KR101634779B1 - Compositions for Preventing or Treating Benign prostatic hyperplasia and Dysuresia Comprising Schisandra chinensis Extracts as Active Ingredients - Google Patents

Abstract

The present invention provides a pharmaceutical composition for preventing or treating enlargement of the prostate gland comprising an extract of Omija as an active ingredient and a food composition for alleviating or improving the enlargement of the prostate gland. The composition of the present invention has an excellent effect for preventing and treating enlargement of the prostate by inducing relaxation of smooth muscle of the prostate gland. The present invention provides an agent for improving urination disorder caused by enlargement of the prostate gland comprising an extract of Omija. The present invention provides a pharmaceutical composition for preventing or treating enlargement of the prostate gland comprising an extract of Omija and an alpha blocker, and an agent for improving urination disorder caused by enlargement of the prostate gland.

Description

TECHNICAL FIELD The present invention relates to a composition for preventing or treating benign prostatic hyperplasia and dysuria comprising an extract of Schizandra chinensis as an active ingredient,

The present invention relates to a composition for preventing or treating enlargement of the prostate gland and urinary incontinence which contains an extract of Omija as an active ingredient.

Benign prostatic hyperplasia (BPH) is a disease of the prostate that is caused by various causes of prostate enlargement around the urethra, which causes pressure on the urethra, resulting in a decrease in urine output. According to recent statistics, the incidence of enlarged prostate has increased 9-fold between 2000 and 2009, with about 50% of men in their 60s and about 90% of men over 85 years of age. α1-adrenergic receptor antagonists and 5α-reductase inhibitors are used as major therapeutic agents for BPH, and phosphodiesterase type 5 inhibitors used for erectile dysfunction therapy are known to have therapeutic effects in patients with BPH (2, 3). Despite the effectiveness of these therapies, efforts are still being made to develop other therapies to prevent the progression of the prostate gland.

Schizandra chinensis Baill. Has been used as a Magnoliaceae plant in ancient Asian countries such as Korea, China and Japan for the purpose of tanning, soothing, calming and anti-aging (Chen and Li, 1993; Huang et al ., 2005). Schizophyllum (Schizandra chinensis) has long been used as a prescription for herbal medicine and its safety has been proven. Omija includes a variety of physiologically active lignan-based compounds having a dibenzo [a, c] -cyclooctadiene skeleton (Huang et al ., 2005; Choi et al ., 2006 Lee and Kim, 2010) In a number of pharmacological studies related to lignans, it has been found that the above-mentioned physiologically active lignan compounds have hepatic toxicity inhibitory action, anti-inflammatory action, anti-cancer action and anti-HIV action (Yasukawa et al ., 1992; Chiu et al ., 2002; Wu et al ., 2003; Choi et al ., 2006; Li et al ., 2009; Oh et al ., 2010).

Recently, it has been reported that Omiza extract and the compounds isolated therefrom can be used as a composition for the prevention and treatment of erectile dysfunction (Han et al ., 2012) Is obtained. However, there is no report that it can be used as a composition for treating and preventing prostatic hyperplasia and dysuria due to it.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors sought to develop a therapeutic agent for the treatment of benign prostatic hyperplasia without side effects using natural extracts. As a result, the inventors of the present invention have completed the present invention by confirming that the Omija extract improves and alleviates prostatic hyperplasia by inducing relaxation of prostate smooth muscle in a concentration-dependent manner.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating enlargement of the prostate gland comprising an extract of Schizandra chinensis as an active ingredient.

Another object of the present invention is to provide a remedy for obesity caused by enlargement of the prostate gland comprising an extract of Omija as an active ingredient.

It is still another object of the present invention to provide a food composition for alleviating or ameliorating the enlargement of the prostate gland comprising an extract of Omija as an active ingredient.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating enlargement of the prostate gland comprising an extract of Omija and an alpha blocker.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention and claims.

According to one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating enlargement of the prostate gland comprising an extract of Omija as an active ingredient.

The present inventors have made intensive researches to develop a therapeutic agent for the treatment of benign prostatic hyperplasia using natural extracts. As a result, the inventors have found that the extract of Omija improves and alleviates prostatic hyperplasia by inducing relaxation of prostate smooth muscle in a concentration-dependent manner.

