CN1282584A - Application of icariin in preventing and treating sexual disfunction and improving diseases associated with vasoconstriction - Google Patents
Application of icariin in preventing and treating sexual disfunction and improving diseases associated with vasoconstriction Download PDFInfo
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- CN1282584A CN1282584A CN00118336A CN00118336A CN1282584A CN 1282584 A CN1282584 A CN 1282584A CN 00118336 A CN00118336 A CN 00118336A CN 00118336 A CN00118336 A CN 00118336A CN 1282584 A CN1282584 A CN 1282584A
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- Prior art keywords
- icariine
- penis
- cavernous body
- erection
- medicine
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- TZJALUIVHRYQQB-UHFFFAOYSA-N icariine Natural products C1=CC(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(C)O2)O)C(=O)C2=C(O)C=C(OC3C(C(O)C(O)C(CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-UHFFFAOYSA-N 0.000 title claims abstract description 91
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/29—Berberidaceae (Barberry family), e.g. barberry, cohosh or mayapple
- A61K36/296—Epimedium
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- Public Health (AREA)
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- General Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Natural Medicines & Medicinal Plants (AREA)
- Endocrinology (AREA)
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Abstract
An application of icariin in preventing and treating sexual disfunction and improving the diseases associated with vasoconstriction is disclosed.
Description
The present invention relates to icariine and be used for the purposes of prophylactic treatment sexual dysfunction medicine in preparation, and with the purposes of improving the vasoconstriction diseases related.
Male's sexual function comprises libido, erection, ejaculation and voluptus, is under the adjusting of nerve-endocrine system, the reflection of the complex physical of penis vascular system.If so diseases such as the weak obstacle of hyposexuality, erectile disfunction, defective ejaculation or penis appear unusually both may having caused in a certain process of said system, and occurring can appear separately or merge mutually in this disease.The sickness rate of male sexual disorder accounts for adult male's 30-60% greatly, and has along with the age increases and the trend of increase.Traditional medical science is commonly referred to as sexual impotence, premature ejaculation to sexual dysfunction, and before 10 years up to date, it is psychological reason that the reason major part of sexual dysfunction is considered to.But along with the prosperity of modern science and technology clear and definite to find that in the sexual dysfunction patient more than 50% nerveous system, blood vascular system, endocrine are arranged be disease and suffer from hypertension, diabetes, take organic reason such as various medicines.
Male's sexual function mainly is when various sexual stimulus is arranged, and the complex physical reflection by vascular system under the adjusting of nerve-endocrine system makes erection.The erection process of this penis at first is to rely on the arteriolar expansion of penis that the penile blood flow amount is increased, the cavernous body of penis smooth muscle loosening appears in succession and the expansion of spongy body aperture, impel a nearly step of blood influx to increase, leading the system penis sponge internal pressure raises, venule occlude blood under the compressing albuginea penis flows out, thereby cause the cavernous body of penis inner blood full and its intensity of the hard erection of penis can reach the insertion vagina, and be enough to come to orgasm and ejaculate the time of keeping erection.
The relexation of cavernous body of penis smooth muscle plays pivotal role in this erection process, and the erection process is subjected to the adjusting of neuroendocrine system.Zoopery shows that the many offices cloth factor influences penile erectile function such as norepinephrine (NA), neuropeptide tyrosine (NPY), acetylcholine (Ach), prostaglandin (PGE), serotonin (5-HT), calcitonin-gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), Endothelin (EDRF) etc.
Recent studies show that nitric oxide (NO) plays an important role in the erection process.NO is discharged by parasympathetic nervous that is distributed in penis and the non-acetylcholine nerve of non-epinephrine (NANC) tip when sexual stimulus, and NO also discharges at endotheliocyte that is distributed in the blood vessel endothelium layer and penis sea body hole endotheliocyte, NO can activate guanylate cyclase in the smooth muscle cell, make the synthetic increase of cyclic guanosine monophosphate (cGMP), but also activator protein enzyme G (PKG), PKG can make calcium channel close and potassium channels opening, and two kinds of effects can cause that all penis sea body smooth muscle loosening causes erection.Cycli phosphate bird sweet (cGMP) is again by phosphodiesterase (PDE) deactivation.
Sexual dysfunction can be divided into hyposexuality, erection problem, orgasm disorder and defective ejaculation.Factors such as that the reason of sexual dysfunction has is angioneurotic, incretion, psychological pathological changes, diabetes, hypertension, neurologic defict, smoking all can cause sexual dysfunction.
Traditional viewpoint thinks that sexual dysfunction mainly is owing to psychological reason causes.Use oral medicine such as tranquilizer trazodone and Yohimbine etc. in the treatment.But the mechanism of action of this medicine is still indeterminate, and its curative effect is not high, and side effect is in various degree arranged.
