CN101229274B - Pharmaceutical composition for preventing or treating impotence induced by hyperlipidemia and/or hypertension - Google Patents
Pharmaceutical composition for preventing or treating impotence induced by hyperlipidemia and/or hypertension Download PDFInfo
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- CN101229274B CN101229274B CN2007103078188A CN200710307818A CN101229274B CN 101229274 B CN101229274 B CN 101229274B CN 2007103078188 A CN2007103078188 A CN 2007103078188A CN 200710307818 A CN200710307818 A CN 200710307818A CN 101229274 B CN101229274 B CN 101229274B
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- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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Abstract
The invention provides a medicine compound for treating or preventing erectile dysfunction caused by hyperlipoidemia and/or hypertension, comprising hot water extracts of dogwood fruit, medlar, bilberry, dodder and schisandra, in a ratio of 5 to 10: 5 to 10: 1 to 5: 1 to 5: 0.5 to 1.5, by dry weight.
Description
[technical field]
The present invention relates to a kind of pharmaceutical composition of the erection function insufficiency disorder that is used for the treatment of or prevents to cause by hyperlipemia and/or hypertension.
[background technology]
Recently, the variation of dietetic life, environmental pollution and over-drastic pressure etc. have changed the disease incidence rate and the cause of death to a great extent, are that the cardiovascular disease of representative increases day by day with myocardial infarction or apoplexy.Till now, though known have multiple ill physiology can bring out the erection function insufficiency disorder, wherein, known vascular morbid state physiology is the greatest factor that causes the erection function insufficiency disorder.
Hypertension, coronary artery disease, tremulous pulse and venous disease, injury of pelvis or hyperlipemia etc. all are to influence the disease of vascular system and the risk factor of erection function insufficiency disorder.Among 8,3 patients that have a heart disease among 10 male that suffer from blood vessel kind disease 2, accepted the erection function insufficiency disorders that all occur more than half among the patient of coronary bypass.In multiple situation, 25% to suffer from the male of erection function insufficiency disorder relevant with its medicine of taking, also showing has 14% erection function insufficiency disorder prevalence among the hypertension drug user, 28% erection function insufficiency disorder prevalence is arranged among the user of renal drug.In addition, half people who occurs the erection function insufficiency disorder among the male of existing report more than 50 years old is brought out by blood vessel kind disease.
The cardiovascular system disease 3 generation one of risk factor hyperlipemia be the state that blood cholesterol or the improper rising of neutral fat occur, be the multi-factor disease of environmental key-elements such as the diet that is subjected to West Europeization for example, pressure, hypomotility and hereditary elements affect.The lipidosis that existing report vascular erection function insufficiency disorder patient occurs is the more and more of hypercholesterolemia, has substantial connection (referring to non-patent literature 1) between the two.Hyperlipemia is the main hazard factor of cardiovascular disease, vascular erection function insufficiency disorder, and the endothelium interdependence relaxation response obstacle that known its reason is the cavernous body of penis smooth muscle and the distortion of smooth muscle cell self have caused the erection function insufficiency disorder.
Hypertension will increase the drag of peripheral vessel owing to the variation of vascular endothelial cell, vascular smooth muscle and extracellular matrix.Hypertension is the cardiovascular system disease of normal appearance of being grown up, and is one of risk factor of erection function insufficiency disorder, has shown that 30% hyperpietic suffers from the erection function insufficiency disorder.Therefore, proportional between the degree that erection function is incomplete and hypertensive degree and inductive phase (referring to non-patent literature 2).The mechanism of hypertension-induced erection function insufficiency disorder is that the artery blood flow that flows to penis reduces, and the influence of this available psychological factor and hypotensive agent is explained.In the pathology that brought out hypertensive animal penile tissue changed, cavernous body of penis endotheliocyte and smooth muscle cell damage and propagation, ossein calmness, albuginea of cavernous body of penis reduction etc. had appearred.In addition, in the variation of its function, also occur nitric oxide (NO) Huo Minus is few, oxidative pressure increases, smooth muscle contraction increases, neural because of the lax Li Minus of property NO interdependence cavernous body of penis is few etc. (referring to non-patent literature 3 and non-patent literature 4).
Nitric oxide (NO) has blood vessel dilating effect, anticoagulant effect admittedly, antioxidation, antiinflammatory action etc., is the most important part of keeping the permanent property of blood vessel.Therefore, the NO that will occur producing during the increase of minimizing, free radical that produces the NOS (nitricoxide synthase) of NO in the blood vessel endothelium is not activatory etc., makes the physiologically active reduction of NO, and the result causes occurring atherosclerosis.The most important task of NO is lax cavernous body of penis, to erection function advanced age of total correlation disease model such as aging, atherosclerosis, hypertension and diabetes result of study show: the reason of erection function insufficiency disorder be with non-adrenal gland's disposition-non-choline cavernous body of penis smooth muscle loosening obstacle, NOS that NO effect produces live that property Minus is few, NOS expresses the minimizing that obstacle is the NO physiologically active shown in the sign in the penis.Therefore, the treatment common point of hyperlipemia, hypertension and erection function insufficiency disorder is to find the material that can improve the NO bioavailability.