Omiza, which is used as an active ingredient in the composition of the present invention, is a deciduous broad-leaved vine, with leaves alternating with ovate or obovate, with sharp tip, serrate, and hairs on the back side. The flower is reddish white, bloomed in June-July, and is migratory. Fruit is used for food, and it grows in the shape of a spike at the end of the branch and ripens red in August-September. The fruit is called Schizandrae Fructus and Schizandrae Fructus. 200-1,600 m above sea level. It is the main region of Jirisan, Jeonbuk and Gangwon provinces. It is wild throughout the country excluding Chungnam and Chungbuk, and is distributed geographically in Japan, Sakhalin, Manchuria and China. Fruits include Schizandrol, Schizandrin A, B, C, angeloylgomisin O, P, epigomisin, pregomoisin, deoxyschizandrin ) And the like. Omija has long been used in medicinal herbs as medicinal materials for medicinal purposes such as astringency, nourishment, tonic, shinhae medicine, ginger poison, thirst, And it has already been confirmed that the human body is stable due to ingestion. Omiza extract stimulates the central nervous system to enhance the tonic and intellectual activities and labor capacity. It affects the metabolism of the carbohydrate and accelerates the digestion of the liver glycogen, thereby increasing the content of glycogen, promoting fatigue recovery, regulating blood pressure, It is used in cosmetics because it has antioxidant effect, antibiotic detoxifying function, function to soothe eczema and skin inflammation, inhibition of skin aging, antibacterial and whitening effect because it has regulating action and is used for hypotension, arteriosclerosis, diabetes and hepatitis.

The Schizandra chinensis , Kadsura japonica , Schisandra viridicarpa , Schisandra repanda or Schisandra nigra , and Schisandra chinensis are preferred in the present invention.

The composition of the present invention contains an extract of Omija as an active ingredient. The term " extract " used in reference to Omija in the present specification means not only the extraction result obtained by treating the extract solvent with Omija, but also an omeza product formulated (for example, powdered) .

When an extract of Omiza used in the composition of the present invention is obtained by treating an extract solvent in Omiza, various extraction solvents can be used. Preferably, a polar solvent or a non-polar solvent can be used. Suitable polar solvents are (i) water, (ii) alcohols (preferably methanol, ethanol, propanol, butanol, n-propanol, iso-propanol, n-butanol, 1-pentanol, Or ethylene glycol), (iii) acetic acid, (iv) dimethyl-formamide (DMFO) and (v) dimethyl sulfoxide (DMSO). Suitable nonpolar solvents are acetone, acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, hexane, 2,2,4-trimethylpentane, decane, cyclohexane, cyclopentane, diisobutylene, 1- But are not limited to, pentane, 1-chlorobutane, 1-chloropentane, o -xylene, diisopropyl ether, 2- chloropropane, toluene, 1- chloropropane, chlorobenzene, benzene, diethyl ether, diethylsulfide, Methane, 1,2-dichloroethane, aniline, diethylamine, ether, carbon tetrachloride, and THF.

According to an embodiment of the present invention, the extraction solvent used in the present invention may be selected from the group consisting of (a) water, (b) an anhydrous or hydrated lower alcohol having 1 to 4 carbon atoms (methanol, ethanol, propanol, butanol, (E) ethyl acetate, (f) chloroform, (g) butyl acetate, (h) 1,3-butylene glycol, (i) hexane, and (j) Diethyl ether.

According to another embodiment of the present invention, the extract of the present invention is obtained by treating ethanol with Omiza.

As used herein, the term " extract " means that it is used in the art as a crude extract as described above, but broadly includes fractions obtained by further fractionating the extract. That is, the Omiza extract includes not only those obtained using the above-described extraction solvent but also those obtained by further applying a purification process thereto. For example, a fraction obtained by passing the above extract through an ultrafiltration membrane having a constant molecular weight cut-off value, and a separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity) The fraction obtained by the purification method is also included in the extract of Omiza of the present invention.

The Schizandra chinensis extract of the present invention can be prepared in a powder state by an additional process such as vacuum distillation and freeze drying or spray drying.

As used herein, the term " benign prostatic hyperplasia (BPH) " refers to a condition accompanied by dysuria, dysfunction, renal dysfunction and the like by enlarging the prostate tissue by abnormal proliferation. The prostate hyperplasia of the present invention means benign prostatic hyperplasia. According to the present invention, the composition of the present invention improves and alleviates prostatic hyperplasia by inducing relaxation of the prostate smooth muscle.

