed mainly that heart rate behind patient's the systolic pressure, pulse pressure, drug use increases and the adverse reaction rate of patient's 8 years survival rates and part medicine.The patient is 2 weeks after medication, are unified in 10:30 measurement in morning blood pressure.
Four, result of the test
1. isosorbide mononitrate and nitrendipine are united the clinical trial of use to the hyperpietic
The patient who participates in this test has 160 examples, and age-based and systolic pressure level is divided into two groups, test group 89 examples, matched group 71 examples at random.Test group is used glad 2 weeks of health of southern Shandong earlier, 20mg/ days, rises with 2 pm in morning respectively and takes; Drug withdrawal re-uses 2 weeks of nitrendipine after 1 week, and 15mg/ days, divide and take for three times, the using dosage of two medicines all is lower than clinical common dose, the 7th week rises to unite and uses above-mentioned two kinds of medicines, and the using dosage of every day is the same.Matched group uses the nitrendipine of 30mg every day, divides and takes for three times.The patient of test group and matched group is carried out secular tracking follow up a case by regular visits to, will or can adhere to that not the patient of medication rejects this test, calculate the survival rate in 8 years because of the dead patient of non-cardiovascular and cerebrovascular disease.The result shows, in the patient of test group, isosorbide mononitrate and nitrendipine drug combination have been obtained significant concertedness hypotensive effect to patient's systolic pressure, and to not significantly influence of diastolic pressure, thereby when obviously reducing systolic pressure, make pulse pressure also produce significant decline, obtained ideal antihypertensive effect, and nitrendipine subclinical dose and routine clinical dosage all make pulse pressure increase.The subclinical dose use in conjunction of isosorbide mononitrate and nitrendipine has significantly been corrected the reflex tachycardia untoward reaction that nitrendipine in use occurs, when having reduced blood pressure, do not cause obviously increasing of sympathetic activity, this may produce wholesome effect to patient's long-term survival rate.8 years survival rates of drug combination group are apparently higher than the nitrendipine matched group of independent medication.
The efficacy of antihypertensive treatment that table 1. isosorbide mononitrate and nitrendipine are united use compares
| Systolic pressure | Diastolic pressure | Pulse pressure | Heart rate increases | 8 years survival rates | |
| The 2nd week of matched group before test group the 2nd all test group the 5th all test group the 9th all matched group medications before the test group medication | 178±12.2 166±9.5 165±12.0 144±9.9 **&&$$ 177±11.8 158±11.7 * | 115±8.9 111±8.6 94±8.7 92±8.1 **$$ 114±9.0 75±8.8 ** | 63±6.5 55±4.3 71±5.2 52±5.6 **&&$$ 63±7.1 83±8.6 ** | 3.0±2.9 8.2±6.7 4.3±2.3 $$ 21.6±15.8 | 87.3％ $$ 65.5％ |
*With comparison before the medication, P＜0.01,
*With comparison before the medication, P＜0.05.
﹠amp; ﹠amp;Compare P＜0.01. with the 5th week of test group
$$Compare P＜0.01. with the 2nd week of matched group
2. isosorbide mononitrate and nifedipine are united the clinical trial of use to the hyperpietic
The patient who participates in this test has 150 examples, and age-based and systolic pressure level is divided into two groups, test group 79 examples, matched group 71 examples at random.Test group is used glad 2 weeks of health of southern Shandong earlier, 20mg/ days, rises with 2 pm in morning respectively and takes; Drug withdrawal re-uses 2 weeks of nifedipine after 1 week, and 15mg/ days, divide and take for three times, the using dosage of two medicines all is lower than clinical common dose, the 7th week rises to unite and uses above-mentioned two kinds of medicines, and the using dosage of every day is the same.Matched group uses the nifedipine of 45mg every day, divides and takes for three times.The patient of test group and matched group is carried out secular tracking follow up a case by regular visits to, will or can adhere to that not the patient of medication rejects this test, calculate the survival rate in 8 years because of the dead patient of non-cardiovascular and cerebrovascular vessel factor.The result shows, in the patient of test group, isosorbide mononitrate and nifedipine drug combination have been obtained significant concertedness hypotensive effect to patient's systolic pressure, and to not significantly influence of diastolic pressure, thereby when obviously reducing systolic pressure, make pulse pressure also produce significant decline, obtained ideal antihypertensive effect, and nifedipine subclinical dose and routine clinical dosage all make pulse pressure increase.The subclinical dose use in conjunction of isosorbide mononitrate and nifedipine has significantly been corrected the reflex tachycardia untoward reaction that heavy dose of nifedipine in use occurs, when having reduced blood pressure, do not cause obviously increasing of sympathetic activity, this may produce wholesome effect to patient's long-term survival rate.8 years survival rates of drug combination group are apparently higher than the nifedipine matched group of independent medication.