Now, erection function insufficiency disorder therapeutic agent is the synthesis of derivatives that plays with the material effect of c GMP (cyclic guanosine monophosphate) competitive reaction, increases the intravital c GMP of penis sponge concentration by the single path of blocking-up PDE-5 (5 type phosphodiesterase).Owing to do not have the activity of excitatory neuron system, in other words be that disease causes n NOS gene expression to reduce or is suppressed by aging and endocrine, and can't increase c GMP concentration in the cavernous body of penis smooth muscle, the effect of erection maybe can't appear in the enzymatic activity that has therefore suppressed PDE-5.More particularly, the notion of therapeutic agent is (though not directly related with life with the notion of QOL (quality of life (Quality Of Life)) goods, make the medicine of living inconvenient symptom and helping to make life to enrich more but be used for the treatment of) akin medicine, only take the therapeutic agent that can keep erection where necessary.In addition, have side effect such as myocardial infarction, cardiac insufficiency, blood pressure reduction, cerebral infarction, flushed face, visual deterioration though reported the one matter of this chemosynthesis, but owing to the urgent needs of the whole world to erection function insufficiency disorder therapeutic agent, it is still used very continually.
Though medicines such as acetone acid derivant, nicotinic acid derivates, inhibin analog derivative are used as remedy for hyperlipemia, side effect such as dyspepsia, liver toxicity, myalgia, striped muscle degeneration, photosensitivity will be brought out but take for a long time, must use cautiously, therefore wish to improve stability of drug by reducing side effect.
Though clinically nifedipine (nifedipine) and captopril (captopril) are used as the hypertension therapeutic agent, because the toxicity of these medicines and drug effect is invalid forthright, a kind of hypotensive agent of neomorph is developed in hope.
On the other hand, by hyperlipidemia patient, the hyperpietic of oral administration with erection function insufficiency disorder therapeutic agent studied, not only finished by improving disease and treated the research report of erection function insufficiency disorder and also finished at the effectiveness of medicine and the research report of side effect.In addition, though can obtain disposable and enforceable erection effect after the full therapeutic agent of the erection function that present commercially available oral administration is used is taken in needs, can't make it return to the effect that nature erects.
Therefore, be necessary to research and develop a kind of when hyperlipemia, hypertensive indivedual diseases are made moderate progress, even keep the medicine that erection function also may be free from side effects fully by chronic administration.
[non-patent literature 1] Juenemann KP, Aufenanger J, Konrad T, Pill J, Berle B, Persson-Juenemann be effect of impaired lipid metabolism on the smoothmuscle cells of rabbits.Urol Res.19:24-28 C.1991.The
[non-patent literature 2] Burchardt M, Burchardt T, Baer L, Kiss AJ, Pawar RV, ShabighA, de la Taille, Hay OR, Shabsigh R.Hypertension is associated with severeerectile dysfunction.J Urol 2000; 164:1181-91
[non-patent literature 3] Behr-Roussel D, Gorny D, Mevel K, Compa gnie S, Kern P, SivanV, Bernabe J, Bedigian MP, Alexandre L, Giuliano F.Erectile dysfunction:anearly marker for hypertension, A longitudinal study in spontaneouslyhypertensive rats.Am J Physiol Regul Integr Comp Physiol 2005; 288:R276R283
[non-patent literature 4] Toblli JE, Stella I, Inerra F, Ferder L, Zeller F, MazzaON.Morphologicai changes in cavernous tissue in spontaneously hypertensive rats.Am J Hypertension 2000; 13:68692
[summary of the invention]
[problem that invention will solve]
Therefore, the inventor concentrates on studies and is free from side effects and can keeps erection function through chronic administration, can effectively treat the medicament of the erection function insufficiency disorder that causes by hyperlipemia and/or hypertension, confirm the Fructus Corni hot water extract of special ratios proportioning, the Fructus Rubi hot water extract, the Semen Cuscutae hot water extract, Fructus Lycii hot water extract and Fructus Schisandrae Chinensis hot water extract's compositions can reduce T-CHOL and LDL-cholesterol in the blood, increase the HDL-cholesterol, bring high blood pressure down, increase nervous system and vascular system NOS protein expression, increase maximum intracavernous pressure, finished the present invention thus.
The pharmaceutical composition that the purpose of this invention is to provide a kind of erection function insufficiency disorder that is used for the treatment of or prevents to cause by hyperlipemia and/or hypertension.
[technological means of dealing with problems]
In order to achieve the above object, according to the present invention, the pharmaceutical composition of the erection function insufficiency disorder that a kind of treatment is provided or has prevented to be caused by hyperlipemia and/or hypertension, it contains the dry weight ratio is 5～10: 5～10: 1～5: 1～5: 0.5～1.5 Fructus Corni hot water extract, Fructus Lycii hot water extract, Fructus Rubi hot water extract, Semen Cuscutae hot water extract and Fructus Schisandrae Chinensis hot water extract.
[invention effect]
To reduce T-CHOL and LDL-cholesterol in the blood according to compound Chinese medicine hot water extract of the present invention, increase the HDL-cholesterol, bring high blood pressure down, increase nervous system and vascular system NOS protein expression, increase maximum intracavernous pressure, not only have the therapeutic effect of keeping the erection of simple property, when improving health NO bioavailability, also scalable is attended by hyperlipemia and/or hypertensive whole ill physiology, keeps the function that nature erects.Therefore, can be effective to the erection function insufficiency disorder for the treatment of or preventing to cause according to compound Chinese medicine hot water extract of the present invention by hyperlipemia and/or hypertension.
[description of drawings]
[Fig. 1] illustrates the graph of a relation according to the numerical value of T-CHOL, HDL-cholesterol and LDL-cholesterol in compound Chinese medicine hot water extract's of the present invention concentration and the white mice blood that has brought out hyperlipemia.
