CN108392487A - A kind of application of icariside II or its pharmaceutical acceptable carrier in erectile dysfunction - Google Patents
A kind of application of icariside II or its pharmaceutical acceptable carrier in erectile dysfunction Download PDFInfo
- Publication number
- CN108392487A CN108392487A CN201810157352.6A CN201810157352A CN108392487A CN 108392487 A CN108392487 A CN 108392487A CN 201810157352 A CN201810157352 A CN 201810157352A CN 108392487 A CN108392487 A CN 108392487A
- Authority
- CN
- China
- Prior art keywords
- icariside
- erectile dysfunction
- acceptable carrier
- pharmaceutical acceptable
- application
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P19/00—Preparation of compounds containing saccharide radicals
- C12P19/44—Preparation of O-glycosides, e.g. glucosides
- C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
Abstract
The present invention provides a kind of application of icariside II or its pharmaceutical acceptable carrier in erectile dysfunction, including icariside II or its pharmaceutical acceptable carrier, are especially but not limited to be applied to prevent and/or treat mammal erectile dysfunction.
Description
Technical field
The invention belongs to field of medicaments, are related to a kind of icariside II or its pharmaceutical acceptable carrier in erectile dysfunction
Application and its application, be especially but not limited to be applied to prevent and/or treatment mammal erectile dysfunction.
Background technology
Nineteen ninety-five, there are about 1.52 hundred million ED patients in the whole world, it is contemplated that the number will increase to 3.22 hundred million within 2025[1].According to statistics, I
The area such as state Beijing middle-aged male (40.2 ± 5.8 years old) ED illness rates are up to 40.2%[2].Currently, oral PDE5 inhibitor is (such as
Silaenafil, Tadalafei) be clinical treatment ED preferred therapy, but different pathogeny ED patient is to the therapeutic response difference of drug
It is larger.For example, (efficient after receiving testosterone replacement therapy with the ED patient of hypogonadism：85%) PDE5 suppressions are taken
Preparation curative effect is best, and (efficient with diabetes：44%) (efficient or after Prostate Cancer after Radical：43%) ED patient
Curative effect is poor[3].In recent years, some scholars think that ED vascular endothelial work(can be improved by continuously taking low dose of PDE5 inhibitor
It can and increase penile blood flow amount[4,5].But studies have found that its ED treated effect is only 24~33%[6-8].In addition, research
It was found that[9], it is not notable to the pathological change improvement of nerve ED animal models continuously to take low dose of silaenafil.
Bibliography：
1.Ayta I A,Mckinlay J B,and Krane R J.The likely worldwide increase
in erectile dysfunction between 1995and 2025and some possible policy
consequences.BJU Int,1999.84(1):50-6.
2. 2226, tri- cities the male erection function epidemiological survey China andrology magazines such as celebrating river, 2003,
17(3):191-193.
3.Mccullough A R,Barada J H,Fawzy A,Guay A T,and Hatzichristou
D.Achieving treatment optimization with sildenafil citrate(Viagra)in patients
with erectile dysfunction.Urology,2002.60(2Suppl 2):28-38.
4.Nakano Y,Miyake H,Chiba K,and Fujisawa M.Impact of penile
rehabilitation with low-dose vardenafil on recovery of erectile function in
Japanese men following nerve-sparing radical prostatectomy.Asian J Androl,
2014.16(6):892-6.
5.Vardi Y,Appel B,Ofer Y,Greunwald I,Dayan L,and Jacob G.Effect of
chronic sildenafil treatment on penile endothelial function:a randomized,
double-blind,placebo controlled study.J Urol,2009.182(6):2850-5.
6.Brock G,Ni X,Oelke M,Mulhall J,Rosenberg M,Seftel A,D'souza D,and
Barry J.Efficacy of Continuous Dosing of Tadalafil Once Daily vs Tadalafil On
Demand in Clinical Subgroups of Men With Erectile Dysfunction:A Descriptive
Comparison Using the Integrated Tadalafil Databases.J Sex Med,2016.13(5):860-
75.
7.Mccullough A R,Levine L A,and Padma-Nathan H.Return of nocturnal
erections and erectile function after bilateral nerve-sparing radical
prostatectomy in men treated nightly with sildenafil citrate:subanalysis of a
longitudinal randomized double-blind placebo-controlled trial.J Sex Med,
2008.5(2):476-84.
8.Padma-Nathan H,Mccullough A R,Levine L A,Lipshultz L I,Siegel R,
Montorsi F,Giuliano F,and Brock G.Randomized,double-blind,placebo-controlled
study of postoperative nightly sildenafil citrate for the prevention of
erectile dysfunction after bilateral nerve-sparing radical prostatectomy.Int
J Impot Res,2008.20(5):479-86.
Invention content
Goal of the invention：The purpose of the present invention is to provide a kind of icariside IIs or its pharmaceutical acceptable carrier in erection function
Application in obstacle.
The technical solution adopted in the present invention：One aspect of the invention is related to icariside II or its pharmaceutical acceptable carrier is used
In prevention and/or treatment mammal erectile dysfunction.It erects especially for the insensitive mammal of PDE5 inhibitor
The prevention and/or treatment of dysfunction.
Another aspect of the invention is related to icariside II and is obtained by biological concentration, and the biological concentration includes following
Step：First in trichoderma medium culture trichoderma, cultured trichoderma is then inoculated into the Liquid Culture containing icariin
Base fermented and cultured, finally obtains the trichoderma thalline for being enriched with icariside II, and it is pure to obtain icariside II after extraction purification
Product.
Preferably, trichoderma is Trichoderma viride to one kind as the present invention.Trichoderma viride convenient sources used in this method are easy
Expand it is numerous, without extracting hydrolase；Zymolysis Equipment is common, and subsequent purification processes are simple, and low boiling point solvent extraction makes concentration be easy,
It only extracts immersion, filtering, adsorption chromatography, recrystallize up to high purity product, be suitable for industrialized production, production cost is low.It can
Icariin is transported into the cell, and hydrolysis is completed by intracellular hydrolase, Sync enrichment hydrolysate makes industrialization system
99% or more the icariside II content that standby icariside II is possibly realized, and prepares, 91% or more yield.This method
It is easy to operate, it is easy to implement, low cost, in high yield, it is pollution-free, be suitable for industrialization large-scale production, have high application before
Scape.
Further, the application of above-mentioned icariside II or its pharmaceutical acceptable carrier in erectile dysfunction, makes first
Then cultured Trichoderma viride is inoculated into the training of the liquid containing icariin by standby PDA solid medium culture Trichoderma virides
Support base fermented and cultured.Icariin can be transported into the cell by Trichoderma viride mould, and complete water by intracellular hydrolase
Solution, Sync enrichment hydrolysate make it possible preparation of industrialization icariside II.
