JPS6251242B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a medicament for the treatment of hypertonic functional conditions around the bladder and to applications of this medicament. Cholinergic neuromuscular dysfunction of the bladder compressor muscles around the bladder manifests as, for example, urinary incontinence, painful bladder spasms, and nocturnal polyuria. Apart from the mental burden, these conditions lead to social exclusion, long absences from work, and large medical expenses. Conventionally, treatments for these disorders have been performed in a variety of ways. Analgesics are used solely symptomatically, phenothiazine derivatives or other antidepressants are used to treat the psychological component, and anticholinergic agents such as atropine and scopolamine butylpromide are used to treat general lubrication. Although it attempts to relieve muscle spasms, it has insufficient effect on the bladder and has many other side effects. The problems mentioned above in the treatment of dysfunctions in the area of the bladder depressor muscles are based on the variable response of patients to the products introduced for treatment and the lack of specificity in the drugs used. . The lack of specificity results in considerable side effects in the sense of undesirable cardiac and circulatory system reactions, dry mouth, impaired adaptation and contraindications or central effects culminating in a state of excitement and hallucinations. Emepronium bromide has been introduced for treatment since 1957, but requires high doses of 600 mg/day (in rats) and has an LD ₅₀ of 1000 mg/Kg (in rats). Comparison with the intravenous dose - 8.35 mg/Kg in rats - suggests a modest absorption rate observed clinically and pharmacodynamically confirmed. Side effects have been described, such as increased pulse rate, dry mouth, and ulcers in the oral cavity and esophagus. Furthermore, diphenyl hydroxyacetic acid induces compounds that exhibit muscle-promoting, antispasmodic, antihistamine, analgesic, and strong anticholinergic effects in the central nervous system.
They are therefore used to experimentally influence parkinsonism, to relieve tension in the smooth muscle system in the gastrointestinal tract (e.g. in the case of gallstone colic) and to suppress reactions caused by histamine in diseases of allergy origin. It is known that it was used for this purpose. On the contrary, there is no specific therapeutic use of diphenylhydroxyacetic acid derivatives for selectively influencing the hypertonic functional state of the bladder depressor muscles in the area of the bladder. This is because the known functional performance did not give any suggestion regarding this. The purpose of the present invention is to be able to effectively treat hypertonic functional conditions around the bladder. The object of the present invention is to develop a medicament that can be used to effectively treat the hypertonic functional state of the bladder depressor muscles around the bladder. Surprisingly, α,α-diphenyl-α-alkoxyacetic acid-1-methylpiperidyl-4-ester derivatives () and their salts with inorganic and organic acids, especially α,α-diphenyl-α-n-propoxyacetic acid- 1-Methylpiperidyl-4-ester hydrochloride () is particularly advantageous for enlarging the bladder capacity after bladder and prostate surgery, but also by miktion in cases of hypertonic overactive bladder. It has been found that it can be used to lower intravesical pressure and relieve painful bladder tenesmus of various origins, as well as for the treatment of urinary frequency, nocturnal polyuria and nocturnal enuresis. This substance was first synthesized by J. Kloss. Preparations of this substance according to the invention include tablets and
All the usual oral and parenteral forms of application such as dragees, capsules, suppositories and ampoules are considered. For this purpose, the active substance is mixed with solid or liquid carrier substances and subsequently brought into the desired pharmaceutical form. The active substance is administered at a daily dose of 15-60 mg for humans;
25-100 mg rectally and 10-30 mg parenterally.
Applicable. The invention offers the advantage that with the use of compounds, in particular in the case of hypertonic functional states of the bladder and the bladder disorders resulting therefrom, a unique treatment and at the same time excellent compatibility is possible. Even if the dosage is high, the side effects that occur are negligible, and there are no changes in blood picture, pulse rate, plasma protein, residual nitrogen, or blood sugar levels. In addition, the possibility of intravenous injection of the active substance should be considered as particularly advantageous. With dosages in the above range, good to very good therapeutic effects were achieved in patients undergoing bladder and prostate surgery aimed at increasing bladder capacity after surgery. This active substance is used to reduce the intravesical pressure due to miktion in cases of hypertonic irritable bladder and urinary incontinence, and to relieve painful bladder spasms of various origin, as well as in hypertonic functional states of the bladder depressor muscles. It has shown excellent results in the treatment of frequent urination, nocturnal polyuria, and nocturnal enuresis caused by. The advantages of the compounds according to the invention over the state of the art are demonstrated by means of some examples. 1. Neurotropism - antispasmodic effect The research was carried out in normal equipment. The ability to suppress intestinal contraction caused by acetylcholine (bath concentration 10 ^-7 g/ml) in isolated guinea pig ileum was tested. The investigated substances were tested at 4 to 6 different concentrations and the dose (ED ₅₀ ) with a 50% inhibitory effect was determined by graph interpolation.