[Fig. 2 a] illustrates the graph of a relation with the expression degree of the white mice penile tissue internal protein NOS that has brought out hyperlipemia according to compound Chinese medicine hot water extract of the present invention and independent Chinese medicine hot water extract.
[Fig. 2 b] illustrates the graph of a relation according to compound Chinese medicine hot water extract's of the present invention concentration with the white mice penile tissue internal protein NOS expression degree of having brought out hyperlipemia.
[Fig. 3] illustrates the concentration and the graph of a relation that has brought out the white mice cavernous body of penis maximum internal pressure of hyperlipemia according to compound Chinese medicine hot water extract of the present invention.
[Fig. 4] illustrates according to compound Chinese medicine hot water extract's of the present invention concentration and brought out the graph of a relation of hypertensive white mice blood pressure.
[Fig. 5 a] illustrates according to compound Chinese medicine hot water extract of the present invention and independent Chinese medicine hot water extract and brought out the graph of a relation of the expression degree of hypertensive white mice penile tissue internal protein NOS.
[Fig. 5 b] illustrates according to compound Chinese medicine hot water extract's of the present invention concentration and brought out the graph of a relation of the expression degree of hypertensive white mice penile tissue internal protein NOS.
[Fig. 6] illustrates the concentration and the graph of a relation that has brought out hypertensive white mice cavernous body of penis maximum internal pressure according to compound Chinese medicine hot water extract of the present invention.
[specific embodiment]
Below, describe the constituent of the present composition in detail from the prescription face.
Fructus Corni is the dry sarcocarp of Cornaceae defoliation small arbor cornus fruit, and sour in the mouth is warm in nature, can be used for essence and blood and loses deficient syndrome or insufficiency of kidney-YANG disease.In addition, reduce the effect of hypertension and blood glucose effect, antiphlogistic antibacterial effect and protection Liver and kidney in addition.Contain ursolic acid (ursolic acid), tartaric acid, malic acid and other four kinds of glucosides (glucoside) etc. in the Fructus Corni extract.Ursolic acid is the liposoluble substance with anti-diabetic activity; 4 kinds of glucosides are morroniside (morroniside), meliatin (loganin), sweroside (sweroside), Methylmorroniside (methylmorroniside) (Lee YC, Kim YE, Lee BY, Kim CJ.Chemical Compositions ofCorni Fructus and Separating Properties of Its Flesh by drying.Korean J FoodSci Technol 1992; 24:447-50).In addition, the single desmosine of the oleanolic acid of known Fructus Corni-3-0-(oleanolic acid 3-0-mono desmosides) has function (the Matsuda H that suppresses glucose absorption, Murakami T, Shimada H, Matsumura N, yoshikawa M, Yamahara J.Inhibitorymechanisms of oleanolic acid 3-0-mono desmosides on glucose absorption in rats, Biological and Pharmaceutical Bulletin 1997; 20:717-9).
Fructus Lycii is a machaka, Gao Keda 2.5m, and the end of the branch is sagging, spinosity on the brachyplast, growing thickly in the long shoot bottom has 2-3 sheet leaf.Effects such as it has the diabetes of improvement, set up, prevent to wear out, blood fat reducing, liver function protecting and anticancer antibiotic.The flavonoid class rutin (rutin) that contains in the known Fructus Lycii has the function of keeping the blood capillary correct tension and reducing vascular permeability, blood capillary in the human body had invigoration effect and contraction, therefore can be used as (the Kim HS such as therapeutic agent, anti-diabetic activity agent, hypotensive agent of blood circulation diseases, Park YS, Kim CI.Changes of SerumLipid Profiles after Eating Lycii Fructus in Rats Fed High Fat Diet.Korean JNutr 1998; 31:263-70).
Fructus Rubi is the immaturity dry fruit of Rosaceae machaka Rubus Parvifolius L., and sour in the mouth is warm in nature, has the effect of protection Liver and kidney.Record Fructus Rubi property is flat, nontoxic among the East Yi Bao Prison, sour in the mouth, and controlling nocturnal emission with astringent drugs, tonifying liver make eye bright, the kidney invigorating gas, pitch-black hair.In addition, it has the kidney of improvement function, infertility, sexual impotence, seminal emission and nocturnal emission in nearest studies have shown that, building body is washed blood clearly, the effect that tonifying liver makes eye bright.In addition, the Rubus Parvifolius L. immature fruit adds and separablely in the water decomposition tannin goes out a kind of tannin (gallotannin) and 3 kinds of elladitannins (ellagitannin), physicochemical character and spectroscopic data also report to have gallic acid, 2,3-(S)-HHDP-D-glucopyranose, sanguiin (sanguiin) H-4 and sanguiin H-6.In Fructus Rubi, confirm that phenoloid such as gallic acid in its composition has stronger inhibition activity to the lipid and the oxidation of enzyme.Phenoloid is distributed widely in 2 metabolites of foodstuff, has multiple structure and molecular weight.In addition, owing to have a phenolic hydroxyl group, therefore have and the bonded character of macromole such as protein, have physiologically active functions such as antioxidant effect, antibiotic property, elimination nitrite.