In recent years along with understanding fully erection mechanism, various have the medicine attempt of relexation to be used for diagnosing and the treatment male sexual disorder to the cavernous body of penis smooth muscle, at present, existingly restraint alkali (paparvarin), fragrant Chlorazene (phentolamine), PGE1 (prostajlandin E1) the direct intracavernous injection therapy of medicine of etc.ing with vasodilation such as cherry and treat erectile disfunction and obtain than the curative effect of being satisfied with.But this therapy can cause that side effect such as an innings cloth pain, persistence erection, penis fibrosis are so often be limited clinically to use.
Recently, the oral drugs Phosphodiesterase V inhibitors (Viagra) of the treatment erection problem of U.S.'s invention is caught people's attention, above-mentioned medicine only is to be used for once bringing out erection as the chemical prosthese, and in various degree side effect arranged, as flushing, headache, visual disorder, hypotension etc., particularly disputable being worth of the patient safety that cardiovascular disease is arranged paid attention to.
Therefore, the medicine of safe and effective enhancement human body instinct erection function awaits research and development, and nearest research is made every effort to be used for the therapeutic dysfunction in developing safely and effectively the NO donor.
The crude drug Herba Epimedii is used in traditional medicine circle in the prescription of tonic invigorator usually as a kind of composition, but its mechanism of action is not understood fully as yet.The recent active ingredient to Herba Epimedii studies have shown that and contains many compositions in the Herba Epimedii, as icariine, volatile oil, ceryl alcohol, state one alkane, plant sterol, tannin, linoleic acid etc.Recently isolate magnoflorin, epimedoside A, the epimedin A of trace again, B, C, Quercetin, dehydration icariine-3-O-rhamnoside etc.Wherein icariine only is used as Herba Epimedii analysis of components standard reagent at present.Some research report Herba Epimedii have antifatigue effect, promote immunologic function and improve liver function.But up to the present, also less than be used for the handicapped research report of therapeutic about the icariine monomer.
The objective of the invention is to seek and develop the new medical usage of icariine
The inventor finds after deliberation, the beat all effect of icariine with strong lax cavernous body of penis smooth muscle, also have the slight relexation of large artery trunks smooth muscle, its pharmacological action is relevant with the increased activity of smooth muscle cell intracellular nitric oxide (NO)-cGMP path.Thereby can be used for improving and promoting penile erectile function and with the symptom of improving the vasoconstriction diseases related.
Therefore, the present invention relates to icariine be used in preparation the prophylactic treatment sexual dysfunction medicine purposes and with improve vasoconstriction diseases related purposes.
The present invention relates to down examination the present invention relates to icariine preparation be used for the prophylactic treatment sexual dysfunction medicine purposes and preparation and improve purposes in the vasoconstriction diseases related medicine.
The present invention relates to be used to prevent or the pharmaceutical composition of therapeutic dysfunction and vasoconstriction diseases related, it comprises as the icariine of active component and pharmaceutical carrier and excipient.
The present invention relates to prevent or the method for therapeutic dysfunction and vasoconstriction diseases related, comprise to the icariine of patient's prevention of needs prevention or therapeutic dysfunction and vasoconstriction diseases related or treatment effective dose or contain the pharmaceutical composition of icariine.
Icariine belongs to flavonoid glycosides monomer, its chemical structural formula: C by what the crude drug Herba Epimedii was separated
33H
40O
15Molecular weight: 676.67, fusing point: 225-230 ℃.
According to the present invention, the icariine that uses among the present invention can use separately or use with pharmaceutical compositions.Pharmaceutical composition comprises as the icariine of active ingredient and pharmaceutical carrier.
According to the present invention, pharmaceutical composition of the present invention, can prepare with perception method by this area also can be by oral or non-intestinal or local by way of administration.Oral formulations comprises as tablet, chewing agent, capsule, suspension, solution etc., and non-intestinal drug delivery agent comprises as injection.Local administration preparation comprises as cream, ointment, patch, spray etc.
The present invention of root a tree name, icariine is that the mixture extraction by organic solvent or organic solvent and water obtains from the Herba Epimedii crude drug.Spendable organic solvent comprises alcohols such as methanol, ethanol etc., halo alkanes such as dichloromethane, chloroform, ethers such as ether, ketone such as acetone, lipid such as methyl acetate, ethyl acetate, hydro carbons such as hexane etc.
