CN101417132A - Use of medicine combination comprising carvedilol and angiotensin II recipient antagon in preparing medicine for treating kidney disease - Google Patents
Use of medicine combination comprising carvedilol and angiotensin II recipient antagon in preparing medicine for treating kidney disease Download PDFInfo
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Abstract
The invention provides the usages of a drug composition comprising the active components of carvedilol and an angiotensin II receptor antagonist for preparing a drug which can cure nephropathy. The cooperation effect of the carvedilol and the angiotensin II receptor antagonist are used for developing a method which is more effective in curing the nephropathy. The drug composition has remarkable effects when being used for curing nephropathy, diabetic nephropathy, hypertensive nephropathy, and the like.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of pharmaceutical composition that contains carvedilol and angiotensin ii receptor antagonist and be used for the treatment of purposes in the medicine of nephropathy in preparation.
Background technology
Continuous development along with medical science, people have had darker understanding to the harm of nephropathy gradually, show by the Epidemiological study evidence, chronic kidney disease has become a principal disease that threatens whole world publilc health, and this is the objective fact that public hygienics expert and medical expert just recognize recently for over ten years.Chronic kidney disease comprises multiple kidney disease: as chronic glomerulonephritis, interstitial nephritis, chronic urinary tract infection, renal tubular disease, diabetic nephropathy, lupus nephritis, renal vascular and renal insufficiency uremia etc.As treat untimelyly or improper, and may cause uremia, make a large amount of metabolic wastes accumulate in vivo, organismic internal environment is destroyed, and finally may cause death.
Carvedilol is a kind of new nonselective adrenergic third generation receptor blocking agent; it is a kind of novel antihypertensive drug that multiple pharmacologically active is arranged; have the dual retardation of beta receptor and α receptor concurrently; has good no endogenous sympathomimetic nerve activity; high concentration fashion has calcium antagonism; and have tangible free radical resisting, antioxidation, heart and neuroprotective, arrhythmia and ischemia resisting effect, the metabolism disorder of adjusting is arranged, stop effects such as smooth muscle cell proliferation and inhibition apoptosis of cardiac muscle.Therefore, carvedilol not only has hypotensive effect preferably, and can reverse Cardiovascular Remodeling, helps treatment of diseases such as heart failure, myocardial infarction, atherosclerosis, vascular restenosis.Carvedilol is considered to a kind of very promising medicine, in clinical trial, be widely used in treatment light, the moderate essential hypertension, the treatment of coronary heart disease and congestive heart failure, and and other depressor use in conjunction in the treatment of chronic heart failure.In the last few years the research of carvedilol was further deepened, by clinical observation, the pharmacotoxicological effect of finding it is than the 1st, 2 generation β, one receptor blocking agent is wider, can block 3 kinds of adrenoreceptors (α, β 1 and beta receptor), and have the adverse effect of adjusting catecholamine to heart, peripheral vessel and kidney, reverse the associating regulating action of angiotensin and receptor change etc.
In recent years the angiotensin ii receptor antagonist of Wen Shiing is described as a milestone of the nineties cardiovascular drugs.Angiotensin II is by the physiology and the pathological reaction of the overwhelming majority in the receptor-mediated body of AT1, and the generation development in hypertension, atherosis, ventricular hypertrophy, diabetes and nephropathy all plays an important role.It is clinical that first non-skin class AT1 receptor antagonist losartan in 1994 is applied to, and a collection of subsequently similar medicine such as valsartan, Irb etc. go on the market in succession.The equal selectively acting of more above-mentioned medicine is in the AT1 receptor, and the hypotensive effect persistent period is longer, only needs 1 time in common one day.Along with people to the clinical practice of AT1 receptor antagonist and going deep into of research, it more and more shows its critical role in the blood pressure lowering field.Clinical research shows; the AT1 receptor antagonist has and similar antihypertensive effect of ACE inhibitor and target organ protection function; and untoward reaction obviously will be less than ACE inhibitor; rare relevant cough and hypotension; this may be because the AT1 receptor antagonist does not influence the ACE activity, thereby can not cause accumulating of Kallidin I.The AT1 receptor antagonist is the effect at acceptor levels blocking-up Angiotensin II, so can more fully suppress the adverse effect of Angiotensin II than ACE inhibitor.Nearest extensive clinical research shows that the AT1 receptor antagonist has direct protective effect to hyperpietic's heart, blood vessel and kidney, and this protective effect does not rely on the pressure reduction effect of medicine.These characteristics have increased the clinical value of AT1 receptor antagonist undoubtedly, particularly high-risk hyperpietic.
