JPH07188005A - Medicine for prevention and therapy of toxicosis - Google Patents

Abstract

PURPOSE:To obtain a medicine for prevention and therapy of toxicosis, capable of improving not only metabolic function of liver, etc., for a medicine, etc., but eccritic function for excreting a metabolized medicine, etc. CONSTITUTION:This medicine for prevention and therapy of toxicosis contains 4,7,10,13,16,19-docosahexaenoic acid(DHA), its salt or its derivative. As the DHA derivative, an ester derivative, especially its ethyl ester is preferably used. Absorption of DHA into the living body not only increases the content of DHA as a fatty acid in the blood but allows n-3 series unsaturated fatty acids to constitute the fatty acids in the blood as the main components. It is considered that absorption of DHA has an effect also on other lipids in the blood or other tissues in the living body, e.g. cells. Consequently, the cell membrane is strengthened and the hepatic function is improved.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is 4, 7, 10, 13, 1
6,19-Docosahexaenoic acid (hereinafter referred to as DHA)
Alternatively, it relates to a drug for preventing or treating toxicosis, which comprises a salt or a derivative thereof.

[0002]

2. Description of the Related Art At present, humans use various drugs for treatment of diseases. However, when a large amount of chemical substances such as these drugs are taken into the body, poisoning may occur. In addition, foreign substances other than drugs such as bacteria and heavy metals may cause poisoning symptoms.

Taking toxicosis due to drugs as an example, the addiction refers to a phenomenon in which a drug which a person usually uses for treatment causes a temporary or persistent disability and sometimes death.

The causes of drug poisoning can be roughly divided into two categories: drug poisoning due to an increase in absolute drug amount in the body and drug poisoning due to an increase in drug sensitivity on the living body side.

Regarding the drug poisoning corresponding to the above, there are cases where the pharmacological action of the drug becomes larger than necessary and cases where the potential drug toxicity becomes apparent depending on the amount, and the causes of these phenomena occur. Examples of such problems include temporary overdose of drugs, deterioration of drug metabolism and excretion function due to age, diseases and the like.

Regarding the drug poisoning corresponding to the above, there are changes in drug allergy, hormonal environment, electrolyte concentration and the like.

As a symptomatic treatment for these drug poisoning, when the causative drug is known, repeated administration of the antagonist or a measure for promoting the excretion of the drug absorbed into the body to the outside of the body. Is effective.

The action of the drug on the living body is an interaction between the drug and the living body, so it cannot be said that it is appropriate to determine the cause of only one of them. However, when the amount or the pharmacological action of the drug is caused, such as when the absolute amount of the drug is large, in order to prevent drug poisoning, the drug is stopped or the intake is reduced or the drug is taken. There is no choice but to change the method.

However, mainly when the cause can be determined in the living body, that is, when the drug metabolism or excretion function is lowered, or when the electrolyte concentration is changed, etc., the metabolic function or excretion function of the living body itself is improved. By doing so, it can be prevented to some extent.

[0010]

By the way, the phospholipids and the fatty acids constituting them play an important role in the constitution and function of the cell membrane of the living body. Phospholipids have a so-called amphipathic character, with an affinity for both polar and non-polar solvents, so that phospholipids form phospholipid bilayers in aqueous solution. Phospholipids having such properties have an arrangement structure based on the phospholipid bilayer even in the cell membrane, and play an important role also in maintaining the structure of the cell membrane itself and in putting in and out various substances through the cell membrane. Is believed to have fulfilled.

Therefore, when the composition and the ratio of the lipids required for the cell membrane are changed, for example, the cell membrane is weakened, and as a result, various substances are transferred, which causes various tissues and organs in the living body. The function also deteriorates.

[0012] When a drug is taken into a living body, the drug absorbed in the living body is usually metabolized in the liver or the like, and its chemical structure is changed, resulting in an increase in water solubility and a decrease or disappearance of pharmacological activity. Occurs. The drug that has undergone such metabolism is then excreted outside the body, but if the cell membrane of the liver or the like becomes weak, the aforementioned drug metabolism function is weakened, and accumulation of unnecessary drugs in the living body occurs, resulting in drug poisoning. And the like easily develop. In addition, since ions such as Na ⁺ and Ca ⁺ easily enter the cells, phenomena such as changes in electrolyte concentration occur, changes in drug sensitivity in the body occur, and drug poisoning easily occurs. It is possible that

The inventors of the present invention are more likely to cause intoxication due to a decrease in metabolic function of drugs such as liver and the like, which is considered to be caused by such weakening of cell membranes, and an increase in sensitivity of the drug of the living body itself. As a result of various studies for the purpose of preventing the living body and treating toxicosis, it was found that the fatty acids constituting lipids such as phospholipids, and particularly various fatty acids are related to the metabolism of various living bodies and physiologically active substances such as hormones. It was found that the ingestion of DHA, which is said to be a polyunsaturated fatty acid, or a salt thereof or a derivative thereof, significantly improves functions such as metabolic function and sensitivity to drugs, etc. The invention was completed.

[0014]

Means for Solving the Problems That is, the preventive and therapeutic agents for toxicosis according to the present invention are 4, 7, 10, 13, 1
It is characterized by containing 6,19-docosahexaenoic acid (DHA) or its salt or its derivative (1).

The drug for preventing or treating toxicosis according to the present invention is characterized in that in the drug for preventing or treating toxicosis described in (1) above, its derivative is an ester (2).

The drug for preventing and treating toxicosis according to the present invention is characterized in that in the drug for preventing and treating toxicosis described in (2) above, the ester is an ethyl ester.

DHA is 4, counting from the carboxyl group,
It is a highly unsaturated fatty acid having a double bond at the positions 7, 10, 13, 16, 19 and has an unsaturated group at the third position from the terminal group on the opposite side of the carboxyl group,
It is also called ω-3 (n-3) unsaturated fatty acid.

DHA is known to exist in fish oil such as rainbow trout, and can be extracted from these by a known method. Further, it can be synthesized by a pure organic chemical method based on synthetic organic chemistry.

DHA can also be used by itself,
It can also be used as a pharmacologically acceptable salt, ester or amide derivative. Examples of advantageous salts for this purpose include sodium or potassium salts and salts with organic bases. Further, preferred esters include esters with polyhydric alcohols such as fatty acid triglycerides, esters with lower alkyl alcohols such as methanol and ethanol, and more preferred amides with lower alkyl amines such as methylamine and ethylamine. Examples include amides.

DHA is blended with a pharmaceutically acceptable carrier and is orally or parenterally as a solid preparation such as tablets, capsules, granules and powders; or an emulsion and liquid preparation such as syrups and injections. Can be administered locally.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances which are commonly used as a formulation material are used, and an excipient, a lubricant, a binder, a disintegrant in a solid formulation; a liquid formulation It is blended as a solvent, a solubilizing agent, a suspending agent, an isotonicity agent, a buffering agent, a soothing agent and the like. If necessary, chemical additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like.
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch,
Examples thereof include carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Suitable examples of the suspending agent include, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, surfactants such as glyceryl monostearate, polyvinyl alcohol, polyvinyl. Hydrophilic polymers such as pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like can be mentioned. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate. Preferable examples of soothing agents include benzyl alcohol and the like. Preferable preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidizing agent include tocopherols, sulfites and ascorbic acid.

The dose of DHA or its salt or its derivative is about 1 to 500 mg as DHA per day for an adult.
/ Kg, preferably 5-300 mg / kg. The acute toxicity of DHA ethyl ester to rats is LD ₅₀ : 2000 mg / kg or more.

[0023]

According to the drug for preventing and treating toxicosis having the above-mentioned constitution, since it contains 4,7,10,13,16,19-docosahexaenoic acid (DHA) or its salt or its derivative, When these are absorbed, the cell membrane is strengthened and its function is also improved. Therefore, the metabolic function for drugs such as the liver is improved, and the excretion function for excreting the metabolized drugs is also improved, resulting in metabolism. Drugs are promptly excreted out of the living body. Further, the sensitivity to drugs and the like is also improved, the resistance to drugs and the like is improved, and intoxication is less likely to occur.

[0024]

EXAMPLES AND COMPARATIVE EXAMPLES Examples of the preventive and therapeutic agents for poisoning according to the present invention will be described below.

In the examples, as an animal for observing the function against drug poisoning, stroke-prone spontaneously hypertensive rats (strokeprone spontaneously hypertensi) were used.
ve rats: SHRSP) was used.

It is known that this SHRSP has a different composition ratio of phospholipids important for cell membranes and free fatty acids such as arachidonic acid constituting the phospholipids. As described above, when the lipid required for the living body is changed, various functions of living cells are deteriorated, and particularly in the liver and the like, the metabolic functions of drugs and the like are affected.

Therefore, for these SHRSP, 95
wt% DHA ethyl ester (Harima Kasei Co., Ltd.)
5% by weight (Examples 1 and 3) or 1% by weight
(Example 2) An average of 20 g of bait containing the ingredients was given per day, which was 1
After continuing for 4 weeks, the content of fatty acid in plasma was measured (Table 1), and various tests shown in Table 2 below were performed to obtain test data. The results are shown in Tables 1 and 2.

On the other hand, as Comparative Examples 1 and 2, an average of 20 g / day of SHRSP having the same composition except that DHA was not contained was given, and this was continued for 14 weeks. The fatty acid content was measured, and various similar tests shown in Table 2 below were performed to obtain test data. The results are also shown in Tables 1 and 2.

The samples used in the examples (SHR
The number of SP) was 9 in Examples 1 and 3, 10 in Example 2, and 11 in Comparative Examples 1 and 2.

[0030]

[Table 1]

[0031]

[Table 2]

As is clear from Table 1, in Examples 1 and 2, by ingesting DHA, D in plasma was increased.
The content of HA is higher than that of Comparative Example 1, and the total content of unsaturated fatty acids of n-6 is reduced accordingly. As a result, n to n-6 unsaturated fatty acid
It can be seen that the ratio of the unsaturated fatty acid of -3 increased and the composition was clearly different from that of Comparative Example 1. Regarding the total amount of fatty acids in the blood, the amount thereof was decreased as compared with Comparative Example 1.

Next, when the data of the biochemical system was examined, when the GOT showing the content of aspartate aminotransferase in serum was compared between Example 3 and Comparative Example 2, a significant level of 0.01% was obtained. , There is a significant difference, and the value of Example 3 is lower than that of Comparative Example 2. It is considered that the destruction of tissue cells in the liver, which is considered to occur in normal SHRSP, is prevented by ingesting DHA.

As is clear from the results of the above Examples and Comparative Examples, by ingesting DHA ethyl ester orally, the DHA ethyl ester is absorbed in the living body. By absorbing the ethyl ester of DHA in vivo, not only the content of the n-3 series unsaturated fatty acid in plasma is increased, but also the amount of the n-6 series unsaturated fatty acid is decreased, In addition, the total fatty acid content is low.

The composition and ratio of fatty acids in plasma of SHRSP shown in Comparative Example 1 are changed by ingestion of DHA, and it is considered that the ratio is also changed in the cell membrane composition of hepatocytes. May be. Therefore, it is considered that ingestion of DHA improved the function of hepatocytes.

It is considered that the improvement of the function of the hepatocytes is due to the fact that the n-3 series fatty acids, especially DHA, strengthened the cell membrane and improved the function. The improvement of these functions improves the metabolic function of the liver and the like for drugs, and also improves the function of excreting metabolites of drugs and the like out of the body.
It makes addiction less likely and allows the drug to be rapidly excreted outside the body.

Further, by strengthening the cell membrane, the sensitivity to drugs and the like is also improved, the resistance to drugs and the like is improved, and intoxication is less likely to occur.

[0038]

INDUSTRIAL APPLICABILITY As described above in detail, the drug for preventing or treating toxicosis according to the present invention contains DHA or a salt thereof or a derivative thereof, and when these are absorbed in the living body. Not only does the content of DHA as a fatty acid in blood increase, but the fatty acid in blood mainly contains n-3 series unsaturated fatty acids. It is considered that the absorption of DHA changes other lipids in blood and other tissues such as cells in the body, and as a result, the cell membrane is strengthened and the function of the liver is improved.

By administering DHA in this manner,
The metabolic function for drugs such as the liver can be improved, and further, the metabolized drug can be rapidly excreted from the body due to the improved excretion function, so that poisoning can be prevented and treated. . Further, since the sensitivity to the drug or the like can be improved, the resistance to the drug or the like can be improved and the onset of poisoning can be prevented.

Claims (3)

[Claims] 1. A drug for preventing or treating toxicosis, which comprises 4,7,10,13,16,19-docosahexaenoic acid or a salt thereof or a derivative thereof. 2. The drug for preventing or treating toxicosis according to claim 1, wherein the derivative is an ester. 3. The drug for preventing or treating toxicosis according to claim 2, wherein the ester is ethyl ester.