The following examples are used for more detailed description the present invention, but do not mean that the present invention only limits to this.The preparation of embodiment 1 icariine
Extracting method (1)
Get dry Herba Epimedii (aerial parts) 500 grams and add 10 liters of MeOH, heat and extracted 3, totally 3 times.Cross the Lu and reclaim solvent, concentrating under reduced pressure obtains the MeOH extract.The MeOH extract adds behind the water suspendible with commensurability hexane extraction 4 times totally, and the water intaking layer is concentrated to 1/3 amount.In this concentrated water layer, add 5% citric acid suspendible (pH=5.5), the CHCl of reuse isodose
3Extract, add an amount of NH again
4OH suspendible (pH=10), the CHCl of reuse isodose
3Extract.This process 3 times repeatedly.Final alkaline water layer extracts 3 times repeatedly with the isodose butanols, obtains icariine crude product (icariin richfraction, IRF) (utilize HPLC assay icariine content be 8%) as a result.
Extracting method (2)
Get dry Herba Epimedii (aerial parts) 500 grams and add 10 liters of EtOH, heat to conflux for 80 ℃ and extract 3 times, each 1 hour, totally 3 times.Filter, decompression recycling ethanol is condensed into pulpous state.Adding 4 times of water gagings disperses the back to remove a little wax fat of chlorophyll etc., merging filtrate after the n-butyl alcohol kingfisher is got 4 times, concentrating under reduced pressure in static 3 hours.With the absorption of 40-60 order polyamide post, 30% ethanol elution is extremely colourless, the eluent concentrating under reduced pressure.Add 70% ethanol (1: 20) dissolving, static 8 hours, filter the Herba Epimedii general glycoside.Herba Epimedii general glycoside and dehydrated alcohol (1: 15) eluting recrystallization repeatedly get Herba Epimedii general glycoside crude product.The total salidroside content 52% of Herba Epimedii.
Icariine separates
Icariine or Herba Epimedii general glycoside crude product dissolve at MeOH, are adsorbed on silica dehydrator, and (in 8 * 60cm), with CHCl: MeOH=5: 1,4: 1,3: 1,2: 1 order stripping, the separatory of each stripping concentrates, reuse MeOH/H to add the silicagel column got ready again
2The mixed liquation of O goes out faint yellow crystallization.
This crystallization is at the UV color development, and pauly reagent shows positive reflection, and TLC analysis result Rf value is 0.6, fusing point: 239 ℃.Confirm as be pure product icariine (icariine, utilize the HPLC assay as a result icariine content be 99.8%)).Test 1 safety experiment
Utilizing SD according to the acute toxicity test rule is that each 5 of rat male and female are 1 group, is divided into 4 groups, and the 1st group of oral administration amount is icariine 3g/kg, the 2nd group of 2g/kg, the 3rd group of 1g/kg, the 3rd group of 0.5g/kg.7 purpose results are observed in the dispensing back, and LD50 is male to be 1.88g/kg, and female is 1.95g/kg.Test 2 drug effects and pharmacological mechanism experimental principle
Male's sexual function mainly is that various sexual stimulus following time is being arranged, and the complex physical reflection by vascular system under the adjusting of nerve-endocrine system impels erection.The erection process of this penis at first is to rely on arteriolar dilating effect of penis and cavernous body of penis smooth muscle relaxation, the cavernous body of penis hole expands and impels cavernous body of penis blood influx to increase, the venule of leading the system penis sponge internal pressure to raise and oppressing under the albuginea penis flows out with occlude blood, thereby causes the cavernous body of penis inner blood to fill and the hard erection of penis.In this erection process, the relexation of cavernous body of penis smooth muscle plays pivotal role.So tool has the medicine of relexation to help penile erectile function to the penis sponge smooth muscle.The relexation of cavernous body of penis smooth muscle also is subjected to the adjusting of the non-phatidylcholine of non-epinephrine (NANC) energy nerve and endotheliocyte relaxation factor (EDRF), and nitric oxide (NO) plays an important role among this EDRF.NO or the material that contains NO are diffused in the smooth muscle cell, activate sGC, make that cGMP is synthetic to be increased and bring out the cavernous body of penis smooth muscle loosening and impel erection.The intravital cGMP of penis sponge is lost activity by the Phosphodiesterase V type again.So impelling penis sponge smooth muscle NO to generate increases, or promote the guanylate cyclase activity, or suppress the active medicine of phosphodiesterase, can make synthetic or active the increasing of cGMP, promote erection so sexual dysfunction is had therapeutical effect.Utilizing the penis sponge biological tissue at external experimentizing (in vitro), observe medicine to its tensile influence, or measure the influence of medicine to phosphodiesterase, is effective experimental technique of research medicine penile erectile function.2.1. icariine is to rabbit penis sea body smooth muscle relaxation:
With male rabbit (new zealand rabbit, body weight: 2.5-3.0kg), isolate penis sea body smooth muscle, in the external pharmacological effect experiment of having carried out icariine.Totally 60 of the rabbit of using have been observed the variable concentrations icariine to the tensile influence of penis sea body smooth muscle, and have observed with the concentration icariine the tensile influence of abdominal aorta smooth muscle.In order to study the pharmacological mechanism of icariine to penis sea body smooth muscle relaxation, observed phatidylcholine (NANC) energy nerve blocker atropine, PGE1 inhibitor indometacin, suppress NO generation or the active reagent N w-nitric-L-of NO arginine (L-NNA) and 1,2,3,-thrihydroxy-benzene, bird phosphoric acid cyclase activity inhibitor serge blue, 1H-[1,2,4] oxadiazoles also [4,3 ,-a] quinoxaline-1-ketone (ODQ) to the influence of icariine to penis sea body smooth muscle relaxation.Experimental technique
Rabbit is excised penis and abdominal aorta with pentobarbital sodium (30-50mg/kg) anesthesia back, at the mixed gas of sustainable supply 95% oxygen and 5% carbon dioxide and fill the Tyrode nutritional solution and keep in the container of 37.5 ℃ of weighing apparatus temperature, cavernous body of penis is separated into the flesh bar of 2 * 2 * 6mm size, and will in large artery trunks, isolate the wide arterial ring of 4mm, respectively in the glass organ pipe that fills the mixed gas of Tyrode solution 10ml and sustainable supply 95% oxygen and 5% carbon dioxide is bathed, one end is fixed in the bottom, and the other end connects on the power displacement transmitter.The variation of the tensity of cavernous body of penis bar and arterial ring, (TSD 105 to utilize polygraph, Biopac Systems, Santa Barbara, CA, USA) mensuration and note chlorine have been observed Herba Epimedii extract and the icariine tensity induced effects to cavernous body of penis bar and large artery trunks ring.
In order to induce the tension force of rest state penis sponge bar and arterial ring originally, penis sea body bar and arterial ring are pulled to the tension force of 2 grams, imitated accurate 1.5-2 hour.When utilizing the secondary woods (PHE of benzene; 5 * 10
-6M) bring out behind the contractile response reuse Tai Shi solution flush away to replying baseline.This method is repeatedly more than three times, when the difference of three contractile response amplitudes is in 10%, is decided to be the tension force of imitating accurate rest state penis sponge bar and arterial ring, carries out next step pharmacodynamic analysis.Each smooth muscle or the priority experiment of ring in experimentation kept 30 minutes at interval, carried out next step experiment again after making its tension force that is returned to rest state penis sponge bar and arterial ring.A. Herba Epimedii extract and icariine are to the tensity induced effects experiment of cavernous body of penis bar and large artery trunks ring
In order to observe Herba Epimedii extract and icariine tensity induced effects, cavernous body of penis bar and large artery trunks ring are utilized phenylephrine (PHE to cavernous body of penis bar and large artery trunks ring; 5 * 10
-6M) bring out contraction, when keeping platform, amount (Herba Epimedii extract 1-50mg/ml, icariine 10 that Herba Epimedii extract and icariine are increased progressively with concentration
-10-10
4M) drop into successively, and observe its each and every one concentration relaxation effect smooth muscle.Each drug level is observed the drug influence of 8 animal flesh bars or flesh ring at least and the credit that takes statistics is analysed.B. icariine has been observed phatidylcholine (NANC) energy nerve blocker atropine (10 to the caused relaxation effect mechanism of cavernous body of penis bar experiment b-1.