Semen Cuscutae is the dry seed of 1 year parasitic draft Semen Cuscutae of life of Convolvulaceae and congener, acrid-sweet flavor, and property is flat, has the effect of anticancer, heart tonifying, blood pressure lowering and blood sugar lowering, protection kidney and spleen." refresh oneself, QI invigorating has better effects to soreness of the waist and knees disease, takes also effective to diabetes after frying in shallow oil at any time in record among the East Yi Bao Prison." in the Shennong's Herbal record " can mend multiple not enough disease, tonifying the kidney to consolidate the essence.Take materials for improving vision, longevity for a long time." in addition; also report its contain the multiple antioxidant that hinders the acetylcholine esterase active improving memory (Lue SY; Park YG, Kang BS.Studies onthe Acetylcholinesterase inhibitors Effects of Cuscutae Semen.Kor J Herbology2003; 18:289-99.).
Fructus Schisandrae Chinensis is the dry mature fruit of Magnoliaceae Fructus Schisandrae Chinensis, tool 5 flavors, effect (Park HJ with liver protection effect, aging resistance effect, antibacterial action, adjustment metabolism and immune function, Lee MS, Chi SC, Lee KT, Shin YH, ChoiJ.Evaluation of a Schzandrin C Derivative DDB-mixed Preparation (DWP-04) onAcetaminophen Detoxification Enzyme System in the Animal Model.Kor J Pharmacogn2005; 36:81-7).
Though Chinese medicine extract of the present invention be utilize Chinese medicine extraction method well known by persons skilled in the art for example water, alcohol or this two kinds mixed solvent extraction, decocting or extract at room temperature etc. make, be not limited to this.
At first, clean Fructus Corni, Fructus Lycii, Fructus Rubi, Semen Cuscutae and Fructus Schisandrae Chinensis, remove impurity, dry back is pulverizing.After Fructus Corni, Fructus Lycii, Fructus Rubi, Semen Cuscutae and the Fructus Schisandrae Chinensis mixing of pulverizing, aqueous precipitation is put into extractor with the precipitate that is settled out, and heating extraction is filtered.After with the concentrating under reduced pressure device filtrate being condensed into the volume of filtrate 1/10, lyophilization obtains Powdered compound Chinese medicine hot water extract.
Give compound Chinese medicine hot water extract of the present invention (50,100,200,300mg/kg) after 8 weeks to the laboratory animal per os that has brought out hyperlipemia, measure blood cholesterol, HDL-C and LDL-C etc., and measure the influential consumption of Zhi Zhi Dai Xie, in addition, in order to investigate it to promoting the influence of erection and persistence, observe NOS protein expression degree with western blotting, measure maximum intracavernous pressure.The result is: the whole administration groups that give compound Chinese medicine hot water extract of the present invention are compared with higher fatty acid diet group, the numerical value of T-CHOL and LDL-C reduces, the numerical value of HDL-C raises, eNOS and n-NOS protein expression increase, shorten the average time that reaches maximum intracavernous pressure, and the numerical value of maximum intracavernous pressure (ICP) also increases.
In addition, give compound Chinese medicine hot water extract of the present invention (100,300mg/kg) after 4 weeks, measure blood pressure, NOS protein expression degree and maximum intracavernous pressure spontaneously hypertensive male white mouse per os.The result is: in giving compound Chinese medicine hot water extract's of the present invention administration group, the contraction of blood pressure is pressed with remarkable reduction (p＜0.05), protein e NOS in the penile tissue and the expressivity of n NOS are compared remarkable increase with matched group, maximum intracavernous pressure also increases.
As mentioned above, compound Chinese medicine hot water extract of the present invention can reduce T-CHOL and LDL-cholesterol in the blood, increase the HDL-cholesterol, blood pressure lowering increases nerveous system and vascular system NOS protein expression, increases maximum intracavernous pressure, not only has the therapeutic effect of keeping the erection of simple property, when improving health NO bioavailability, also scalable is attended by hyperlipemia and/or hypertensive whole ill physiology, keeps the nature erection function.
Therefore, compound Chinese medicine hot water extract of the present invention can be used for the erection function insufficiency disorder for the treatment of or preventing to be caused by hyperlipemia and/or hypertension.
The present composition also can contain more than one known effective ingredient that the erection function insufficiency disorder that is caused by hyperlipemia and/or hypertension is had prevention or therapeutic effect when containing the compound Chinese medicine hot water extract.
Compositions of the present invention is when carrying out administration, and the carrier that allows on can at least a pharmacopedics outside above-mentioned effective ingredient makes.The carrier that allows on the pharmacopedics can use saline solution, aquesterilisa, Ringers solution, buffer saline, dextrose solution, maltodextrin solution, glycerol, methanol and composition thereof, if necessary also can add other conventional additives, for example antioxidant, buffer, biocide etc.In addition, also can add diluent, dispersant, surfactant, binding agent and lubricant extraly and make injectable dosage forms, ball, capsule, Teeth grain or lozenge such as aqueous solution, suspension, opacifiers.Perhaps, the method that illustrates with the proper method of this area or document [Remington ' s PharmaceuticalScience (latest edition), Mack Publishing Company, Easton PA] is made suitable dosage form according to the difference of various diseases or composition.
Compositions of the present invention can adopt the mode of oral administration or non-oral administration (for example, intravenous, subcutaneous, intraperitoneal or local being suitable for) according to purpose, and dosage can different scopes occur according to the serious symptom degree of patient's body weight, age, sex, health status, diet, administration time, medication, excretion rate and disease etc.Above-mentioned compound Chinese medicine hot water extract's dosage on the 1st is about 1～500mg/kg, preferred about 50～300mg/kg, 1 time on the preferred in addition 1st or several separate administration.