Angiotensin ii receptor antagonist (ARB) has been widely used in clinical at present.1, hypertension: comprise that various light, moderate hypertensions are all had good curative effect, clinical trial so far confirms that ARB has identical curative effect with other class medicines at least aspect resisting hypertension.2, heart failure: the main diseases of congestive heart failure is because due to many cardiovascular disease such as hypertension, coronary heart disease (comprising myocardial infarction), valvular heart disease, cardiomyopathy, RAS plays an important role in the heart failure pathophysiological mechanism, obtain better curative effect in the treatment of ACEI to heart failure, therefore, it is as the choice drug of treatment heart failure, and also Chang Zhiwei treats the goldstandard of heart failure.3, left ventricular hypertrophy: studies have shown that Angiotensin II causes the synthetic increase of myocardium protein, the cell hypertrophy, substrate increases, and mainly is that the AT1 receptor works, so ARB can reverse LVH.4, to the kidney protective effect: in non-renal hypertension patient and kidney disease patient with ARB treatment to not influence of glomerular filtration rate, ARB can reduce that renal insufficiency increases the weight of due to hypertension or the diabetes.The carrying out property deterioration of renal function and RAS activate relevant, mainly are that ANGII both can cause infringement to kidney by increasing intrinsic pressure this indirect approach of glomerular capillary, also can cause kidney injury by stimulating the various cytokines of kidney emiocytosis.Discover that losartan can obviously reduce the albuminuria with diabetes or the normal hyperpietic of renal function, and the uric acid of promotion, natriuretic kidney protective effect are arranged.Johanne S etc. is used for the renal insufficiency patient with valsartan, can bring high blood pressure down, and effective renal blood flow increasing also reduces urine albumen amount, and Microalbuminuria and hypertension are to impel diabetic nephropathy that the important risk factor of development takes place.There is experiment to show that Irb has the effect of improving renal function and Microalbuminuria to the hyperpietic of concurrent diabetes.5, to the protective effect of brain: RAS and local AngII participate in cerebral blood flow and regulate automatically, keep the relatively stable of cerebral blood flow, and ARB can produce the self-regulating useful variation of cerebral blood flow, thus with ARB whole body blood pressure is reduced, but can not cause the cerebral blood flow minimizing.6, to the protective effect of blood vessel: increasing of hyperpietic's peripheral vascular resistance is relevant with the function and the structural change of blood vessel itself; because vessel side voltage rise height; make platelet aggregation; platelet derivation growth factor release, vascular smooth muscle cell proliferation, hypertrophy and migration, substrate increases; vessel wall thickening; tube chamber dwindles blood vessel is increased the active substance reactivity, and the blood vessel reserve function descends, and this blood vessel is reinvented the patient very harmful.7, myocardial infarction (MI) is acted on: myocardium inner RAS plays a major role in may taking place, develop at MI, ARB, ACEI or renin inhibitor, all can reduce the persistent period of ventricular arrhythmia, and only ARB has the effect of obvious minimizing ventricular arrhythmia persistent period, and the result shows that ARB may be better than ACEI in the using value of MI.In a word; angiotensin ii receptor antagonist (ARB) is as a new class medicine; extensive prospect is arranged in hypertension, heart failure, myocardial infarction, nephropathy, diabetes and cardiovascular disease prevention; existing clinical data shows Angiotensin II (AngII) receptor antagonist class preparation safety, effective; better tolerance is had the inclination, brain, kidney protective effect.