According to one embodiment of the present invention, prostate smooth muscle relaxation by the composition of the present invention is due to activation of the K ⁺ channel.

According to a preferred embodiment of the present invention, the composition of the present invention comprises (a) a pharmaceutically effective amount of the above-mentioned Omija extract of the present invention; And (b) a pharmaceutically acceptable carrier. As used herein, the term " pharmaceutically effective amount " means an amount sufficient to achieve efficacy or activity of the above-mentioned Omija extract.

The pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the formulation and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. But is not limited thereto. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, or local administration).

The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . Typical dosages of the pharmaceutical compositions of this invention are in the range of 0.001-100 mg / kg on an adult basis.

The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

According to another aspect of the present invention, there is provided an agent for improving urination disorder caused by enlargement of the prostate gland comprising an extract of Omija as an active ingredient.

As used herein, the term " dysuria due to hyperplasia of the prostate " refers to a symptom in which urine such as urinary frequency, delayed urine, hematuria, and urine can not be smoothly discharged due to enlargement of the prostate tissue and compression of the urethra.

The agent for improving micturition disorder of the present invention comprises an extract of Omija as an active ingredient. The Omija extract of the present invention is as described above, and the carriers, excipients, formulations, administration methods and doses which can be added to the agent for improving micturition disorder are as described above The description thereof is omitted in order to avoid excessive redundancy.

According to still another aspect of the present invention, there is provided a food composition for alleviating or ameliorating enlargement of the prostate gland comprising an extract of Omija as an active ingredient.

When the composition of the present invention is prepared with a food composition, it includes not only the above-mentioned effective ingredient of the present invention but also ingredients normally added in food production, for example, protein, carbohydrate, fat, nutrients, And flavoring agents. Examples of the above-mentioned carbohydrates are monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavorings such as tau martin and stevia extract (e.g., rebaudioside A and glycyrrhizin) and synthetic flavorings (saccharine, aspartame, etc.) can be used as flavorings. For example, when the food composition of the present invention is prepared as a drink, it may further contain citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, mulberry extract, jujube extract, licorice extract, have.

According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating enlargement of the prostate gland comprising an extract of Omija and an alpha blocker.

The term " alpha-blocker " in the present invention is widely used in the bladder neck and prostate smooth muscle to block alpha adrenergic receptors that cause pressure and tension in the bladder neck and prostate urethra, and is the most commonly used drug for treatment of benign prostatic hyperplasia It is medicine. Alpha blockers improve vasomotor occlusion by reducing bladder outlet resistance by relaxing smooth muscle in the prostate and bladder neck, which can relieve symptoms quickly and effectively.

The alpha-blockers used in the present invention are one or more alpha-blockers selected from the group consisting of Tamslosin, Terazosin, Alfuzosin, Doxazocin and Silodosin .

According to one embodiment of the present invention, the alpha-blocker used in the present invention is tamoxifen.

According to one embodiment of the present invention, simultaneous treatment of Omiza extract and alpha blocker exhibits a synergistic prostate smooth muscle relaxation effect as compared with the case where Omiza extract or alpha blocker alone is treated. Thus, the compositions of the present invention have excellent improvement and palliative efficacy against prostate hyperplasia as compared to either the Omija extract or the alpha blocker.

According to still another aspect of the present invention, there is provided an agent for improving urination disorder caused by enlargement of the prostate gland comprising an extract of Omija and an alpha blocker as an active ingredient.

The features and advantages of the present invention are summarized as follows:

(I) The present invention provides a pharmaceutical composition for preventing or treating enlargement of the prostate gland comprising an extract of Omija as an active ingredient, and a food composition for alleviating or improving enlargement of the prostate gland.

(Ii) The composition of the present invention induces relaxation of the smooth muscle of the prostate gland to exert an excellent effect in the prevention and treatment of enlargement of the prostate gland.

(Iii) The present invention provides an agent for improving urination disorder caused by enlargement of the prostate gland comprising an extract of Omija.

(Iv) The present invention provides a pharmaceutical composition for preventing or treating enlargement of the prostate gland comprising an extract of Omija and an alpha blocker, and an agent for improving urination disorder caused by enlargement of the prostate gland.