The efficacy of antihypertensive treatment that table 2. isosorbide mononitrate and nifedipine are united use compares
| Systolic pressure | Diastolic pressure | Pulse pressure | Heart rate increases | 8 years survival rates | |
| The 2nd week of matched group before test group the 2nd all test group the 5th all test group the 9th all matched group medications before the test group medication | 176±14.3 167±10.4 162±12.6 136±10.2 **&&$ 178±13.4 150±12.8 ** | 114±10.1 111±9.0 96±7.5 90±8.0 **$ 115±11.7 81±8.5 ** | 62±7.8 56±6.3 66±5.8 46±5.1 **&&$$ 63±6.0 83±7.2 ** | 3.6±3.1 7.5±4.8 4.7±2.1 $$ 18.6±7.7 | 86.6％ $$ 70.5％ |
*With comparison before the medication, P＜0.01.
﹠amp; ﹠amp;Compare P＜0.01. with the 5th week of test group
$$Compare with the 2nd week of matched group, P＜0.01,
$Compare P＜0.05. with the 2nd week of matched group
3. isosorbide mononitrate and enalapril are united the clinical trial of use to the hyperpietic
The patient who participates in this test has 165 examples, and age-based and systolic pressure level is divided into two groups, test group 86 examples, matched group 79 examples at random.Test group is used glad 2 weeks of health of southern Shandong earlier, 20mg/ days, rises with 2 pm in morning respectively and takes; Drug withdrawal re-uses 2 weeks of enalapril after 1 week, 10mg/ days, once took morning, and the using dosage of two medicines all is lower than clinical common dose, the 7th week rises to unite and uses above-mentioned two kinds of medicines, and the using dosage of every day is the same.Matched group uses the enalapril of 30mg every day, divides secondary to take.The patient of test group and matched group is carried out secular tracking follow up a case by regular visits to, to observe the situation of curative effect of medication and untoward reaction.The result shows, in the patient of test group, isosorbide mononitrate and enalapril drug combination have been obtained significant concertedness hypotensive effect to patient's systolic pressure, and to not significantly influence of diastolic pressure, thereby when obviously reducing systolic pressure, make pulse pressure also produce significant decline, obtained ideal antihypertensive effect, and the enalapril subclinical dose can not produce significant pressure reduction effect, because this tests selected case all is more refractory obstinate hypertension, clinical heavy dose of the use can not obtained ideal curative effect yet, and adverse reaction rate such as dry cough is higher.The subclinical dose use in conjunction of isosorbide mononitrate and enalapril has significantly been corrected untoward reaction such as erythra that heavy dose of enalapril in use occurs, dry cough.The result of long term follow-up investigation shows that patient's compliance of drug combination group is better, and the patient all can adhere to medication mostly, and heavy dose of enalapril matched group untoward reaction is more serious, and a lot of patients can not adhere to that medication is more than 1 year.
The efficacy of antihypertensive treatment that table 3. isosorbide mononitrate and enalapril are united use compares
| Systolic pressure | Diastolic pressure | Pulse pressure | Adverse reaction rate such as erythra, dry cough | |
| The 2nd week of matched group before test group the 2nd all test group the 5th all test group the 9th all matched group medications before the test group medication | 177±13.9 167±12.5 166±13.6 148±11.8 **&&$$ 178±12.7 160±12.4 * | 114±9.6 112±8.7 110±9.0 100±7.9 * 117±9.2 101±8.3 ** | 62±6.0 55±4.8 56±5.7 48±4.5 **&&$$ 61±6.4 59±5.3 | 9.6％ 8.9％ $$ 17.8％ |
*With comparison before the medication, P＜0.01,
*With comparison before the medication, P＜0.05.
