JPH11222439A - Inhibitor of cerebral vasospasm - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical useful for the prophylaxis and therapy of cerebral vasospasm after subarachnoid hemorrhage and cerebral ischemic symptoms associated therewith. SOLUTION: This inhibitor of cerebral vasospasm contains alacepril chemical name: 1-(D-3-acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine or (S)- N-[1-[3-(acetylthio)-2-methyl-1-oxopropyl]-L-prolyl]-L-phenylalanine} as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a cerebral vasospasm inhibitor containing alacepril as an active ingredient.

[0002]

2. Description of the Related Art Alacepril [chemical name: 1- (D-3-
(Acetylthio-2-methylpropanoyl) -L-prolyl-L-phenylalanine or (S) -N- [1- [3
-(Acetylthio) -2-methyl-1-oxopropyl] -L-prolyl] -L-phenylalanine;
Merck Index, 12th edition, 202 (1996)] is used as a persistent antihypertensive drug having angiotensin converting enzyme (ACE) inhibitory action in the treatment and prevention of essential hypertension and renal hypertension. . JP-B-61-34409, JP-B-63-18599, and U.S. Patent No. 4,248,883
Discloses the preparation of alacepril and its usefulness as an antihypertensive agent.

Conventionally, a report on the antihypertensive effect and clinical usefulness of alacepril for essential hypertension complicated with cerebrovascular disease [for example, see New Drugs and Clinical Practice, 40 , 357 (1991)]
Reports of the effects of alacepril on cerebral circulation in hypertensive patients with a history of stroke or stroke [e.g., Cur
r. Ther. Res., 55 , 1446 (1994)]. However, as far as we know,
There are no reports on the effects of alacepril on cerebral vasospasm.

[0004] In advanced countries, stroke (cerebrovascular disease) is counted as one of the three major lifestyle-related diseases together with malignant tumors and heart diseases, but the Japanese are characterized by a particularly high risk of stroke. The main types of stroke include cerebral hemorrhage, cerebral infarction and subarachnoid hemorrhage. Since the appearance of delayed neurological deficits due to cerebral vasospasm that develops from about 4 days after the attack of subarachnoid hemorrhage to 2 weeks impairs the prognosis, prevention of rebleeding and prevention and treatment of cerebral vasospasm are considered. It is said to be a pillar of treatment for subarachnoid hemorrhage.

[0005]

At present, calcium antagonists, antiplatelet aggregating agents, cerebral vasodilators and the like are used for the prevention of cerebral vasospasm after subarachnoid hemorrhage, but they are not always satisfactory in terms of efficacy. It is not possible, but the emergence of effective new drugs is expected.

[0006]

Means for Solving the Problems The present inventors have found that alacepril has an excellent cerebral vasospasm inhibitory effect in rats with subarachnoid hemorrhage, and have completed the present invention.

[0007] The present invention provides a cerebral vasospasm inhibitor containing alacepril as an active ingredient.

[0008]

DETAILED DESCRIPTION OF THE INVENTION Alacepril is described in, for example,
No. 34409, JP-B-63-18599 and U.S. Pat. No. 4,248,883.

The results of pharmacological tests of alacepril and enalapril maleate, which is a typical long-acting ACE inhibitory antihypertensive drug (see, for example, Merck Index, 12th edition, 3605 (1996)), are shown below. Explain the usefulness as an anticonvulsant.

[0010] Statistical analysis of the experimental results is provided by Dunn.
ett Dunnett's multiple comparison t
est).

Test Example— Effects on Basal Artery Spasm in Subarachnoid Hemorrhage (SAH) Rats— Preparation of SAH Rats— Experiment was Pre-Ked for One Week
Ten-week-old male Jcl-SD rats (purchased from CLEA Japan) were used. The animals were kept in an environment with a temperature of 24 ± 2 ° C., a humidity of 60 ± 5%, and a light cycle of 12 hours, and had free access to food and water.

Under ether anesthesia, a polyethylene cannula (SP-10, Natsume Seisakusho) was placed in the large tank of the rat.
On the first or second day after the cannula was placed, 0.3 ml of whole blood (allogeneic blood) collected without addition of an anticoagulant from another group of rats under ether anesthesia while tilting the head of the rat by about 40 °
By injecting through a cannula for 30 seconds,
AH rats were produced.