Figure 1 shows the results of treatment of Omiza extract (n = 18) and tamsulosin (n = 10) on a human prostate tissue strip and the resulting concentration-dependent relaxation response. The relaxation effect is expressed as a percentage of norepinephrine-induced contraction. At low concentrations, there was no significant difference in the relaxation effect of the omija extract and the tamsulosin, but a statistically significant relaxation effect was observed at the fresh concentration of 10 ^-7 M-test than the 2.0 mg / mL of the omija extract (*: P <0.05).
NE, norepinephrine; SCE, Omija extract; TAMS, Tamsuro Shin.
Figure 2 shows the synergistic relaxation effect (68.9 +/- 8.7%, * P < 0.05) of Omiza extract (1.0 mg / ml) and tamsulosin 10 ^-8 M (n = 8) in human prostate tissue strips contracted by NE The result is confirmed. 26.7 ± 4.6% for the single dose of Omiza extract and 38.7 ± 8.2% for the single dose of tamsulosin.
SCE, Omija extract; TAMS, Tamsuro Shin.
FIG. 3 shows that the prostate relaxation effect (26.7 ± 4.6% at 1.0 mg / mL) of Omija extract was inhibited by pretreatment with TEA 1 mM (-0.9 ± 4.2%, n = 7, * P <0.05). Pretreatment with L-NAME 10 ^-4 M did not affect the relaxation effect (29.0 ± 7.2%, n = 7, P = 0.793) of Omiza extract.
SCE, Omija extract; TEA, tetraethylammonium; L-NAME, N-nitro-L-arginine methyl ester.
FIG. 4 shows the results of measurement of whole-cell BK _Ca current activation by human prostatic smooth muscle cells (HPRSMC) by Schizandra chinensis extract.
A, -80 to +80 mV Represents a typical current-voltage relationship obtained using a 500 ms ramp pulse. Membrane currents were recorded in the presence or absence of (control) Omija extract. The current activated by B, Omija extract is completely blocked by IbTX (Iberiotoxin). C, peak current density at +60 mV (normalized to cell capacitance). Measured values are expressed as mean ± standard error, n = 12, * p <0.001, and #p <0.05.
SCE, Omija extract; IbTX, Iberiotoxin.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Materials and methods

This study was approved by the Institutional Review Board of the Samsung Medical Center (IRB No. SMC 2012-03-061).

Plant material

Obsidian fruit was obtained from Korean longevity in September, 2009. Dried Schizosaccharomyces japonica fruit (50 g) was pulverized and ground in a shade, then 200 ml ethanol was treated three times for 3 hours and extracted with an ultrasonic bath (model 8510 DHT; Branson, USA). After filtration, the extract was evaporated in vacuo and lyophilized to give the final extract. A sample of evidence (accession number SC-1) was kept at the KIST Natural Resources Research Institute (Kangreung, Korea) (11).

Organization preparation

Human prostate tissue was obtained from 14 male patients who had undergone resection for prostate cancer sites. The mean age of the patients was 63.5 years (range: 51-73 years). All patients had positive cores on one side only. In the opposite tissue, the normal visible tissue was cut from the transition zone and the urethral area. The cut tissue was immediately immersed in a cold Krebs solution and then used in the experiment.

Prostate tissue strip preparation

3-4 rectal rigid prostate tissue strips of the same size (2x2x10 mm) were obtained from each patient. Tissue strips were prepared for an organ bath study. Each prostate strip was silk-lined in the organ chamber, one end fixed to the tissue holder, and the other prosthesis fixed to a force transducer. The latter was connected to a properly calibrated 4-channel polygraph (PowerLab; ADInstruments, Australia) where the converter output was recorded. The prostate strips were placed in a Krebs solution maintained at 37 ° C with thermostatic circulation during the experiment and in an organ bath continuously bubbled with a 95% O ₂ and 5% CO ₂ mixture. Each prostate strip was stretched to an optimal isometric tension of 1.0 g and maintained equilibrium for 60 minutes. During the equilibration period, the tissue was washed every 30 minutes with fresh Krebs solution and the tension was adjusted as needed.