﹠amp; ﹠amp;Compare P＜0.01. with the 5th week of test group
$$Compare P＜0.01. with the 2nd week of matched group
4. isosorbide mononitrate and valsartan are united the clinical trial of use to the hyperpietic
The patient who participates in this test has 156 examples, and age-based and systolic pressure level is divided into two groups, test group 79 examples, matched group 77 examples at random.Test group is used glad 2 weeks of health of southern Shandong earlier, 20mg/ days, rises with 2 pm in morning respectively and takes; Drug withdrawal re-uses 2 weeks of valsartan after 1 week, 40mg/ days, took every morning, and the using dosage of two medicines all is lower than clinical common dose, the 7th week rises to unite and uses above-mentioned two kinds of medicines, and the using dosage of every day is the same.Matched group uses the valsartan of 120mg every day, and once take every morning.The patient of test group and matched group is carried out secular tracking follow up a case by regular visits to, to observe the situation of curative effect of medication and untoward reaction.The result shows, in the patient of test group, isosorbide mononitrate and valsartan drug combination have been obtained significant concertedness hypotensive effect to patient's systolic pressure, and to not significantly influence of diastolic pressure, thereby when obviously reducing systolic pressure, make pulse pressure also produce significant decline, obtained ideal antihypertensive effect, and the valsartan subclinical dose can not produce significant pressure reduction effect, because this tests selected case all is more refractory obstinate hypertension, though clinical heavy dose of valsartan that uses makes patient's blood pressure that certain decline be arranged, and can not obtain ideal curative effect aspect the reduction systolic pressure.The subclinical dose use in conjunction of isosorbide mononitrate and valsartan has obtained the desirable antihypertensive effect that valsartan or the independent use of isosorbide mononitrate can't obtain, and patient's compliance of drug combination group is better, and the patient all can adhere to medication mostly.
The efficacy of antihypertensive treatment that table 4. isosorbide mononitrate and valsartan are united use compares
| Systolic pressure | Diastolic pressure | Pulse pressure | 5 years heart cerebrovascular events incidence rates | |
| The 2nd week of matched group before test group the 2nd all test group the 5th all test group the 9th all matched group medications before the test group medication | 182±16.9 170±11.2 172±13.9 150±12.9 **&&$$ 181±13.0 151±11.3 * | 115±11.3 112±9.3 108±8.5 107±8.1 * 113±9.0 90±7.9 ** | 67±7.0 58±4.3 66±7.0 43±5.1 **&&$$ 68±8.9 61±8.6 | 3.8％ $$ 22.5％ |
*With comparison before the medication, P＜0.01,
*With comparison before the medication, P＜0.05.
﹠amp; ﹠amp;Compare P＜0.01. with the 5th week of test group
$$Compare P＜0.01. with the 2nd week of matched group
5. isosorbide mononitrate and pinacidil are united the clinical trial of use to the hyperpietic
The patient who participates in this test has 168 examples, and age-based and systolic pressure level is divided into two groups, test group 91 examples, matched group 77 examples at random.Test group is used glad 2 weeks of health of southern Shandong earlier, 20mg/ days, rises with 2 pm in morning respectively and takes; Drug withdrawal re-uses 2 weeks of pinacidil slow releasing capsule after 1 week, and 25mg/ days, to take at twice, the using dosage of two medicines all is lower than clinical common dose, the 7th week rises to unite and uses above-mentioned two kinds of medicines, and the using dosage of every day is the same.Matched group uses the pinacidil slow releasing capsule of 75mg every day, takes at twice.The patient of test group and matched group is carried out secular tracking follow up a case by regular visits to, to observe the curative effect and the untoward reaction of medication.The result shows, in the patient of test group, isosorbide mononitrate and pinacidil drug combination have been obtained significant concertedness hypotensive effect to patient's systolic pressure, and to not significantly influence of diastolic pressure, thereby when obviously reducing systolic pressure, make pulse pressure also produce significant decline, obtained ideal antihypertensive effect, and pinacidil subclinical dose and routine clinical dosage all make pulse pressure increase.The subclinical dose use in conjunction of isosorbide mononitrate and pinacidil has significantly been corrected the reflex tachycardia untoward reaction that pyrrole sodium ground that in use occurs, when having reduced blood pressure, do not cause obviously increasing of sympathetic activity, this may produce wholesome effect to patient's long-term survival rate.In addition, the consumption of matched group pinacidil is relatively large, and the edema incidence rate is higher, and drug combination has significantly reduced the incidence rate of edema when obtaining effective antihypertensive effect.Among more the observing of 8 years survival rates of drug combination group and matched group.
