JPH0748269A - Treating agent for toxemia of pregnancy - Google Patents

Abstract

PURPOSE:To obtain a treating agent for toxemia of pregnancy having reducing activity against proteinuria, urine beta2-MG and urine NAG and excellent in safety by compounding haptoglobin as an active agent. CONSTITUTION:This treating agent is obtained by compounding (A) haptoglobin as an active component optionally with (B) a adrenocorticotropic steroid hormone or antithrombin III. Further, the haptoglobin is preferably administered around 1-5 times every day or every two days at a single dose of 1000-5000 unit.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel use of haptoglobin. More specifically, it relates to a therapeutic agent for pregnancy toxemia which contains haptoglobin as an active ingredient.

[0002]

2. Description of the Related Art Toxemia of pregnancy is a disease having hypertension, edema and proteinuria as three major symptoms, and is regarded as a maternal maladaptation syndrome during pregnancy. Toxemia of pregnancy has a high incidence (5-10%) in pregnant women and is still the leading cause of maternal mortality and is closely associated with perinatal mortality. In most cases of toxemia of pregnancy, fetal / placental function is impaired. In addition, if you give birth during 28 to 30 weeks of gestation due to aggravation,
Respiratory management is often required due to incomplete fetal lung formation, presenting safety and economic concerns for the newborn. On the other hand, if the mother also gives birth due to toxemia of pregnancy, proteinuria may persist after delivery, requiring medical treatment, and may lead to mental and physical breakdown for childcare. The principle of treatment for toxemia of pregnancy is early detection and rest, diet, ie low salt, calorie restriction, high protein diet. If symptoms do not improve, drug therapy centered on antihypertensive drugs will be given. In severe cases, it is known to be in the state of chronic DIC (general vascular drug coagulation syndrome),
Anticoagulants such as heparin, antithrombin III, aspirin and dipyridamole, and platelet aggregation inhibitors are used.

On the other hand, haptoglobin is a plasma glycoprotein having a molecular weight of 85,000 to 400,000, and plays an important role in the metabolism of hemoglobin released into blood. Haptoglobin has the property of binding specifically to hemoglobin and forming a haptoglobin-hemoglobin complex. Haptoglobin in plasma forms a complex with hemoglobin produced by hemolysis, and is transported to the liver, which is a normal metabolic pathway of hemoglobin. It is present in the plasma in the free state and causes hemoglobinemia and hemoglobinuria via the kidneys. Therefore, haptoglobin is
It is said to be effective in treating hemoglobinemia and hemoglobinuria associated with hemolytic reactions such as burns, burns, blood transfusion, and open-heart surgery under external circulation.

[0004]

The object of the present invention is to provide another pharmaceutical use of haptoglobin.

[0005]

[Means for Solving the Problems] The inventors of the present invention have conducted various studies to achieve the above-mentioned objects, and as a result, the haptoglobin amount has been drastically reduced in severe cases of preeclampsia, and haptoglobin is administered. As a result, it was found that improvement of symptoms such as reduction of proteinuria was observed, and the present invention was completed.

The present invention has been completed on the basis of such new findings, and relates to a novel use of haptoglobin, specifically, a therapeutic agent for pregnancy toxemia containing haptoglobin as an active ingredient.

Haptoglobin, which is an active ingredient of the therapeutic agent for pregnancy toxemia of the present invention, is of human origin and is not particularly limited as long as it has the above-mentioned properties. As haptoglobin, those prepared by any method of plasma origin, cell culture, and genetic engineering can be used. Specifically, JP-A-50-77516, JP-A-50-77527, and JP-A-63-1.
It can be prepared according to the method disclosed in Japanese Patent No. 7899. Further, a commercially available preparation (trade name “Haptoglobin Injection-Midori” (Midori Cross Co., Ltd.) can also be used.

In the therapeutic agent for pregnancy toxemia of the present invention, haptoglobin can be used alone or in combination with known agents generally used for the treatment of pregnancy toxemia. As a result, it is expected that the therapeutic effect can be further improved. Specific examples of the drug that can be used in combination with haptoglobin include steroidal corticosteroids, antithrombin-III, and the like.

Among these, corticone (cortisone, hydrocortisone, etc.), fluoridation type (dexamethasone, triamcinolone, parameterzone, fludrocortisone, beclomethasone, betamethasone, etc.), prednisolone (prednisolone, methylprednisolone) are used as steroidal adrenocortical hormones. Etc.), others (halopredone, plasterone, etc.), or their fatty acid ester bodies or mineral acid ester bodies and the like. Examples of the fatty acid include monocarboxylic acids or dicarboxylic acids having 2 to 20 carbon atoms. It may be either aliphatic or aromatic.
Specific examples of the aliphatic monocarboxylic acid include acetic acid, propionic acid, butylacetic acid, palmitic acid and the like.
Examples of the aromatic monocarboxylic acid include metasulfobenzoic acid and the like. Moreover, succinic acid etc. are illustrated as an aliphatic dicarboxylic acid. Examples of the mineral acid include phosphoric acid and sulfuric acid.

