Medicinal Composition for Prevention of Transition to Operative Treatment for Prostatic Hypertrophy

Abstract

The present invention provides an agent useful for the prevention of transition to surgical therapy for benign prostatic hyperplasia and the like. The present invention relates to a pharmaceutical composition for the prevention of transition to surgical therapy for benign prostatic hyperplasia, which comprises an indoline derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof (in the formula, R represents an optionally substituted aliphatic acyl group, a hydroxyalkyl group, an aliphatic acyloxyalkyl group, a substituted lower alkyl group, an optionally substituted aromatic acyl group, a furoyl group, a pyridylcarbonyl group or the like; R1 represents a cyano group or a carbamoyl group; and R2 represents an optionally substituted lower alkyl group).

Description

EXAMPLES

The present invention is further illustrated in more detail by way of the following Example. However, the present invention is not limited thereto.

Example 1

Clinical effects in patients who are subject to surgical therapy for benign prostatic hyperplasia

Based on the results of a placebo-controlled, parallel groups-comparing double blind trial carried out in patients of benign prostatic hyperplasia, clinical effects of silodosin and tamsulosin hydrochloride in patients who are subject to surgical therapy were evaluated. As the patients who are subject to surgical therapy, patients whose overall severity before administration was “severe” based on the criteria for judging overall severity (Non-patent Reference 3) were extracted.

Objects: 147 patients who are subject to surgical therapy for benign prostatic hyperplasia

Administration method: oral administration for 12 weeks

Administered groups: Silodosin group (4 mg silodosin/once, twice a day, 63 patients), Tamsulosin group (0.2 mg tamsulosin hydrochloride, once a day, 55 patients) and Placebo group (placebo drug, 29 patients).

Primary endpoints: I-PSS total score, QOL score

Criteria for judging overall severity: in the severity of respective judging items shown in Table 1, the overall severity is regarded as “severe” when “severe” is present in 2 items or more. In this connection, the Qmax in the table means maximum flow rate (mL/second), RU means residual urine volume (mL) and PV means estimated prostate volume (mL) by ultrasonic tomography.

TABLE 1
Criteria for judging overall severity
Respective judging
items	Moderate	Severe
1. I-PSS total	8-19	20-35
score
2. QOL score	2, 3, 4	5, 6
3. Qmax, Residual	Qmax: 5 mL/sec or more	Qmax: less than 5 mL/
urine volume	and RU: less than 100 mL	sec or RU: 100 mL or
		more
4. Estimated	20 mL or more, and less	50 mL or more
prostate volume	than 50 mL
(PV)

I-PSS items questioned

• • (1) Sensation of residual urine

“Have you had a sensation of not emptying your bladder completely after you finished urinating?”

• • (2) Urination within 2 hours

“Have you had to urinate again less than two hours after you finished urinating?”

• • (3) Intermittency of urinary stream

“Have you found you stopped and started again several times when you urinated?”

• • (4) Urgency

“Have you found it difficult to postpone urination?”

• • (5) Power of urinary stream

“Have you had a weak urinary stream?”

• • (6) Straining during urination

“Have you had to push or strain to begin urination?”

The scores of (1) to (6) are as follows.

Not at all: 0 point, less than 1 time in 5: 1 point, less than 1 time in 2: 2 points, about 1 time in 2: 3 points, more than 1 time in 2: 4 points, almost always: 5 points.

• • (7) Nocturia

“How many times did you get up to urinate from the time you went to bet at night until the time you got up in the morning?”

The scores are as follows.

None: 0 point, 1 time: 1 point, 2 times: 2 points, 3 times: 3 points, 4 times: 4 points, 5 times or more: 5 points.

QOL score

“How do you feel if the present condition of urination will continue from now on?”

Very satisfied 0 point, satisfied: 1 point, generally satisfied: 2 points, neither satisfied nor unsatisfied: 3 points, a little unsatisfied: 4 points, unsatisfied: 5 points, very unsatisfied: 6 points.

Results

Regarding the case of patients whose overall severity before administration was severe based on the criteria for judging overall severity (Non-patent Reference 3), changes in I-PSS total score and QOL score at the final evaluation were compared. The results are shown in Table 2 and Table 3, respectively. In this connection, comparison between the administration groups was carried out by two sample t-test, and in the tables, “*” and “**” show that significant differences were found at significance levels of less than 5% and less than 1%, respectively, and “N.S.” means that a significance was not found.