-6M) icariine has been observed PGE1 inhibitor indometacin (10 to the b-2. that influences of the caused relaxation effect of cavernous body of penis bar
-4M) icariine has been observed to the b-3. that influences of the caused relaxation effect of cavernous body of penis bar that inhibition NO generates or the active reagent N of NO
w-nitric-L-arginine (L-NNA) (10
-4M) and 1,2,3,-thrihydroxy-benzene (10
-4M) icariine has been observed bird phosphoric acid cyclase activity inhibitor serge blue (10 to the b-4. that influences of the caused relaxation effect of cavernous body of penis bar
-4M), 1H-[1,2,4] oxadiazoles be [4,3 ,-a] quinoxaline-1-ketone (ODQ) (10 also
-4M) to the influence of icariine to penis sea body smooth muscle relaxation
In order to observe above-mentioned all ingredients, the cavernous body of penis bar is utilized phenylephrine (PHE to the influence of icariine to cavernous body of penis bar relaxation effect; 5 * 10
-6M) bring out contraction, when keeping platform, after all ingredients dropped into respectively according to separately concentration, wait for 20 minutes, again amount (the icariine 10 that positive leaves of pulse plants glycoside is increased progressively with concentration
-10-10
-4M) drop into successively, and observe its each and every one concentration icariine relaxation effect smooth muscle.Make comparisons with the relax level before the saturating all ingredients, analyze it the influence of icariine to cavernous body of penis bar relaxation effect.Each drug level is observed the drug influence of 5 animal flesh bars or flesh ring at least and the credit that takes statistics is analysed.Solution is used in experiment
Phenylephrine hydrochloride, acecoline, atropine sulfate, 1,2,3,-thrihydroxy-benzene, indometacin, N
ω-nitric-L-arginine, 1H-[1,2,4] oxadiazoles also [4,3 ,-a] quinoxaline-1-ketone is from Sigma Chemical Co. (St.Louis, MO, USA) product, serge blue is from Mallinckrodt Chemical Co. (St.Louis, MO, USA) product.The composition of Tyrode solution (mEq/l) Na
+(153.6), K
+(5.3), Ca
++(3.0), Mg
++(1.2), Cl
-(157.2), H
2PO
4 -(0.6), SO
4 -(1.2), HCO
3 -(7.1), glucose (11.4).Statistical analysis
Data computer analysis (Acqkowlege 3.2 program, Biopac systems, USA) and all relaxation responses represent with maximum relaxation response percentage ratio, maximum lax refer in all tests the distance between the downward deviation of maximum in the inductive maximum collapse point of PHE and curve.Statistical analysis Student ' st test is carried out.Smooth muscle tension variation under the different pharmaceutical concentration is measured with the log attenuation analysis.Be considered to meaningful on the statistics as the p value less than 0.05 o'clock.All values is represented with standard error of mean.Experimental result c. Herba Epimedii extract and icariine are to the tensity induced effects experiment of cavernous body of penis bar and large artery trunks ring
Observe Herba Epimedii extract and icariine tensity induced effects result, the results are shown in Table 1 and table 2 cavernous body of penis bar and large artery trunks ring.Can see that by the data in table l and the table 2 Herba Epimedii extract and icariine are to utilizing phenylephrine (PHE:5 * 10
-6) bring out the cavernous body of penis bar and the large artery trunks ring of contraction, demonstrate the relexation (p＜0.001) of the interdependent victory of concentration.Medium effective concentration (the EC of icariine
50) be respectively 4.67 * 10 at penis sponge and arterial ring
4M, 2.71 * 10
3M.This result show icariine to the relexation of cavernous body of penis to the relexation of arterial ring strong 5.8 times (p＜0.001).Table 1.Herba Epimedii extract (IRF) is to utilizing phenylephrine (PHE:5 * 10
-6M) bring out the cavernous body of penis bar of contraction and the relexation that the large artery trunks ring shows the concentration interdependence.
Table 2.Icariine is to utilizing phenylephrine (PHE:5 * 10
-6M) bring out the cavernous body of penis bar of contraction and the relexation that the large artery trunks ring shows the concentration interdependence.
Medium effective concentration (the EC of icariine crude product (IRF) and icariine
50)
Smooth muscle tension variation under different pharmaceutical concentration log attenuation analysis result, icariine crude product (IRF) is at the medium effective concentration (EC of cavernous body of penis and arterial ring
50) be respectively 4.08mg/ml, 22.4mg/ml.Icariine is at the medium effective concentration (EC of cavernous body of penis and arterial ring
50) be respectively 4.67 * lO
-4M, 2.83 * 10
-3M.Calculate according to icariine content in the icariine crude product (IRF) 8% and can convert that to draw icariine concentration be 4.08 * lO
4M, 2.64 * lO
-3M, the medium effective concentration (EC of this result and icariine
50) 4.67 * 10
-4M, 2.83 * 10
-3Very nearly the same.Illustrate that icariine is the main pharmacodynamics composition in the Herba Epimedii composition, and strong more than 5.5 times to the relaxation effect of cavernous body of penis than the large artery trunks ring.Icariine is to the experiment of the caused relaxation effect mechanism of cavernous body of penis bar
1. observing hexanoyl choline (NANC) energy nerve blocker atropine (10
-6M) result of icariine to the influence of the caused relaxation effect of cavernous body of penis bar shown, icariine does not have significant difference (p＞0.05) to the caused relaxation effect of cavernous body of penis bar with the pre-pre-treatment of atropine than matched group, and this illustrates that this relaxation effect is not subjected to atropinic the influence.
