JPS5896021A - Remedy for oxygen poisoning - Google Patents

Abstract

PURPOSE:To provide a remedy for oxygen poisoning, easily absorbable in erythrcyte membrane, having antioxidation activity, and useful as a remedy and preventive of diseases caused by oxygen poisoning, by using tocotrienol or its ester as an active component. CONSTITUTION:The objective remedy for oxygen poisoning contains alpha-(5,7,8- trimethyl-), beta-(5,8-dimethyl-), gamma-(7,8-dimethyl-), or delta-(8-methyl-), tocotrienol or its ester, preferably nicotinic acid ester, as an active component. The remedy is effective to prevent the dialuric acid hemolysis at an extremely low dose compared with tocols, and exhibits nearly the same preventive effect at a dose of about 1/3 of alpha-tocopherol. Although the acute toxicity and chronic toxicity are not found in the above remedy, it is preferable to administer at a dose of about 100-3,000mg daily for the remedy of adult to prevent the possibility of side effects caused by administration at high dose.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a treatment for anxiety disorders using tocotrienols or esters thereof as an active ingredient.

Vitamin E is a fat-soluble vitamin that is mainly related to reproductive function and has an anti-infertility effect, but it also has an effect on improving peripheral circulation failure and a non-specific antioxidant effect. Known as a powerful antioxidant.

This vitamin EK has homologs of tocols and tocotrienols.In nature, the tocols include α-tofufep-(5,7,8-)limethyltocol), β
-Tocopherol ('5゜8-dimethyltocol), γ
-Tocofurol (7,8-dimetaterutocol), δ-
There are four tocopherols (8-methyl tocol), and tocotrienols include α-to:1 trienol (5
,7,8-) Re-methyl-to-coto
/9-tocotrienol (S, S-dimethyltocotrienol), γ-toftrienol (7,8-dimethyltocotrienol), δ
-Tocotrienols (8-notyltocotrienol) are known. Conventionally, it has been believed that alpha-1 tofuferol has the greatest biological effects, and its anti-tolerance effect can be used to treat various diseases caused by oxygen disorders, such as premature death. Attempts have been made to treat bronchopulmonary dysplasia in infants, retinopathy of prematurity (which develops as a side effect of oxygen therapy for premature infants), hypoxia (which develops as a side effect of hyperbaric oxygen therapy, etc.), and chronic lung disorders. However, sufficient and clear therapeutic effects have not yet been obtained.

Vitamin E is easily incorporated into biological membranes due to its antioxidant properties (-), which is said to prevent oxidative damage to biological membranes due to its physiological or pharmacological effects (σ). It is thought that t and its antioxidant effect, and thus its effect as a treatment or prevention agent for oxygen disorders, are strong.

From this perspective, the present inventors investigated the antioxidant effects of vitamin E analogues and found that tocotrienols or their esters, whose biological effects had not been studied in the past, were incorporated into biological membranes much more than tofurs. We realized that it is easy to do so and arrived at the present invention.

That is, the present invention is a therapeutic agent for oxygen disorders containing tocotrienol or its ester as an active ingredient.

Tocotrienol in the present invention is represented by the following formula,
α-(5,7,R-)limethyl)l β-(S, S
-dino'thyl-), γ-(7,8-dimethyl-)l β
-(8-Methyl-)tocotrienols are known. There may be 6 bodies, 1 body, or 41 bodies, respectively.

1 Moreover, the ester means a compound in which the hydroxyl group at the 6-position of tocotrienol forms an ester, such as an acetate ester, a succinate ester, and a nicotinate ester. Particularly preferred in the present invention are α-toftrienol and nicotinic acid esters of α-tocotrienol. All of these are known compounds or compounds that can be easily obtained by known methods.