The efficacy of antihypertensive treatment that table 5. isosorbide mononitrate and pinacidil are united use compares
| Systolic pressure | Diastolic pressure | Pulse pressure | Heart rate increases | The edema incidence rate | |
| The 2nd week of matched group before test group the 2nd all test group the 5th all test group the 9th all matched group medications before the test group medication | 179±13.2 165±10.8 163±11.9 141±11.2 **&&$ 178±12.5 157±13.0 ** | 115±9.1 111±8.7 91±9.5 89±8.4 **$$ 114±8.8 70±8.9 ** | 64±6.3 54±6.2 72±5.7 52±6.6 **&&$$ 64±6.1 87±7.2 ** | 2.0±3.0 10.5±5.3 6.7±5.7 $$ 25.5±10.4 | 19.3％ 8.6％ &$$ 35.8％ |
*With comparison before the medication, P＜0.01.
﹠amp; ﹠amp;Compare with the 5th week of test group, P＜0.01,
﹠amp;Compare P＜0.05. with the 5th week of test group
$$Compare with the 2nd week of matched group, P＜0.01,
$Compare P＜0.05. with the 2nd week of matched group
6. isosorbide mononitrate and metoprolol are united the clinical trial of use to the hyperpietic
The patient who participates in this test has 180 examples, and age-based and systolic pressure level is divided into two groups, test group 81 examples, matched group 99 examples at random.Test group is used glad 2 weeks of health of southern Shandong earlier, 20mg/ days, rises with 2 pm in morning respectively and takes; Drug withdrawal re-uses 2 weeks of metoprolol after 1 week, and 100mg/ days, to take at twice, the using dosage of two medicines all is lower than clinical common dose, the 7th week rises to unite and uses above-mentioned two kinds of medicines, and the using dosage of every day is the same.Matched group uses the metoprolol of 300mg every day, takes at twice, and starting dose is suitable decrement as the case may be.The patient of test group and matched group is carried out secular tracking follow up a case by regular visits to, will or can adhere to that not the patient of medication rejects this test, calculate the survival rate in 8 years because of the dead patient of non-cardiovascular and cerebrovascular vessel factor.The result shows, in the patient of test group, isosorbide mononitrate and metoprolol drug combination have been obtained significant concertedness hypotensive effect to patient's systolic pressure, and it is little to the diastolic pressure influence, thereby when obviously reducing systolic pressure, make pulse pressure also produce significant decline, obtained ideal antihypertensive effect.That the subclinical dose use in conjunction of isosorbide mononitrate and metoprolol has corrected significantly that heavy dose of metoprolol in use occurs is dizzy, headache, untoward reaction such as tired.The metoprolol matched group of a little higher than independent medications of survival rate in 8 years of drug combination group does not have significant difference, but the patients ' life quality of matched group descends obviously.
