JP2727343B2 - Thalassemia disease treatment - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel therapeutic agent for thalassemia, and more particularly to a therapeutic agent for thalassemia comprising dilazep or a salt thereof as an active ingredient.

[Prior art and its problems] Thalassemia is a hereditary disease that causes hypopigmentary anemia, which is attracting attention in Southeast Asian countries and the Mediterranean region. For example, in Thailand, about 6% of couples have children with this disease. It has been reported.

Above all, patients with β-thalassemia HbE disease are 4,8 in Thailand.
It reaches 76,000 out of a million people, has a life expectancy of 20 years, and has 3,800 new cases each year (1 in 300 newborns affected). β-thalassemia HbE disease is a β-thalassemia disease gene in which the structural gene of the β-chain of hemoglobin is defective and normal β-chain production is suppressed,
It is a disease caused by double heterozygosity with the gene for HbE disease, which has abnormal hemoglobin in which glutamic acid, the 26th amino acid in the chain, has been replaced with lysine. In this disease, stomach, liver, kidney and other organs are abnormal due to anemia due to shortened life of red blood cells and excessive intake of iron due to frequent transfusions, and death is most common due to heart failure .

Currently, there is only a cure for this disease, such as removal of the spleen, blood transfusion, administration of an iron chelator,
There are problems in terms of cost, side effects, etc. However, although many reports have been reported on biochemical studies on the genes of thalassemia, abnormal hemoglobin, etc., classification of clinical symptoms, medical statistics, etc., pathophysiological studies in the direction of developing treatments for thalassemia are discussed. Little has been done and it is hoped that these studies will be performed and, through this, a more effective symptomatic treatment for thalassemia patients will be established.

[Means for Solving the Problems] Thalassemia is found to have numerous thrombus findings in lungs and the like at autopsy findings, and thrombus is considered to be a cause of heart failure. Therefore, the present inventors focused on this thrombus, and examined the platelet aggregation ability using blood of a patient with this disease. As a result, in patients, especially those who underwent splenectomy, they found that blood cell components promoted platelet aggregation. Therefore, when examining the inhibition of platelet aggregation promoting action by this blood cell component using various drugs,
The basic fact that dilazep or a salt thereof has a remarkable inhibitory effect and furthermore that
-The inventors have found that the present invention is useful as a therapeutic agent for thalassemia HbE disease and completed the present invention.

That is, the present invention provides a therapeutic agent for β-thalassemia which contains dilazep or a salt thereof as an active ingredient.

The chemical name of zirajib, which is an active ingredient of the therapeutic agent of the present invention, is
A known compound represented by tetrahydro-1H-1,4-diazepine-1,4 (5H) -dipropanol bis (3,4,5-trimethoxybenzoate) (JP-B-44-23334) and its hydrochloride (Dihydrochloride monohydrate: hereinafter referred to as diradip hydrochloride) is a typical example. Dilazep hydrochloride is known to have a coronary vasodilator action, a renal function improving action, a cerebral vasodilator action, and the like, and is also known to be useful for the treatment of sickle cell anemia (Japanese Patent Application Laid-Open No. 58
-96019). However, it has never been reported that this product is useful for treating β-thalassemia.

The therapeutic agent of the present invention can be in various dosage forms, for example, oral preparations such as tablets, granules and capsules, as well as suppositories and injections. The dosage of the therapeutic agent of the present invention varies depending on the condition of the patient, but it is usually preferable to administer 0.1 to 1000 mg of dilazep or a salt thereof in one to four doses per day.

[Actions and Effects of the Invention] Tests performed for examining the platelet aggregation ability of β-thalassemia patients and the effect of dilazep on the ability are shown below.

Experiment 1 Comparison of platelet function with and without splenectomy in patients with β-thalassemia HbE disease (Method) Blood sampling with sodium citrate from patients with and without splenectomy surgery in β-thalassemia HbE disease patients and healthy subjects Whole blood, platelet-rich plasma (PRP)
And platelet-rich plasma plus a blood cell component (PRP + blood cell component), and the mixture was stirred in a platelet aggregometer, and the residual ratio of free platelets in each sample was measured over time.

(Results) The free erythrocyte remaining rate (%) after 8 minutes in each sample is shown in Table 1.

From this result, it can be seen that, in a patient who has undergone removal of the spleen, blood cell components that have not been destroyed in the spleen have enhanced platelet aggregation ability.