2. observing PGE1 inhibitor indometacin (10
-4M) result of icariine to the influence of the caused relaxation effect of cavernous body of penis bar shown, icariine does not have significant difference (p＞0.05) to the caused relaxation effect of cavernous body of penis bar with the pre-pre-treatment of indometacin than matched group, and this illustrates that this relaxation effect is not subjected to the influence of indometacin.The results are shown in Table 3.
3. observing inhibition NO generation or the active reagent N of NO
w-nitric-L-arginine (L-NNA) (10
-4M) and 1,2,3,-thrihydroxy-benzene (10
-4M) result of icariine to the influence of the caused relaxation effect of cavernous body of penis bar shown that icariine is to using N
w-nitric-L-arginine (L-NNA) (10
-4M) and 1,2,3,-thrihydroxy-benzene (10
-4M) the caused relaxation effect of cavernous body of penis bar of pre-pre-treatment significantly is suppressed (p＜0.001) than matched group, and this illustrates that this relaxation effect generates with NO or the NO activation is relevant.The results are shown in Table 3.
4. observing bird phosphoric acid cyclase activity inhibitor serge blue (10
-4M), 1H-[1,2,4] oxadiazoles be [4,3 ,-a] quinoxaline-1-ketone (ODQ) (10 also
-4M) result of icariine to the influence of penis sea body smooth muscle relaxation shown that icariine is to using serge blue (10
-4M), 1H-[1,2,4] oxadiazoles be [4,3 ,-a] quinoxaline-1-ketone (ODQ) (10 also
-4M) the caused relaxation effect of cavernous body of penis bar of pre-pre-treatment is suppressed (p＜0.001) than matched group is remarkable, the results are shown in Table 4.
Above-mentioned experimental result shows that icariine is relevant with nitric oxide (NO)-bird phosphoric acid cyclase (GMP) activation to the relaxation effect of smooth muscle.The results are shown in Table 3.Table 3 destroys endotheliocyte, 1,2,3,-thrihydroxy-benzene, and serge blue, ODQ, atropine, after the indometacin pre-treatment, icariine is to utilizing phenylephrine (PHE; 5 * 10
-6M) bring out the influence of the cavernous body of penis bar relaxation effect of contraction.
Table 4 variable concentrations ODQ gives processing contacts the relexation of cavernosus cutlet in advance to PHE to icariine reaction (PHE; 5 * 10
-6M)
Test the influence experimental technique of 3 icariines to phosphodiesterase activity
| Icariine concentration (M) | ????10 -6 | ????10 -5 | ????10 -4 | The P value |
| Matched group (n=8) | 1．23±0．82 | ?4．42±1．08 | ?23．12±1．36 | |
| Destroy endotheliocyte (n=5) | 0．82±0．58 | ?3．23±0．89 | ?15．68±1．15 | ＜0．001 |
| 1,2,3,-thrihydroxy-benzene pre-treatment (n=5) | 0．85±0．45 | ?3．45±0．73 | ?18．12±1．08 | ＜0．01 |
| Serge blue pre-treatment (n=5) | 0．52±0．68 | ?2．02±0．45 | ?13．45±1．12 | ＜0．001 |
| ?ODQ(n=5) | 0．42±0．48 | ?1．85±0．35 | ?10．45±1．08 | ＜0．001 |
| Atropine pre-treatment (n=5) | 1．21±0．58 | ?4．11±0．98 | ?21．78±1．06 | ＞0．05 |
| Indometacin pre-treatment (n=5) | 1．18±0．48 | ?4．09±1．08 | ?20．12±1．14 | ＞0．05 |
| ODQ concentration | ????10 -7?? | ????10 -6 | ????10 -5 | ????10 -4 | ?Pvalue |
| Icariine relexation (%) | 4．33±1．22 | ?14．55±2．45 | ?48．02±3．78 | ?87．76±4．78 | ＜0．001 |
1. separate phosphodiesterase in the human blood platelets
Acid diesters enzyme V-type not only is distributed in cavernous body of penis, also is distributed in platelet.Utilize platelet to isolate the Phosphodiesterase V type, analyzing medicine is a kind of normal experiment method to its active influence.Its method is with Freshman blood (360gm) centrifugalize (360g) 10 minutes, draws platelet and enriches blood plasma (PRP), again with 10 minutes precipitations of PRP centrifugalize (1400g) platelet.Get the sedimentary platelet of 1ml, with ice-cold buffer (Hepes 20nM, Sucrous 0.25M, EDTA 1mM, phenylmethyl sulfonylfluoride (PMSF) 1mM, pH 7.2) after mixing is floating, with ultrasonic wave concussion device (Cell distuptor, Burkard Scientific, Uxbridge, Middlesex UK) destroys cell membrane.The cytolysis thing heart far away separated (799g) after 10 minutes, separated (165.000g) 60 minutes at inferior continuous centrifugal, get upper strata liquid with Pharmacia FPLC (Pharmacia LTD., Milton Keynes, UK) compound enzyme is separated standby.