The efficacy of antihypertensive treatment that table 6. isosorbide mononitrate and metoprolol are united use compares
| Systolic pressure | Diastolic pressure | Pulse pressure | Dizzy, headache, untoward reaction such as tired | 8 years survival rates | |
| The 2nd week of matched group before test group the 2nd all test group the 5th all test group the 9th all matched group medications before the test group medication | 177±13.5 165±11.8 160±16.0 142±12.7 **& 177±13.9 148±16.6 ** | 114±8.5 111±6.7 102±9.3 96±8.7 ** 115±7.8 88±10.4 ** | 63±5.1 54±4.8 58±5.4 46±5.0 **&&$$ 62±6.1 60±5.2 | 3.6％ 12.5％ 1.8％ &&$$ 22.0％ | 88.6％ 81.5％ |
*With comparison before the medication, P＜0.01.
﹠amp; ﹠amp;Compare with the 5th week of test group, P＜0.01,
﹠amp;Compare P＜0.01. with the 5th week of test group
$$Compare P＜0.01. with the 2nd week of matched group
7. isosorbide mononitrate and felodipine, enalapril are united the clinical trial of use to the hyperpietic
Calcium ion antagonist and angiotensin-convertion enzyme inhibitor have good synergism aspect bringing high blood pressure down, external early existing compound preparation listing, the patient who participates in this test has 215 examples, and age-based and systolic pressure level is divided into two groups at random, test group 90 examples, matched group 125 examples.Test group was used southern Shandong glad health 20mg/ days, rose with 2 pm in morning respectively and took; Felodipine 10mg/ days, take at twice, enalapril 5mg/ days, once took morning, and the using dosage of three kinds of medicines all is lower than clinical common dose.Matched group used felodipine 10mg/ days, took at twice, and enalapril 5mg/ days, once took morning.The 2nd week after medication and carry out the mensuration of blood pressure the 10th week, and the patient is carried out secular tracking follow up a case by regular visits to, will or can adhere to that not the patient of medication rejects this test because of the patient of non-cardiovascular and cerebrovascular vessel factor death, calculate the survival rate in 8 years.The result shows, in the patient of test group, used for 2 weeks after, the adding of isosorbide mononitrate has obtained significant concertedness hypotensive effect to the further reduction of patient's systolic pressure.In the 20th week of medication, drug resistance has to a certain degree appearred in the matched group patient, and the adding of test group isosorbide mononitrate has effectively prevented the drug-fast generation of patient.8 years survival rates of test group are significantly higher than matched group.
The efficacy of antihypertensive treatment that table 7. isosorbide mononitrate and felodipine, enalapril are united use compares
| Systolic pressure | Diastolic pressure | Pulse pressure | 8 years survival rates | |
| The 2nd all the 20th weeks of matched group of matched group before test group the 2nd all test group the 20th all matched group medications before the test group medication | 179±13.0 132±11.5 ** 136±10.8 **$$ 179±12.9 147±12.0 ** 157±11.4 * | 116±9.3 90±7.9 ** 92±8.2 ** 115±9.0 91±8.1 ** 98±8.6 ** | 63±5.6 42±5.1 ** 44±5.8 **$$ 64±6.7 56±5.9 * 59±6.2 | 93.5％ $$ 78.6％ |
*With comparison before the medication, P＜0.01,
*With comparison before the medication, P＜0.05.
$$Compare P＜0.01. with the 20th week of matched group
Embodiment 10
Glad health of southern Shandong and angiotensin-convertion enzyme inhibitor use in conjunction are relatively screened the curative effect of Hypertensive Rats
We unite on the basis of using clinical test results at glad health of southern Shandong (isosorbide mononitrate) and enalapril, according to the new development of clinical hypertension therapeutic theory now, angiotensin-convertion enzyme inhibitor and isosorbide mononitrate are united the effect of use and done further screening study, investigated some indexs relevant that clinical hypertension therapeutic pays close attention to and the organ injury that causes by hypertension with patient's long-term survival rate.
Concrete experimental data is as follows:
Laboratory animal: SHH rat (SHR), available from Shanghai Slac Experimental Animal Co., Ltd..
Experimental technique:
Animal grouping: the SHR rat of 165 200-250g is divided into 11 groups, 15 every group at random according to the level of blood pressure.Be followed successively by model control group, Captopril group, enalapril group, benazepril group, perindopril group, lisinopril group, fosinopril group, ramipril group, quinapril group, cilazapril group and trandolapril group.Other establishes 10 SD rats as normotensive matched group.