Angiotensin ii receptor antagonist is well-known to the protective effect of kidney; find the existing report that uses carvedilol and valsartan treatment refractory heart failure of uniting by retrieval; do not find as yet to have both at home and abroad to unite the pertinent literature that uses carvedilol and angiotensin ii receptor antagonist class Drug therapy nephropathy; the present invention discloses known angiotensin ii receptor antagonist class medicine nephropathy is had special efficacy and carvedilol in the remarkable effect aspect the hypertension therapeutic utilizing, and found through experiments the treatment aspect that The combined is applied in nephropathy has synergism really.
Summary of the invention
The invention provides a kind of pharmaceutical composition that contains active component carvedilol and angiotensin ii receptor antagonist and be used for the treatment of purposes in the medicine of nephropathy in preparation.The objective of the invention is to utilize the two the method for a kind of more effective treatment nephropathy of synergistic combinations medication invention of carvedilol and angiotensin ii receptor antagonist.This pharmaceutical composition is used for the treatment of nephropathy, especially diabetic nephropathy and hypertensive nephropathy.Described angiotensin ii receptor antagonist comprises losartan, valsartan, telmisartan, eprosartan, irbesartan, Candesartan, Tasosartan.
Treat nephropathy effect and not really desirable based on using angiotensin ii receptor antagonist class medicine now clinically, and present situation with serious adverse reaction, our Lunan Pharmacy Co. Ltd introduces the beta-blocker carvedilol according to clinical and patient's demand creation in existing scheme, obtained extraordinary synergy.By embodiment 11, embodiment 12 and embodiment 13 as can be seen angiotensin ii receptor antagonist than the simple angiotensin ii receptor antagonist medicine that uses suitable remarkable advantages is being arranged with the carvedilol use in conjunction aspect the treatment nephropathy.
The advantage of the treatment nephropathy of the present composition is embodied in following several aspect:
One, angiotensin ii receptor antagonist and carvedilol use in conjunction have good synergistic therapeutic effect to nephropathy.
Two, according to zooperal result, the medicine of clinical life-time service preparation of compositions of the present invention, long-term survival rate to the nephrotic can produce wholesome effect, can produce active influence to patient's prognosis, and this also is the clinical treatment problem that has meaning most solved by the invention.
Three, of the present invention applied widely.The present invention is particularly useful for hypertensive renal patient and diabetic nephropathy patient because its synergism mechanism is applicable to polytype nephrotic.The Secondary cases nephropathy that causes for acute renal insufficiency, chronic renal insufficiency and all kinds of disease has good effect in addition.
According to the character of medicine and patient's medication needs easily, we become tablet, capsule, granule, drop pill, powder, oral liquid, injection with preparation of pharmaceutical compositions of the present invention.Wherein tablet comprises dosage forms such as conventional tablet, dispersible tablet, slow releasing tablet.Wherein the proportion of composing of carvedilol and angiotensin ii receptor antagonist is 1:3～1:25, and preferred proportion is 1:5～1:10.
Specific embodiment
Now further specify content of the present invention, but range of application of the present invention is not limited to the following example by following embodiment.
Embodiment 1
Compound tablet
Carvedilol 10g
Valsartan 30g
Microcrystalline Cellulose 10g
Starch 140g
Magnesium stearate 2g
Carboxymethyl starch sodium 20g
10% starch slurry is an amount of
Preparation technology: the carvedilol and the valsartan of recipe quantity are crossed 100 mesh sieves, and carboxymethyl starch sodium, starch, microcrystalline Cellulose are crossed 80 mesh sieves, add an amount of 10% starch slurry behind the mixing and granulate, tabletting after the dry back adding magnesium stearate, promptly.
Embodiment 2
Compounding powder
Carvedilol 2.5g
Irbesartan 62.5g
Microcrystalline Cellulose 10g
Starch 10g
Preparation technology: the carvedilol and the irbesartan of recipe quantity are crossed 100 mesh sieves, and starch, microcrystalline Cellulose are crossed 80 mesh sieves, mix homogeneously, and packing, promptly.
