WO2012006865A1 - Use of xanthoceras sorbifolia and xanthoceras sorbifolia extract in preparing medicaments for curing urinary incontinence or overactive bladder - Google Patents

Abstract

A use of Xanthoceras sorbifolia and Xanthoceras sorbifolia extract in preparing medicaments for curing urinary incontinence or overactive bladder. A medicine composition for curing urinary incontinence or overactive bladder is provided, which contains 1%-99% Xanthoceras sorbifolia or Xanthoceras sorbifolia extract.

Description

 Application of extract of Xanthoceras sorbifolia and Radix Scutellariae in preparing medicine for treating urinary incontinence or overactive bladder

 The present invention relates to a composition of a canopy and a plant extract thereof for preventing or treating the following urinary system diseases: urinary incontinence, enuresis, frequent urination and overactive bladder. Background technique

 Overact ive Bladder (OAB) is a syndrome characterized by urgency symptoms, often accompanied by frequent urination and nocturia symptoms, with or without urge incontinence; urodynamics can be expressed as Detrusor overactivity can also be other forms of urethral-bladder dysfunction. Urinary incont inence (UI) is the involuntary loss of urine caused by impulsive (impulsive incontinence) or physical or mental stress (stress incontinence) caused by the inability of the bladder to retain urine.

 The normal bladder fills up at physiological speed. The bladder can accommodate large volumes of urine due to the physical properties of the bladder and the neurosuppression system. It is believed that the inhibition mechanism involves inhibition of parasympathetic activity or increased sympathetic tone resulting in detrusor relaxation and filling. The bladder sphincter contracts during filling to prevent it from leaking. The process of urination consists in relaxation of the bladder sphincter and subsequent contraction of the detrusor. When the bladder is empty, the urinary muscles relax and the sphincters contract to seal the bladder and maintain restraint.

 It is estimated that 48% of the total population has had urinary incontinence, although in most countries only about 15% of these patients are diagnosed. Only about 70% of those diagnosed are receiving medical treatment. Impulsive incontinence is more prevalent among the elderly, and more than 80% are women. According to reports, there are about 400-500 million middle-aged and elderly people with urinary incontinence in the world, of which about 10% to 20% are treated with drugs.

Overactive bladder is an annoying and unwilling question, both men and women can develop symptoms. Currently, treatment for urinary incontinence includes non-pharmacological treatments and medications. Non-pharmacological treatment mainly involves self-training of the bladder. This method has a long course of treatment. The patient must have firm stamina and need to endure physical discomfort for a long time. Medication can quickly relieve symptoms and adjust the body and mind of the patient. Currently, anticholinergic drugs are widely used in the treatment of overactive bladder and urge incontinence to relax the tension of bladder muscles. However, the existing drugs of this type are less selective, There are a series of side effects such as dry mouth and constipation. Therefore, despite the effectiveness of existing therapies, there is still a large market demand for therapeutic drugs for UI and OAB.

 Xanthoceras is a fruit of the genus Xanthoceras sorbifol ia Bunge, a perennial herb of the genus Corydalis. Xanthoceras is a perennial plant native to northern China and is now cultivated. Wenguan is mainly used for the treatment of rheumatoid arthritis, rheumatoid arthritis, and skin rheumatism. It was included in the Chinese Pharmacopoeia in 1977. The present inventors have found that the preparation containing the extract of Xanthocera or C. sinensis as the main component has an effective pharmacological action and an excellent therapeutic effect on UI and 0AB, and has no toxic side effects. Summary of the invention

 The object of the present invention is to prove that the preparation of the extract of Xanthoceras sorbifolia and the extract of Xanthoceras sorbifolia is effective and less toxic for the treatment of urinary incontinence and overactive bladder for use in medicines and functional health foods.

 The present invention antagonizes the effect of Ach (acetylcholine)-induced contraction of isolated bladder smooth muscle in rats by the effect of extract of Xanthoceras sorbifolia on isolated bladder smooth muscle of rats, and proves that the extract of Xanthoceras sorbifolia has a relaxing effect on bladder detrusor, possibly Antagonizing choline-like effects. The effects of extracts of Xanthoceras sorbifolia L. on the in vitro bladder sphincter and the bioelectricity of extracellular electrodes of rabbit bladder external sphincter were demonstrated by the effect of extracts of Xanthoceras sorbifolia L. on the bladder sphincter. The effects of extracts of Xanthoceras sorbifolia L. on the frequency of urinary excretion in water-loaded mice and the leakage of urinary pressure after pudendal nerve injury in rats demonstrate that extracts of Xanthoceras sorbifolia can improve the symptoms of urinary frequency, enuresis, urinary incontinence and other symptoms of 0AB. Through the effect of extract of Xanthoceras sorbifolia L. on the urinary kinetics of citric acid-induced overactive bladder, it was proved that extract of Xanthoceras can increase the bladder capacity of 0AB rats, but has no effect on normal bladder.

 Experimental Example 1 : Effect of extract of Xanthoceras sorbifolia and imipramine on isolated bladder smooth muscle of rats

 The test animal strain used in the experimental examples of the present invention is a clean-grade Wi s tar rat. The experimental method is to surgically extract the bladder and make a smooth muscle strip; the smooth muscle is placed in a constant temperature nutrient solution, and under the condition of oxygen supply, the crown is added. Fruit extract, Ami. Qin, observe the changes of smooth muscle.

 Criteria: By transducer calibration, when the baseline decreased by 0.5, the smooth muscle was completely relaxed, the baseline did not become smooth muscle, and the baseline rose to smooth muscle contraction.

Table 1 Solution concentration of rat bladder smooth muscle in complete relaxation Group experiment times solution concentration (mg/ml) Amimethine Qin 12 0. 15 Xanthoceras extract 12 0. 80 Experimental results show: The extract of Xanthoceras can directly act on the smooth muscle of the bladder to relax.

 Experimental Example 2: The extract of Xanthoceras sorbifolius antagonizes the effect of Ach contraction on isolated bladder smooth muscle of rats. The experimental method was the same as Experimental Example 1.

Table 2 Echinacea extract + Ach and Ach contracted EC _{5 of} isolated bladder smooth muscle. Determination

Drug EC ₅ o( mg/ml ) P (f=∞) (t=2.5)

Ach 3. 4 χ ^10-11

Sorbifolia extract ^{+ Ach 2. 9 x 10- 10 <} 0. 05 The results showed that: sorbifolia extract antagonistic Ach contraction of isolated urinary bladder smooth muscle, smooth muscle complete relaxation shrinkage.

 EXPERIMENTAL EXAMPLE 3: Effect of extract of Acanthus chinensis, acetylcholine, and tolterodine tartrate on bladder and urethral sphincters in female non-fertility rats

 The experimental animal strain used in the experimental examples of the present invention is a clean-grade Wi s tar rat. The experimental method is to remove the bladder and urethra by surgery, remove the peripheral connective tissue, and take the material at the junction of the bladder and urethra to wake up and hang from the constant temperature nutrient solution. In the bath, under the conditions of oxygenation, the extract of Xanthoceras sorbifolia, acetylcholine, and tolterodine tartrate were added to observe the effects on the contraction rhythm and the amplitude of contraction.

 Table 3A Effects of different concentrations of acetylcholine on contraction rhythm and contraction amplitude of bladder/urethral sphincters in non-fertile rats

Acetylcholine concentration ( mo l /L ) contraction rhythm (seconds) contraction amplitude (g)

 0 (balanced state) 18. 4 ± 1. 87 0. 035 soil 0. 005

 10-'

 19. 5 ± 2. 49 0. 038 ± 0. 006

^{10- 8 16. 5 ± 1. 86 0.} 040 ± 0. 007

10 ⁷

15. 6 ± 1. 64 0. 052 ± 0. 01 * 10" ⁶

 13.3± 1.76* 0.06 ± 0.011**

10- ⁵

 10.6 ± 0.71*** 0.104 ± 0.016*** Table 3B Effects of Different Concentrations of Extracts of Radix Coronaria on Contraction Rhythm and Contraction Amplitude of Bladder / Urethral Sphincter in Non-fertile Rats

 Extract of Coleoptera extract Constriction rhythm (seconds) Contraction amplitude (g)

 ( mg/ml )

 0 (balanced state) 24.4 ±2.7 0.043 ± 0.004

 0.3

 27.4 ± 3.1 0.056 ± 0.007**

1

 27.2± 3.7 0.059 + 0.008**

3

 23· 6± 3.8 0.067 ± 0.009**

10

 22.7± 3.0 0.068 ± 0.009** Table 3C Effects of different concentrations of tolterodine tartrate on contraction rhythm and contraction amplitude of bladder/urethral sphincters in sterile rats

Tolterodine concentration of tartrate (μ contraction rhythm (seconds) contraction amplitude (g)

 g/ml )

 0 (balanced state) 28.1 ±2.7 0.045 ± 0.005

 0.6

 26.7 ±2.7 0.044 ± 0.006

0 (balanced state) 36.0±4.9 0.043 ± 0.005

 20 0.051 soil 0.005***

 37.0± 4.8

0 (balanced state) 35.3 ±4.1 0.053 ± 0.006

 60

32.9 ±4.0 0.067 ± 0.007** υ,丁i*ji

 20.7 ± 3.3 0.030 ± 0.005

 200

 21.2± 3.2 0.048 ± 0.008* The experimental results show that: The extract of Xanthoceras sorbifolia can increase the dose-dependent increase of bladder and urethral sphincter in female non-fertility rats, which is statistically significant. The contraction rhythm has an increasing trend, but it is not statistically significant. , affecting with tolterodine tartrate.

 Experimental Example 4: Effect of extract of Acanthus chinensis, acetylcholine, and tolterodine tartrate on recovery of bladder and urethral sphincter in female rats after childbirth

 The method was the same as Experimental Example 3.

 Table 4A Effects of different concentrations of acetylcholine on contraction rhythm and contraction amplitude of bladder/urethral sphincter in female postpartum recovery

Acetylcholine concentration (mol/L) contraction rhythm (seconds) contraction amplitude (g)

 0 (balanced state) 22.3 ± 3.1 0.031 soil 0.003

 10-'

 25.9 ± 5.4 0.030 ± 0.002

^10-8

 24.2 ±4.6 0.034 ± 0.003

 10"

 21.8 ± 3.3 0.039 ± 0.005*

10" ⁶

 12.4 ± 1.6** 0.089 ± 0.013**

10 ⁵

 10.4 ± 0.8*** 0.175 ± 0.018*** Table 4B Effects of Different Concentrations of Extracts of Elaeagnus glabra L. on Contraction Rhythm and Contraction of Bladder / Urethral Sphincter in Rats

 Extract of Coleoptera extract Constriction rhythm (seconds) Contraction amplitude (g)

 ( mg/ml )

 0 (balanced state) 42.9 ± 10.6 0.068 ± 0.012

 0.3

 39.4 ± 11.0 0.072 ± 0.012

 1

25.8 ± 3.2*** 0.095 soil 0.019* 3

 19.2 ± 1.2*** 0.099 soil 0.018**

10

 20.8 ±4.1** 0.104 soil 0.021** Table 4C Effects of different concentrations of tolterodine tartrate on contraction rhythm and contraction amplitude of bladder/urethral sphincter in female after recovery

Tolterodine concentration of tartrate (μ contraction rhythm (seconds) contraction amplitude (g)

 g/ml )

 0 (balanced state) 24.7 ±6.4 0.051 ± 0.006

 0.6

 34.7 ± 8.2 0.055 ± 0.006

0 (balanced state) 43.3 ± 17.4 0.046 ± 0.008

 20

 36.2 ±9.5 0.070 ± 0.018**

0 (balanced state) 35.8 ±4.1 0.048 ± 0.007

 60

 37.7 ±6.8 0.069 ± 0.010***

0 (balanced state) 41.4 ± 3.7 0.058 ± 0.008

 200

 32.6 ± 3.4** 0.099 ± 0.021*** The results of the experiment showed that the extract of Xanthoceras sorbifolia could restore the dose-dependent increase of bladder and urethral sphincter in rats after birth, and the contraction rhythm was accelerated, which was statistically significant. Trojanin also reduced the dose-dependent increase of bladder and urethral sphincter in male rats after birth, which was statistically significant. The contraction rhythm has a changing trend.

Experimental Example 5: Effect of extract of Xanthoceras sorbifolius on the bioelectricity of extracellular electrodes of rabbit bladder external sphincter Experimental method: The buried electrode was surgically placed, and the changes of extracorporeal sphincter in rabbits were recorded by physiological recorder. Mode of administration: Administration by intragastric administration. Midodrine, a drug called adrenaline, is a selective alpha. Adrenergic receptor agonists, commonly used in stress urinary incontinence.

 Table 5 Effect of extract of Xanthoceras sorbifolius on bladder external sphincter

 Group Number of cases (only) Dose Frequency (times / min) Amplitude (mv) Duration (min)

* *

 Control group 30 5.5 ± 3· 0 4.2 ± 1· 8 0.2 ± 0.1 m Duo 10 0.4rag/kg 35.4 soil 11.6* ·= 14.9 ± 6.7** 18.7 low soil dose 10 0. lg/kg 25.6 soil 10.1* * 9.7 ± 4.2** 8.2 high soil dose 10 0.2g/kg 31.3 ± 12.8*' * 13.9 ± 5.4** 12.6 soil

6.3** Note *: Ρ < 0.05 compared to the blank group. **: Compared with the blank group Ρ< 0.01

 The experimental results show that: extracts of C. sinensis (derived from refined example 4, capsules) and midodrine can significantly increase the frequency and amplitude of bioelectrical activity of extracorporeal sphincters in rabbits, indicating that the bladder sphincter excitability is significantly enhanced. The role.

 Experimental Example 6: Effect of extract of Xanthoceras on the frequency of urination in water-loaded mice

 The test animal strain used in the experimental examples of the present invention was a clean-grade Kunming mouse, and was administered orally. The extract of Xanthoceras sorbifolia was derived from Refining Example 4, and was made into a capsule. The control drug Imipramine has a strong antidepressant effect and a weak atropine-like effect, and is often used in depression and enuresis in children. The experimental method is based on the color reaction of potassium iodide and starch drying in urine, and the number of urination is calculated.

 Table 6 Effect of extract of Xanthoceras sorbifolius on the frequency of urination in water-loaded mice

排尿次数（次 /只） X土 SD Number of animals in the group

Number of urination (times / only) X soil SD

(only) (g/kg*d) 0.5h 1. Oh 2. Oh 3. Oh saline 10 equal volume χ 10 1.2 ± 1.1 2.9 ± 1.4 2.4 ± 1.6 1.2 ± 1.1 丙咪 calls 10 0.01 X 10 0.9 ± 0.7 2.9 ± 1.3 2.6 ± 1.5 1.3 ± 0.8 Low-dose extract 10 0.10 x 10 1.0 ± 0.7 2.4 ± 1.3 2.0 ± 1.5 1.4 1.1

High dose extract 10 0.20 x 10 0.8 ± 0.6 1.9 ± 1.0* 1.9 ± 1.6 0.8

 Note *: Compared with the blank group P < 0. 05

 The experimental results show that a certain dose of extract of Xanthoceras sorbifolia can reduce the number of urination in water-loaded mice within a certain period of time.

 Experimental Example 7: Effect of extract of Xanthoceras sorbifolia L. on leakage point pressure after pudendal nerve injury in rats Experimental method: Wi s tar rats were anesthetized with 10% hydrated chlorinated phenol, fixed on the operating table, and disinfected in double groin The posterior opening is separated from the tibia to the sciatic nerve fossa along the abdominal wall, and the vaginal nerve under the occlusion of the bilateral sciatic nerve is cut off and sutured. Sham-operated animals were only isolated to the sciatic nerve fossa. Animals were dosed 18 days after surgery, and administered 1 hour before the test on 21 days, and the bladder leak point pressure was measured.

 Table 7 Effect of extract of Xanthoceras sorbifolia L. on leakage point pressure after pudendal nerve injury in rats ( ###p<0. 001 Vs sham, **p<0. 01 Vs con )

 Sham operation group Model group Administration group (600mg/kg)

N 12 10 10

 Leakage point pressure 16. 42±2. 096##

 38. 04 士 3. 061 29. 26±2. 642**

( cmH ₂ 0 )

 The experimental results show that a certain dose of extract of Xanthoceras sorbifolia can significantly improve the symptoms of decreased urinary pressure after pudendal nerve injury in rats.

 Experimental Example 8: Effect of extract of Xanthoceras sorbifolia on urinary motility induced by citric acid in rats with overactive bladder

 Experimental methods: Wis tar rats were intravesically implanted with PE- 50 catheter for bladder pressure measurement at 7, 10, and 14 days, and the bladder volume and maximum pressure during urination were observed. Twenty bladder pressure measuring solutions were citric acid, and 10 rats in the control group were physiological saline; 20 rats were intraperitoneally implanted with PE- 50 catheter and then infused with the extract of C. elegans. Bladder pressure was measured before perfusion, 2 days and 6 days after perfusion. Ten pressure-measuring solutions were citric acid and 10 were normal saline.

 Table 8 Effect of extract of Xanthoceras sorbifolia on urinary kinetics induced by citric acid in rats with overactive bladder ( X soil

S) (* represents a comparison with the extract of the extract of the genus Corollae before p<0. 01)

Group average bladder pressure measurement volume (ml) Xanthoceras sorbifolia extract perfusion of the extract of the extract of the corolla fruit, 2 days after the infusion of the extract of the corolla fruit

 OAB group 0. 42 ± 0. 43 0. 58 ± 0. 53* 1. 02 ± 0. 43· Normal group 1. 12 ± 0. 44 1. 09 ± 0. 42 1. 15 ± 0. 53

 The experimental results show that the extract of Xanthoceras sorbifolia can increase the bladder capacity of rats with citric acid-induced overactive bladder, but has no obvious effect on normal bladder.

Claims

Rights request The application of the extract of Xanthoceras sorbifolia and the extract of the genus Coronaria in the preparation of a medicament for treating urinary incontinence. The application of the extract of Xanthoceras sorbifolia and the extract of Xanthoceras sorbifolia in the preparation of a medicament for treating overactive bladder. The use according to claim 1, wherein the preparation of the treatment of urinary incontinence refers to stress, urgency or mixed urinary incontinence. The use according to Claim 3, characterized in that the preparation of the treatment of urinary incontinence means antagonizing Ach contraction of isolated bladder smooth muscle. The use according to claim 3, characterized in that the preparation of the treatment of urinary incontinence means relaxation of the bladder detrusor. The use according to claim 3, wherein the preparation of the treatment of urinary incontinence is contraction of the bladder sphincter. The use according to claim 2, characterized in that the preparation of the treatment of overactive bladder refers to relaxation of the bladder detrusor. The use according to claim 2, characterized in that the preparation of the treatment of overactive bladder refers to antagonizing Ach contraction of the bladder detrusor. The use according to any one of claims 1 to 8, wherein the extract of the dried fruit of the crown is obtained by water extraction, alcohol extraction or other conventional methods. A pharmaceutical composition for treating urinary incontinence or overactive bladder, characterized in that the pharmaceutical composition contains 1% to 99% of the crown of the fruit or the extract of the crown of the crown of claim 9.