TABLE 2
Change in I-PSS total score
			Change in I-PSS at
			the end
Administration		I-PSS before	Mean ± standard
groups	Cases	administration	deviation
Silodosin	63	22.8	−12.0 ± 7.11) *2) **
Tamsulosin	55	21.9	−8.6 ± 6.23) N.S.
Placebo	29	23.5	−8.2 ± 8.2
1)Silodosin group vs. Placebo group
2)Silodosin group vs. Tamsulosin group
3)Tamsulosin group vs. Placebo group
*: P < 0.05;
**: P < 0.01;
N.S.: no significance

TABLE 3
Change in QOL score
			Change in QOL at
Administration		QOL before	the end
groups	Cases	administration	Mean ± SD
Silodosin	63	5.5	−2.3 ± 1.61) ** 2) **
Tamsulosin	55	5.3	−1.5 ± 1.33) N.S.
Placebo	29	5.3	−1.4 ± 1.3
1)Silodosin group vs. Placebo group
2)Silodosin group vs. Tamsulosin group
3)Tamsulosin group vs. Placebo group
**: P < 0.01;
N.S.: no significance

As shown in Table 2, Silodosin group significantly improved the I-PSS total score in the patients of benign prostatic hyperplasia whose overall severity before administration was severe. The effect of Silodosin group was statistically significant in comparison with Placebo group and Tamsulosin group. In addition, as shown in Table 3, Silodosin group also improved QOL score statistically significantly in comparison with Placebo group and Tamsulosin group. Based on this, it was shown that silodosin significantly improves I-PSS total score in patients of benign prostatic hyperplasia who are subject to surgical therapy and has an effect to avoid transition to surgical therapy.

Next, the effect of each administration group to improve the severity of I-PSS total score was evaluated in the patients of benign prostatic hyperplasia whose overall severity before administration was severe. The results are shown in Table 4. In this connection, comparison between the administration groups was carried out by two sample Wilcoxon test, and in the table, “*” and “**” show that significant differences were found at significance levels of less than 5% and less than 1%, respectively, and “N.S.” means that a significance was not found.

TABLE 4
Improving effect on severity of I-PSS total score
	Severity of subjective
	symptoms at the end.
	Number of patients
	(%)
Administration		Mild	Moderate	Severe	Comparison
groups	Cases	(0-7)	(8-19)	(20-35)	between groups
Silodosin	63	24	33	6	1) **
		(38.1%)	(52.4%)	(9.5%)	2) *
Tamsulosin	55	12	34	9	3) N.S.
		(21.8%)	(61.8%)	(16.4%)
Placebo	29	6	11	12	—
		(20.7%)	(37.9%)	(41.4%)
1) Silodosin group vs. Placebo group
2) Silodosin group vs. Tamsulosin group
3) Tamsulosin group vs. Placebo group
*: P < 0.05;
**: P < 0.01;
N.S.; no significance

As shown in Table 4, Silodosin group significantly improved the severity of I-PSS total score in the patients of benign prostatic hyperplasia whose overall severity before administration was severe. That is, it can be seen that the severity of I-PSS total score in about 38% of the patients who were subject to surgical therapy was improved to mild. The improving effect of Silodosin group was a statistically significant deference in comparison with Placebo group and TamsulQsin group.

As shown above, in the placebo-controlled, double blind, comparative clinical test, silodosin was able to significantly improve I-PSS total score and QOL score of the patients of benign prostatic hyperplasia whose overall severity before administration was severe and to improve symptoms of the patients who are subject to surgical therapy to a level outside of surgical therapy object, and thereby to avoid transition to surgical therapy.

Example 2

Effects on the objective symptoms of patients who are subject to surgical therapy for benign prostatic hyperplasia

Based on the results from a long-term administration test in patients of benign prostatic hyperplasia, effects of silodosin on objective symptoms of patients who are subject to surgical therapy were examined. As the patients who are subject to surgical therapy, patients whose overall severities before administration were “moderate” and “severe” according to the criteria for judging overall severity described in the above Table 1 were extracted.