In vitro organ bath experiment

After an equilibration time of 60 minutes, 10 ⁵ M norepinephrine (NE) was added to each organ bath containing the prostate strip with optimal static tension, and NE subsequently caused prostate strip contraction. After reaching the shrinkage stabilizer, the relaxation effect of the Omiza extract was measured. The concentration of 0.1-2.0 mg / ml of Omija extract was accumulated in the NE-induced shrinkage stabilizer. In order to compare with the relaxation effect of alpha-adrenergic potency blockers, Tamsulosin was treated to accumulate in the 10 ^-10 -10 ^-7 M concentration range. The synergistic effect of the extracts of tamsulosin and omija was evaluated by treating simultaneously 1.0 mg / ml of Omija extract and 10 ^-8 M of tomosrox.

(TEA, 1 mM) and nitric oxide synthase (NOS) inhibitor N-NAME (N-nitro-L-arginine methyl ester, 10 ^-4 M) was pretreated on strips for 30 min and then the effect of Omiza extract on NE-induced contraction was evaluated. The inventors compared the degree of relaxation between TEA and L-NAME before and after treatment.

Cell culture

Primary human prostate smooth muscle cells (HPrSMC) were purchased from PromoCell (C-12573, Germany). Cells were cultured in RPMI 1640 medium supplemented with 5% fetal calf serum, 0.5 ng / ml epidermal growth factor, 2 ng / ml basic fibroblast growth factor (FGF), 5 μg / ml insulin (Promocell), 100 U / ml penicillin, The cells were cultured in a smooth muscle cell growth medium 2 (PromoCell) containing 100 μg / ml streptomycin (Gibco, USA) at 37 ° C, 5% CO ₂ , 95% O ₂ wetting conditions. HPrSMC was subcultured with 0.05% trypsin-EDTA every 48-72 hours. For electrophysiological recording, the cells were seeded onto the glass cover slip for 30-40 minutes prior to use.

Electrophysiological experiment

The whole-cell patch-clamp technique has been shown to induce intracellular Ca ²⁺ in HPrSMC Was used to measure the potassium current (BK _Ca ) that was activated. The cells were transferred to a small chamber (0.6 ml) and mounted on an inverted microscope (TMD Diaphot, Japan). Membrane currents were recorded using a patch clamp amplifier (Axopatch-200B, USA). The patch electrode was made of a borosilicate glass capillary (World Precision Instruments, USA) having a resistivity of 2.5-4 MΩ. The uncorrected liquid junction potential between the pipette solution and the bath solution was below 3 mV. In all experiments, whole cell centrifugation was not performed until the seal resistance was greater than 5 GΩ. pCLAMP software v.9 (Axon Instruments) and Digidata-1322A (Axon Instruments) were used for data preparation and command pulse application. The membrane current was measured during ramping and filtered at 5 kHz (-3 dB frequency). The current signal was filtered at 5 kHz and digitized and analyzed on a personal computer using pCLAMP and Origin software (Microcal Software, USA). Standard bath solution includes the following: (mmol / l): 135 NaCl , 5 KCl, 10 HEPES, 1.8 CaCl 2, 1 MgCl 2, and 5 glucose (adjusted to pH 7.4 using NaOH). The pipette solution contained (mmol / l): 140 KCl, 10 HEPES, 5 Na ₂ ATP, 1 MgCl ₂ , 5 EGTA (ethyleneglycol-bis- [2-aminoethyl ether] -N, tetraacetic acid) and 0.5 GTP (adjusted to pH 7.2 with KOH). The Ca ²⁺ -free concentration in the pipette solution was adjusted to 3.16 nM by adding the appropriate amount of CaCl ₂ determined using Max Chelator Sliders software (C. Patton, Stanford University).

compound

The Krebs solution has the following composition: NaCl, 118 mM l ^-1 ; NaHCO ₃ , 25 mM 1 ^-1 ; Glucose, 5.6 mM &lt; RTI ID = 0.0 &gt;¹; KCl, 4.7 mM &lt; RTI ID = 0.0 &gt;¹; KH ₂ PO ₄ , 1.2 mM 1 _-1 ; MgSO ₄ 7H ₂ O, 1.17 mM 1 ^-1 ; And _{CaCl 2 2H 2 O, 2.5 mM} l -1. Tomslo was purchased from Astellas (Korea). Stock solutions of tomatoes and omija extract were prepared by dissolving in dimethyl sulfoxide (DMSO). The final concentration of DMSO did not exceed 0.1%, and this concentration did not affect prostate strip tone or membrane current. All other compounds were purchased from Sigma Chemical (St. Louis, USA) and dissolved in distilled water.

Data interpretation and statistical analysis

All data are expressed as mean ± standard error, and the 'n' value means the number of distinct prostate tissue strips or HPrSMC. The relaxation response of isolated prostate strips was expressed as a relaxation percentage for maximum contraction induced by NE. The nonspecific relaxation of the strip was excluded from the data reading. Each reagent was tested using at least six tissue strips from at least two other patients. Statistical significance was determined using the corresponding or non-corresponding Student T-test and the one-way ANOVA. The Shapiro-Wilk test was used to test the normal distribution of data. The P-value <0.05 was considered statistically significant.

Experiment result

The mean volume of the obtained prostate gland was 36.5 ± 3.1 mL, and the mean prostate specific antibody level of the patient was 7.3 ± 1.5 ng / mL. The average pre-contracted tone produced by NE was 0.85 ± 0.08 g. The cumulative dose of Omiza extract induced concentration-dependent relaxation in contracted prostate tissue: 3.9 ± 2.3% at 0.1 mg / mL, 13.9 ± 4.0% at 0.5 mg / mL, 26.7 ± 4.6% at 1.0 mg / mL, 40.7 ± 5.9% (n = 18, P <0.05) at 2.0 mg / mL. By Tom worn to induce relaxation in a concentration-dependent manner in a retracted prostate tissue: ^10-10 at M 0 ± 3.1%, 10 ^-9 in M 5.7 ± 3.0%, 38.7 ± 8.2% at 10 ^-8 M, 10 ^-7 M To 70.6 ± 6.4% (Fig. 1). At low concentrations, there was no significant difference in the relaxation effect of Omiza extract and tamsulosin. However, a statistically significant relaxation effect was observed at the fresh concentration of 10 ^-7 M-test than 2.0 mg / mL of Omiza extract (*: P <0.05).

Simultaneous administration of Omija extract and tamsulosin exhibited a synergistic relaxation effect: 1.0 mg / ml of Omija extract and 68.9 ± 8.7% (Fig. 2) in 10 ^-8 M testosterone. In the pretreatment of TEA, the relaxation effect of Omija extract was inhibited, but the pretreatment of L-NAME did not change the relaxation effect of Omija extract (Fig. 3).

The inventors of the present invention found in the previous study that the extract of Omija activates the BK _Ca channel in human CSM (corporal smooth muscle). In the present invention, whole cell patch-clump recording was carried out to examine whether or not the Omiza extract has similar effects on the HPrSMC BK _Ca channel. Membrane current changes were recorded before and after treatment of Omija extract (100 μg / mL) with membrane potential at 60 mV and extracellular fluid at 5 mM K ⁺ conditions. Representative measurement records are shown in Figures 4A, B. The extracellular addition of Omiza extract significantly increased the external current, and this effect was markedly attenuated by treatment with 100 nM IbTX (iberiotoxin), a high specific inhibitor of the BK _Ca channel (Fig. 4B). These results indicate that the increase in total cell current is mainly due to activation of the BK _Ca channel. Figure 4C shows the mean value at +60 mV and shows that the Omiza extract increases the current density by 1.9 times from 12.6 ± 1.7 pA to 24.3 ± 2.8 pA (P <0.01, n = 12). These results indicate that the relaxation of HPrSM induced by Omiza extract is due, at least in part, to the regulation of BK _Ca activity.

Argument

According to the present invention, the Schizandra chinensis extract showed a concentration-dependent relaxation effect on human prostate strip pre-contracted with NE. Relaxation effect of Schisandra chinensis extract was similar in God and Tom except between the new 10 ^-7 M to 2.0 mg Schisandra chinensis extract, and Tom. After oral administration of 0.4 mg of testosterone, the testosterone concentration (Cmax) in plasma was 8.18 ng / ml, which is the same as 18 nM (12). Therefore, it is considered that the effect of Omiza extract is comparable to that of the testosterone at physiological concentrations. The relaxation effect of the combination of Omiza extract and Tomroz Shin was more remarkable than that of the individual treatment of Omiza extract or tamsulosin. Pretreatment of L-NAME did not affect the effect of Omiza extract, and pretreatment of TEA suppressed the effect of Omiza extract. These results indicate that the relaxation effect of Omija extract in human prostate tissue is not mediated by the NO pathway and mediated by K ⁺ channel activation. In the present invention, it was revealed that the extract of Omija activates the K ⁺ channel to exhibit the prostate gland relaxation effect.

In studies using rat aortic rings, Omija extract induced vascular relaxation through endothelium-dependent NO pathway as well as direct effects on vascular smooth muscle (9). Omiza extract strongly relaxed endothelium-innervated rat aorta contracted by PE, and this relaxation effect was inhibited by pretreatment of L-NAME and ODQ but not by TEA and indomethacin. This means that the relaxation mechanism of the prostate tissue is different from the vascular tissue.

The major pharmaceutical targets of BPH therapy are the? 1-adrenergic receptor antagonist and the 5? -Reductase inhibitor. Although the therapeutic effect of BPH is very good, there is still a need to develop new therapies that can stop disease progression and reduce surgery. Active smooth muscle tone in the human prostate is regulated by the adrenergic nervous system (14), and a variety of other signal transduction processes are involved in the regulation of the contractility of prostate smooth muscle cells. Phosphodiesterase type 5 inhibitors exhibit clinical efficacy against BPH and are considered a treatment option for BPH. Many other therapeutic targets for BPH include beta-adrenergic receptor agonists, muscarinic receptor antagonists and P2X1-purine receptor antagonists (1). Many herbal medicines have been studied as alternative therapies for BPH, and some have shown clinical efficacy (15). However, the effects of Omija on the human prostate are not yet known.

conclusion

The extract of Omija showed a concentration-dependent relaxation effect on the degree of tension of the human prostate tissue induced by NE treatment and showed a more excellent relaxation effect when administered simultaneously with the conventional treatment of benign prostatic hyperplasia, tamsulosin. In the future, it is expected that the extract of Omija will be able to be used alone or as a combination therapy for benign prostatic hyperplasia and dysuria due to it.

Resources

1. Ventura S et al., Br J Pharmacol 2011; 163: 891-907

2. McVary KT et al., J Urol 2007; 177: 1401-1407

3. Roehrborn CG et al., BJU Int 2010; 105: 502-507

4. Huang T et al., J Chromatogra 2005; 1066: 239-242

Panossiane, Wikman G. J Ethnopharmacol 2008; 118: 183-212

6. Gnabre J et al., J Chromatogr B Analyt Technol Biomed Life Sci 2010; 878: 2693-2700

7. Smejkal K et al., Planta Med 2010; 76: 1672-1677

8. Song JX et al., Phytother Res 2011; 25: 435-443

9. Park JY et al., J Ethnopharmacol 2009; 121: 69-73

10. Kim HK et al., Phytother Res 2011; 25: 1776-1782

11. Han DH et al., BJU Int 2012; 109: 1404-1413

12. Prasaja B, Harahap Y, Lusthom W, Setiawan EC, Ginting MB, Hardy, Lipin. A bioequivalence study of two tamsulosin sustained-release tablets in Indonesian healthy volunteers. Eur J Drug Metab Pharmacokinet 2011; 36: 109-113

13. Reason EA, Muti P, Schunemann HJ. Pol Arch Med Wewn 2008; 118: 183-193

14. Roehrborn CG in Schwinn. J Urol 2004; 171: 1029-1035

15. Ma CH et al., Asian J Androl 2013; 15: 471-482

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (10)

A pharmaceutical composition for preventing or treating prostatic hyperplasia comprising Schizandra chinensis single extract as an active ingredient.
The composition according to claim 1, wherein the Omiza extract is obtained by treating water, methanol, ethanol or a combination thereof with an ozone.
2. The composition of claim 1, wherein the composition relaxes the smooth muscle of the prostate.
4. The composition of claim 3, wherein the prostate smooth muscle relaxation is by activation of a K ⁺ channel.
An agent for improving urination disorder caused by enlargement of the prostate gland comprising the composition of any one of claims 1 to 4.
A food composition for alleviating or ameliorating the enlargement of the prostate gland comprising an extract of Omija as an active ingredient
A pharmaceutical composition for the prophylaxis or treatment of hyperplasia of the prostate, comprising an extract of Omija and Tamslosin.
delete 8. The composition of claim 7, wherein the composition relaxes the smooth muscle of the prostate.
An agent for improving urinary incontinence caused by enlargement of the prostate gland including an omyza extract and Tamslosin.

Images