Embodiment 3
Compound tablet
Carvedilol 10g
Candesartan Cilexetil 10g
Microcrystalline Cellulose 35g
Starch 140g
10% starch slurry is an amount of
Carboxymethyl starch sodium 20g
Magnesium stearate 2g
Preparation technology: the carvedilol and the candesartan Cilexetil of recipe quantity are crossed 100 mesh sieves, and carboxymethyl starch sodium, starch, microcrystalline Cellulose are crossed 80 mesh sieves, add an amount of 10% starch slurry behind the mixing and granulate, tabletting after the dry back adding magnesium stearate, promptly.
Embodiment 4
Compound dispersed tablet
Carvedilol 10g
Losartan 50g
Carboxymethylcellulose calcium 30g
Crospolyvinylpyrrolidone 30g
Microcrystalline Cellulose 100g
10% starch slurry is an amount of
Magnesium stearate 2g
Preparation technology: the carvedilol and the losartan of recipe quantity are crossed 100 mesh sieves, carboxymethylcellulose calcium, crospolyvinylpyrrolidone, microcrystalline Cellulose are crossed 80 mesh sieves, add an amount of 10% starch slurry behind the mixing and granulate, tabletting after the dry back adding magnesium stearate, promptly.
Embodiment 5
The compound granular agent
Carvedilol 10g
Valsartan 50g
Lactose 120g
Crospolyvinylpyrrolidone 40g
75% alcoholic solution is an amount of
Preparation technology: the carvedilol and the valsartan of recipe quantity are crossed 100 mesh sieves, and 75% alcoholic solution is granulated mixing behind crospolyvinylpyrrolidone and the lactose crushing screening, adding, carry out the granule packing after dry, total the mixing gets final product.
Embodiment 6
Compound capsule
Carvedilol 8g
Losartan 80g
Microcrystalline Cellulose 160g
Magnesium stearate 2g
Micropowder silica gel 1g
Preparation technology: with medicine and above-mentioned adjuvant mix homogeneously, make uniform micro powder, be filled in the Capsules, seal then, finishing and packing, promptly.
Embodiment 7
Compound dripping pill
Carvedilol 2.5g
Valsartan 12.5g
Polyethylene Glycol-6000 135g
Preparation technology: the carvedilol and the valsartan of recipe quantity are crossed 100 mesh sieves,, be heated to molten condition with Polyethylene Glycol-6000 mixing, stir, under keeping warm mode, adopt machinery spice to be splashed in the cold dimethicone cooling forming, the flush away dimethicone, promptly.
Embodiment 8
Compound slow-release tablet
Carvedilol 10g
Telmisartan 30g
Ethyl cellulose 50g
Microcrystalline Cellulose 100g
Lactose 45g
80% alcoholic solution is an amount of
Magnesium stearate 2g
Preparation technology: carvedilol, telmisartan and ethyl cellulose, microcrystalline Cellulose, the lactose mix homogeneously of recipe quantity are added the granulation of 80% alcoholic solution, descend dry, granulate at 70 ℃～80 ℃, the back adds the magnesium stearate mix homogeneously of recipe quantity, tabletting, promptly.
Embodiment 9
Compound slow-release tablet
Carvedilol 10g
Valsartan 50g
Guar gum 340g
Microcrystalline Cellulose 30g
95% alcoholic solution is an amount of
Magnesium stearate 4g
Preparation technology: carvedilol, valsartan, guar gum, the microcrystalline Cellulose mix homogeneously of recipe quantity are added the granulation of 95% alcoholic solution,, in granule, add the magnesium stearate mixing of recipe quantity at 70 ℃～80 ℃ dry down, granulate, tabletting, promptly.