Objects: 229 patients who are subject to surgical therapy for benign prostatic, hyperplasia

Administration method: 4 mg silodosin/once (can be optionally reduced to 2 mg/once), twice a day, oral administration for 52 weeks

Analyzed groups: 101 severe patients (reduced to 2 mg/once in 9 cases among them), 128 moderate patients (reduced to 2 mg/once in 17 cases among them)

As an objective symptom, results of maximum flow rate (Qmax) (mL/sec) are shown in Table 5

TABLE 5
Improving effect on maximum flow rate (Qmax)
			Before	Change after
	Administration		administration	52 weeks
Group	group	Cases	(mean ± SD)	(mean ± SD)
Severe	Silodosin	101	8.9 ± 3.0	3.2 ± 4.9
Moderate	Silodosin	128	10.3 ± 3.0	2.3 ± 5.3

As shown in Table 5, the changes after 52 weeks of silodosin administration were 3.2 mL/sec in the severe group and 2.3 mL/sec in the moderate group, and the improvement of the objective symptom was observed in each group in comparison with the case of before administration. Particularly, the effect was significant in the severe group.

INDUSTRIAL APPLICABILITY

The pharmaceutical composition of the invention is markedly useful as an agent for the prevention of transition to surgical therapy, because it can significantly improve subjective and objective symptoms of patients who are subject to surgical therapy for benign prostatic hyperplasia.

Claims

1. A pharmaceutical composition for the prevention of transition to surgical therapy for benign prostatic hyperplasia, which comprises an indoline derivative represented by a general formula (I):

2. A pharmaceutical composition for the prevention of transition to surgical therapy for benign prostatic hyperplasia as claimed in claim 1, wherein the indoline derivative is silodosin.

3. A pharmaceutical composition for the prevention of transition to surgical therapy for benign prostatic hyperplasia as claimed in claim 1 or 2, wherein the surgical therapy is transurethral resection of the prostate.

4. A pharmaceutical composition for the prevention of transition to surgical therapy for benign prostatic hyperplasia as claimed in any one of claims 1, which comprises administering to a patient who is subject to surgical therapy.

5. A pharmaceutical composition for the prevention of transition to surgical therapy for benign prostatic hyperplasia as claimed in any one of claims 1, wherein daily dose of the indoline derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is from 2 to 16 mg.

6. A pharmaceutical composition for treating a patient of benign prostatic hyperplasia whose overall severity is moderate or more, which comprises an indoline derivative represented by a general formula (I):

7. A pharmaceutical composition for treating a patient of benign prostatic hyperplasia whose overall severity is moderate or more as claimed in claim 6, wherein the indoline derivative is silodosin.

8. A pharmaceutical composition for treating a patient of benign prostatic hyperplasia whose overall severity is moderate or more as claimed in claim 6 or 7, wherein daily dose of the indoline derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is from 2 to 16 mg.

9. A method for the prevention of transition to surgical therapy for benign prostatic hyperplasia, which comprises administering an effective amount of an indoline derivative represented by a general formula (I):

10. A method for the prevention of transition to surgical therapy for benign prostatic hyperplasia as claimed in claim 9, wherein the indoline derivative is silodosin.

11. A method for the prevention of transition to surgical therapy for benign prostatic hyperplasia as claimed in claim 9 or 10, wherein the surgical therapy is transurethral resection of the prostate.

12. A method for the prevention of transition to surgical therapy for benign prostatic hyperplasia as claimed in claim 9 or 10, which comprises administering to a patient who is subject to surgical therapy.

13. A method for the prevention of transition to surgical therapy for benign prostatic hyperplasia as claimed in claim 9 or 10, wherein daily dose of the indoline derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is from 2 to 16 mg.

14. A method for treating a patient of benign prostatic hyperplasia whose overall severity is moderate or more, which comprises administering an effective amount of an indoline derivative represented by a general formula (I):

15. A method for treating a patient of benign prostatic hyperplasia whose overall severity is moderate or more as claimed in claim 14, wherein the indoline derivative is silodosin.

16. A method for treating a patient of benign prostatic hyperplasia whose overall severity is moderate or more as claimed in claim 14 or 15, wherein daily dose of the indoline derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof is from 2 to 16 mg.

17-19. (canceled)