Compositions of the present invention can be used separately when the erection function insufficiency disorder that is used for the treatment of or prevents to be caused by hyperlipemia and/or hypertension or with operation, hormone therapy, Drug therapy and utilize the method for biologically regulator merge to use.
Below show and help to understand preferred embodiment of the present invention.Provide following embodiment in order to make the present invention be easier to understand, but content of the present invention is not limited to this.
Embodiment 1: compound Chinese medicine hot water extract's preparation
Clean Fructus Corni, Fructus Lycii, Fructus Rubi, Semen Cuscutae and Fructus Schisandrae Chinensis, remove impurity, after the drying, manual (hand mixer) is pulverizing.Mix Fructus Corni 32g, Fructus Lycii 32g, Fructus Rubi 16g, Semen Cuscutae 16g and Fructus Schisandrae Chinensis 4g after pulverizing, add 1L water, precipitate after 4 hours, complete sedimentary precipitate is packed in the extractor, heating extraction was filtered after 5 hours in the time of 100 ℃.With the concentrating under reduced pressure device filtrate is condensed into the liquid of filtrate 1/10 volume, lyophilization obtains Powdered compound Chinese medicine hot water extract.
Reference examples 1: single medicinal material hot water extract's preparation
Same procedure with embodiment 1 is extracted Fructus Corni, Fructus Lycii, Fructus Rubi, Semen Cuscutae and Fructus Schisandrae Chinensis respectively, obtains various Powdered single medicinal material hot water extracts.
Experimental example 1: the relation of measuring T-CHOL, HDL-cholesterol and LDL-cholesterol and compound Chinese medicine hot water extraction substrate concentration of the present invention in the blood with the white mice of having brought out hyperlipemia
For the numerical value of investigating T-CHOL, HDL-cholesterol and LDL-cholesterol in the white mice blood that brings out hyperlipemia and compound Chinese medicine hot water extract's of the present invention concentration relationship, as described below experimentizing.
1-1. inducing and the administration of sample of diet hyperlipemia
Laboratory animal is (strain) Korea S SAMTAKO biotech firm (Ebony Hill city, Korea S) 48 of 360g white mice in 16 ages in week of providing, is divided into 6 groups, 8 every group.1 group as normal group, supplies with general diet, and 5 groups of experimental grouies are freely supplied with 4 weeks of higher fatty acid diet of having added 1.5% cholesterol, 0.25% cholic acid and 25% Adeps Bovis seu Bubali in addition, induce the diet hyperlipemia.
Normal group gives 1mL distilled water, 1 group in the experimental group give 1mL distilled water, remain 4 groups with syringe (entry needle) in 8 weeks once-a-day per os dissolved the compound Chinese medicine hot water extract's that the foregoing description 1 makes (50,100,200,300mg/kg) 1mL distilled water.
1) normal group
2) higher fatty acid diet group
3) the compound Chinese medicine hot water extract 50mg/kg that makes of higher fatty acid diet group+embodiment 1
4) the compound Chinese medicine hot water extract 100mg/kg that makes of higher fatty acid diet group+embodiment 1
5) the compound Chinese medicine hot water extract 200mg/kg that makes of higher fatty acid diet group+embodiment 1
6) the compound Chinese medicine hot water extract 300mg/kg that makes of higher fatty acid diet group+embodiment 1
1-2. the mensuration of T-CHOL, HDL-cholesterol and LDL-cholesterol in the blood
In order to determine whether the white mice that above-mentioned higher fatty acid diet is raised has brought out hyperlipemia, gets blood from the eye socket vein, gets blood from the white mice abdominal aorta after experiment is over.Get blood after going on a hunger strike in 12 hours, solidified 2 hours 37 ℃ the time, behind the 15000rpm centrifugalize serum, get supernatant.With commercial reagent box (Kit) (ASAN pharmacy, Korea S) when the UV absorbance 500nm by Richmon enzymatic assays cholesterol, by enzymatic assays high density lipid cholesterol (HDL-C) such as No ma.Calculate low-density lipid cholesterol (LDL-C) according to Fridewald formula formula.
Low-density lipid cholesterol (LDL-C)=T-CHOL-[high density lipid cholesterol (HDL-C)-(neutral fat/5)]
Fig. 1 shows the result.
As shown in Figure 1, at picked-up higher fatty acid diet in the time of 30 days, illustrate between the blood cholesterol concentration of normal group and higher fatty acid diet group that there were significant differences, hypercholesterolemia has been brought out in affirmation.Give 8 weeks of compound Chinese medicine hot water extract of the present invention (50,100,200,300mg/kg) to higher fatty acid diet group per os, the T-CHOL of higher fatty acid diet group and the trend that LDL-C numerical value has minimizing are shown, and HDL-C numerical value there is the trend of increase.Wherein, the T-CHOL that gives compound Chinese medicine hot water extract 50mg/kg group of the present invention is 104.5 ± 32mg/dL, the T-CHOL of higher fatty acid diet group is 174.2 ± 38.1mg/dL, the administration group that gives compound Chinese medicine hot water extract 50mg/kg of the present invention is shown has compared significant minimizing with higher fatty acid diet group.In addition, the HDL-C that gives the administration group of compound Chinese medicine hot water extract 50mg/kg of the present invention is 29.7 ± 4.9mg/dL, the HDL-C of higher fatty acid diet group is 15.5 ± 8.4mg/dL, and the administration group that gives compound Chinese medicine hot water extract 50mg/kg of the present invention has been compared significant increase with higher fatty acid diet group.