Effects on Basilar Artery Spasm—The SAH rats used in this experiment have biphasic cerebral vasospasm, ie, S
Early phase cerebral vasospasm peaked 10 minutes after AH and late phase cerebral vasospasm peaked 24 hours later. In this experiment, the effect of the drug on cerebral vasospasm in the late phase was examined.

In the group administered with 7 drugs per group, 1 hour before and 9 hours after blood injection into the cisterna magna, alacepril (10 mg / kg or 30 mg / kg) or maleic acid suspended in 0.5% aqueous tragacanth solution was used. Enalapril acid (30 mg / kg) was administered orally.
A control group of 6 animals / group was orally administered a 0.5% aqueous tragacanth solution in the same manner. By the way, 10 mg / kg of alacepril and 30
The mg / kg is a dose that exerts a clear hypotensive effect in renal hypertensive rats (RHR) and spontaneously hypertensive rats (SHR), respectively. On the other hand, enalapril maleate 30 m
g / kg is about 10 times the antihypertensive dose of RHR and SHR.
Double and about three times.

Brain angiography was performed 24 hours after blood injection.
SAH rats are anesthetized with urethane (250 mg / kg, ip) and ketamine (100 mg / kg, ip) and cannulated in both axillary arteries (PE50, Becton, Dickinson and Company, USA)
Was inserted. While injecting 1.4 ml of the contrast agent amidotrizoic acid from both arterial cannulas,
10m using a wire device (Softex CMB, Softex Corporation)
An image was taken under the conditions of A, 60 kV, 5 seconds and a height of 50 cm.

From the obtained X-ray photograph, an image analyzer (MC
ID, Imaging Research Inc., Canada), the length and area of the basilar artery were measured, and the average arterial diameter was calculated from the following equation.

[Equation 1] Average arterial diameter (mm) = area (mm ² ) / length (mm)

In order to measure physiological parameters in SAH rats, blood pressure immediately before cerebral angiography was measured by connecting an arterial cannula to a pressure transducer (AT-641G, Nippon Koden Kogyo) and heart rate was measured. The pulse wave was measured by an instantaneous heart rate monitor (AT-601G, Nihon Kohden Kogyo). In addition, 0.2 ml of blood was collected via an arterial cannula, and the gas partial pressure of arterial blood was measured using an automatic blood gas analyzer (IL 1306, Instr.
umentation Laboratory, Italy).

Table 1 shows the effect of alacepril and enalapril maleate on physiological parameters in SAH rats. Numerical values in the table represent mean value ± standard error.

[0019]

Table 1 Effect on physiological parameters in SAH rats ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Test drug administration Amount Animal blood pressure Heart rate O ₂ partial pressure CO ₂ partial pressure (mg / kg × 2) Number (mmHg) (1 minute) (mmHg) (mmHg) ━━━━━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━━ Vehicle administration group ― 6 94 ± 5 277 ± 17 92.0 ± 3.5 34.4 ± 1.6 Alacepril 10 7 87 ± 4 290 ± 18 91.6 ± 3.9 34.8 ± 1.0 30 7 86 ± 3 291 ± 12 98.3 ± 3.5 32.6 ± 1.1 Maleic acid 30 7 81 ± 7 273 ± 14 92.6 ± 0.9 34.1 ± 0.6 Enalapril ━━━━━━━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━

As is evident from Table 1, neither alacepril nor enalapril maleate had any effect on blood pressure, heart rate or blood gas partial pressure. This means
This shows that the SAH rat used in this experiment is an appropriate model animal.

FIG. 1 shows the effects of alacepril and enalapril maleate on changes in basilar artery diameter (cerebral vasospasm) induced by allogeneic blood injection into the rat cisterna magna.
The vertical line in the figure represents the standard error, * is p <0.05, ** is p
<0.01 indicates that there is a significant difference compared to the vehicle administration group.

The basilar artery diameter of SAH rats was significantly reduced as compared to normal rats. That is, the basilar artery average diameter of normal rats was 0.34 ± 0.05 mm, whereas that of SAH rats was 0.09 ± 0.02 mm.