Embodiment 10
Compound oral liquid
Carvedilol 12g
Valsartan 40g
Lactose 240g
Sodium benzoate 0.5g
Purified water adds to 1000ml
Preparation technology: the water that carvedilol, valsartan, the lactose mix homogeneously of recipe quantity is added the prescription about 80% stirs, and adds water to full dose, adds promptly get sodium benzoate and stir, and filters, and fill is sterilized, promptly.
Embodiment 11 carvedilols and valsartan compound recipe are to the therapeutic effect of rat accelerating type glomerular sclerosis
The foundation of method accelerating type glomerular sclerosis model: take on the basis of extracing a side kidney, to pass through twice tail vein injection daunorubicin, set up nephrosis animal model.Excise a side kidney, can cause HT residual kidney, the high filtration, high transmembrane pressure state concentrates on a side kidney with the former daunorubicin that is distributed in two kidneys, has reduced consumption, has weakened side effect, has quickened the development of pathological changes, impels the pathological changes trend consistent.Daunorubicin can produce the toxic and side effects of free radical and lipid peroxidation and the direct toxicity that produces at glomerule and renal cells.We adopt the rat one side nephrectomy to add and repeat the gentle red mould rope of injection, obtained the glomerular sclerosis animal model of histological type homogeneous.
1. experiment material
32 of SPF level SD rats, body weight 80-100g, male 32
2. operating procedure
With sub-cage rearing in the metabolic cage.Freely drink water, standard feed is fed.Adapted to for 1 week, behind the fasting 12h, 0.5% pentobarbital intraperitoneal injection of anesthesia is extractd left kidney through the back otch, and extracts the 7th, 14 day at kidney, respectively by tail vein injection daunorubicin 5mg/kg.Be divided into 4 groups at random, every group 8, model group (irritate stomach with volume 1% saline every day), valsartan group (dosage 40mg/kg.d), carvedilol group (dosage 4mg/kg.d), valsartan carvedilol group (dosage valsartan 40mg/kg.d+ carvedilol 4mg/kg.d).Each group is gastric infusion.All animals are all drunk 1% saline.In the experimentation, observe animal diet followed, survival condition and behavioral activity every day, measure body weight every day, adjust drug dose according to body weight.
3. observation index
1. the mensuration of microalbumin in urinating:
Reagent: 1, the glacial acetic acid solution of 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 257,36mgBPB, 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 2.5mlTriton X-100, be diluted to 500ml with glycine-glacial acetic acid buffer, the room temperature sealing can be preserved 1 year.
The collection of specimen and detection: the 10th week of kidney rat is put in respectively in the metabolic cage in plucking, normal diet is collected 12 hours overnight urine, accurate recording urine amount.Get 4ml, after sodium azide was handled, centrifugal (2000r/min) 10min got supernatant and puts one 20 ℃ of refrigerators and preserve urinaryalbumin to be measured.Get rat urine 4ml in the cup of correspondence, respectively add the 2ml developer, mixing (preventing to produce bubble) is used ultraviolet spectrophotometer, measures absorbance A down in 600nm.
Table 1 is respectively organized the absorbance of micro-little albumin measuring in the rat urine
#Compare P＜0.05. with model group
Albumin standards absorbance and microalbumin content are linear, and absorbance can be used for comparison rat protein urine content.
Model group rat urine protein began behind the daunorubicin to increase from the 2nd injection in 1 week, and urine protein quantitation 24h shows a large amount of albuminuria during the 2nd week, and constantly increases, the peak when (9 week) 24h reach maximum.The result shows, the use in conjunction of carvedilol and valsartan has good synergism aspect the rat glomerular sclerosis microdose urine protein influencing.
2. renal function index:, measure every group of rat blood serum creatinine (Cr), serum urea nitrogen (BUN) respectively in plucking the 2nd, 7,9 weeks of kidney.