Specifically include following steps：A, Trichoderma viride is in small test tube medium slant culture；B, by cultured green wood
It is mould to be inoculated into fermented and cultured in the fluid nutrient medium containing Herba Epimedii；C, when icariin converts hydrolysis completely, by zymotic fluid
Filtering, obtains " filter residue " containing Trichoderma viride and icariside I I (and a small amount of icariin)；D, " filter is impregnated with methanol
Slag " filters again, obtains the filtrate containing icariside I I (and a small amount of icariin), repeats this process, until all
Icariside I I and a small amount of icariin be dissolved in methanol solution；E, efficient liquid phase detects, if icariside I I's turns
Rate is more than 50%, is less than 85%, then through silica gel absorption column chromatography, is purified；F, conversion ratio is more than in 85% and step e
The method for crossing the secondary glycosides II recrystallizations of silicagel column is further purified, and obtains icariside I I sterlings.
Further, the step of preparing medium culture Trichoderma viride is as follows：Potato and glucose is first used to prepare PDA solids
Culture medium cultivates Trichoderma viride 3-5 days in PDA solid mediums, and condition of culture is 26-29 DEG C of temperature, obtained green
Trichoderma is high activity thalline.
Further, the PDA solid mediums culture Trichoderma viride is specifically utilized in the training of small test tube medium slant
It supports.The preparation method of the PDA solid mediums is as follows：Potato 200g, distilled water 1L are weighed, by potato plus distillation boiling to soft
Rotten, glucose 20g, agar 15-20g are heated and added to filtrate by filtering, is dispensed into small test tube after its dissolving, at 121 DEG C
At a temperature of sterilize 15-20 minutes, shaken up after taking-up, 45° angle slant setting, it is cooling after PDA solid mediums.
Further, the preparation method of the fluid nutrient medium containing icariin is as follows：Addition 0.5-10g is smashed
Potato, 0.8-16g icariin add distilled water to 0.05-1L in the triangular pyramidal bottle of 0.1L-3L, and bottleneck is pricked with sealed membrane
It tightly fastens, is put into 121 DEG C of sterilization tank, sterilize 15-20 minutes, wait for that it is cooled to 20-30 DEG C, obtain containing icariin
Fluid nutrient medium.
Preferably, the preparation of the fluid nutrient medium described above containing icariin, potato are fresh potato, blend and go out
Bacterium, ratio are the fresh potatoes of 10g, the distilled water of 1L, the Herba Epimedii of 16g.
Further, the fermentating culturing process is：Cultured Trichoderma viride is inoculated on superclean bench and is contained
Have in the fluid nutrient medium of icariin, and it is 28 DEG C to be put into temperature, rotating speed is the shaking table culture after 9 days of 165r/min, will be sent out
Zymotic fluid filters, and the filter residue being obtained by filtration is impregnated with methanol, is filtered again, repeats this process 2-5 times, until Trichoderma viride is steeped
Whiten, icariside I I is all dissolved in methanol；Then methanol soak is concentrated, obtains the powder containing icariside I I
End, the purified processing of powder, obtains the sterling of icariside I I.Icariside I I and icariin solubility in methyl alcohol
Preferably, Trichoderma viride not solution and methanol can come Trichoderma viride is separated.
Further, the inoculation is that the icariin of 16g needs the trichoderma culture 9 of 4 small test tubes (diameter 1.2cm)
It, in this conversion ratio highest.
Further, the method by the powder purification process containing icariside I I is as follows：It will contain first
The powder of icariside I I crosses the conversion ratio of liquid phase detection icariside I I, and the conversion ratio of icariside I I is more than
50%, it is less than 85% mixed-powder, sample, 6-8 times of 200-300 mesh industrial layers is mixed through 1.5-2 times of macroreticular resin DM301 dry method
Silicone filler upper prop is analysed, dichloromethane is used：Methanol volume ratio is 15：The eluent of 1 mixtures of eluents and pure methanol, stream
Go out the monitoring of liquid thin-layer chromatography, icariside I I single component solution will be contained and merged, 60 DEG C are concentrated under reduced pressure at powder, with conversion
Powder one of the rate more than 85% is reinstated the method being heated to reflux and is dissolved with methanol at a temperature of 65-70 DEG C, removes and contains after dissolving
There are the methanol solution of icariside I I, room temperature to wait for that it is precipitated crystal, leaching crystal, 45 DEG C or less are dried under vacuum to perseverance
Weight, obtains the icariside I I sterlings of 99% or more content.When conversion ratio is between 50%-85%, icariside I I
Recrystallization purifying again after silica gel adsorption column chromatographic purifying, when conversion ratio then directly recrystallize more than 85% icariside I I it is pure
Change, the quality of the icariside I I of preparation can be effectively ensured.
Mammal of the present invention is boar.In the present invention, the mammal be for example people,
Dog, monkey, ox, horse, cat, bear, tiger, sheep, mouse etc..
Wherein, the icariside II is with unit dose, the amount of such as 0.1-100 mg kg of body weight/day makes
With.
According to the purposes of any of the above item of the present invention, wherein the product is used by enteron aisle or non-bowel form.
The invention further relates to product, containing a effective amount of icariside II and pharmaceutically acceptable carrier or
Excipient；Obtain the drug packet or other forms in independently packing container.
The product of the I containing icariside I of the present invention can give the host such as people of needs by enteron aisle or parenteral route.
The product of the present invention given by enteron aisle can be given by the form of oral preparation, oral preparation for example there are：Tablet, capsule,
Granula, suspending agent, sustained release agent etc..The product of the present invention given by non-bowel can be injection, local administration preparation such as skin
The forms such as skin patch or spray.
Usual product of the present invention contains the active ingredient (icariside II) of 0.1-90 weight %.Icariside II
It can be prepared according to methods known in the art or is prepared by biological concentration method of the present invention.When for this purpose, if needed
It wants, active ingredient can be combined with one or more solids or liquid pharmaceutical excipients and/or adjuvant, be made and can be used as people's
Administration form or dosage form appropriate.