In order to utilize Mono-Q ion exchange chromatography purification phosphodiesterase, (5ml * 50mm), after buffer A 5ml and buffer B 10ml washed repeatedly, the heart far away separated the supernatant 10ml that (165.000g) obtains to utilize the Mono-Q post, put into the Mono-Q post, flow velocity is decided to be 1ml/min.Allow the active component of compound enzyme analyze various enzyme components by linear gradient salt (lineargradient salt) (0-0.5M NaCl) again with 1ml/ minute flow velocity.Measure its activity respectively at resulting various enzyme components, collect the organized enzyme composition, it is standby to put into liquid nitrogen bottle.
2. screen the inhibitory enzyme activity material
The activity analysis of phosphodiesterase is carried out at end reaction capacity 0.5ml, and prepares to operating on ice of reaction beginning from adding enzyme.Analyze with buffer (Tris 40mM pH8.0, MgCl
210mM, BSA 0.125mg/ml, 2 mercapto ethanol 3.75mM) use freshly prepared buffer, enzyme substrate [2H] cGMP (ca.28 ci/mmol at every turn; Ca.100,000cpm/100 μ L) be ready standby with analyzing in advance with buffer.The activity test method of PDE V-type is an isotope two-step analysis method of utilizing [3H] cGMP labelling.During mensuration [3H] cGMP 200 μ L are added in vitro, add tested material (icariine 10 again
-10M-10
-4M) or the commensurability DMSO of tester) the phosphodiesterase 10 0 μ L of 100 μ L and purification, add buffer again to 0.5ml,, after 20 minutes test tube is immersed in the boiled water with cessation reaction in the reaction of 30 ℃ of weighing apparatus relaxing the bowels with purgatives of warm nature.Reaction in vitro adds snake venom (Ophiophagus Hannah after ending; Sigma Chemical Co) 100 μ L (1mg/ml), 30 ℃ of weighing apparatus relaxing the bowels with purgatives of warm nature hatching 10 minutes changes into [3H] guanosine with [3H] 5-GMP.[3H] guanosine that is converted is in AG1-X2 resion (Bio-Rad) reactor, and the sample that utilizes NaOH (0.1N) to obtain behind ion exchange column type chromatography eluting is measured the activity that its radioactivity is analyzed Phosphodiesterase V,
3. experimental result
This experimental result icariine has concentration dependent inhibitory action (10 to the Phosphodiesterase V activity
-8M, 0.06%; 10
-7M, 32.7%; 10
-6M, 56.2%; 10
-5M, 83.7%; 10
-4M, 99.9%), EC50 is 0.43 μ M.See the following form.Table 5.Icariine is to the active inhibitory action of Phosphodiesterase V (%).
| Concentration | 10 -4M | ?10 -5M | ?10 -6M | ?10 -7M | ?10 -8M | ?10 -9M |
| Icariine | 99．7 | ?87．9 | ?63．2 | ????42 | ????2 | ????0 |
Prove by experiment, icariine has powerful relexation to cavernous body of penis comparison large artery trunks ring, and the mechanism of the relexation of the cavernous body of penis smooth muscle of icariine is, by increasing generation and the effect of bird phosphoric acid cyclase activating of NO, and the activity that suppresses phosphodiesterase stops the deactivation of cGMP, cGMP concentration is increased and loose cavernous body of penis brings out erection.Experiment 4.Clinical effectiveness
In order to understand the clinical effectiveness of icariine, 56 sexual dysfunctions be main state and the volunteer international functional evaluation questionnaire (International Index forSexual Function.IIEF-V) has carried out placebo for object utilizes, double double blinding prepares clinical experiment.Subjects's mean age is 39 ± 6.1 years old, is 5.4 ± 3.7 years between period of disease.Wherein suffer from diabetes 17 examples, hypertension 9 examples, heart disease 8 examples.
Experimental drug (containing icariine 50mg/ sheet) and placebo packing is identical, and transdermal person and pill taker all do not know to experimentize under the condition of Di.Selected volunteer not at random be divided into two groups, come into operation placebo or experimental drug (2 slices/time, 3 times/day), oral 1 month.The patient is before dispensing and take medicine and add sexual function after being over respectively and estimate questionnaire (totally 5, every 5 degree scorings), and relatively the sexual function before and after the medication changes and analyzes evaluate efficacy by Student t test.
