JP2003238411A - Agent for administration before prostatic operation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent for suppressing the bleeding of the prostate gland by the surgical treatment of the prostate gland. <P>SOLUTION: The agent to be administered prior to the surgical treatment of the prostate gland for suppressing the bleeding of the gland contains chlormadinone acetate as an active component. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a drug for preoperative administration of prostate for reducing bleeding of prostate associated with surgical treatment of prostate.

[0002]

BACKGROUND OF THE INVENTION Prostatic hypertrophy (BPH) and prostate cancer are diseases that are rapidly increasing in Japan.
BPH, also called benign prostatic hyperplasia, is characterized by pressure on the urethra due to increased prostate volume and is said to cause histological BPH in at least 70% of men reaching the age of 70 years. If the urethral compression caused by BPH is left untreated, not only the urine output gradually deteriorates, but also urinary tract infection, urethral obstruction, bladder diverticulum, bladder stones, neurogenic bladder and other diseases are caused (prostatic hypertrophy). Clinics and Medicine Book Publishing Co., Ltd. (2001)). On the other hand, prostate cancer is mainly derived from the external gland of the prostate, and, like BPH, androgens are strongly involved in its development and development. Most prostate cancers can be controlled by endocrine therapy with antiandrogens, gonadotropin-releasing hormone, etc. in the early stage, but gradually lose their androgen responsiveness and become hormone refractory. Cancers that have relapsed due to hormone refractory have a very poor prognosis, and most of them die of cancer within a few years after the appearance of symptoms due to relapse.

Bleeding from the prostate can be caused by diseases such as benign prostatic hyperplasia and prostate cancer, and can be caused by surgical procedures such as transurethral resection of the prostate (TURP) and prostate needle biopsy. . Bleeding due to benign prostatic hyperplasia is bleeding from bleeding from the capillaries of the enlarged prostate in benign prostatic hyperplasia. However, this is the only cause of bleeding due to disease, and in most cases, the detailed cause is unknown. In the case of surgical treatment, some bleeding (about 150 mL in TURP) is said to be unavoidable, but excessive bleeding may cause serious postoperative complications, so it is unnecessary. Bleeding should be avoided.

[0004] TURP is a surgery for transurethrally removing the prostate gland using a resectoscope to remove the obstruction of the urethral prostate. TURP was 145,000 in the US in 1994.
Examples were implemented (Kirby, Brochut Medi
cal Journal, 309, 716-718 (1
994)), and about 40,000 cases are practiced annually in the UK. Postoperative complications of TURP include fever, bleeding, urinary incontinence, recurrence from residual adenoma, urethral stricture, bladder neck stricture,
Retrograde ejaculation and the like are seen, and hemorrhagic shock caused by persistent bleeding is often a serious symptom. Therefore, to prevent bleeding and infection from the resection site, TU
Various measures have been taken such as indwelling a balloon catheter after RP.

On the other hand, a prostate needle biopsy is carried out for definite diagnosis of prostate cancer and evaluation of malignancy, and is performed by transperineally or transrectally collecting prostate tissue using a fine needle suction needle. It is a diagnostic method. Prostate needle biopsy also shows complications such as hematuria, hemospermia, fever, and infection (Japanese clinical practice, 58 (766), 147-149 (200).
0)).

Surgical difficulty and patient burden in surgical procedures
As an attempt to reduce the burden, for example, in uterine fibroid surgery
For patients who are planning to have uterine fibroids resected,
Administration of nadtropin-releasing hormone for a certain period before surgery,
There is a known method to reduce the diseased tissue to be resected beforehand.
(The practice of hormone therapy in obstetrics and gynecology, Nagai Sho
Store, 132-134). On the other hand, for the prostate,
Nasteride or bicalutamide reduce blood flow in the prostate
Report to let (BJU International
(2000),85, 962-965) and TURP
Finasteri to reduce prostate bleeding
Report on preoperative administration of doro (UROLOGY,55
(5), 684 (2000), THE JOURNAL
  OF UROLOGY,165(5), 262 (20
01)).

[0007]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a drug useful in reducing prostate bleeding associated with prostate surgical procedures.