Table 2
*Compare with model group, P＜0.05,
*Compare P＜0.01. with model group
Model group rat Cr began to increase in the 2nd week of medication, reached peak (366.2 scholar 63.4) μ mol/L during the 9th week, and BUN reaches peak (68.9 scholar 39.4) mmol/L during the 7th week, and lasted till for the 9th week always from beginning rising in the 2nd week of medication.The result shows that valsartan group, carvedilol group are compared with model group, and the protection effect to renal function in this model is not clearly.Valsartan carvedilol drug combination group and model group relatively have significant difference (p＜0.01).The use in conjunction that carvedilol and valsartan be described has good synergism aspect rat blood serum creatinine (Cr), the blood urea nitrogen (BUN) influencing.
3. collagen content is measured: at first the quantitative approach of collagen protein is investigated, established the method that suitable collagen content is measured (in hydroxyproline).The oxidation product and the dimethylaminobenzaldehyde effect that are produced under the effect of oxidant according to hydroxyproline present mauve principle, calculate the content of hydroxyproline according to the depth of its colour generation, by formula obtain the content of the hydroxyproline of sample, unit is hydroxyproline μ g/mg.Hydroxyproline is peculiar by collagen fiber, measures the content of hydroxyproline, can be converted into the content of kidney collagen protein, with reflection renal fibrosis degree.
Accurately take by weighing respectively and respectively organize normal rat nephridial tissue weight in wet base 61.4mg, measure the content of hydroxyproline in the kidney by measuring the test kit description, record blank pipe absorbance 0.015, the standard pipe absorbance is 0.538, the hydroxyproline computing formula is as follows: hydroxyproline content (μ g/mg weight in wet base)=(measuring pipe absorbance-blank pipe absorbance)/(standard pipe absorbance-blank pipe absorbance) * standard pipe content (5ug/ml) * hydrolyzed solution cumulative volume (ml)/tissue wet (mg), convert out total collagen content in the kidney by hydroxyproline content again, formula is: collagen content (μ g/mg)=hydroxyproline/13.5%.
Table 3
#Compare P＜0.01. with model group
The result shows that the use in conjunction of carvedilol and valsartan has the certain protection effect and suppressing aspect the kidney of rats fibrosis good synergism is arranged kidney.
Embodiment 12 carvedilols and telmisartan compound recipe are to the protective effect of renal hypertensive rat kidney
1. experiment material
32 of male SD rats, body weight 240～260g
2. operating procedure
3% pentobarbital sodium is adopted in operation, and (40-60mg/kg) behind intraperitoneal injection of anesthesia, rat is placed warm operating-table, through the flank otch, expose left kidney, separate renal artery and branch, ligation left renal artery epimere branch with in, keep the hypomere branch group, the right kidney of excision makes up the rat model that renal hypertension is accompanied renal failure behind the postoperative 3d.The rat postoperative is raised in cleaning level Animal Lab., freely gets food and drinking-water.Be divided into 4 groups at random, every group 8, model group (irritate stomach with volume 1% saline every day), telmisartan group (dosage 40mg/kg.d), carvedilol group (dosage 4mg/kg.d), telmisartan+carvedilol group (dosage telmisartan 40mg/kg.d+ carvedilol 4mg/kg.d).Each group is gastric infusion.All animals are all drunk 1% saline.In the experimentation, observe animal diet followed, survival condition and behavioral activity every day, measure body weight every day, adjust drug dose according to body weight.
3. observation index
1. the mensuration of microalbumin in urinating:
The collection of specimen and detection: right the 10th week of kidney rat is put in respectively in the metabolic cage in plucking, normal diet is collected 12 hours overnight urine, accurate recording urine amount.Get 4ml, after sodium azide was handled, centrifugal (2000r/min) 10min got supernatant and puts-20 ℃ of refrigerators and preserves urinaryalbumin to be measured.Go bail for deposit respectively organize rat urine 4ml in the cup of correspondence, respectively add the 2ml developer, mixing (preventing to produce bubble) use ultraviolet spectrophotometer, in the following mensuration absorbance A of 600nm.
Table 4
#Compare P＜0.05. with model group
Albumin standards absorbance and microalbumin content are linear, and absorbance can be used for comparison rat protein urine content.The use in conjunction of presentation of results carvedilol and valsartan has good synergism aspect the renal hypertensive rat microdose urine protein influencing.
