JP2000212080A - Erection dysfunction remedy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an erection dysfunction remedy having the activity to increase the level of cyclic guanosine monophosphate declined in production by NG-monomethyl-L-arginine or the like including symmetry-NG,N'G-dimethyl-L- arginine as effective ingredient. SOLUTION: This remedy is obtained by including, as effective ingredient, symmetry-NG,N'G-dimethyl-L-arginine(SDMA) or a salt thereof (e.g. hydrochloride, acetate), optionally in combination with sildenafil citrate salt or the like. To prepare this remedy in the form of a solid oral preparation, a vehicle, binder, disintegrant, etc., are added. As for the method for administrating this remedy, it is administered pref. 30 min to one hour before desiring penis erection, its dose being appropriately 5-100 mg at a time orally; it is recommended that in the form of a patch, e.g. a tape containing SDMA (salt) at 1-50 mg/cm2 is used; and in the form of a liniment, e.g. an ointment, cream containing SDMA (salt) at 1-100 mg/g.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an agent for improving penile erectile dysfunction.

[0002]

2. Description of the Related Art It is said that the number of male patients with penile erectile dysfunction is rapidly increasing with an increase in the elderly population. Erectiles require increased penile arterial blood flow, suppression of blood leakage from the penile vein, and relaxation of the corpus cavernosum tissue. The current treatments in urology are drug therapy and penile prostheses. The drug therapy, although injection or the like into the corpus cavernosum of papaverine hydrochloride and prostaglandin E ₁ has been mentioned as a possibility, effectiveness, side effects, there is a problem in terms of convenience, etc., little is done .

On the other hand, recently, sildenafil citric acid
Salt (hereinafter called sildenafil) is orally administered by FDA
Manufactured and approved for the treatment of erectile dysfunction
Was. The erection-promoting effect of sildenafil is caused by penile vascular
It is based on smooth muscle dilation and, more specifically,
Of cyclic guanosine monophosphate (cGMP)
Degradation enzyme phosphodiesterase-5 (PDE-
Due to the inhibitory action of 5), cG in vascular smooth muscle cells of the penis
MP concentration, thereby increasing the intracellular Ca ²⁺Dark
Decreases the degree of relaxation of vascular smooth muscle (vasodilation) and increases blood flow
And thus erecting the penis
Things.

[0004]

However, the effective rate of sildenafil is only about 50%, and there is no vascular selectivity to increase blood flow, so that side effects are also a problem. Accordingly, an object of the present invention is to provide a new agent for improving erectile dysfunction based on a new mechanism of action.

[0005]

In order to elucidate the causal relationship between the development of erectile dysfunction and various biological components in the blood, the present inventors have studied ^NG -monomethyl-L-.
Arginine (L-NMMA) and asymmetry- ^NG ,
It was discovered that ^NG -dimethyl-L-arginine (ADMA) levels were significantly increased in erectile dysfunction patients compared to healthy individuals. On the other hand, these L-NMMA and ADM
A has the effect of inhibiting the step of nitric oxide biosynthesis from nitric oxide synthase from L-arginine in vascular endothelial cells (Journal of Cardiovascnlar Ph.
armacology, 1992; 20: S60-S62, British Journal of
Pharmacology, 1995; 115: 1001-1004), and it has also been shown that L-NMMA and ADMA are taken up into endothelial cells prior to the onset of such action (Americ.
an Journal of Physiology, 1995; C750-C756). That is, in patients with erectile dysfunction, L-NMMA and ADMA
As a result, nitric oxide biosynthesis ability in penile vascular endothelial cells decreases, and cG from guanosine triphosphate (GTP) in penile vascular smooth muscle cells as a result.
Increased blood levels of L-NMMA and ADMA were thought to be one of the major causes of erectile dysfunction, as reduced MP biosynthesis, i.e., reduced vasodilator action of the corpus cavernosum.

[0006] Based on this viewpoint, the present inventor searched for substances that inhibit the transport of L-NMMA and ADMA from blood into vascular endothelial cells, and surprisingly found that Symmetry- ^NG , N ' ^G -dimethyl-L-arginine (SDMA) or a salt thereof has the effect of increasing the amount of cGMP reduced in production by L-NMMA or ADMA, and is useful as an erectile dysfunction ameliorating agent due to the effect of increasing cGMP And completed the present invention.

That is, the present invention provides an erectile dysfunction improving agent comprising SDMA or a salt thereof as an active ingredient.

[0008]

DETAILED DESCRIPTION OF THE INVENTION The SDMA used in the present invention is as follows.
This is a compound known per se, but L-
There has been no report on the effect of increasing the amount of cGMP reduced in the amount produced by NMMA or ADMA, and further on the relationship with the erectile function.

According to the study of the present inventor, as described above, SD
MA or a salt thereof erectile dysfunction due to the action of re-elevating a decrease in cGMP production in vascular smooth muscle cells of the penis caused by L-NMMA and ADMA specifically increased in the blood of erectile dysfunction patients To improve.

The SDMA salt used in the present invention includes mineral salts such as hydrochloride and sulfate, and organic acid salts such as acetate.