[Table] The neurotropic and antispasmodic effects of the compound in the guinea pig ileum are clearly lower than that of the control substance. This may explain the significant lack of adverse side effects (eg constipation) in the gastric and intestinal tract regions. 2. Clinical effects The effects of the compounds on the tone of the bladder depressor muscles in various urinary diseases were investigated in terms of their effects on bladder capacity. Bladder capacity and pressure measurements were performed by measuring bladder sphincter pressure, and the inflow rate,
The study was conducted while keeping parameters such as water column height and catheter thickness constant. The bladder capacity existing before application of the compound was determined as the average value of three individual measurements and recorded as a comparative or reference value. 10mg of compound per patient
was administered intravenously, and 30 minutes later, bladder capacity was measured again. It has been found that the effects of this substance are particularly evident in the bladder, which has a small initial volume, and in the functional state of excessive tension around the bladder depressor muscles. The mean increase in bladder capacity for this group of patients was 67%. Comparison of the action with atropine particularly shows the advantage of the selective action of the compound. A corresponding study on the same group of patients found that for an intramuscular injection of 0.5 mg of atropine per patient, the average bladder capacity increase 45 minutes after injection was 12% with atropine compared to the intramuscular effect of 15 mg of the compound per patient. and 60% for the compound. Furthermore, it has been confirmed that it is particularly advantageous that even at the above-mentioned dosage, atropine causes dry mouth, mydriasis, and accommodative disorders, whereas the compound does not cause any contraindications. Oral administration of the compound confirmed in principle all the results of the acute experiments during intravenous application. The study was carried out in a total of 75 patients in the form of a one-time dose of 15 to 30 mg bolus and in a long-term study with an average of 180 days at doses of 3 x 15 mg to 4 x 15 mg of active substance. In the long-term study, the average number of micturitions before the treatment trial was 14 times a day. With the application of the active substance, the frequency of urination was reduced to 5 times a day. No clear effect could be demonstrated in the placebo group. What was most impressive was the effect of the compound on nocturnal polyuria. The average nocturnal micturition frequency before the treatment trial was 5 times per night. With the application of the active substance, the number of micturitions was no longer 0-1. Placebo treatment had no effect. Long-term treatment also showed very strong changes in bladder capacity. With long-term administration of the active substance, an average increase of 200% could be recorded in patients with an initial bladder capacity of 50-80 ml. Bladder capacity increased by an average of 130% in patients with an initial volume of 80-150 ml. Placebo treatment had no demonstrable effect here. The compatibility of the active substances was excellent both in patients with short-term application and during long-term treatment. All clinical and extra-clinical parameters investigated such as blood picture, urinary status, blood sedimentation rate and liver function tests were normal. Patients with high serum creatinine levels also showed no deterioration or increase in urinary nitrogen compounds. 3. Pharmacodynamic behavior The tissue distribution of the compound in rats showed that 72 hours after oral administration, relatively high concentrations appeared in adipose tissue (reflecting the lipophilic nature of the substance), and minimal amounts appeared in the liver, uterus, and muscle system. 80% of the applied dose was found in urine. The course of renal excretion is as follows: 6 hours after oral administration, 30% and 24 hours after application, 50% were already excreted from the kidneys and could be detected in the urine. This particular pharmacodynamic behavior explains the little or no anticholinergic effect in the central nervous system and the selective action around the bladder and bladder depressor muscles. In addition, due to the lipophilic nature of this substance, a strong action of the compound on the bladder wall by reabsorption must be considered. 4. Toxicological behavior Average pore dose for adults is only 3 x 15 = 45 mg
It's nothing more than that. The LD ₅₀ (rat, caliber) is 2250 mg/Kg, and intravenously the LD ₅₀ (rat) is 29 mg/Kg. Therefore, the toxicity is emepronium. significantly less than that of bromides. Advantageous therapeutic breadth is achieved. Other side effects characteristic of anticholinergic agents do not occur at therapeutic doses of the compounds. Using 5% of LD ₅₀ for six months (rat)
General toxicity studies did not result in macroscopic or histological organ changes or effects on fertility. The invention will be explained in more detail below with reference to the examples: The active substances of the invention can be mixed with solid carrier substances using lactose, starch, talc, methylcellulose, magnesium stearate and gelatin. In that case, the formulation for a 100 mg tablet is, for example, as follows: Compound 15 mg Potato starch 45 mg Lactose 30 mg Talc 10 mg In this case, for tablet production, the active substances are 75% of the potato starch, the total amount of lactose and about 10%. of gelatin solution and granulate using a suitable device. After drying at a maximum of 30°C, the granules are mixed with talc and remaining starch and pressed into tablets. Example of ampoule solution: Compound 1.0g Propylene glycol 50.0ml 1N Hydrochloric acid 2.6ml Add water for injection to 200.0ml Example of suppository manufacturing 100g of suppository contains 2.5g of compound Add Raspol to 200.0g. The results of tests carried out using the agents of the invention using urinary mechanisms that are internationally standardized and detailed in the literature are detailed below. (1) Explanation of bladder capacity The effects of the agonist of the present invention on bladder capacity were investigated in patients with various urinary diseases. Measurement of bladder capacity and left values with VEB Medizin
―Zysto―Sphinktero manufactured by und Labortechnik
This was done using a Tonometer. Measurements are made of certain parameters (perfusion rate, volume on the suprapubic symphysis crest)
It was performed using a 100ml Irligator container (the diameter of the catheter). Physiological maximal bladder filling was determined as the average of three cystometric measurements. Cystometric measurements were performed and compared at various times after administration of the agents of the invention. Increases in bladder capacity ranged from approximately 35% to 117% (or up to 217%), depending on initial volume and symptoms. An example is given below.