2. renal function index:, measure every group of rat blood serum creatinine (Cr), serum urea nitrogen (BUN) respectively in plucking right the 2nd, 5,8 weeks of kidney.
Table 5
*Compare with model group, P＜0.05,
*Compare P＜0.01. with model group
The result shows, the use in conjunction of carvedilol and telmisartan has good synergism aspect renal hypertensive rat serum creatinine (Cr), the blood urea nitrogen (BUN) influencing.
3. collagen content is measured:
Accurately take by weighing respectively and respectively organize normal rat nephridial tissue weight in wet base 61.4mg, measure the content of hydroxyproline in the kidney by measuring the test kit description, record blank pipe absorbance 0.015, the standard pipe absorbance is 0.538, the hydroxyproline computing formula is as follows: hydroxyproline content (μ g/mg weight in wet base)=(measuring pipe absorbance-blank pipe absorbance)/(standard pipe absorbance-blank pipe absorbance) * standard pipe content (5ug/ml) * hydrolyzed solution cumulative volume (ml)/tissue wet (mg), convert out total collagen content in the kidney by hydroxyproline content again, formula is: collagen content (μ g/mg)=hydroxyproline/13.5%.
Table 6
#Compare P＜0.05. with model group
The result shows that the use in conjunction of carvedilol and telmisartan has protective effect and suppressing than with a kind of medicine better therapeutic is arranged separately aspect the renal hypertensive rat renal fibrosis kidney.
Embodiment 13 carvedilols and losartan compound recipe are to the kidney protective effect of diabetic nephropathy
1. experiment material
32 of male SD rats, body weight 180-200g, SPF level.
2. experimental procedure
After all rat adaptabilities fed for 1 week, fasting 10h pressed the disposable injection STZ of 56mg/kg left lower quadrant intracavity, and STZ faces with preceding usefulness sodium citrate one citric acid trisodium buffer (0.1mol/L, pH 4.2) preparation, uses up in the 5min.Each rat is sub-cage rearing in same Animal House, standard diet.Survey the 3d random blood sugar continuously, if rat blood sugar value 〉=16.67mmol/L is diabetic nephropathy modeling success.
Be divided into 4 groups at random, every group 8, model group (irritate stomach with volume 1% saline every day), losartan group (dosage 40mg/kg.d), carvedilol group (dosage 4mg/kg.d), losartan carvedilol group (dosage losartan 40mg/kg.d+ carvedilol 4mg/kg.d).Each group is gastric infusion.All animals are all drunk 1% saline.In the experimentation, observe animal diet followed, survival condition and behavioral activity every day, measure body weight every day, adjust drug dose according to body weight.
3. observation index
3.1 renal function index: in the 2nd, 6,9 weeks after the rat blood sugar value reaches 16.67mmol/L, measure every group of rat blood serum creatinine (Cr), serum urea nitrogen (BUN) respectively.
Table 8
*Compare with model group, P＜0.05,
*Compare P＜0.01. with model group
The use in conjunction of presentation of results carvedilol and losartan has significant difference aspect diabetic nephropathy rat blood serum creatinine (Cr), the blood urea nitrogen (BUN) influencing, and good synergism is arranged.
3.2 collagen content is measured:
Accurately take by weighing respectively and respectively organize normal rat nephridial tissue weight in wet base 61.4mg, measure the content of hydroxyproline in the kidney by measuring the test kit description, record blank pipe absorbance 0.015, the standard pipe absorbance is 0.538, the hydroxyproline computing formula is as follows: hydroxyproline content (μ g/mg weight in wet base)=(measuring pipe absorbance-blank pipe absorbance)/(standard pipe absorbance-blank pipe absorbance) * standard pipe content (5ug/ml) * hydrolyzed solution cumulative volume (ml)/tissue wet (mg), convert out total collagen content in the kidney by hydroxyproline content again, formula is: collagen content (μ g/mg)=hydroxyproline/13.5%.