The pharmaceutical composition of the present invention can be administered in a unit, and administration route can be enteron aisle or non-bowel, such as mouth
Clothes, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc..Form of administration such as tablet, capsule, dripping pill, aerosol
Agent, pill, pulvis, solution, suspension, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, freeze drying powder injection
Deng.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery systems.In order to which unit dosage forms for administration is made
Various carriers well known in the art can be widely used in tablet.Example about carrier is, such as diluent and absorbent, such as
Starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, white bole, microcrystalline cellulose
Element, alumina silicate etc.；Wetting agent and adhesive, such as water, glycerine, polyethylene glycol, ethyl alcohol, propyl alcohol, starch slurry, dextrin, syrup, bee
Honey, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, lac, methylcellulose, potassium phosphate, polyethylene
Pyrrolidones etc.；Disintegrant, such as dry starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, carbonic acid
Calcium, polyoxyethylene, sorbitan fatty acid ester, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.；Disintegration inhibits
Agent, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat etc.；Sorbefacient, such as quaternary ammonium salt, dodecyl sulphate
Sodium etc.；Lubricant, such as talcum powder, silica, cornstarch, stearate, boric acid, atoleine, polyethylene glycol etc..Also
Tablet can be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double-layer tablets and multilayer
Piece.In order to which pill is made in administration unit, various carriers well known in the art can be widely used.Example about carrier is,
Such as diluent and absorbent, as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone,
Gelucire, kaolin, talcum powder etc.；Adhesive such as Arabic gum, bassora gum, gelatin, ethyl alcohol, honey, liquid sugar, rice paste or face
Paste etc.；Disintegrant, such as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, ethyl cellulose
Deng.In order to which suppository is made in administration unit, various carriers well known in the art can be widely used.Example about carrier is,
Such as ester, gelatin, the semi-synthetic glyceride etc. of polyethylene glycol, lecithin, cocoa butter, higher alcohol, higher alcohol.In order to which prescription will be given
Capsule is made in member, active ingredient is mixed with above-mentioned various carriers, and thus obtained mixture is placed in hard obviously glue
In capsule or soft capsule.Also microcapsules can be made in active ingredient, be suspended in aqueous medium and forms suspension, can also be packed into ebonite
In capsule or it is made injection application.In order to which injection preparation is made in administration unit, as solution, emulsion, freeze drying powder injection and
Suspension can use all diluents commonly used in the art, for example, water, ethyl alcohol, polyethylene glycol, 1,3-PD, ethyoxyl
The isooctadecanol of change, polyoxygenated isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc..In addition, in order to prepare isotonic injection
Liquid can add suitable sodium chloride, glucose or glycerine into injection preparation, further, it is also possible to add conventional hydrotropy
Agent, buffer, pH adjusting agent etc..
In addition, if desired, can also be added into pharmaceutical preparation colorant, preservative, fragrance, corrigent, sweetener or
Other materials.
The dosage of the drug of the present invention depends on many factors, such as to be prevented or be treated the property of disease and tight
Gender, age, weight and the individual reaction of weight degree, patient or animal, administration route and administration number of times etc..Above-mentioned dosage can be with
Single dose form is divided into several, such as two, three or four dosage forms for administration.Dosage level must be according to specific administration way
Diameter, the patient's condition of the severity of the treated patient's condition and patient to be treated and medical history etc. are selected.But this field is done
Method is, dosage gradually increases dosage, until obtaining since less than obtaining required therapeutic effect and desired level
The effect needed.
Term " effective quantity " refers to that can realize to treat, prevent, mitigate and/or alleviate disease of the present invention in subject
Or the dosage of illness.
It is to be understood that total consumption per day of the drug of the present invention must be made by attending physician in reliable medical judgment scope
Go out to determine.For any specific patient, specific treatment effective dose level must be depending on many factors, the factor packet
Include the severity of treated obstacle and the obstacle；Used concrete composition；The age of patient, weight, general health
Situation, gender and diet；Administration time, administration route and excretion rate；Duration for the treatment of；Be applied in combination or used at the same time
Drug；And similar factor well known to medical field.For example, the way of this field is, the dosage of administration is from less than needed for obtaining
Therapeutic effect and desired level start, and dosage are gradually increased, until obtaining required effect.It is, in general, that the medicine of the present invention
Compositions are calculated with active ingredient (icariside II) can be between 0.001- for the dosage of mammal especially people
1000mg/kg body weight/days, such as between 0.01-100mg/kg body weight/days, such as between 0.01-10mg/kg body weight/days.
The beneficial effects of the invention are as follows：Icariside II of the present invention or its pharmaceutical acceptable carrier hinder in erection function
Application in hindering, significant effect.On the one hand, due to after neurotrosis nNOS+ nerve fibres it is impaired, synthesize cCMP obstacles, take
Further cGMP cannot be made to accumulate after the PDE5 inhibitor such as silaenafil, therefore the general PDE5 inhibitor curative effect of such patient is not
It is good.Icariside II makes cGMP restore synthesis, makes the PDE5 inhibitor such as silaenafil by the nerve fibre of reparation nNOS+
There is the basis to play a role.Caused by icariside II can be damaged with nNOS+ nerve fibres after effective compensation neurotrosis
CCMP obstacles are synthesized, therefore overcome further cannot be such that cGMP accumulates with after the PDE5 inhibitor such as silaenafil, solve such trouble
The problem of person's general PDE5 inhibitor unsatisfactory curative effect.
On the other hand, after for denervation, smooth muscle disuse atrophy, or due to anorthosis anoxic etc.
The problem of causing smooth muscle to reduce, making telotism most important structural damage.On the one hand icariside II promotes EdU+'s
Penis endogenous retinal stem cells repair the effector cell of telotism to mixed with smooth muscle.Separately therefore, after the two shares, in penis
On the basis of the pathological change of erection linked groups is repaired, to make stomodaeum take the insensitive patient of PDE5 inhibitor again to the medicine
Object works.
Therefore, the application of icariside II of the present invention or its pharmaceutical acceptable carrier in erectile dysfunction, can
Penile tissue pathological change is repaired, for preventing and treating erectile dysfunction, PDE5 inhibitor is unwise especially for curing
Sense type erectile dysfunction has important clinical significance.