[0008]

[Means for Solving the Problems] As a result of intensive studies aimed at achieving the above-mentioned object, the present inventors have found that chlormadinone acetate reduces blood flow in the prostate and atrophy of capillaries in the prostate. It was found that the present invention has an effect, and that the double effect can significantly reduce the prostatic bleeding associated with the surgical treatment of the prostate gland, and completed the present invention. Thus, the present invention provides a prostatic bleeding reducing agent for administration prior to surgical treatment of the prostate, characterized by containing chlormadinone acetate as an active ingredient.

Hereinafter, the drug provided by the present invention will be described in more detail.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Chlormadinone acetate used as an active ingredient in the drug of the present invention has the following formula:

[0011]

[Chemical 1]

It is a known steroidal anti-androgen represented by: and is put to practical use as a therapeutic drug for benign prostatic hyperplasia and prostate cancer.

However, it has not been known at all that chlormadinone acetate has the effects of reducing blood flow in the prostate and atrophying capillaries in the prostate.

The drug of the present invention takes advantage of this dual effect of chlormadinone acetate and administers it prior to the surgical treatment of the prostate, thereby significantly reducing the prostatic bleeding associated with the surgical treatment of the prostate. is there.

However, the drug of the present invention is accompanied by considerable bleeding during surgical treatment of the prostate. For example, trans-urethral resection of the prostate (TURP), prostate needle biopsy, etc. Bleeding from the prostate during surgical procedures can be greatly reduced.

Chlormazine acetate can be administered orally or parenterally (for example, subcutaneously, intravenously, or intrarectally), and in use, it is used together with a non-toxic pharmaceutically acceptable additive. It can be formulated into a dosage form suitable for the administration route.

Examples of the dosage form of the preparation of the present invention include tablets, powders, granules, capsules, troches, syrups, suppositories, injections, etc., and oral preparations are particularly preferable. Further, these preparations may have a sustained release function.

Non-toxic additives that can be used in the production of such a preparation include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methyl cellulose, carboxymethyl cellulose or the like. Salt, gum arabic,
Examples thereof include polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol, petrolatum, carbowax, glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid, and distilled water for injection.

The content of the active ingredient in the preparation of the present invention varies depending on the form of the preparation, etc., but is usually about 0.1 to about 99% by weight, preferably about 0.5 to about 8% by weight relative to the whole preparation.
It may be 0% by weight, more preferably 1 to 50% by weight.

The daily dose of chlormadinone acetate in the present invention can be widely varied depending on the type of warm-blooded animal including human being, the administration route, the severity of symptoms, the diagnosis of a doctor and the like. Yes, but preferably 25-800 mg, particularly preferably 50-600 m
It can be in the range of g. However, it is also possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range depending on the severity of the patient's symptoms and the diagnosis of the doctor.
The above-mentioned dose is divided into one or several times a day, every day from 6 months before the surgical treatment of the prostate to the day before the surgical treatment, preferably from 3 months before to the previous day, and particularly preferably. Can be administered daily from 2 months before to the day before. The low dose is suitable for long-term administration, and the high dose is suitable for short-term administration.

Hereinafter, the present invention will be described in more detail with reference to experimental examples and formulation examples.

[0022]

Experimental Example 1 (Measurement of Blood Flow in Prostate) 10-week-old male rats are preliminarily bred for 10 days and then grouped into drug groups at a rate of 10 animals per group. Chlormadinone acetate 20 mg / Kg administration group, chlormadinone acetate 30 m
For each of the g / Kg administration groups, a chlormadinone acetate injection solution (dimethyl sulfoxide: olive oil = 5: 1 mixture) was used on the back of the rat to give a dose of 0.1.
Chlormadinone acetate dissolved in a concentration of 5 mL) is subcutaneously administered once a day for 4 consecutive days.
As a control, 48 hours after castration in the castrated group and untreated rats in the normal group, each rat was subcutaneously injected with a mixed solution of dimethyl sulfoxide: olive oil = 5: 1 for 4 days. Administer.