Normal control group and model control group are irritated stomach and give normal saline 5ml/kg every days;
Captopril group is irritated stomach and give captopril 8.2mg/kg and isosorbide mononitrate 2.8mg/kg every day;
The enalapril group is irritated stomach and give enalapril 2.8mg/kg and isosorbide mononitrate 2.8mg/kg every day;
Benazepril group is irritated stomach and give benazepril 2.8mg/kg and isosorbide mononitrate 2.8mg/kg every day;
The perindopril group is irritated stomach and pay for diindyl Puli 1.4mg/kg and isosorbide mononitrate 2.8mg/kg every day;
The lisinopril group is irritated stomach and give lisinopril 2.8mg/kg and isosorbide mononitrate 2.8mg/kg every day;
The fosinopril group is irritated stomach and give fosinopril 2.8mg/kg and isosorbide mononitrate 2.8mg/kg every day;
The ramipril group is irritated stomach and give ramipril 0.7mg/kg and isosorbide mononitrate 2.8mg/kg every day;
The quinapril group is irritated stomach and give quinapril 2.8mg/kg and isosorbide mononitrate 2.8mg/kg every day;
The cilazapril group is irritated stomach and give cilazapril 0.7mg/kg and isosorbide mononitrate 2.8mg/kg every day;
The trandolapril group is irritated stomach and give trandolapril 0.28mg/kg and isosorbide mononitrate 2.8mg/kg every day.
Each organizes rat through irritating stomach after 15 weeks, connects rat urine with metabolic cage, measures the microalbumin content of respectively organizing in the rat urine according to the bromjophenol blue method, with the degree of reflection Hypertensive Rats (SHR) kidney injury.Potassium chloride 1.5ml through arterial cannulation injection 1mol/L makes animal hearts stop at diastole state.Extract heart and aorta (ascending aorta is to thoracic aorta) immediately, weighing chamber, a left side and aorta weight in wet base, the aorta weight of the left ventricular mass of unit of account body weight and unit length.
The concrete grammar of the microalbumin content in the bromjophenol blue method mensuration rat urine is as follows:
All ingredients
The glacial acetic acid solution of 1.10% (v/v) (pH2.8).
2.0.303mol/L glycine-glacial acetic acid buffer (pH3.0): take by weighing the 22.72g glycine, be diluted to 1000ml, add NaN with 10% glacial acetic acid solution
3100mg, the room temperature sealing can be stablized 1 year.
3. bromophenol blue (1.924mmol/L) stock solution: accurately take by weighing 257.36mg bromophenol blue (BPB), molten to 200ml with dehydrated alcohol, 4 ℃ of refrigerators can be stablized 1 year.
4. bromophenol blue (0.231mmol/L) developer: get the 60mlBPB stock solution, add 2.5mlTritonX-100, be diluted to 500ml with glycine-glacial acetic acid buffer, room temperature seals and can preserve 1 year.
Assay method
Get rat urine sample (cloudy urine is answered the centrifuging and taking supernatant) 2ml in reaction cup, add BPB developer 1ml, mixing, behind the 1min with 721 type spectrophotometers in the 10mm of 600nm place optical path colorimetric.
Experimental result
1. isosorbide mononitrate and angiotensin-convertion enzyme inhibitor are united the influence of use to Hypertensive Rats left ventricular hypertrophy and aortic hypertrophy
The result shows, in all angiotensin-convertion enzyme inhibitors, except that the effect of captopril be not very desirable, other angiotensin-convertion enzyme inhibitor and isosorbide mononitrate are united left ventricular hypertrophy and the aortic hypertrophy that use forms after to the long-term hypertension of Hypertensive Rats very remarkable influence, our zoopery result indicating angiotensin-convertion enzyme inhibitor and isosorbide mononitrate unite use in the future clinically hyperpietic's treatment have significant effects, the effective prophylaxis of hypertension patient's of meeting various complication improve patient's long-term survival rate.Concrete the results are shown in Table 8.