Description of the drawings
Fig. 1 is the influence of the ICAII and silaenafil of 2 various dose of the embodiment of the present invention to rat penile erectile function
Detection figure (* p<0.05vsBCNI-3wgroup,#p<0.05vsICAII-1.25group)；
Fig. 2 is 4 penile erectile function of embodiment of the present invention assessment figure (* p<0.05vsVehiclegroup,#p<
0.05vsSilgroup,@p<0.05vsICAⅡgro up&p<0.05vsICAⅡ+Silgroup)；
Fig. 3 is statistical chart (the * p that the embodiment of the present invention 5 organizes interior cGMP contents<0.05vsVehiclegroup,#p<
0.05vsSilgroup,&p<0.05vsICAⅡgrou p)；
Fig. 4 is detection figure (the * p of 6Masson trichrome stain smooth muscle contents of the embodiment of the present invention<
0.05vsVehiclegroup,#p<0.05vsSilgroup)；
Fig. 5 is detection figure (the * p of 7 α-SMA immunofluorescence dyeing smooth muscle contents of the embodiment of the present invention<
0.05vsVehiclegroup,#p<0.05vsSilgroup)；
Fig. 6 is detection figure (the * p of 8nNOS+ nerve fibre quantity of the embodiment of the present invention<0.05vsVehiclegroup,#p<
0.05vsSilgroup)；
Fig. 7 is the detection figure of 9EdU+ cell quantities of the embodiment of the present invention；Right side is the enlarged drawing of left side box；
Fig. 8 is detection figure (the * p of 9 SMC differentiation of the embodiment of the present invention<0.05vsShamgroup,#p<
0.05vsVehiclegroup,&p<0.05vsSilgrou p)
Fig. 9 is efficient liquid phase testing result in 10 step e of embodiment of the present invention；
Figure 10 is efficient liquid phase testing result in 10 step f of embodiment of the present invention；
Figure 11 is efficient liquid phase testing result in 11 step e of embodiment of the present invention；
Figure 12 is efficient liquid phase testing result in 11 step f of embodiment of the present invention.
Specific implementation mode
Below will be by several specific embodiments, the present invention is furture elucidated, these embodiments simply to illustrate that problem,
It is not a kind of limitation.
Embodiment 1：
(1) experimental method：
(1) experimental animal and grouping
Newborn 1 day male SD rat 96.
After 12 weeks, it is sham-operation group to randomly select 12 (Sham opens abdomen but do not damage cavernosal nerve, n=12).Remaining 84
SD rats damage bilateral cavernous nerve and establish nerve ED models (see 2)；It therefrom randomly selects 12 and gavages Xi Dina
It is non-, 1.25mg/kg/d；It randomly selects 12 and gavages silaenafil, 2.5mg/kg/d；It therefrom randomly selects 12 and gavages Xi Dina
It is non-, 5mg/kg/d；It randomly selects 12 and gavages icariside II, 2.5mg/kg/d；It randomly selects 12 and gavages Herba Epimedii
Glycosides II, 2.5mg/kg/d；It randomly selects 12 and gavages icariside II, 5mg/kg/d；Remaining and 12 is only used as model group (BCNI-
3w)。
(2) nerve ED Establishment of Rat Model：
SD rats are born after 12w, damage its corpora cavernosa penis god and establish ED animal models, process is as follows：
1) 5% yellow Jackets of SD rats by intraperitoneal injection are anaesthetized, dosage 30mg/kg；
2) after SD rat anesthesias, it is fixed on operating table, belly shaving, disinfection；
3) lower abdomen median incision finds pelvic ganglia on the outside of the bilateral prostate back of the body under surgical operation microscope, distinguishes sea
The branches such as continuous somatic nerves, hypogastric nerve, nervi erigentes；Cavernosal nerve is from after being sent out pelvic ganglia, in Prostatic Surface to urethra
Direction extends, and enters crus penis in the rear of pubic symphysis；
4) it is being sent out at 5mm from pelvic ganglia away from cavernosal nerve, clamp cavernosal nerve, each 2min in left and right；
5) after damaging cavernosal nerve, abdominal cavity, abdominal incision position iodophor disinfection are successively closed.Control group not clamp sponge
Somatic nerves, other operate same experimental group.
(3) intracavernous pressure and mean arterial pressure are measured
1) after 5% yellow Jackets of SD rats (30mg/kg) intraperitoneal injection of anesthesia, dorsal position cuts off abdomen hair, lower abdomen
Median incision, exposure bladder and prostate find pelvic ganglia and cavernosal nerve (being located at outside after prostate)；
2) 2 24G puncture needles are taken, interior to be full of 200IU/ml heparin, the other end leads physiology more by PE-50 pipes with Biopac
Recorder (MP150) connects；
3) skin of penis is cut, a puncture needle is inserted into corpora cavernosa penis sinus by exposed Rats corpora cavernosa penis；A free left side
Side arteria carotis communis is inserted into another puncture needle；
4) by Biopac polygraph stimulators stimulate cavernous nerves of penis, 50 seconds, parameter 1.5mA,
20Hz.Synchronous recording intracavernosal pressure (ICP) and mean arterial pressure (MAP) are assessed animal model by ICP/MAP ratios and are controlled
Treat front and back penile erectile function variation.
(4) drug infusion：
Low dose of ICAII groups：Success built ED models after 7 days, gives ICAII (1.25mg/kg) gavage and treats, and continuous 4
Week；
Middle dosage ICAII groups：Success built ED models after 7 days, gives ICAII (2.5mg/kg) gavage and treats, and continuous 4
Week；
High dose ICAII groups：Success built ED models after 7 days, gives ICAII (5mg/kg) gavage and treats, continuous 4 weeks
Low dose of silaenafil group (Sildenafil)：Success built ED models after 7 days, gave Sildenafil
(1.25mg/kg) gavage is treated, continuous 4 weeks；Note：After drug therapy, if after 2 weeks phases of elution, carrying out subsequent experimental.
Middle dosage silaenafil group (Sildenafil)：Success built ED models after 7 days, gave Sildenafil
(2.5mg/kg) gavage is treated, continuous 4 weeks；Note：After drug therapy, if after 2 weeks phases of elution, carrying out subsequent experimental.
High dose silaenafil group (Sildenafil)：Success built ED models after 7 days, gave Sildenafil (5mg/
Kg) gavage is treated, continuous 4 weeks；Note：After drug therapy, if after 2 weeks phases of elution, carrying out subsequent experimental.
Embodiment 2：
Penile erectile function is assessed
As shown in Figure 1, gavaging silaenafil daily, unobvious are improved to the penile erectile function of nerve ED rat models
(VSBCNI-3w groups)；ICA II 1.25mg/kg, 2.5mg/kg and 5mg/kg are gavaged, nerve ED rat models can be significantly improved
Penile erectile function (VSBCNI-3w groups)；And II 2.5mg/kg and 5mg/kg groups of ICA and II 1.25mg/kg group phases of ICA
Than having significant difference；And II 2.5mg/kg with 5mg/kg groups of ICA are compared, II 5mg/kg groups of ICA are dynamic to the telotism of rat
Unobvious can be improved.
Embodiment 3：
Experimental method：
(1) label retaining cell technology label whole body endogenous retinal stem cells/precursor is utilized
50mgEdU is dissolved into 2.5mlDMSO, deionized water 2.5ml after addition sterilizing, mixing, 37 degree of water-bath heat preservations.Breast
After mouse life in 12h, intraperitoneal injection EdU solution 50 μ l, dosage 50mg/kg.