As is clear from FIG. 1, alacepril significantly and dose-dependently suppressed the expression of cerebral vasospasm induced by SAH. The arterial diameter at the time of oral administration of alacepril 10 mg / kg is 0.16 ± 0.03 mm (p <0.05) and 30 m
It is 0.18 ± 0.01mm (p <0.01) when g / kg is orally administered.
Met. On the other hand, oral administration of enalapril maleate 30 mg / kg showed a tendency to suppress the onset of cerebral vasospasm, but it was not significant.

As is clear from the test results, alacepril exhibits an excellent inhibitory effect on cerebral vasospasm at a dose of an antihypertensive effect and has low toxicity. It can be used for prevention and treatment of cerebral vasospasm after bleeding and cerebral ischemic symptoms associated therewith. The administration route may be any of oral administration, parenteral administration and rectal administration, but should be appropriately selected according to the level of the consciousness of the patient. . The dose of alacepril varies depending on the route of administration, the degree of symptoms, the age of the patient, etc., but is usually 0.4 to 2.0 mg / kg / day.
It can be administered once or twice.

Alacepril is used as a cerebral vasospasm inhibitor as it is or in the form of a pharmaceutical composition prepared by mixing with a pharmaceutical carrier. As specific examples of the pharmaceutical composition,
Examples include tablets, capsules, granules, powders, powders, jellies, syrups, injections, suppositories, and sprays for nasal mucosal administration. These pharmaceutical compositions are prepared according to a conventional method. In addition, a tablet sold as an antihypertensive drug can be applied to a patient who can swallow as a cerebral vasospasm inhibitor.

As the pharmaceutical carrier, a substance which is commonly used in the pharmaceutical field and does not react with alacepril is used. Specific examples of pharmaceutical carriers used in the production of tablets, capsules, granules, powders, and powders include excipients such as lactose, starch, sucrose, xylitol, D-mannitol, calcium sulfate, crystalline cellulose, and crystals. Disintegrants such as cellulose, carmellose sodium, starch, carmellose calcium, binders such as methylcellulose, gelatin, acacia, ethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, light anhydrous silicic acid, magnesium stearate, talc, hardened Lubricants such as oils are included. The orally disintegrating tablet is preferably added with a cooling agent such as dl-menthol, l-menthol, peppermint oil and the like. In preparing a powder for tube administration, a dispersing agent such as crystalline cellulose and carmellose sodium is preferably added.

Specific examples of carriers used in the production of jelly-like agents include sweeteners such as sucrose, glucose and fructose, suspending agents such as sodium alginate and carrageenan, macrogol 300, polyoxyethylene hydrogenated castor oil. 60,
Dispersants such as polysorbate 80 are included. In the production of jellies, flavoring agents, fragrances,
Preservatives and the like can be added.

Specific examples of carriers used in the production of syrups include sweeteners such as sucrose, glucose and fructose, gum arabic, tragacanth powder, carmellose sodium, methylcellulose, sodium alginate, crystalline cellulose and aluminum magnesium silicate. And a dispersant such as sorbitan fatty acid ester, sodium lauryl sulfate, and polysorbate 80. In producing the syrup, a flavoring agent, a fragrance, a preservative, and the like can be added as necessary. Further, it may be in the form of dry syrup which is dissolved or suspended at the time of use.

Specific examples of suppository bases include cocoa butter,
Saturated fatty acid triglyceride (hard fat) (eg, various witepsol; trademark) and macrogol. In the manufacture of suppositories, if necessary, surfactants,
Preservatives and the like can be added.

The spray for nasal mucosa administration is usually prepared by uniformly dispersing alacepril in sterile purified water, but if necessary, a solubilizing agent, a thickening agent, a pH adjusting agent, an isotonic agent, and a preservative. Agents and the like can be added. Specific examples of the dispersant include a carboxyvinyl polymer.

These pharmaceutical compositions can generally contain alacepril as an active ingredient in a proportion of 0.5% or more, preferably 2 to 60%. These pharmaceutical compositions may also contain other therapeutically effective substances.