Experimental result, experimenter's sexual function evaluation score is respectively before treatment, it is 1.82 ± 0.54 that the sense of confidence of keeping function of erecing and erecing is marked, the erection frequency scoring that penis can insert vagina is 1.89 ± 0.67, the frequency scoring that penis inserts vagina and keeps erection during sexual intercourse is 1.82 ± 0.65, to keep difficulty scores be 1.89 ± 0.61 for erection and erection during sexual intercourse, is 1.79 ± 0.62 to the satisfaction scoring of sexual life.Treatment back sexual function is respectively, to icariine group in the sense of confidence scoring of keeping function of erecing and erecing is 3.32 ± 0.39, placebo is 2.04 ± 0.63, the icariine group was 3.11 ± 0.32 during the erection frequency that penis can insert vagina was commented, placebo is 2.07 ± 0.88, penis inserts vagina and keeps that the icariine group is 3.18 ± 0.47 in the frequency scoring of erection during sexual intercourse, placebo is 2.17 ± 0.97, erection and erection keep that the icariine group is 3.25 ± 0.43 in the difficulty scores during sexual intercourse, placebo is 2.18 ± 0.92, to icariine group in the satisfaction scoring of sexual life is 3.36 ± 0.47, placebo is 2.14 ± 0.95, and the scoring comparison placebo of taking icariine sheet group significantly increases (p＜0.01).Overall clinical effectiveness icariine sheet group and placebo are respectively 75.4% and 35.4%.Except that having the slight gastrointestinal reaction, 4 patients do not find significant side effects.Suffer from diabetes, hypertension and cardiac are not having significant difference aspect clinical effectiveness and the side effect.The results are shown in following table.
Table 5.Icariine is to the IIEF grade form of treatment of sexual dysfunctions effect
Claims (5)
1. icariine is used for preventing or the purposes of therapeutic dysfunction and vasoconstriction diseases related medicine in preparation.
2. be used to prevent or the pharmaceutical composition of therapeutic dysfunction and vasoconstriction diseases related, it comprises as the icariine of active component and will use carrier and excipient.
3. according to the pharmaceutical composition of the purposes or the claim 2 of claim 1, wherein said medicine or pharmaceutical composition contain the icariine of 10-500 milligram.
4. be with tablet according to the purposes of claim 1-3 or the wherein said medicine of pharmaceutical composition or pharmaceutical composition, pill, capsule, suspension, solution, injection, cream, ointment, spray, the chewing agent, the patch form is used.
5. according to purposes or the pharmaceutical composition of claim 1-3, wherein said drug administration is by way of can be for oral, the Sublingual, and percutaneous, mucocutaneous through muscle or subcutaneous, urethra, vagina, or vein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR199922665 | 1999-06-17 | ||
| KR19990022665 | 1999-06-17 |
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|---|---|
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| CN1199647C CN1199647C (en) | 2005-05-04 |
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|---|---|---|---|
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|---|---|
| JP (1) | JP4864259B2 (en) |
| KR (1) | KR100394329B1 (en) |
| CN (1) | CN1199647C (en) |
| AU (1) | AU5386700A (en) |
| WO (1) | WO2000078323A1 (en) |
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| ITMI20020994A1 (en) * | 2002-05-10 | 2003-11-10 | Indena Spa | USEFUL FORMULATIONS IN THE TREATMENT OF MALE AND FEMALE IMPOTENCE |
| ITMI20031427A1 (en) * | 2003-07-11 | 2005-01-12 | Indena Spa | COMBINATIONS OF VASOACTIVE AGENTS, THEIR USE IN THE PHARMACEUTICAL AND COSMETIC FIELD AND THE FORMULATIONS THAT CONTAIN THEM |
| KR100821683B1 (en) * | 2006-11-01 | 2008-04-15 | 우석대학교 산학협력단 | A composition containing icariside ii for preventing and treating diseases associated with abnormal angiogenesis |
| WO2009066712A1 (en) * | 2007-11-21 | 2009-05-28 | Kracie Pharma, Ltd. | Aromatase inhibitor |
| US8530433B2 (en) | 2008-06-13 | 2013-09-10 | Bjo-Biomed Ltd | Use of icariside II in manufacture of products for preventing or treating male or female sexual dysfunction |
| KR101019340B1 (en) | 2008-07-07 | 2011-03-07 | 전북대학교산학협력단 | a confirmation method for effectiveness of Rubus coreanus concerning |
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| CN1199647C (en) * | 1999-06-17 | 2005-05-04 | 北京东方百奥医药开发有限公司 | Application of icariin in preventing and treating sexual disfunction and improving diseases associated with vasoconstriction |
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