Table 9
#Compare P＜0.05. with model group
The result shows; carvedilol and losartan 1 drug combination group collagen content are minimum; illustrate that this group kidney of rats fibrosis is the lightest, can learn that the use in conjunction of carvedilol and losartan has the certain protection effect and suppressing aspect the diabetic nephropathy kidney of rats fibrosis good synergism is arranged kidney.
Claims (6)
1. a pharmaceutical composition that contains carvedilol and angiotensin ii receptor antagonist is in the purposes that is used for preparing the medicine for the treatment of nephropathy.
2. purposes as claimed in claim 1 is characterized in that described pharmaceutical composition is used to prepare the medicine of treatment diabetic nephropathy or hypertensive nephropathy.
3. purposes as claimed in claim 1 is characterized in that the proportion of composing of carvedilol and angiotensin ii receptor antagonist is 1:1～25 in the described pharmaceutical composition.
4. purposes as claimed in claim 1 is characterized in that the proportion of composing of carvedilol and angiotensin ii receptor antagonist is 1:5～10 in the described pharmaceutical composition.
5. purposes as claimed in claim 1 is characterized in that described pharmaceutical composition can be prepared into tablet, capsule, granule, pill, drop pill, oral liquid, powder, injection, and wherein Tabules comprises conventional tablet, dispersible tablet, slow releasing tablet.
6. purposes as claimed in claim 1 is characterized in that described angiotensin ii receptor antagonist comprises losartan, valsartan, telmisartan, eprosartan, irbesartan, Candesartan or Tasosartan.
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| CN2007101131787A CN101417132B (en) | 2007-10-22 | 2007-10-22 | Use of medicine combination comprising carvedilol and angiotensin II recipient antagonist in preparing medicine for treating kidney disease |
| HK09108134.1A HK1130178A1 (en) | 2007-10-22 | 2009-09-04 | Use of pharmaceutical composition comprising carvedilol and angiotensin ii recipient antagonist in preparing medicine for treating nephropathy |
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| CN105250268A (en) * | 2015-10-26 | 2016-01-20 | 白玲强 | Irbesartan composition and application thereof in preparation of drug for treating acute kidney injury |
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| US8492426B1 (en) * | 2012-07-12 | 2013-07-23 | Anis Ahmad | Use of carvedilol for treatment of diabetes mellitus |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1301545A (en) * | 1999-12-27 | 2001-07-04 | 王德山 | Compound depressor |
-
2007
- 2007-10-22 CN CN2007101131787A patent/CN101417132B/en active Active
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2009
- 2009-09-04 HK HK09108134.1A patent/HK1130178A1/en unknown
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102485227A (en) * | 2010-12-02 | 2012-06-06 | 鲁南制药集团股份有限公司 | Medicine composition and applications thereof |
| CN102485227B (en) * | 2010-12-02 | 2015-06-10 | 鲁南制药集团股份有限公司 | Medicine composition and applications thereof |
| CN102525977A (en) * | 2011-12-28 | 2012-07-04 | 辰欣药业股份有限公司 | Carvedilol combination for direct tablet compressing |
| CN102631355A (en) * | 2012-04-12 | 2012-08-15 | 卞毓平 | Medicine composite containing aspirin and application thereof |
| CN105250268A (en) * | 2015-10-26 | 2016-01-20 | 白玲强 | Irbesartan composition and application thereof in preparation of drug for treating acute kidney injury |
| CN105250268B (en) * | 2015-10-26 | 2018-08-03 | 白玲强 | Irbesartan composition and its application in the drug for preparing treatment acute kidney injury |
| US10357476B1 (en) | 2018-10-30 | 2019-07-23 | Anis Ahmad | Method for treating coronary artery disease |
Also Published As
| Publication number | Publication date |
|---|---|
| HK1130178A1 (en) | 2009-12-24 |
| CN101417132B (en) | 2010-12-29 |
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