Experiment 2 Effect of dilazep hydrochloride on platelet aggregation in patient's whole blood (Method) Blood of four patients with β-thalassemia HbE disease who underwent splenectomy was subjected to sodium citrate blood sampling, and the final concentration of dilazep hydrochloride was 10 μM. And the mixture was stirred in a platelet aggregometer to measure the residual ratio of free platelets in whole blood over time. As a control, the patient's blood (whole blood) to which dilazep hydrochloride was not added was used.

(Results) The results are shown in FIG. From this figure, it is understood that the platelet aggregation promoting effect of the blood cell component is inhibited by dilazep.

Experiment 3 Acute toxicity test Table 2 shows the results of an acute toxicity test by oral administration of dilazep hydrochloride to mice and rats. The results show that dilazep has very low acute toxicity.

From the results of these tests, it can be seen that dilazep can prevent thrombus formation by inhibiting platelet agglutination in patients with β-thalassemia, and is also highly safe for living organisms. Therefore, the therapeutic agent of the present invention containing it as an active ingredient is very useful for treating β-thalassemia.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Sugar-coated tablets Dilazep hydrochloride 50mg Corn starch 27mg Crystalline cellulose 10mg Carboxymethyl cellulose 10mg Hydroxypropyl cellulose 2mg Magnesium stearate 1mg Subtotal 100mg Coating (sugar coating) 150mg Total (per tablet) 250mg Of the above ingredients, from dilazep hydrochloride to magnesium stearate And uncoated tablets were produced according to a conventional method. Next, this was sugar-coated to obtain a product.

Example 2 Tablets Dilazep hydrochloride 25 mg Excipient (lactose) 20 mg Starch 50 mg Cellulose 5 mg Binder Appropriate Lubricant Appropriate The above compositions were mixed and tabletted to produce a tablet.

Example 3 Granules Dilazep hydrochloride 50mg Lactic acid 447mg Corn starch 119mg Hardened castor oil 80mg Carboxymethylcellulose sodium 40mg Carboxymethylcellulose calcium 119mg Hydroxypropylcellulose 45mg 2-Methyl-5-vinylpyridine methyl acrylate
Methacrylic acid copolymer 52 mg Polyethylene glycol 6000 8 mg Polyoxyl stearate 40 2 mg Talc 8 mg Sucrose 30 mg Total 1000 mg Of the above components, fine granules were produced from dilazep hydrochloride to hydroxypropyl cellulose according to a conventional method. Then, the remaining product was coated to obtain a product.

Example 4 Injection Dilazep hydrochloride 0.5 mg Sodium chloride 8.9 mg or more The composition was completely dissolved in distilled water for injection, and the total amount was 1.
After adjusting the volume to 0 ml, the solution was aseptically filtered and filled into ampoules to produce an injection.

Example 5 Suppository (fat-soluble) Dilazeb hydrochloride 50 mg Witepsol E-85 100 mg Witepsol E-35 778 mg Polyoxyethylene sorbitan monooleate 10 mg Sorbitan monolaurate 10 mg Hardened castor oil 2 mg Silica anhydride 10 mg Total (per piece) 960 mg Of the above components, Witepsol E-85 to hardened castor oil were heated and melted, and dilazep hydrochloride and silicic anhydride were added thereto, sufficiently stirred and dispersed, poured into a container and cooled and molded.

Example 6 Suppositories (water-soluble) dilazep hydrochloride 50 mg polyethylene glycol 4000 1257.9 mg polyethylene glycol 400 80 mg 2,6-di-tert-butyl-p-cresol 2 mg sodium thiosulfate 0.1 mg total (per piece) 1300 mg polyethylene glycol 4000 and Heat and melt 400
The remaining components were added thereto and sufficiently stirred and dispersed, then poured into a container and cooled and molded.

Example 7 Suppository (Rectal capsule) Dilazep hydrochloride 50mg Cottonseed oil 663mg Hardened castor oil 15mg Polyoxyethylene sorbitan monooleate 2mg Sorbitan monolaurate 20mg Total (per 1 piece) 750mg Was filled.

[Brief description of the drawings]

FIG. 1 shows whole blood of a β-thalassemia HbE disease patient who underwent splenectomy surgery, plus dilazep hydrochloride. And the ones not added FIG. 5 is a view showing the results of measuring the residual ratio (%) of free platelets over time.

Claims (3)

(57) [Claims] (1) A therapeutic agent for thalassemia which comprises dilazep or a salt thereof as an active ingredient. 2. The method according to claim 1, wherein the active ingredient is dilazep hydrochloride.
The agent for treating thalassemia described in the above. 3. The therapeutic agent for thalassemia according to claim 1, wherein the thalassemia is β-thalassemia HbE.