As explained below, tocotrienols or their esters are highly absorbed into the red bulge membrane of vitamin E-deficient rats, and have very strong antioxidant effects as evaluated by the diallic acid dissolution test. Oxygen disorders such as bronchopulmonary dysplasia and retinopathy of prematurity, which tend to occur secondary to premature infants undergoing artificial ventilation therapy using artificial ventilation, and pre-V prime syndrome and chronic lung disorders, which tend to occur in the field of hyperbaric oxygen therapy and space medicine. Based on this, it is expected to be applied as a therapeutic or preventive agent.

The effect of preventing oxygen damage will be explained below.

0) Diarylic acid hyperemia test (DHT) Red blood cells from vitamin E-deficient rats undergo oxidative damage to their membranes and hemolysis due to diallic acid. Therefore, in vitro
or in viv.

By measuring the rate of diallic acid hemolysis of red blood cells in the presence of vitamin E using this system, it is possible to know the effect of vitamin F on preventing oxidative damage to biological membranes.

Experimental Animals Male Wistar rats weighing 100 g were fed on a commercially available vitamin E-deficient diet for 8 to 10 weeks immediately after purchase. The body weight at the time of the experiment was approximately 2,509 pounds.

Blood collection was performed by cardiac puncture under ether anesthesia 5- became.

Preparation of vitamin E or its ester Vitamin E or its ester is prepared by adding twice the amount of surfactant (T(CO-60)), heating to 70°C, adding an appropriate amount of physiological saline, and treating with ultrasound. Disperse, each o
, 25η/ml suspension was prepared, and based on that, 10
A test solution with a concentration of 0 to 1000 μg/d' was prepared.

In vitro experiments and results Blood collected from vitamin E-deficient rats (heparinized blood collected by injecting heparin into the inner cylinder of the syringe with the piston) was dispensed as whole blood into 0.24 ml portions, and then kneaded with vitamin E. 0 and 01 mJ each of the prepared test solution were added to the predetermined concentration of the solution, kept at 37°C for 30 minutes (stirred with a multi-stirrer), washed twice with physiological saline, and added Dial solution ( Concentration 1m prepared before use!
7/I+Il phosphate buffer solution) 21 was added to prepare a red blood cell suspension, which was then subjected to a diallic acid hemolysis test.

6- In addition, vitamin E present in the red blood cell membrane and plasma at that time was quantified.

■ Dialic acid hemolysis test Prepare three test tubes A, B, and C. Take 0.25 ml of red blood cell suspension into each of them.

Then, 0.25 ml of 005M phosphate buffer was added to A[,0
, 2011/ is added to B and C. B.

To C, gently add 0.05 ml of 1-dialic acid solution along the wall of the test tube, and immediately mix gently. The three test tubes were then kept at 37° C. for 30 minutes with occasional shaking. For the transfer, add a mixture of physiological saline and phosphate buffer from No. 51 to A and H, and add distilled water from No. 5111 to CK. After mixing, centrifuge at 3000 rpm for about 10 minutes, and top. The absorbance of the supernatant is measured at s40 nmVc using a spectrophotometer or a colorimeter.

The hemolysis rate is calculated from the following formula.

(2) The reaction solution for quantitative measurement of vitamin E or its ester is used in an amount 10 times that for diallic acid hemolysis.

Quantification is performed by high performance liquid chromatography (PLC). In other words, the sample is dissolved in n-hexane, subjected to HPLC, and vitamin E or its ester is detected using fluorescence at a wavelength of 325 nm. , quantification is performed from a predetermined inspection line.

The relationship between the concentration after the addition of vitamin E and the dialylic acid hemolysis rate when using α-tocotrienol and α-tocopherol, β-tofuferol, r-tocopherol, and δ-tocopherol for comparison was first determined.
Table 2 shows the amount of vitamin E present in red blood cell membranes and plasma.

Note that the data are average values of 3 to 4 rats.