The medicament of the present invention may contain SDMA or a salt thereof as an active ingredient, and may be used in combination with sildenafil or the like in addition to SDMA. In addition, the pharmaceutical composition of the present invention can be formulated into various dosage forms by adding necessary additives in addition to SDMA or a salt thereof.

In order to prepare a solid oral preparation, an excipient and, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, a flavoring agent, etc. are added to SDMA or a salt thereof, and then the preparation is usually added. Tablets, coated tablets, granules, powders, capsules and the like can be produced by the method. To prepare a liquid formulation for oral use, SD
By adding a flavoring agent, a buffering agent, a stabilizing agent, a flavoring agent and the like to MA or a salt thereof, an oral solution, a syrup, an elixir and the like can be produced by a conventional method. When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, an isotonic agent, a local anesthetic, etc. are added to SDMA or a salt thereof, and a subcutaneous, intramuscular and intravenous injection is prepared by a conventional method. Can be manufactured. When preparing an ointment, a base, a stabilizer, a wetting agent, a preservative, and the like, which are usually used for SDMA or a salt thereof, are blended as required, and mixed and formulated by a conventional method. When a patch is produced, the above-mentioned ointment, cream, gel, paste or the like may be applied to a usual support in a usual manner.

The method of administration of the medicament of the present invention is preferably 30 minutes to 1 hour before the erection of the penis is desired, and a suitable dosage is 5 to 100 mg once orally. In the case of a patch, a tape or the like containing 1 to 50 mg / cm ² may be used, and in the case of application, an ointment or cream containing 1 to 100 mg / g may be used.

[0014]

Next, the present invention will be described in more detail by way of examples, but the present invention is not limited thereto.

Reference Example 1 Healthy adult males (10) and patients with erectile dysfunction (14
L) blood L-NMMA and ADMA concentrations were measured.
L-NMMA and ADMA in plasma were quantified according to a known method. That is, the plasma separated according to the usual method,
Add trichloroacetic acid to a final concentration of 5%,
Centrifuge at 1300 xg for 10 minutes. Obtained supernatant 1
00 microliters were separated by high performance liquid chromatography, and L-NMMA and ADMA were quantified.

[0016]

[Table 1]

As a result, as shown in Table 1, in the group of patients with erectile dysfunction, it was found that the blood concentration of both L-NMMA and ADMA was significantly (p <0.005) higher than that of healthy individuals. .

Example 1 cGMP production in arterial smooth muscle cells stimulated by acetylcholine and noradrenaline was also measured according to a known method. That is, the rabbit carotid artery was excised, and a strip with a wet weight of about 5 mg preserving endothelial cells was prepared. Kreb
The mixture was pre-incubated at 37 ° C. for 20 minutes in the liquid s.
Subsequently, 15 minutes after adding 10 ^-6 M noradrenaline, 3 ×
10 ^-6 M acetylcholine was added and incubated for a further 15 minutes. Immediately after the end of the reaction, 5%
It was transferred into trichloroacetic acid and frozen with liquid nitrogen. According to a conventional method, cGMP in the tissue was extracted and quantified using a commercially available cGMP assay kit.

As a result, as shown in FIG. 1, cGMP production by acetylcholine and noradrenaline stimulation in vascular smooth muscle cells was clearly suppressed by the addition of L-NMMA. And it turned out that this cGMP production inhibitory effect is significantly recovered by SDMA.

Example 2 The following experiment was performed to explain the increase in L-NMMA blood concentration in patients with erectile dysfunction obtained in Reference Example 1 and the mechanism of the effect of SDMA obtained in Example 1 on increasing cGMP. Done. A rabbit thoracic aorta specimen was prepared by covering the periphery with a dental resin and exposing only endothelial cells, and was prepared at 10 μM [ ³ H] -LN.
The plate was incubated with MMA (0.537 μCi / ml) at 37 ° C. for 2 minutes. By this treatment, endothelial cells are selectively [
^[3 H] -L-NMMA is incorporated. As is clear from FIG. 2, this uptake was almost completely suppressed by 100 μM SDMA. Thus, SDMA can be reduced by L
-It was found that the NMMA uptake action was strongly suppressed.

Example 3 SDMA was orally administered to 10 mice at 2000 mg / kg.
General condition and death were observed over a week. As a result, no change was observed in changes in body weight and spontaneous exercise, and no deaths occurred. There were no changes attributable to medication in the autopsy findings of major organs and tissues. Therefore, the acute toxicity of oral administration of SDMA was estimated to exceed 2000 mg / kg, confirming high safety.

[0022]

According to the present invention, in patients with erectile dysfunction, erectile dysfunction is caused by increasing the cGMP concentration in the vascular smooth muscle cells of the penis, which is lowered, based on excessive uptake of L-NMMA and ADMA. Can be improved.

[Brief description of the drawings]

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is a graph showing a cGMP concentration lowering effect of L-NMMA in an artery and a recovery effect of SDMA on the effect.

FIG. 2: L-NMMA uptake into vascular endothelial cells,
It is a figure which shows the uptake inhibitory effect of SDMA with respect to this.

Claims (1)

[Claims] 1. Symmetry- ^NG , N ' ^G -dimethyl-L
-An erectile dysfunction improving agent containing arginine or a salt thereof as an active ingredient.