Experimental example 2: brought out the expression degree of penile tissue internal protein NOS of white mice of hyperlipemia and the relation of compound Chinese medicine hot water extraction substrate concentration of the present invention
For the expression degree of investigating the white mice penile tissue internal protein NOS that has brought out hyperlipemia and the relation of compound Chinese medicine hot water extraction substrate concentration of the present invention, as described below experimentizing.
2-1. taking and the preparation in enzyme source of tissue
After raise finishing, make white mice anesthesia with the exsiccator of having filled ether after, cut hypogastric region and get blood from abdominal aorta, make it death after, extraction penis and testis.With the flush away blood in the 0.9% Sheng Li Shi salt water that is organized in of extraction, inhale the solution that desalts with filter paper, after weighing, use the liquid nitrogen IQF immediately.On the other hand, the blood of obtaining is transferred to immediately in the pipe of heparin processing, centrifugalize is 15 minutes when 2500rpm (4 ℃), separated plasma.With isolating blood plasma and internal organs before use in-70 ℃ of preservations.In 200nM Hepes, 320mM sucrose, 1mM ethylenediaminetetraacetic acid (EDTA), 1mM dithiothreitol, DTT (DTT), 10g/mL leupeptin, 2g/mL aprotinin, 1g/mL pepsin inhibitor, 10g/mL trypsin inhibitor, 1mM phenylmethyl sulfonylfluoride (PMSF) solution, make organize the endoenzyme source to homogenize after, centrifugalize (4 ℃, 10000rpm, 15 minutes), behind the quantification of protein with supernatant in-70 ℃ of preservations.
2-2. western blotting (Western blotting)
Get the quantitative protein 30g of Ford (Bradford) method at 95 ℃ of time variations after 5 minutes, carry out electrophoresis with bovine serum albumin (bovine serum albumin, B S A) according to Bradley with 12% discontinuous SDS-PAGE (discontinuous sodium dodecylsulfate)-polyacrylamide gel (polyacrylamide gel).Carrying out electrophoretic protein moved 2 hours 30 minutes on poly-(two) fluorothene (PVDF (poly-vinylidenedifluoride), Amershambioscience, the USA) film partially of 0.2m under 25volt.Carry out electrophoretic film and be reacting blocking-up after 30 minutes at room temperature with suppressing buffer (blocking buffer) (the TBS-T buffer that contains 5% skimmed milk breast).Make e NOS (endothelial cell nitric oxide synthase (endothelial nitric oxide synthase)), n NOS (neurogenic nitricoxide synthase (neuronal nitric oxide synthase)) (B D Biosciences, USA) each antibody response after 2 hours, cleaned 3 times every 10 minutes with T T B S (the buffered normal saline of Tris-Tween (Buffered saline)).Make at room temperature 2 antibody anti--mice IgG-HRP, anti--goat IgG-HRP (dilution in 1: 2000) (Zymed Laboratories, USA) reaction are after 1 hour, reuse T T B S washed 6 times in 5 minutes after the clean stage.Reaction is 2 minutes in developer ECL (enhanced chemiluminescence method (enhanced chemiluminescence)) solution, the thickness of the wave band that sensitization occurs on the comparative film determine to have or not marking protein with and difference.Giving for higher fatty acid diet group to give viagra is that the sldenafil 1mg/kg of main component is as positive controls.
Fig. 2 a shows the expression degree of protein N OS in the white mice penile tissue that has brought out hyperlipemia and compound Chinese medicine hot water extract of the present invention and independent Chinese medicine hot water extract's relation, and Fig. 2 b shows the relation of the expression degree of the white mice penile tissue internal protein NOS that has brought out hyperlipemia and compound Chinese medicine hot water extract's of the present invention concentration.
Shown in Fig. 2 a, can confirm compound Chinese medicine hot water extract of the present invention is delivered medicine to the white mice of having brought out hyperlipemia, the expression of its penile tissue internal protein NOS more only gives the single medicinal material hot water extract remarkable increase.
In addition, shown in Fig. 2 b, can confirm compound Chinese medicine hot water extract of the present invention is delivered medicine to the white mice of having brought out hyperlipemia, the expression of its penile tissue internal protein NOS has been compared remarkable increase with positive controls (sldenafil).Consider this result, sldenafil will be to increase the medicine that the machine-processed concentration that also increases c GMP is kept erection function by not only increasing the NOS expression of enzymes.In addition, this result also can explain the number of mechanisms according to compound Chinese medicine hot water extract of the present invention.Especially, low more according to compound Chinese medicine hot water extract's of the present invention concentration, the expression degree of NOS enzyme is good more, and wherein 50mg/kg administration group is the most obvious.Though hyperlipemia and high-cholesterol disease can cause the erection function insufficiency disorder owing to the obstacle of the nitric oxide generation structure of one of endotheliocyte interdependence relaxation factor (EDRF), but can improve vascular erection function insufficiency disorder largely by increasing e NOS and n NOS protein expression degree according to compound Chinese medicine hot water extract of the present invention.
Experimental example 3: the relation of measuring cavernous body of penis maximum internal pressure and compound Chinese medicine hot water extraction substrate concentration of the present invention with the white mice of having brought out hyperlipemia
In order to investigate the white mice cavernous body of penis maximum internal pressure that brought out hyperlipidemia and the relation of compound Chinese medicine hot water extraction substrate concentration of the present invention, as described below experimentizing.