From Table 1 (Table 1) to Table 2 (Table 1), it can be seen that the α-toco)IJ enol of the present invention prevents diaric acid extraction in a much smaller amount than tocols. Among tocols, α〉β〉γ〉
The protective effect is strongest in the order of δ, but α-tocotrienol is
- It can be seen that approximately 1/3 of the amount of tocopherol exhibits the same preventive effect as α-tocopherol.

10- From Table 2, it can be seen that the α-tocotrienol of the present invention is much more easily incorporated into red blood cell membranes than tocols.

From the above, it was found that α-tocotrienol has a much stronger antioxidant effect than α-tocopherol, and this indicates that α-tocotrienol is clinically superior to α-tocopherol. 4N clearly indicates its use as a treatment or prevention agent for oxygen disorders.

In vivo experiments and results A predetermined amount of vitamin E or ester test solution (vitamin E
or ester (10 μ/y) was injected intravenously into the rat's leg. Immediately thereafter, blood was collected at predetermined time intervals to determine the diallic acid hemolysis rate in each case.

The amount of vitamin E or its ester present in red blood cell membranes and plasma was measured in the same manner as in vitro, and the ester was measured from vitamin E produced by alkaline hydrolysis.

α-tocotrienol and α-tocotrienol nicotinic acid ester of the present invention, and as a comparison α-tocotrienol p-
Table 3 shows the results when using L and β-tocopherol. In addition, the take is the average i1 of 3 to 5 rats.
It is 1.

Table 3 shows that the α-tocotrienol of the present invention is more rapidly accumulated in red blood cell membranes than tocols, and exhibits an antioxidant effect (anti-dial acid solubility inhibiting effect). α-Tocotrienol nicotinic acid ester also accumulates in red blood cell membranes more quickly than tocols, but there is an induction period before it exerts its antioxidant effect (possibly because hydrolysis of the ester is required). ).

It is also seen that the antioxidant power of α-tocotrienol or its nicotinic acid ester is not as durable as tocols. In other words, the antioxidant power of tocols is excellent) IJ
Although it is inferior to enols, its sustainability is said to be superior. This suggests that depending on the target disease genus, it may be better to use both in combination.

(2) Dosage, method of administration, and toxicity The therapeutic agent for #disability of the present invention is prepared by formulating tocotrienols or their esters into lipsticks or injections such as tablets or capsules in the same manner as vitamin E preparations. 1
reactor.

The administration method is similar to that of vitamin E preparations, and is administered via a bond mouth.

Administration methods include skin injection) or intravenous injection.Among the fat-soluble vitamins, only vitamin E is known as a vitamin that does not cause excess.Therefore, the agent for treating oxygen disorders of the present invention However, if the therapeutic agent for oxygen disorders of the present invention is administered in too large a dose, it may cause adverse reproductive effects, hypothyroidism, and blood coagulation disorders. Since gender is also a consideration, the dosage is preferably on the order of W used for the treatment of adults, or about 100 to 3000 μl per day as the active ingredient.

Examples of formulations of the therapeutic agent for oxygen disorders of the present invention will be described below with reference to Examples.

Example 1 Oral Tablet Oral tablets having the following composition were manufactured by a conventional method.

Ingredients Weight: 15 - Example 2 Injection for intramuscular injection 100 ml of tocotrienol or its ester was dissolved in 11 parts of purified corn oil to prepare an injection for intramuscular injection.

Example 3 Intravenous injection Tocotrienol or its ester 50 μm was mixed with polyoxyethylene sorbitan monostearate (Tween 8
0) 5■ was emulsified and dispersed in purified water of 1-, and propylparaben 02~ was added thereto to prepare an intravenous injection.

16-

Claims (1)

[Scope of Claims] l A therapeutic agent for oxygen disorders containing tocotrienol or its ester as an active ingredient. 2. The therapeutic agent for oxygen disorder according to claim 1, wherein the tocotrienol is α-tocotrienol. 3. The ester of tocotrienol is α-tocoto IJ-
1. The agent for treating oxygen disorders of claim 1, which is r-/-runicotinic acid ester.