Alacepril can also be used as a cerebral vasospasm inhibitor in the form of the substance itself dissolved in an infusion solution or enteral nutrition.

[0033]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

Example 1 -Tablets-Alacepril 25 g Lactose 28 g Corn starch 60 g Microcrystalline cellulose 30 g Hydroxypropyl cellulose 5 g Light anhydrous silicic acid 1 g Magnesium stearate 1 g 150 150 g in total

Of the above components, alacepril, lactose, corn starch and crystalline cellulose are mixed, and hydroxypropylcellulose dissolved in water is added, kneaded, and dried to obtain granules. Add magnesium stearate and light anhydrous silicic acid to this and press-mold to form 1 tablet.
Prepare 1000 tablets of 150 mg.

Example 2- Orally disintegrating tablets-Alacepril 25 g D-mannitol 263 g Xylitol 4.5 g Polyvinylpyrrolidone 4.5 g l-Menthol 1 g Magnesium stearate 2 g 300 Total 300g

Alacepril and D-mannitol are mixed,
After spraying and granulating polyvinylpyrrolidone and xylitol dissolved in 100 ml of a water / ethanol equivalent mixture, the mixture is dried and sized. L-Menthol and magnesium stearate are added thereto and mixed to obtain granules for tableting.
Prepare 1000 tablets of 300 mg orally disintegrating tablets.

Example 3-5% powder-Alacepril 50 g Lactose 869 g Hydroxypropyl cellulose 20 g Light anhydrous silicic acid 1 g合計 Total 940g

When the above components were mixed using a high-speed stirring granulator, 200 g of an ethanol solution containing 40 g of ethylcellulose and 20 g of hydroxypropylcellulose was sprayed and granulated, followed by drying and sizing to give a 5% powder. Prepare.

Example 4- Powder for 25% tube administration-Alacepril 50 g Lactose 107 g Crystalline cellulose / carmellose sodium 40 g Hydroxypropyl cellulose 2 g Light silicic anhydride 1 g 200 Total 200g

The above-mentioned components other than hydroxypropylcellulose are mixed using a high-speed stirring granulator, added with hydroxypropylcellulose dissolved in water, granulated, and dried to obtain a 25% powder for tube administration. Prepare.

Example 5 -Suppositories-Alacepril 50 g Witepsol H-15 1150 g 1200 Total 1200 g

Alacepril is added while witepsol H-15 is heated and melted at about 50 ° C., and mixed uniformly. While maintaining the mixture at about 35 ° C., the mixture is filled into a suppository container and then cooled and solidified to prepare 1,000 suppositories of 1200 mg each.

Example 6- Spray for nasal mucosa administration-Alacepril 6.25 g Sodium chloride 0.50 g Benzalkonium chloride 0.01 g Carboxyvinyl polymer 0.50 g Concentrated glycerin 1.00 g Sodium hydroxide Appropriate amount Sterilized purified water Appropriate amount 100 Total 100 ml

Sodium chloride, benzalkonium chloride and concentrated glycerin are added to a part of the sterilized purified water and dissolved.
To this solution, separately added a liquid in which a carboxyvinyl polymer is uniformly dispersed in a part of sterilized purified water, and then add alacepril to mix uniformly. Then, a sterilized purified aqueous solution of sodium hydroxide is added to adjust the pH to 6 to 7. To prepare a spray for the nasal mucosa.

This solution is placed in a container for intranasal administration, and is administered 2 times a day.
Spray both nasal passages. A single spray volume is 100 μl, which contains 6.25 mg as alacepril.

[0047]

As described above, alacepril exhibits an excellent inhibitory effect on cerebral vasospasm at an antihypertensive dose. It is useful for prevention and treatment of cerebral ischemic symptoms associated with.

[Brief description of the drawings]

FIG. 1 is a graph showing the effects of alacepril and enalapril maleate on changes in basilar artery diameter (cerebral vasospasm) induced by allogeneic blood injection into the cisterna magna of male Jcl-SD rats.

Claims (2)

[Claims] A cerebral vasospasm inhibitor comprising alacepril as an active ingredient. 2. The cerebral vasospasm inhibitor according to claim 1, wherein the cerebral vasospasm is spasm after subarachnoid hemorrhage.