In the intraperitoneal mouse that has brought out hyperlipemia injection free from worries (Zoletil) 0.2mL with its general anesthesia after, tracheostomize inserts pneumatic duct (PE 240 polyethylene tubes) to guarantee air flue.After polyethylene tube (PE-50 polyethylene tube) insertion right carotid artery, cut hypogastric region to the Centromedian skin of glans penis epidermis, expose the abdominal cavity to the subcutaneous tissue of penis spongy body, the 23G pin is inserted in the cavernous body of penis of right side, polyethylene tube is connected between pressure converter and the physiology recorder, measures systemic blood pressure and penis sponge internal pressure simultaneously., as the zooming data handling system whole effective 250U/mL heparin is handled with iwory.With prostate from the hypogastric region that exposes after carefully separate between bladder, hook-shaped needle electrode is suspended on behind the prostate of right side on the external position, come electricity irritation pelvic plexus and cavernosal nerve.After 10V, the 2.4mA electricity irritation, measure intracavernous pressure and systemic blood pressure simultaneously.The main erection function index that compares with experimental group is maximum intracavernous pressure (intracavernosal pressure, ICP) and maximum intracavernous pressure/mean arterial blood pressure (ICP/mean arterial pressure, ICP/MAP).Behind the nerve stimulation spongy body, get blood 3cc, the penis of weighing extraction and the weight of testis are preserved in the liquid nitrogen.
Fig. 3 shows the result.
As shown in Figure 3, compound Chinese medicine hot water extract administration group of the present invention reaches has compared remarkable shortening with higher fatty acid diet group the average time of maximum intracavernous pressure, does not have difference with normal group.Show the increase of the maximum intracavernous pressure (ICP) that compound Chinese medicine hot water extract administration group of the present invention compares with higher fatty acid diet group, wherein administration compound Chinese medicine hot water extract 50mg/kg group has significant difference.Aspect maximum intracavernous pressure/mean arterial blood pressure (ICP/MAP), significantly increase according to the order of normal group＞compound Chinese medicine hot water extract 50mg/kg administration group＞compound Chinese medicine hot water extract 100mg/kg administration group.Therefore, in fact act in the penis according to compound Chinese medicine hot water extract of the present invention, this is to show that itself and erection function have the positive evidence of substantial connection.
Experimental example 4: the relation of having brought out hypertensive white mice blood pressure and compound Chinese medicine hot water extraction substrate concentration of the present invention
In order to investigate the blood pressure of having brought out hypertensive white mice and the relation of compound Chinese medicine hot water extraction substrate concentration of the present invention, as described below experimentizing.
4-1. hypertensive inducing and the sample administration
Laboratory animal is (strain) Korea S SAMTAKO biotech firm (Ebony Hill city, Korea S) 15 of 250～300g spontaneously hypertensive male white mouses (spontaneous hypertensive rat, SHR) in 16 ages in week of providing.Experimental group is divided into 3 groups (matched groups, 1 group of experiment, and experiment 2 groups), and dividing in per 1 group has 5 of SHR white mice.The matched group per os gives distilled water, and the experimental group per os is dissolved with the compound Chinese medicine hot water extract's that makes according to the foregoing description 1 (100,300mg/kg) 4 weeks of water.
4-2. the mensuration of blood pressure
The SHR male white mouse plastic barrel of packing into is made it to maintain static, on tail, measure systolic pressure 3 times before and after the drug administration, relatively meansigma methods with electronic blood pressure Meter (electro-sphygmomanometer) PE-300 (IITC, the USA) rotameter (plethysmography) that curls.
Fig. 4 shows the result.
As shown in Figure 4, the systolic pressure of matched group before and after drug administration is respectively 254.3 ± 14.5mmHg, 237.7 ± 24.8mmHg, do not have significant difference.The systolic pressure of administration group before and after drug administration that gives compound Chinese medicine hot water extract 100mg/kg of the present invention is respectively 266.7 ± 14.0mmHg, 187.5 ± 21.6mmHg, and the systolic pressure of compound Chinese medicine hot water extract 300mg/kg administration group before and after drug administration is respectively 271.8 ± 23.9mmHg, 178.0 ± 14.6mmHg.As mentioned above, the systolic pressure of whole compound Chinese medicine hot water extract administration groups of the present invention all has remarkable reduction (p＜0.05).
Experimental example 5: brought out the relation that hypertensive white mice penile tissue internal protein NOS expresses degree and compound Chinese medicine hot water extraction substrate concentration of the present invention
To have brought out hypertensive white mice penile tissue internal protein e NOS, the expression degree of n NOS and the relation of compound Chinese medicine hot water extraction substrate concentration of the present invention in order investigating, to have observed with the western blotting of above-mentioned experimental example 2-2.
Fig. 5 a illustrates the expression degree of having brought out hypertensive white mice penile tissue internal protein NOS and relation according to compound Chinese medicine hot water extract of the present invention and independent Chinese medicine hot water extract, and Fig. 5 b illustrates the expression degree of having brought out hypertensive white mice penile tissue internal protein NOS and relation according to compound Chinese medicine hot water extract's of the present invention concentration.
Shown in Fig. 5 a, can confirm compound Chinese medicine hot water extract of the present invention delivered medicine to and bring out hypertensive white mice, the expression degree of its penile tissue internal protein NOS only gives the increase that the single medicinal material hot water extract has highly significant separately.