[Table] (2) Measurement of bladder tone Cystotonometry was planned using a Biomonitor.
To determine the starting value of cystotonometry, the bladder was continuously filled with a 0.9% NaCl solution at body temperature (50 ml/min) and the venous pressure was recorded at the same time. Occasional delayed or involuntary contractions of the depressor muscles appeared in the pressure recordings. On the recording strip, all individual data of the patient during the filling tonometry were recorded. The basis for the statistical comparison between the measurements before and after treatment with the active substance is the venous pressure immediately after reaching the maximum bladder capacity, as well as the volume of fluid instilled up to this point. In addition, the number and amplitude of involuntary depressor muscle contractions;
Take into account data such as the patient's emergency symptoms, incontinence, and frequency of nocturia. In the case of treatment with the agents of the invention, the mean value of the venous pressure recorded at maximal bladder filling was 2.59 ± 0.55 kPa before treatment and after 4 weeks of treatment.
It was only 2.23±0.51kpa. This reduction is statistically significant and is based on 100% of the venous pressure at the start of treatment.
This means that the venous pressure decreased by 8.47%. (3) Measurement of urinary flow rate The urinary flow rate, that is, the flow of urine per unit time, was measured using a uroflowmeter. A uroflowmeter is a device that graphs and automatically records the amount of urine discharged from the bladder per unit time. The evaluation is carried out on the basis of the recorded course of the curve. As a result of the action of the agents of the invention, the urine flow rate was reduced by 5 to 8 ml/sec and there was no residual urine. (4) Enlargement of the bladder In addition, it has been demonstrated radiographically by conventional methods that the administration of the agents of the invention causes enlargement of the bladder. (5) Decrease in urination frequency. Patients who used to urinate 14 times per day decreased to 5 times per day.
It was observed that the frequency of micturition decreased to 0 to 1 micturition per night in a patient who had urinated 5 times per night while urinating during sleep. (6) Elimination of urinary incontinence Patients with various urinary diseases were uniformly treated according to a fixed study plan. In this case, in addition to the group of patients treated with the active substance of the invention, a comparison group of patients was prepared, each treated with Buscolysin and Placebo.
Drug effects and side effects were ascertained and recorded based on clinical symptoms and findings through patient interviews. The agents of the invention eliminated or significantly reduced urinary incontinence in more than 52% of patients, and the effect was greater than that of buscolydin and placebo.

Claims (1)

[Claims] 1. At least one α,α-diphenyl-α-alkoxyacetic acid-1-methyl-4 as active substance.
- piperidyl ester derivatives and their non-toxic and pharmacologically acceptable salts with organic and inorganic acids;
A medicament for the treatment of hypertonic functional conditions around the bladder, characterized in that it contains both or either one of them in admixture with a solid or liquid pharmaceutical diluent or carrier substance. 2. A medicament according to claim 1, wherein the active substance is α,α-diphenyl-α-n-propoxyacetic acid-1-methyl-4-piperidyl-ester-hydrochloride. . 3. A medicament according to claim 1 or 2, which is characterized in that it is used orally, in the intestinal tract, or extraintestinally. 4. In the statement of claim 1, 2, or 3, tablets, drops, capsules,
A medicine characterized by being used in the form of a suppository or ampoule.