(2) experimental animal and grouping
Newborn 1 day male SD rat 48, intraperitoneal injection EdU mark endogenous retinal stem cells/precursor.
After 12 weeks, it is sham-operation group to randomly select 12 (Sham opens abdomen but do not damage cavernosal nerve, n=12).Remaining 48
SD rats damage bilateral cavernous nerve and establish nerve ED models (see 4)；It therefrom randomly selects 12 and gavages Xi Dina
It is non-, 2.5mg/kg/d；Remaining 12 gavage icariside II, 2.5mg/kg/d).
It continuously gavages 4 weeks, the detection of row erection function and acquisition sample prodrug elute 7 days phases.
(3) nerve ED Establishment of Rat Model：With embodiment 1
(4) intracavernous pressure and mean arterial pressure are measured：With embodiment 1
(5) cavernous nerves of penis damage and each group treatment are to penile tissue endogenous stem cell/precursor cell differentiation
Influence
Obtain above-mentioned each group penile tissue sample, frozen section after OCT embeddings.By immunofluorescence dyeing, penis is detected
The coexpression situation of cavernous body internal labeling cell (EdU+) and smooth muscle cell marker α-SMA, overlapping then prompt has differentiation existing
As.
(6) statistical analysis
All experiment packets are all made of randomly assigne；After collecting data, Statistics Application software SPSS unites to data
Count credit analysis；With p<0.05 is considered as with notable significant difference, with p<0.01 is considered as with extremely notable significant difference.
Embodiment 4：
1. penile erectile function is assessed
As shown in table 1 and Fig. 2, silaenafil is gavaged daily, and the penile erectile function of nerve ED rat models is improved
Unobvious (VS Vehicle groups, ICP/MAP=0.24 ± 0.08, p=0.867)；II 2.5mg/kg of ICA are gavaged, can significantly be changed
The penile erectile function (VS Vehicle groups, ICP/MAP=0.50 ± 0.05, p=0.047) of kind nerve ED rat models,
But still there is significant difference with the telotism kinetic energy of normal rat.
Table 1：Penile erectile function is assessed
Embodiment 5：
The influence of cGMP contents in 2 pairs of tissues
As shown in Table 2 and Fig. 3, after neurotrosis, cGMP contents significantly reduce in fresh penis sponge body, after taking merely
CGMP can not be made further to accumulate.CGMP contents increase after taking ICA II, keep cGMP in penis sponge body further notable
Increase, prompt can be combined PDE5 inhibitor, the defect for overcoming PDE5 inhibitor effects bad.
Table 2：The influence of cGMP contents in tissue
Since PDE5 inhibitor mainly plays therapeutic effect by reducing by cyclic GMP (cGMP) hydrolyzes.SoProperty life Before work " disposable " take PDE5 inhibitor can only respite ED symptoms, can not thoroughly remove the cause of disease and improve histopathology Variation.Moreover, for ED, cavernosal nerve tip caused by blood vessel/neuropathy (after diabetes and Prostate Cancer after Radical)
And/or endothelial cell nitric oxide (NO) release is reduced, and causes cyclic GMP in smooth muscle cell (cGMP) synthesis insufficient, PDE5
Inhibitor due to lack play therapeutic effect molecular basis and unsatisfactory curative effect.
Icariside II makes cGMP restore synthesis by the nerve fibre of reparation nNOS+, and the PDE5 such as silaenafil is made to press down
Preparation has the basis to play a role.Icariside II can be made so that nNOS+ nerve fibres after effective compensation neurotrosis are impaired
At synthesis cCMP obstacles, therefore overcome further cannot be such that cGMP accumulates with after the PDE5 inhibitor such as silaenafil, solve this
The problem of class patient general PDE5 inhibitor unsatisfactory curative effect.
Embodiment 6：
3.2.1 the influence to smooth muscle content (Masson trichrome stains)
As shown in table 3 and fig. 4, after neurotrosis, fibrosis aggravates in cavernous body, and oral silaenafil cannot be notable
Improve cavernous body fibrosis；Cavernous body fibrosis significantly improves after taking ICA II.
Table 3：Influence (Masson trichrome stains) to smooth muscle content
Embodiment 7：
3.2.2 the influence to smooth muscle content (α-SMA immunofluorescence dyeings)
As shown in table 4 and fig. 5, after neurotrosis, smooth muscle content substantially reduces in penis sponge body, takes orally silaenafil
Smooth muscle content in cavernous body cannot be significantly improved；Take after ICA II that smooth muscle content increased in cavernous body.
Table 4：Influence (α-SMA immunofluorescence dyeings) to smooth muscle content
Embodiment 8：
Influence to nNOS+ nerve fibre quantity
As shown in table 5 and fig. 6, after neurotrosis, nNOS+ nerve fibres quantity substantially reduces in penis sponge body, takes orally
Silaenafil cannot significantly improve nNOS+ nerve fibres quantity in penis sponge body；Take after ICA II nNOS in penis sponge body
+ nerve fibre quantity increased, prompt penis sponge body in the increase of nNOS+ nerve fibre quantity may mainly with gavage ICA
II is related.
Table 5：Influence to nNOS+ nerve fibre quantity
Embodiment 9：
Influence to EdU+ cell quantities
As shown in table 6 and Fig. 7-8, in addition to sham-operation group, excess-three group is all made of Cavernous Nerve Injury ED animal models,
Immunofluorescence dyeing finds that EdU+ cell quantities are dramatically increased compared with sham-operation group in these groups, but no difference of science of statistics between three groups.
The cell quantity for further counting EdU+ SMA+ simultaneously, find take EdU+ in II group of ICA simultaneously SMA+ cell quantity compared with
Other groups dramatically increase, but cell quantity no difference of science of statistics between two groups.The Notes of Key Data, EdU+ cells can be after taking ICA II
To SMC differentiation.