In addition, shown in Fig. 5 b, compound Chinese medicine hot water extract of the present invention delivered medicine to brought out hypertensive white mice, the expression degree of its penile tissue internal protein NOS has been compared remarkable increase with matched group, particularly the eNOS of compound Chinese medicine hot water extract 100mg/kg administration group, nNOS expression degree have bigger increase.We find, have compared increase though eNOS, the nNOS of compound Chinese medicine hot water extract 300mg/kg administration group express degree with matched group, compare then with compound Chinese medicine hot water extract 100mg/kg administration group and have reduced.
Experimental example 6: measure the relation of cavernous body of penis maximum internal pressure and compound Chinese medicine hot water extraction substrate concentration of the present invention with having brought out hypertensive white mice
In order to investigate the relation of having brought out hypertensive white mice cavernous body of penis maximum internal pressure and compound Chinese medicine hot water extraction substrate concentration of the present invention, behind the method nerve stimulation spongy body with above-mentioned experimental example 3, write down the result.
Fig. 6 shows the result.
As shown in Figure 6, the maximum intracavernous pressure of matched group is 27.1 ± 4.5mmHg, the maximum intracavernous pressure that gives compound Chinese medicine hot water extract's of the present invention (100mg/kg, 300mg/kg) administration group is respectively 83.3 ± 1.9mmHg, 55.0 ± 4.6mmHg, and the administration group that gives compound Chinese medicine hot water extract of the present invention is compared with whole matched groups has remarkable increase (p＜0.05) statistically.The percentage ratio of the maximum intracavernous pressure/mean arterial pressure of matched group (ICP/MAP) is 14.9 ± 1.4%, give compound Chinese medicine hot water extract of the present invention (100mg/kg, 300mg/kg) the administration group be respectively 62.8 ± 3.9%, 44.1 ± 3.9%, the administration group that gives compound Chinese medicine hot water extract of the present invention is compared with whole matched groups has remarkable increase (p＜0.05) statistically.Giving does not have significant difference between the administration group of compound Chinese medicine hot water extract of the present invention (100mg/kg, 300mg/kg).
Next, the illustrative formulation example that shows the present composition.
Formulation example 1: the preparation of powder
The compound Chinese medicine hot water extract 2g of embodiment 1
Lactose 1g
Mentioned component is mixed, in the cloth bag of the sealing of packing into, make powder.
Formulation example 2: the preparation of lozenge
The compound Chinese medicine hot water extract 100mg of embodiment 1
Corn starch 100mg
Lactose 100mg
Magnesium stearate 2mg
After mixing mentioned component, play ingot, make lozenge according to the lozenge preparation method of routine.
Formulation example 3: the preparation of capsule
The compound Chinese medicine hot water extract 100mg of embodiment 1
Corn starch 100mg
Lactose 100mg
Magnesium stearate 2mg
After mixing mentioned component, be packed in the gelatine capsule, make capsule according to the preparation method of conventional capsule.
Claims (3)
1. pharmaceutical composition that is used for the treatment of or prevents the erection function insufficiency disorder that is caused by hyperlipemia, it is 5～10: 5～10 by the dry weight ratio: 1～5: 1～5: 0.5～1.5 Fructus Corni hot water extract, Fructus Lycii hot water extract, Fructus Rubi hot water extract, Semen Cuscutae hot water extract and Fructus Schisandrae Chinensis hot water extract form.
2. pharmaceutical composition that is used for the treatment of or prevents the erection function insufficiency disorder that is caused by hypertension, it is 5～10: 5～10 by the dry weight ratio: 1～5: 1～5: 0.5～1.5 Fructus Corni hot water extract, Fructus Lycii hot water extract, Fructus Rubi hot water extract, Semen Cuscutae hot water extract and Fructus Schisandrae Chinensis hot water extract form.
3. pharmaceutical composition that is used for the treatment of or prevents the erection function insufficiency disorder that is caused by hyperlipemia and hypertension, it is 5～10: 5～10 by the dry weight ratio: 1～5: 1～5: 0.5～1.5 Fructus Corni hot water extract, Fructus Lycii hot water extract, Fructus Rubi hot water extract, Semen Cuscutae hot water extract and Fructus Schisandrae Chinensis hot water extract form.
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| KR1020060138262A KR100761938B1 (en) | 2006-12-29 | 2006-12-29 | Pharmaceutical composition for preventing or treating impotence induced hyperlipidemia and/or hypertension |
| KR10-2006-0138262 | 2006-12-29 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1143502A (en) * | 1993-11-10 | 1997-02-26 | 吴新光 | Medicine for curing diseases and prolonging life |
| CN1357347A (en) * | 2000-12-14 | 2002-07-10 | 孟宪茹 | Chinese medicine with physique enhancing and disease treating functions |
| CN1546072A (en) * | 2003-11-28 | 2004-11-17 | 王庆正 | Chinese traditional medicine for treating prostate disease and nephritis and preparing process thereof |
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| KR100463130B1 (en) * | 2001-05-25 | 2004-12-23 | 한국식품연구원 | The food to improve the sexual function of man |
| KR100364684B1 (en) * | 2002-09-04 | 2002-12-16 | Korea Medical Science Inst | Composition containing plant extract for promoting and maintaining erection |
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| CN1143502A (en) * | 1993-11-10 | 1997-02-26 | 吴新光 | Medicine for curing diseases and prolonging life |
| CN1357347A (en) * | 2000-12-14 | 2002-07-10 | 孟宪茹 | Chinese medicine with physique enhancing and disease treating functions |
| CN1546072A (en) * | 2003-11-28 | 2004-11-17 | 王庆正 | Chinese traditional medicine for treating prostate disease and nephritis and preparing process thereof |
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