Twenty-four hours after the final administration, the rat was anesthetized with pentobarbital (50 mg / Kg), the neck of the rat was incised to expose the carotid artery, the head side was ligated, and 0.5 cm from the site to the heart side. To clamp blood flow and temporarily stop blood flow. A cannula is inserted from the carotid artery at the ligation site to the aortic arch (about 2 cm) to fix the cannula to the blood vessel. Then, 0.3 mL (corresponding to 15 μCi) of [ ⁵¹ Cr] -microsphere is injected from the cannula, and the microsphere is completely administered by washing out the inside of the cannula with physiological saline.
2.5 minutes after administration, the animals are dissected, the prostate, the kidney, and the bladder are removed, the weight of each organ is measured, and the radioactivity in each organ is measured by a γ-counter, and the tissue in each organ is determined from the measured value. Determine internal blood flow. The index of the blood flow in the tissue can be obtained by calculating the radioactivity per tissue weight. The experimental results are shown in Table 1 below.

[0024]

[Table 1]

Experimental Example 2 (Measurement of inner space area of prostatic capillaries) After 9-week-old male rats were preliminarily reared for 7 days, 5 groups (control group, 1-day administration group, continuous administration for 2 days) were administered on the 8th day. Groups, 5 day continuous administration group, 10 day continuous administration group). Chlormadinone acetate injection solution 10 mg / Kg is subcutaneously administered to the rat back of each group once a day according to the number of days in each group. 1% saline solution of Tween80 2 in the control group
mL is subcutaneously administered once a day for 10 consecutive days.

After the administration in each group, the abdomen of the rat is opened under ether anesthesia, the prostate is excised, and immediately fixed in formaldehyde solution. After fixing the aldehyde, it is divided into 1 mm blocks and further fixed with aldehyde.

The aldehyde-fixed strip tissue is dehydrated and then embedded in Quetol 812 resin. This is sliced into ultrathin sections and double stained with uranium acid and lead. The specimen thus prepared is photographed under an electron microscope to calculate the lumen area of the blood vessel. The results are shown in Table 2 below.

[0028]

[Table 2]

From the results of Experimental Examples 1 and 2 described above, it can be seen that chlormadinone acetate has an effect of specifically reducing the blood flow in the organ and atrophying the capillaries of the prostate in a prostate-specific manner. Formulation Example 1 (tablet) Chlormadinone acetate 25.0 mg Starch 23.4 mg Lactose 143.6 mg Carboxymethyl cellulose calcium 5.0 mg Talc 2.0 mg Magnesium stearate 1.0 mg 200.0 mg Chlormadinone acetate crystals were ground to a particle size of 70 microns or less. Then, add starch, lactose and carboxymethylcellulose calcium to it and mix well. 10% starch paste is added to the above mixed powder and mixed by stirring to produce granules. After drying, the particles were sized to a particle size of about 1000 microns, talc and magnesium stearate were mixed and compressed to give chlormadinone acetate 25 mg tablets. Formulation Example 2 (tablets) Chlormadinone acetate 200.0 mg Starch 41.7 mg Lactose 144.3 mg Carboxymethylcellulose calcium 9.0 mg Talc 3.5 mg Magnesium stearate 1.5 mg 400.0 mg According to the above formulation, in the same manner as in Formulation Example 1 A 200 mg tablet of chlormadinone acetate was obtained. The tablets are particularly useful when administering high doses.

[0030]

INDUSTRIAL APPLICABILITY The drug of the present invention has the effects of reducing blood flow in the prostate and atrophying the capillaries of the prostate. This enables treatment of bleeding associated with prostate disease as well as reduction of bleeding associated with surgical treatment of the prostate.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C086 AA01 AA02 DA10 MA04 MA35                       MA52 NA14 ZA53 ZA81                 4C091 AA01 BB05 BB08 CC01 DD01                       EE07 FF04 FF13 GG01 HH01                       JJ03 KK01 LL00 MM03 NN01                       PA03 PA09 PA12 PB02 QQ01

Claims (2)

[Claims] 1. A prostatic bleeding reducing agent for administration prior to surgical treatment of the prostate, which contains chlormadinone acetate as an active ingredient. 2. The drug according to claim 1, wherein the surgical treatment of the prostate is transurethral resection of the prostate (TURP) or a needle biopsy of the prostate.