Embodiment 10：
From 8g icariin bioconversion and it is enriched with the method for obtaining icariside I I, it includes the following steps：
A, the Trichoderma viride of 4 DEG C of freezen protectives is taken to expand in potato culture medium numerous 4 days, it is 28 DEG C to expand numerous cultivation temperature, is waited for
Test tube slant covers with thalline, is put into 4 DEG C of refrigerator freezings and preserves its high activity；The potato culture medium is fresh potato, anhydrous Portugal
Grape sugar, agar add distilled water to configure, i.e. the fresh potatoes of 200g first add distillation boiling to soft rotten, filtering with iron pan, again by filtrate
Secondary heating simultaneously adds 20g DEXTROSE ANHYDROUSs, and 18g agar is dispensed into after its dissolving in the small test tube of a diameter of 1.2cm, culture medium
Height be no more than test tube total height 1/3, be stoppered with test tube plug, every 7 test tubes be a bundle, wrapped with brown paper, at 121 DEG C
At a temperature of sterilize 20 minutes, shake up after taking-up, 45° angle slant setting, stored for future use after cooling；
B, 0.5g potatoes (smashing) are added into the triangular pyramidal bottle of 100mL, 0.8g icariin adds distilled water to arrive
50mL, bottleneck are tightened with sealed membrane and are fastened, totally 10 bottle, are put into 121 DEG C of sterilization tank, are sterilized 20 minutes, are waited for that it is cooled to
25 DEG C or so, the Trichoderma viride of cultured 1 test tube in step a is inoculated into the liquid of triangular pyramidal bottle on superclean bench
In body culture medium, and it is 28 DEG C to be put into temperature, the shaking table culture that rotating speed is 165r/min 9 days；
C, after cultivating 9 days, Trichoderma viride, icariside I I and icariin not soluble in water will be contained with Suction filtration device
(a small amount of) filters out；
D, the icariside I I and icariin that are filtered out in step c are dissolved with pure methanol, until Trichoderma viride
That is steeped whitens, and icariside I I and icariin are all dissolved in methanol；
It is impregnated 3 times with methanol, is that the amount of 1000ml, 500ml, 500ml filter out Trichoderma viride respectively.
E, the methanol soak in step d is concentrated, obtains the mix powder for mainly containing icariside I I, weighed
Obtain 6.2430g；Liquid phase is crossed, conversion ratio is surveyed, the result measured is calculated as 91.56% (Fig. 9)；
F, the powder in step e is dissolved at a temperature of 65-70 DEG C with minimum methanol with the method being heated to reflux, it is molten
The methanol solution containing icariside I I is removed after solution, room temperature waits for that it is precipitated crystal, leaching crystal, continues room temperature and puts
It sets, waits for that it is precipitated crystal for the second time, leaching crystal and the crystal for merging first time leaching, 45 DEG C or less are dried under vacuum to constant weight,
Obtain the icariside I I sterling 5.5371g of content 99%, yield 91.07% (Figure 10).
Embodiment 11：
From 192g icariin bioconversion and it is enriched with the method for obtaining icariside I I, it includes the following steps：
A, the Trichoderma viride of 4 DEG C of freezen protectives is taken to expand in potato culture medium numerous 4 days, it is 28 DEG C to expand numerous cultivation temperature, is waited for
Test tube slant covers with thalline, is put into 4 DEG C of refrigerator freezings and preserves its high activity；The potato culture medium is fresh potato, anhydrous Portugal
Grape sugar, agar add distilled water to configure, i.e. the fresh potatoes of 200g first add distillation boiling to soft rotten, filtering with iron pan, again by filtrate
Secondary heating simultaneously adds 20g DEXTROSE ANHYDROUSs, and 18g agar is dispensed into after its dissolving in the small test tube of a diameter of 1.2cm, culture medium
Height be no more than test tube total height 1/3, be stoppered with test tube plug, every 7 test tubes be a bundle, wrapped with brown paper, at 121 DEG C
At a temperature of sterilize 20 minutes, shake up after taking-up, 45° angle slant setting, stored for future use after cooling；
B, 10g potatoes (smashing) are added into the triangular pyramidal bottle of 3L, 16g icariin adds distilled water to 1L, bottleneck use
Sealed membrane, which tightens, to be fastened, and totally 12 bottles, is put into 121 DEG C of sterilization tank, is sterilized 20 minutes, is waited for that it is cooled to 25 DEG C or so, will walk
The Trichoderma viride of cultured 6 test tubes is inoculated on superclean bench in the fluid nutrient medium of triangular pyramidal bottle in rapid a, and
It is 28 DEG C to be put into temperature, the shaking table culture that rotating speed is 165r/min 9 days；
C, after cultivating 9 days, Trichoderma viride, icariside I I and icariin not soluble in water will be contained with Suction filtration device
(a small amount of) filters out；
D, the icariside I I and icariin that are filtered out in step c are dissolved with pure methanol, until Trichoderma viride
That is steeped whitens, and icariside I I and icariin are all dissolved in methanol；
It is impregnated 3 times with methanol, is that the amount of 36L, 18L, 18L filter out Trichoderma viride respectively.
E, the methanol soak in step d is concentrated, obtains the mix powder for mainly containing icariside I I, weighed
Obtain 143.5265g；Liquid phase is crossed, conversion ratio is surveyed, the result measured is calculated as 93.12% (Figure 11)；
F, the powder in step e is dissolved at a temperature of 65-70 DEG C with minimum methanol with the method being heated to reflux, it is molten
The methanol solution containing icariside I I is removed after solution, room temperature waits for that it is precipitated crystal, leaching crystal, continues room temperature and puts
It sets, waits for that it is precipitated crystal for the second time, leaching crystal and the crystal for merging first time leaching, 45 DEG C or less are dried under vacuum to constant weight,
Obtain icariside I I sterling 133.4286g, product content 99.12%, yield 91.44% (Figure 12).
The application of icariside II shown in the present invention or its pharmaceutical acceptable carrier in erectile dysfunction, the mechanism of action
May be：On the one hand, nNOS+ nerve fibres are impaired after neurotrosis, synthesize cCMP obstacles, therefore taking cannot after silaenafil
Further cGMP is made to accumulate, therefore the general PDE5 inhibitor unsatisfactory curative effect of such patient.On the other hand, it after denervation, puts down
Sliding flesh disuse atrophy, or cause smooth muscle to reduce due to anorthosis anoxic etc., make the most important knot of telotism
Structure is impaired.On the one hand icariside II promotes the penis endogenous retinal stem cells of EdU+ to mixed with smooth muscle, repair telotism
Effector cell.On the other hand, the nerve fibre for making reparation nNOS+ makes cGMP restore synthesis, and the PDE5 such as silaenafil is made to inhibit
Agent has the basis to play a role.Therefore, after the two shares, on the basis of the pathological change of telotism linked groups is repaired,
To make stomodaeum take the insensitive patient of PDE5 inhibitor again to the drug effect.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, without departing from the principle of the present invention, several improvement can also be made, these improvement also should be regarded as the present invention's
Protection domain.
Claims (10)
1. a kind of application of icariside II or its pharmaceutical acceptable carrier in erectile dysfunction, it is characterised in that：Herba Epimedii
Secondary glycosides II or its pharmaceutical acceptable carrier are for preventing and/or treating mammal erectile dysfunction.