2. isosorbide mononitrate and angiotensin-convertion enzyme inhibitor are united use the result that influences of Hypertensive Rats microdose urine protein are shown, in the angiotensin-convertion enzyme inhibitor of being tested, the microdose urine protein of each experimental group Hypertensive Rats all has significant reduction than model group, through comparative analysis, except that the effect of captopril is not especially the ideal, other angiotensin-convertion enzyme inhibitor and isosorbide mononitrate are united the microdose urine protein increase that use caused after to the long-term hypertension of Hypertensive Rats very remarkable influence, and this is indicating that angiotensin-convertion enzyme inhibitor and isosorbide mononitrate unite use hyperpietic's kidney injury is had the good preventing effect.Concrete experimental result sees Table 8.
Table 8 is respectively organized the comparison of rat left chamber's ponderal index, aorta weight and microdose urine protein
| Group | n | Left side chamber weight/mg100g -1 | Aorta weight/mgmm -1 | Microdose urine protein/absorbance (A) |
| The many Puli's groups of normal control group model matched group Captopril group enalapril group benazepril group perindopril group lisinopril group fosinopril group ramipril group quinapril group cilazapril cohort | 10 15 15 15 15 15 15 15 15 15 15 15 | 180.3±33.6 311.2±40.6 272.7±20.5 * 223.6±32.9 **& 230.1±22.3 **& 225.9±37.3 **& 218.7±31.9 **& 213.8±40.1 **& 215.7±33.7 **& 220.6±28.6 **& 209.4±50.1 **& 218.5±39.7 **& | 1.31±0.15 2.10±0.22 1.87±0.20 * 1.61±0.18 **& 1.50±0.17 **&& 1.58±0.22 **& 1.53±0.21 **& 1.60±0.20 **& 1.49±0.19 **& 1.55±0.11 **& 1.51±0.18 **& 1.52±0.21 **& | 0.38±0.12 0.99±0.37 0.71±0.31 0.45±0.22 **& 0.40±0.20 **& 0.39±0.19 **& 0.44±0.18 **& 0.49±0.22 **& 0.53±0.35 ** 0.46±0.20 **& 0.51±0.26 **& 0.53±0.17 **& |
*Compare with model control group, p＜0.05,
*Compare p＜0.01. with model control group
﹠amp;Compare p＜0.05. with Captopril group
﹠amp; ﹠amp;Compare p＜0.01. with Captopril group
Glad health of southern Shandong and angiotensin receptor antagonist are united use the curative effect of Hypertensive Rats are relatively screened
We unite on the basis of using clinical test results at glad health of southern Shandong (isosorbide mononitrate) and valsartan, according to the new development of clinical hypertension therapeutic theory now, angiotensin receptor antagonist and isosorbide mononitrate are united the effect of use and done further screening study, investigated some indexs relevant that clinical hypertension therapeutic pays close attention to and the organ injury that causes by hypertension with patient's long-term survival rate.
Concrete experimental data is as follows:
Laboratory animal and experimental technique are the same substantially, and every kind of used dosage of experiment medicine is to convert according to body surface area with clinical common dose.
Experimental result
1. isosorbide mononitrate and angiotensin receptor antagonist are united the influence of use to Hypertensive Rats left ventricular hypertrophy and aortic hypertrophy
The result shows, all angiotensin receptor antagonists and isosorbide mononitrate are united left ventricular hypertrophy and the aortic hypertrophy that use forms after to the long-term hypertension of Hypertensive Rats very remarkable influence, our zoopery result indicating angiotensin receptor antagonist and isosorbide mononitrate unite use in the future clinically hyperpietic's treatment have significant effects, the effective prophylaxis of hypertension patient's of meeting various complication improve patient's long-term survival rate.Concrete the results are shown in Table 9.
2. isosorbide mononitrate and angiotensin receptor antagonist are united the influence of use to the Hypertensive Rats microdose urine protein
The result shows, angiotensin receptor antagonist and isosorbide mononitrate are united the microdose urine protein increase that use caused after to the long-term hypertension of Hypertensive Rats very remarkable influence, and this is indicating that angiotensin receptor antagonist and isosorbide mononitrate unite use hyperpietic's kidney injury is had the good preventing effect.Concrete experimental result sees Table 9.