As such an acetic acid ester form, cortisone acetate, hydrocortisone acetate, dexamethasone acetate,
Fludrocortisone acetate, betamethasone acetate, prednisolone acetate, methylprednisolone acetate, and halopredone acetate are formulated and marketed. Beclomethasone propionate is formulated and marketed as a propionate. Prednisolone butyl acetate has been formulated and marketed as a butyl acetate ester. Dexamethasone palmitate is formulated as palmitate
It is commercially available. Dexamethasone metasulfobenzoate is formulated and marketed as a metasulfobenzoate ester. Hydrocortisone succinate, prednisolone succinate, and methylprednisolone succinate have been formulated and marketed as succinate esters. Hydrophosphates, dexamethasone phosphate, betamethasone phosphate, and prednisolone phosphate are formulated and marketed as phosphate esters. Plasterone sulfate is prepared and marketed as a sulfate ester.

Further, as antithrombin-III, a trade name "Noiart" (made by Midori Cross Co., Ltd.),
"Anthrobin-P" (manufactured by Hoechst) is formulated and marketed.

Haptoglobin, which is an active ingredient of the therapeutic agent for pregnancy toxemia of the present invention, has a proteinuria-reducing action, a urinary β ₂ -MG-, and a urinary NAG-reducing action in patients with pregnancy toxemia. Is.

In the therapeutic agent for pregnancy toxemia of the present invention, haptoglobin is appropriately mixed with pharmaceutically necessary components such as pharmacologically acceptable additives (eg, carriers, additives, excipients, diluents). Powder, granules, tablets, capsules, syrups,
It can be administered orally or parenterally in the form of an injection or the like. In particular, it is preferable that haptoglobin is prepared as a lyophilized product together with a pharmacologically acceptable additive to prepare a formulation that dissolves at the time of use. For example, it is diluted with distilled water for injection to prepare a solution of haptoglobin of about 1 to 100 units / ml, and more preferably, a salt concentration is adjusted to a physiologically isotonic concentration, and intravenous administration is performed.

The therapeutic agent for pregnancy toxemia of the present invention containing haptoglobin as an active ingredient is used for patients with pregnancy toxemia, particularly severe cases. Specifically, the amount of haptoglobin in serum is 45
It is preferable to target patients who have decreased to mg / dl or less. It is preferable that the administration time is a period of pregnancy intoxication. Further, even after the birth of the same pregnant woman, if the same symptom (for example, high proteinuria) continues, it may be an indication target. The dose is, for example, 1000 to 5000 units once to about 1 to 5 times on consecutive days or every other day. In addition, this "1 unit" means the amount which binds 1 mg of hemoglobin. Also, corticosteroids,
Alternatively, when antithrombin-III is used in combination, the above-mentioned amount of haptoglobin and corticosteroids are based on a known clinical dose, and antithrombin-III is 1000 to 3000 units per day (1 unit is a normal person). (Corresponding to the amount of antithrombin-III contained in 1 ml of plasma) is administered by intravenous injection or intravenous infusion.

[0015]

TEST EXAMPLES Test examples are given to explain the present invention in more detail, but the present invention is not limited to these.

Test Example 1 At 29 weeks of gestation, urinary protein (3+) and blood pressure were 160/100
When gestational toxemia patients (25 years old) who had an increase in mmHg and edema were also administered with 2000 units of haptoglobin [product name "Haptoglobin Injection-Midori" manufactured by Midori Cross Co., Ltd.] by intravenous injection, urinary protein , And decrease in urinary β ₂ -MG and NAG levels were confirmed, and improvement of symptoms was confirmed.
The test findings before and after administration of haptoglobin are shown in Table 1.

[0017]

[Table 1]

Test Example 2 A toxicosis patient (29 years old) hospitalized with urinary protein (2+) at 29 weeks of gestation (+5 days) was given rest and diet, but 30 weeks of gestation. Blood pressure is 150 on (+3 days)
/ 90 mmHg, and no improvement in urinary protein was observed. Therefore, the same day, 3 days, and 6 days later, when 2000 units of haptoglobin [product name “Haptoglobin Injection-Midori” manufactured by Midori Cross Co., Ltd.] was administered by intravenous injection, decrease in urinary protein and urinary β ₂ -MG And a decrease in NAG value,
Improvement of symptoms was confirmed. Table 2 shows the test findings before and after administration of haptoglobin.

[0019]

[Table 2]

Test Example 3 A gestational toxicosis patient (30 years old) who underwent a cesarean section at 30 weeks of gestation had no improvement in proteinuria even after 8 days postpartum, and therefore haptoglobin [product name "haptoglobin" was given on the same day. Note-Midori "(Midori Cross Co., Ltd.) 2000 units and betamethasone sodium phosphate 2 mg (trade name" Linderon ") were administered by intravenous injection, and a significant decrease in urinary protein was observed the next day ( The amount of urine was 6.3 g / day the day before administration, but 3.1 g / day the day after administration.
It was confirmed that the symptoms had improved. This case was suggested to be a case of pregnancy poisoning with antiphospholipid antibody syndrome.

[0021]

EFFECTS OF THE INVENTION The therapeutic agent for pregnancy toxemia containing haptoglobin as an active ingredient of the present invention is found to improve symptoms such as reduction of proteinuria in patients with pregnancy toxemia, as is clear from the above test examples. , Is extremely effective in treating the patient.

Claims (2)

[Claims] 1. A therapeutic agent for pregnancy toxemia containing haptoglobin as an active ingredient. 2. The therapeutic agent for preeclampsia according to claim 1, which is used in combination with a steroidal adrenocortical hormone or antithrombin-III.