2. the application of icariside II according to claim 1 or its pharmaceutical acceptable carrier in erectile dysfunction,
It is characterized in that：The icariside II is obtained by biological concentration, and the biological concentration includes the following steps：First in trichoderma
Then cultured trichoderma is inoculated into the solution culture fermentation culture containing icariin, finally by medium culture trichoderma
The trichoderma thalline for being enriched with icariside II is obtained, icariside II sterling is obtained after extraction purification.
3. the application of icariside II according to claim 2 or its pharmaceutical acceptable carrier in erectile dysfunction,
It is characterized in that：The trichoderma is Trichoderma viride.
4. the application of icariside II according to claim 3 or its pharmaceutical acceptable carrier in erectile dysfunction,
It is characterized in that：Include the following steps：
（a）Trichoderma viride is in medium slant culture；
（b）Cultured Trichoderma viride is inoculated into fermented and cultured in the fluid nutrient medium containing icariin；
（c）Fermentation culture is filtered, the Trichoderma viride thalline for being enriched with icariside II is obtained；
（d）Detect enrichment degree：It filters, repeats 2-5 times again after impregnating filter residue with methanol, collect filtrate and be concentrated to give concentration
Powder simultaneously detects icariside I I contents in powder；
（e）When detect icariside I I in condensed powders conversion ratio be more than 50%, be less than 85% when, condensed powders are through silica gel
Adsorpting column chromatography obtains purified powder after purification；
（f）The sterling of the icariside I I is obtained after purified powder recrystallization purifying；
（g）When detecting that the conversion ratio of icariside I I in condensed powders is more than 85%, after condensed powders recrystallization purifying
The sterling of the icariside I I.
5. the application of icariside II according to claim 4 or its pharmaceutical acceptable carrier in erectile dysfunction,
It is characterized in that：The step（a）Middle trichoderma is cultivated 3-5 days in PDA solid mediums, and condition of culture is 26-29 DEG C of temperature.
6. the application of icariside II according to claim 4 or its pharmaceutical acceptable carrier in erectile dysfunction,
It is characterized in that：The step（b）Include the following steps：The potato smashed and icariin are added in distilled water, after sealing
It is put into 121 DEG C of sterilization tank, sterilizes 15-20 minutes, wait for its cooling fluid nutrient medium；By step（a）It is middle to cultivate
Trichoderma viride be added in fluid nutrient medium in an aseptic environment, and be put into that temperature is 28 DEG C, rotating speed is shaking for 165r/min
Bed culture 9 days.
7. the application of icariside II according to claim 4 or its pharmaceutical acceptable carrier in erectile dysfunction,
It is characterized in that：The step（c）Middle filtering fermentation culture is will be containing Trichoderma viride, excessive sheep not soluble in water with Suction filtration device
The filter residue of the leaves of pulse plants time glycosides II and icariin filters out.
8. the application of icariside II according to claim 4 or its pharmaceutical acceptable carrier in erectile dysfunction,
It is characterized in that：The step（e）Middle silica gel adsorption column chromatographic purifying includes the following steps：The condensed powders are big through 1.5-2 times
Hole resin dry method mixes sample, and 6-8 times of 200-300 mesh chromatographic silica gels fill upper prop, with eluent, efflux thin-layer chromatography
Monitoring, efflux is merged, 60 DEG C are concentrated under reduced pressure to obtain the purified powder.
9. the application of icariside II according to claim 4 or its pharmaceutical acceptable carrier in erectile dysfunction,
It is characterized in that：The step（f）And/or（g）Middle recrystallization purifying includes the following steps：With the method being heated to reflux in 65-70
It is dissolved with methanol at a temperature of DEG C, the methanol solution containing icariside I I is removed after dissolving, it is brilliant to wait for that it is precipitated for room temperature
Body, leaching crystal, 45 DEG C or less are dried under vacuum to constant weight, obtain the icariside I I sterlings of 99% or more content.
10. the application of icariside II according to claim 1 or its pharmaceutical acceptable carrier in erectile dysfunction,
It is characterized in that：The erectile dysfunction is Neurogenic erectile dysfunction.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810157352.6A CN108392487B (en) | 2018-02-24 | 2018-02-24 | Application of icariside II or pharmaceutically acceptable carrier thereof in erectile dysfunction |
| PCT/CN2019/072160 WO2019161719A1 (en) | 2018-02-24 | 2019-01-17 | Use of icarisid ii or pharmaceutically acceptable carrier thereof in erectile dysfunction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810157352.6A CN108392487B (en) | 2018-02-24 | 2018-02-24 | Application of icariside II or pharmaceutically acceptable carrier thereof in erectile dysfunction |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108392487A true CN108392487A (en) | 2018-08-14 |
| CN108392487B CN108392487B (en) | 2023-09-01 |
Family
ID=63096792
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810157352.6A Active CN108392487B (en) | 2018-02-24 | 2018-02-24 | Application of icariside II or pharmaceutically acceptable carrier thereof in erectile dysfunction |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN108392487B (en) |
| WO (1) | WO2019161719A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019161719A1 (en) * | 2018-02-24 | 2019-08-29 | 苏州广奥医药开发有限公司 | Use of icarisid ii or pharmaceutically acceptable carrier thereof in erectile dysfunction |
| CN112870211A (en) * | 2021-02-05 | 2021-06-01 | 遵义医科大学 | Application of icariside II in preparation of medicine for preventing and treating acute liver injury |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20070056674A (en) * | 2005-11-30 | 2007-06-04 | (주)아모레퍼시픽 | Cosmetic composition containing hydrolysates of icariin |
| CN101516325A (en) * | 2006-09-19 | 2009-08-26 | 株式会社太平洋 | Method for preparing icariside II, cosmetic composition containing the same and the use thereof for skin whitening |
| WO2009149621A1 (en) * | 2008-06-13 | 2009-12-17 | 北京东方百奥医药开发有限公司 | Use of icariside ii in manufacture of products for preventing or treating male or female sexual dysfunction |