Table 9 is respectively organized the comparison of rat left chamber's ponderal index, aorta weight and microdose urine protein
| Group | n | Left side chamber weight/mg100g -1 | Aorta weight/mgmm -1 | Microdose urine protein/absorbance (A) |
| Normal control group model matched group losartan group valsartan group Candesartan group olmesartan medoxomil group irbesartan group telmisartan group eprosartan group | 10 15 15 15 15 15 15 15 15 | 180.3±33.6 311.2±40.6 232.5±21.6 ** 225.8±30.8 ** 236.1±25.3 ** 245.2±40.3 ** 216.5±33.2 ** 253.8±51.3 ** 238.0±34.6 ** | 1.31±0.15 2.10±0.22 1.57±0.23 ** 1.63±0.18 ** 1.58±0.27 ** 1.67±025 ** 1.56±0.27 ** 1.69±0.34 ** 1.62±0.31 ** | 0.38±0.12 0.99±0.37 0.41±0.20 ** 0.55±0.22 ** 0.41±0.21 ** 0.43±0.29 ** 0.55±0.18 ** 0.58±0.20 ** 0.52±0.19 ** |
*Compare with model control group, p＜0.05,
*Compare p＜0.01. with model control group
Claims (4)
1. a pharmaceutical composition that contains isosorbide mononitrate and angiotensin-convertion enzyme inhibitor is being used to prepare the purposes for the treatment of hypertension drug.
2. as claimed in claim 1 being used to prepares the purposes for the treatment of hypertension drug, it is characterized in that described angiotensin-convertion enzyme inhibitor is enalapril, benazepril, perindopril, lisinopril, fosinopril, ramipril, quinapril, cilazapril or trandolapril.
3. as claimed in claim 1 being used to prepares the purposes for the treatment of hypertension drug, it is characterized in that described angiotensin-convertion enzyme inhibitor is enalapril, perindopril, lisinopril or fosinopril.
4. as claimed in claim 1ly be used to prepare the purposes for the treatment of hypertension drug, it is characterized in that also containing in the described pharmaceutical composition in the following non-active ingredient one or more, they are starch, low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl emthylcellulose 4000 (HPMC--4M), HPMC--15M, microcrystalline Cellulose, polyvinylpyrrolidone (PVP), micropowder silica gel, magnesium stearate, lactose, carboxymethyl starch sodium, pregelatinized Starch, Rikemal B 200, glyceryl monostearate, Pulvis Talci, ethyl cellulose (EC), stearic acid, Polyethylene Glycol-6000, mannitol, crospolyvinylpyrrolidone, sodium carboxymethyl cellulose (CMC-Na), polyvinyl alcohol (PVA), hexadecanol, octadecanol, cross-linking sodium carboxymethyl cellulose, sodium alginate or ethylene-vinyl acetate copolymer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200810006975XA CN101229374A (en) | 2005-11-23 | 2005-11-23 | Medicine compounds containing isosorbide mononitrate for treating high blood pressure |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200810006975XA CN101229374A (en) | 2005-11-23 | 2005-11-23 | Medicine compounds containing isosorbide mononitrate for treating high blood pressure |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510125589 Division CN1813707A (en) | 2004-12-01 | 2005-11-23 | Medicinal composition containing isosorbide mononitrate for treating hypertension |
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|---|---|
| CN101229374A true CN101229374A (en) | 2008-07-30 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107868009A (en) * | 2016-09-28 | 2018-04-03 | 珠海同源药业有限公司 | A kind of metoprolol tartrate crystal and the pharmaceutical composition containing the crystal and preparation method thereof |
-
2005
- 2005-11-23 CN CNA200810006975XA patent/CN101229374A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107868009A (en) * | 2016-09-28 | 2018-04-03 | 珠海同源药业有限公司 | A kind of metoprolol tartrate crystal and the pharmaceutical composition containing the crystal and preparation method thereof |
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