JPH0653679B2 - Urethral pressure enhancer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION a. TECHNICAL FIELD The present invention relates to an agent for enhancing urethral pressure. More specifically, the present invention relates to an urethral pressure-enhancing agent that can be used for treating various dysuria caused by a decrease in urethral pressure.

b. 2. Description of the Related Art The basic function of the bladder and urethra is to store the urine sent from the kidney and discharge it outside the body when necessary. That is, the urinary bladder is highly stretchable during the urine storage period, and normally 300 to 400 ml of urine can be stored without increasing the intravesical pressure. At the same time, the urethral sphincter (both internal and external sphincter) is contracted to prevent urinary incontinence. On the other hand, during the micturition period, the micturition reflex occurs under conscious control, and the detrusor muscle (smooth muscle) that forms the bladder muscle layer contracts, and at the same time, the urethral sphincter group relaxes simultaneously. It is known that in the physiological cycle consisting of urine storage and urination, the reflex mechanisms of the peripheral and central nerves that control the bladder and urethra work in a complicated manner.

By the way, the bladder is divided into a top part, a body part, and a bottom part, and the urethra is divided into a proximal part and a distal part which are connected to the bottom part of the bladder. And
Regarding distribution of sympathetic nerve receptors (receptors), α receptors are predominantly in the bladder floor and proximal urethra, and β receptors are predominantly in the bladder body part. In general, when the α receptor is stimulated, the smooth muscle contracts, and when the β receptor is stimulated, the smooth muscle relaxes.However, during the urinary storage period, the β receptor of the detrusor muscle of the bladder is stimulated, so that the bladder relaxes and the proximal urethra at the same time. Stimulation of the α-receptor causes the urethral sphincter to contract and increase urethral pressure. Therefore, stimulation of β-receptors with, for example, β-agonists relaxes the smooth muscles of the bladder body, creating a favorable condition for storing urine in the bladder. It has been found that the subtype of β receptor is β ₂ receptor, and so-called β ₂ agonists have been attempted to be applied to the treatment of motor urge incontinence in particular.

c. Problems to be Solved by the Invention In a healthy person, the urethral pressure is always higher than the bladder pressure,
It can be said that urinary incontinence occurs when the bladder pressure becomes higher than the maximum urethral pressure, so that urine easily leaks. The cause of this increase in bladder pressure is considered to be an increase in contractile force due to uninhibited contraction of detrusor muscle, and a decrease in maximum urethral pressure may be due to neuropathy or weakening of supporting tissues.
Therefore, theoretically, for the treatment of urinary incontinence, it is considered that a drug that lowers the tone of the detrusor muscle or raises the urethral pressure, or has both of these actions. Β _{2 in} this sense
As described above, the agonist has a relaxing effect on the bladder smooth muscle, and is considered to be theoretically appropriate as a therapeutic drug for urinary incontinence.

However, the effect of β ₂ agonists on urethral pressure is
Little has been studied, and only a few adverse reports have been reported regarding the treatment of urinary incontinence, in which the use of certain β ₂ agonists (terbutaline) reduced urethral closure pressure.

Therefore, a drug that increases urethral pressure is also necessary to treat dysuria such as neuropathy or weakening of the supporting tissue of the urethral region, resulting in decreased urethral pressure and involuntary urine leakage. is there.

d. Means for Solving the Problems As a result of earnest search for a drug capable of enhancing urethral pressure, the present inventors have newly found that it has an action effect on a β ₂ agonist, and arrived at the present invention.

That is, the present invention is a urethral pressure enhancer containing a β ₂ agonist as an active ingredient.

The intraurethral pressure-enhancing agent of the present invention is used for various dysuria caused by a decrease in urethral pressure due to neuropathy, weakening of urethra-supporting tissue or uncontrolled contraction, for example, neurogenic bladder, unstable bladder, and neural tachycardia. It can be used as a treatment for urine, stress urinary incontinence, and nocturnal enuresis.

The β ₂ agonist is generally known as a relaxant for airway smooth muscle via the β ₂ receptor and is widely used as a therapeutic agent for asthma.

The β ₂ agonist in the present invention may be any agent as long as it has an action via the β ₂ receptor, but a drug having a high β ₂ selectivity and acting for a long time is preferable. Examples of these include salbutamol, terbutaline, hexoprenaline, bitolterol, pirbuterol, fenoterol, turoterol, procaterol,
Formoterol, mabuterol, clenbuterol and the like can be mentioned.

The dose and administration method of the drug of the present invention are not particularly limited, as long as each β ₂ agonist is used as a standard for the usual dose and usual method when used as an asthma therapeutic agent. The administration period is also not particularly limited, but administration of at least 1 week to 2 weeks is required for the onset of effects.

e. Examples Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1 Clenbuterol, which is a β ₂ agonist having high β ₂ selectivity and long-acting at a low dose, was treated with neurogenic bladder, unstable bladder, nervous frequency, and stress urine at ages 9 to 89 years. 20 μ in a total of 174 cases (patients) including diseases such as incontinence and nocturnal enuresis
Oral administration was performed twice a day in the morning and in the evening for 2 weeks in the range of g / day to 60 μg / day. Measurement of urethral pressure before and after administration, along with examination of clinical symptoms such as frequency of urination, urgency, residual urine, discomfort during or after urination, urinary incontinence, urinary incontinence amount, investigation of side effects, evaluation of the effect by the attending physician Was done. Of the 174 cases where clenbuterol was administered, the urethral pressure was measured, and there were 66 cases in which both the data before and after administration were complete. Average 6.
It increased by 712 mmH ₂ O.

When the agent of the present invention was administered, the overall improvement rate (170 cases) including neurogenic bladder, unstable bladder, nervous frequency, abdominal pressure incontinence, nocturnal enema, etc. was 57.0% (slightly improved or higher). ), And showed quite high effectiveness. Looking at each disease,
After a slight improvement, neurogenic bladder (83 cases) 49.4%, unstable bladder (19 cases) 52.6%, nervous frequency (24 cases) 62.6%, stress incontinence (27 cases) 81.4%, nocturnal enuresis ( 11 cases) 36.4%, other cases (6 cases) 83.3%.

It is clear that administration of the drug of the present invention increases the urethral pressure, and that various therapeutic effects on dysuria are obtained.

It should be noted that administration of the drug of the present invention caused slight side effects such as finger tremor, lower abdominal discomfort, palpitations, malaise and constipation in 21.7%, but it was not a problematic one.

[Method of measuring urethral pressure] In the present invention, the urethral pressure was measured by the following method. Insert a catheter with a small hole in the side wall of the tip into the urethra, contact the distal end with a drip infusion device and an intraurethral pressure recorder, and slowly inject water until the water is in close contact with the side of the urethral mucosa. ， Overcome muscle layer resistance (urethral wall pressure: Pw),
The pressure (fluid pressure of the catheter: Pf) when flowing out through the gap between the catheter and the mucous membrane is drawn. At this time Pf-P
w is so small that it can be ignored. That is, it may be considered that Pf≈Pw, and the fluid pressure of the catheter can be measured as the urethral wall pressure. When the tip part is gradually pulled out from the bladder and continuously recorded, Pw is drawn as a profile as shown in FIG.

Example 2 First, the effect of clenbuterol on the contractile response of the rabbit external urethral sphincter was examined. The external urethral sphincter of a male Japanese white rabbit weighing 3 kg was separated from the urethra and sliced in the annulus, then suspended in a high temperature liquid bath containing Krebs Henseleit solution (37 ℃, pH7.4) and contracted. The force was measured isometrically. An initial tension of 1 gram was applied followed by equilibration for at least 1 hour. Wear platinum electrodes so as to sandwich the muscles, and apply 0.5 millisecond length of electrical stimulation for 15 seconds at 40Hz for 15 seconds.
Repeated every second, 1 to 1 by transmural electrical stimulation
2 grams of shrinkage occurred. 15 stimulation for this muscle
When clenbuterol (10 ⁻⁸ M) was added as shown in FIG. 2 after the contraction magnitude became constant at intervals of seconds, clenbuterol gradually enhanced the contraction due to transmural electrical stimulation. The increase in the contraction force is
It was about 40% in 10 to 20 minutes. Therefore, in this system as well, it was confirmed that clenbuterol had an effect of enhancing urethral pressure.

Next, the presence or absence of inhibition of this action by propranolol was examined. Propranolol (Sigma, Hydrochloride, 3 × 10 ^-6
M) had little effect on contraction by transmural electrical stimulation, but as shown in FIG. 2, the enhancing effect of clenbuterol was propranolol (3 × 10 ⁻⁶ M).
It was competitively inhibited by the addition of. This clearly shows that the urethral pressure-enhancing effect of clenbuterol is a result of clenbuterol functioning as a β agonist.

Furthermore, the action of isoproterolol (sigma, hydrochloride), which is the most typical β agonist and has the activity as a β ₂ agonist but no β ₂ selectivity, was examined. That is, the same test as above using the external urethral sphincter isolated from rabbit was conducted while comparing with clenbuterol. The results are shown in FIG. From this data, it can be seen that isoproterenol, which is not β ₂ -selective, has a dose-dependent activity to enhance the contraction of the external urethral sphincter, similarly to clenbuterol, but to a lesser extent than clenbuterol. From this, it is understood that the urethral pressure-enhancing effects of these drugs are based on their functions as β ₂ agonists.

[Brief description of drawings]

FIG. 1 is a schematic diagram when measuring the urethral pressure. FIG. 2 shows the effect of clenbuterol and propranolol on transmural electrical stimulation contraction of the external urethral sphincter.
FIG. 3 shows the effect of clenbuterol and isoproterenol on transmural electrical stimulation contraction of the external urethral sphincter.

Claims (3)

[Claims] 1. A urethral pressure enhancer comprising a β ₂ agonist as an active ingredient. _2. The urethral pressure enhancer according to claim 1, wherein the β ₂ agonist is clenbuterol hydrochloride. 3. Claims for the treatment of dysuria.
The urethral pressure-enhancing agent according to the item.