| KR20150019630A (en) * | 2013-08-14 | 2015-02-25 | 주식회사 엘지생활건강 | Composition for skin cell regeneration, anti-wrinkle, antioxidant, anti-imflamation, and skin whitening |
| CN105079013A (en) * | 2014-04-23 | 2015-11-25 | 北京东方百奥医药开发有限公司 | Uses of icariside II in preparation of products for prevention and treatment of reproduction dysfunction |
| CN105925635A (en) * | 2016-05-04 | 2016-09-07 | 宁波旋光医药科技有限公司 | Production process of icariside II |
| CN106995829A (en) * | 2017-05-12 | 2017-08-01 | 南京林业大学 | A kind of method that enzymatic conversion method barren wort total chromocor prepares epimedium aglucone |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104711312B (en) * | 2015-03-15 | 2018-02-23 | 北京化工大学 | The method that Astragaloside IV is prepared using Trichoderma viride |
| CN107964555B (en) * | 2018-01-05 | 2021-07-20 | 苏州广奥医药开发有限公司 | Method for biological enrichment and production of icariside II |
| CN108392487B (en) * | 2018-02-24 | 2023-09-01 | 北京东方百奥医药开发有限公司 | Application of icariside II or pharmaceutically acceptable carrier thereof in erectile dysfunction |
-
2018
- 2018-02-24 CN CN201810157352.6A patent/CN108392487B/en active Active
-
2019
- 2019-01-17 WO PCT/CN2019/072160 patent/WO2019161719A1/en active Application Filing
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20070056674A (en) * | 2005-11-30 | 2007-06-04 | (주)아모레퍼시픽 | Cosmetic composition containing hydrolysates of icariin |
| CN101516325A (en) * | 2006-09-19 | 2009-08-26 | 株式会社太平洋 | Method for preparing icariside II, cosmetic composition containing the same and the use thereof for skin whitening |
| WO2009149621A1 (en) * | 2008-06-13 | 2009-12-17 | 北京东方百奥医药开发有限公司 | Use of icariside ii in manufacture of products for preventing or treating male or female sexual dysfunction |
| KR20150019630A (en) * | 2013-08-14 | 2015-02-25 | 주식회사 엘지생활건강 | Composition for skin cell regeneration, anti-wrinkle, antioxidant, anti-imflamation, and skin whitening |
| CN105079013A (en) * | 2014-04-23 | 2015-11-25 | 北京东方百奥医药开发有限公司 | Uses of icariside II in preparation of products for prevention and treatment of reproduction dysfunction |
| CN105925635A (en) * | 2016-05-04 | 2016-09-07 | 宁波旋光医药科技有限公司 | Production process of icariside II |
| CN106995829A (en) * | 2017-05-12 | 2017-08-01 | 南京林业大学 | A kind of method that enzymatic conversion method barren wort total chromocor prepares epimedium aglucone |
Non-Patent Citations (4)
| Title |
|---|
| J. ZHANG等: "Icarisid II, a PDE5 inhibitor from Epimedium wanshanense, increases cellular cGMP by enhancing NOS in diabetic ED rats corpus cavernosum tissue", 《ANDROLOGIA》 * |
| JIAN ZHANG等: "Effect of icarisid II on diabetic rats with erectile dysfunction and its potential mechanism via assessment of AGEs, autophagy, mTOR and the NO–cGMP pathway", 《ASIAN JOURNAL OF ANDROLOGY》 * |
| TAO CHENG等: "Optimized Biotransformation of Icariin into Icariside II by -Glucosidase from Trichoderma viride Using Central Composite Design Method", 《BIOMED RESEARCH INTERNATIONAL》 * |
| 张建等: "淫羊藿次苷Ⅱ对大鼠阴茎海绵体压力、平均动脉血压的影响及其作用机制的研究", 《中国男科学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019161719A1 (en) * | 2018-02-24 | 2019-08-29 | 苏州广奥医药开发有限公司 | Use of icarisid ii or pharmaceutically acceptable carrier thereof in erectile dysfunction |
| CN112870211A (en) * | 2021-02-05 | 2021-06-01 | 遵义医科大学 | Application of icariside II in preparation of medicine for preventing and treating acute liver injury |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2019161719A1 (en) | 2019-08-29 |
| CN108392487B (en) | 2023-09-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100356935C (en) | Formulations useful in the treatment of male and female impotence | |
| CN103665080B (en) | Triterpenoid compounds and application thereof in diabetes treatment drugs | |
| TWI598104B (en) | Use of Antrodia cinnamomea extract to improve side effects of chemotherapy | |
| CN108392487A (en) | A kind of application of icariside II or its pharmaceutical acceptable carrier in erectile dysfunction | |
| CN104352552B (en) | A kind of food, health products or pharmaceutical composition | |
| CN1840162B (en) | Compound total extract of compound cape jasmine, ginger and fermented soybean, its preparation and use | |
| CN102485237A (en) | Sweet wormwood herb brewed liquid, brewing technology thereof, and preparation method of starter thereof | |
| CN100490843C (en) | Prince's-feather preparation and its preparation process and application | |
| CN105902535A (en) | Application of baicalein to preparation of medicament for preventing and treating Parkinson's disease | |
| CN101723997A (en) | Puerarin glycosylation derivative, medicine compound, preparation method and application thereof | |
| CN1249072C (en) | Preparation method of golden peach glycoside and its new use in medicine | |
| CN102764294A (en) | Cough relieving and sputum eliminating combination and preparation method thereof | |
| CN107744571B (en) | Pharmaceutical composition for improving vascular endothelial dysfunction and preparation method and application thereof | |
| CN103860565B (en) | Medicinal composition for treating diabetes hepatic fibrosis | |
| CN105056172A (en) | Compound Norfloxacin slow-release capsules and preparing method thereof | |
| CN101974011B (en) | New compound methyl brevicate with medical activity | |
| CN1230191C (en) | Health care combination of propolis for reducing blood sugar and fat as well as method for mfg. its capsule | |
| CN104161871B (en) | Tinea capitis (tinea alba) external is rubbed with the hands and is coated with medicated wine and preparation method thereof | |
| CN107334793A (en) | The purposes of wintersweet platymiscium helicobacter pylori resistant | |
| CN101766676B (en) | Extract of Albizia chinensis (Osbeck) Merr, preparation method, combination and purpose thereof | |
| CN101974012B (en) | Novel compound ethyl brevicate with pharmaceutical activity | |
| CN104840747B (en) | Chinese medicine composition with antithyroid cancer activity and its preparation method and application | |
| CN101766674B (en) | Medicament composition for preventing and controlling restenosis after intracoronary stent implantation | |
| KR20030049063A (en) | Composition for prevention and treatment of erectile dysfunction | |
| CN107693752A (en) | A kind of oral products and preparation method for psoriasis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20230803 Address after: 102600 Beijing city Daxing District Huangcun emperor Road No. 12 Applicant after: BEIJING DONGFANG BAIAO MEDICAL DEVELOPMENT Co.,Ltd. Address before: 215400 biomedical industry park, Shaxi Town, Taicang City, Suzhou City, Jiangsu Province Applicant before: SUZHOU GUANG'AO HEALTHCARE Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |