JPH0193531A - Detoxicant for treating poisoning of bipyridinium quaternary cationic salt herbicide - Google Patents

Abstract

PURPOSE: To prepare an antidote for therapy, comprising a polysaccharide sulfate ester or its ester salt as an active ingredient and capable of removing various symptoms in acute poisoning with the subject herbicide and preventing long-term complications from developing. CONSTITUTION: This antidote for treating poisoning comprises a polysaccharide sulfate ester or its ester salt, preferably a compound having any one of formulae I and II [R is H or SO3 H (M is a metallic cation; hydrogen ion or other cations); (n) is <=600,000] as a partial structure, e.g. dextran sulfate ester or cellulose sulfate ester as an active ingredient therein. The dose of the compound represented by formula I is about 10 times the intake of a bipyridylium quaternary cationic salt-based herbicide (e.g. 1,1'-dimethyl-4,4'-bipyridylium dichloride).

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a detoxifying agent used for the treatment of poisoning caused by bipyridylium quaternary cation salt herbicides.

(Prior Art) Salts of bipyridylium quaternary cations are widely used worldwide as excellent herbicides. However, salts of bipyridylium quaternary cations have relatively high group compatibility with living organisms such as humans, and are therefore designated as medicinal substances and deleterious substances. Even though safe usage is instructed based on laws and regulations, accidents resulting in poisoning and death due to accidental ingestion, misuse, or abuse are often a problem.

Poisoning due to bipyridylium quaternary cation salts is caused by impaired lung function, and various studies have been conducted on treatment methods when poisoning due to the same item occurs.

For example, when bipyridylium quaternary cation salts are ingested, the sulfur oxide anion 02°
is generated, so it is necessary to administer rounding, superoxide dismutase and catalase to decompose and remove this, and to prevent the accumulation of lipid peroxide due to 02°, administration of daltathion peroxidase and vitamin E1.
It has been proposed to administer vitamin C and the like. However, its effect has not been clearly confirmed;
There have been no reported cases of severe illness.

As described above, there are almost no effective and reliable treatments for bipyridylium quaternary cation salt poisoning, and if bipyridylium M quaternary cation salt enters the body, drug poisoning may occur. - Following the general treatment, activated carbon, natural aluminum silicate,
This involves simply administering insoluble substances such as bentonite or sodium polystyrene sulfonate, or performing hemodialysis or blood perfusion to excrete substances absorbed into body fluids such as blood or tissues from the body. In the former case, since the adsorbent is a non-bathable solid, it is difficult to administer a large amount or repeatedly because of the foreign body sensation when taking it. In addition, the administered adsorbent must be forcibly excreted, and laxatives are generally required to round it up, but this causes significant physical exhaustion, and when sodium polystyrene sulfonate is administered, low potassium plasma This will induce In the latter case, it cannot be said to be an effective countermeasure because it is not sufficiently removed from the body.

(Problems to be Solved by the Invention) In view of the current situation, the present invention aims to eliminate various symptoms caused by bipyridylium quaternary cation salt herbicides and to prevent the development of long-term complications. The aim is to provide an effective therapeutic antidote.

(Means for Solving the Problem) As a result of research, the present inventor has found that polysaccharide sulfate ester or its ester salt has an excellent therapeutic effect on acute poisoning caused by bipyridylium quaternary cation salt. I found it. The present invention was completed based on such findings by the inventor.

Various polysaccharide sulfate esters or esters thereof exhibit therapeutic effects. For example, a polysaccharide sulfate ester having as a partial structure any of the formulas (wherein R represents H or 505M, M represents a metal cation, hydrogen ion or other cation, and n represents an integer of 600,000 or less) or its ester salts are particularly useful. For example, dextran sulfate, cellulose sulfate, starch sulfate, etc. have excellent properties.

Examples of the salt include monovalent metals such as sodium and potassium, metal salts such as calcium, magnesium, and aluminum, and ammonium salts. Dextran sulfate or its sodium salt is a compound represented by the formula (Il, where R is H or SONa. In the formula, n is preferably an integer of 3000 or less. 3
If it is more than 000, it will become viscous, so it is not suitable when working in an aqueous solution, but if it is used in granule form, it becomes viscous.
Particularly preferred sodium salts of dextran sulfate are those in which n is 2-50;
It has a sulfur content of -1i16-20%.

The sodium salt of dextran sulfate is an almost white, hygroscopic powder with no odor or taste. L for mouse
D50 is 21,000 ■/K9 when administered orally, and safety is high.

Examples of polysaccharide sulfate esters or ester salts thereof include glucose, mannose, galactose, fructose, arabinose, xylose, fucose, rhamnose, curcuronic acid, iduronic acid, Mannue I:Iy8
Sulfuric acid esters of polymeric compounds whose main constituents are one or two to five monosaccharides such as galacteronic acid, glucosamine, mannosamine, and galactosamine, or esters thereof can be used. For example, chondroitin i sodium sulfate, which contains both glucuronic acid and galactosamine as constituent components, exhibits excellent detoxifying properties.

Sodium chondroitin sulfate has the formula chondroitin sulfate A C0OHI'l 5
o3R5H Condro 4fn sulfur dlB f(CooH
5O3R' H chondroitin sulfate CC00HHH5
o3R1con't'roofingic acid D C0C)H
H5O3R'5O3R' (in the formula, R5 represents H, a metal cation, or another cation). A.

There are four ponds: B, C, and D. It is a tasteless and odorless powder that is hygroscopic. The LD5o in rats is more than 10 g/dose orally, and the drug is highly safe.

The herbicide targeted for the poisoning treatment of the present invention is a bipyridylium quaternary cation salt, which is a compound represented by the following formula.

In the above formula, R and R1 may be the same or different, each being an alkyl group having 1 to 4 carbon atoms, hydroxy, halogen, carboxyl, alkoxy,
It- represents an alkyl having 1 to 4 carbon atoms substituted by a group selected from alkylcarbonyl, alkoxycarbonyl, carbamoyl and N-substituted carbamoyl. (X)
"" represents an anion, and n represents an integer from 1 to 4.

Examples of such bipyridylium quaternary salts include the following.

1.1/-dimethyl-4,4'-bipyridylium di(
Methyl sulfate) (Pack Auto Dimethosal 7)
1-t), 1.1'-nitere-2,2'-bipyridylium dipromide (diquot dipromide), 1.1'-dimethyl-4,4'-bipyridylium dichloride (.
1-(2-hydroxyethyl)-1'-methyl-4,4'-bipyridylium dichloride, 1.1'-di-carbamoylmethyl-4,4'-bipyridylium dichloride, 1.1'- Bis-N,N-dimethylcarnomimoylmethyl-4,4'-bipyridylium dichloride r11.
1'-dimethyl-4,4'-bipyridylium sulfate (baraquat sulfate), 1, 1/
-His(3,5-dimethylmorpholinecarbonylmethyl)-4,4'-bipyridylium chloride (Morhamcote dichlorite 9) 1.1'-bis-N,N-diethylcarnosylmethyl-4,4'-bipyridylium Dichloride, 1.
1'-Diacetonitrile-4,4'-bipyridylium
Dichlorite9. 1.1'-Jethoxycarbonylmethyl-4,4'-bipyridylium dipromide, The name within 0 in the above compound is the common name for the cationic moiety of the compound. For example, '/raquat@
is the common name for the 1,1'-dimethyl-4,4'-bipyridylium cation.

The bipyridylium cation of interest for the antidote of the present invention is /cerafute.

The anion (X)n- of the above herbicide compound is generally a chloride ion, but any other ion that provides a water-soluble salt may be of interest.

The antidote containing the polysaccharide sulfate ester or its salt of the present invention can be administered internally after poisoning with bipyridylium herbicides, as well as by intravenous injection or drip drip.

When applied internally, polysaccharide sulfate esters or salts thereof can be used in the form of an aqueous solution or in the form of powder, granules, tablets, or capsules. For granulation,
Alternatively, when formulating into tablets, capsules, etc., a suitable binder etc. can be used. When orally administered in the form of an aqueous solution, it is preferably in the form of a 20-60% aqueous solution.

Administer approximately 10 times the amount of the herbicide component compound ingested. For example, herbicide stock solution (1,1'-dimethyl-4,4'
- Contains 24% as bibilisilicum cyclolide) approx. 1
If there is an accidental ingestion of n = 5-300, within about one month (an analogy based on the average lifespan of a mouse, one hour for a mouse is equivalent to about one day for a human).
0, sulfur content 16-20%, intrinsic viscosity 0.027
-0.028 of dextran + 1000-2oooT11y/Kp per dose of 1000-2oooT11y/Kp can produce a revitalizing effect.

Intravenous injections are generally effective in treating outcomes following oral administration. For example, in the treatment of prognosis one day after the oral administration as described above, further effects can be expected by administering intravenous injections of 300-600 ~/Kg at a time.

When applied intravenously, it is applied in the form of an aqueous solution. For example, it is appropriate that 5Kl (1 ampoule) contains 300 to 30% of sodium dextran sulfate.

When applied by intravenous infusion, dextran sulfate sodium 30 ("+") in 10 mA' (1 ampoule)
An aqueous solution containing 0η is crystallized at 500 dK with butosucrose injection (5 t) or physiological saline and administered intravenously.

For intravenous injection, dextran sulfate sodium
~50, sulfur content 3.0-6.0%, intrinsic viscosity 0.
030-0.040 is preferred, and a dosage of 30-601q/Kq per day is appropriate.

In the case of sodium chondroitin sulfate, the formula (l[ll
In general, n is 40-100,
The appropriate dosage is 20.00-3000'mq/Kf. For intravenous injection, dissolve in physiological saline before use. Sodium chondroitin sulfate t-20 mg, 40 to 60, for example in 2d (1 ampoule)
It is appropriate to set the proportion to contain (1), and a dosage of 2 to 6 rrli/K9 per day is suitable.

When administered for the first time after poisoning (ζ, it is preferable to drink it in an aqueous solution form as soon as possible, and when applied afterwards, take it orally,
It may be administered by either intravenous injection or drip. However, it is not limited to this embodiment. There is no problem in administering the drugs in any order.

Polysaccharide sulfate esters or salts thereof can be administered singly or in combination.

For example, it is possible to use sodium dextran sulfate and sodium gondroitin sulfate together.

Dextran sulfate sodium salt has been used as a hyperlipidemia agent internally and as an intravenous injection.

However, it has never been shown that polysaccharide sulfate esters or their salts, such as dextran sodium sulfate, exhibit excellent effects in the treatment of acute poisoning caused by bipyridylium quaternary cation salt herbicides, and this is therefore surprising. Met. Dextran sulfate sodium salt preparations are highly safe, with no side effects such as anticoagulant effects or hypokalemic plasma effects.

(Action) Although it is not conclusively clear whether the effect of the dehydrogenase of the present invention is due to the specific action, it is probably due to the removal of lipid peroxide produced by the poisoning of the herbicide, as well as the removal of lipid peroxides from polysaccharide sodium sulfate molecules. The ionic bonding action between the anion -0SO37 group and the bipyridylium quaternary cation, as well as the large number of hydroxyl groups present in the polysaccharide sodium sulfate molecule, which is a high-molecular compound, are formed by the inclusion action based on the higher-order structure. This is thought to be due to the fact that the quaternary cations are encapsulated within polysaccharide sodium sulfate molecules, preventing absorption into the body and promptly excreting them outside the body.

However, this explanation is my current recommendation! 1K, and is not intended to limit the invention.

(Test Example) Detoxification test using mice: 4-week-old aaY strain mice (118 to 20 g body weight) were used. Food was removed 24 hours before administration and fed again 6 hours after administration.

All administrations are oral.

Table 1 below shows the therapeutic index of the antidote of the present invention against acute toxicity in mice caused by varaquat dichloride.

Table 1 Baraquot 132 806
6.11 Dichloride Sodium Dextran Sulfate Table 2 compares the capacity of the dissociating agent of the present invention against acute poisoning of mice with barquat dichloride with that of sodium polystyrene sulfodate, a conventional adsorption removal agent. . It can be seen that it is superior to sodium polystyrene sulfonate up to 20 minutes after administration of the poison.

Amount of poison Amount (■/Kf) Type of antidote (~/
9) 200 Sodium Dextranate Sulfate
2000200 ydSodium polystyrene sulfodate 2000200 Sodium dextranate sulfate 2000200 Sodium polystyrene sulfonate 2000200
Sodium dextran sulfate 2000
200 Sodium polystyrene sulfonate
2000200 Sodium dextranate sulfate
2000200 Sodium polystyrene sulfonate 2000200 Sodium dextran sulfate 2000200 Sodium polystyrene sulfone 1f 2000 Top poison level! Table 3 shows the capacity of sodium dextran sulfate for acute toxicity in mice by increasing the dose of baraquat dichlorite 1 t sequentially. Table 4 shows the capacitance of the antidote by decreasing the amount of dextran sulfate sodium in sequence. From the diagram, it can be seen that the antidote of the present invention can neutralize varquat dichloride if it is used 5 times or more immediately after ingestion of varquat dichloride.

Table 5 shows the therapeutic effects of dextran sulfate sodium and chondroitin sulfate on acute poisoning of mice by baraquat dichloride. It can be seen that chondroitin sulfate also exhibits therapeutic effects similar to dextran sodium sulfate.

Table 6 shows the therapeutic effects of dextran sodium sulfate administration method on acute poisoning of mice by varaquat dichloride. From this table, it can be seen that the combined use of oral administration and intravenous injection increases the therapeutic effect.

Amount of Table 3 Toxic Substances Antidote Dosage ■ ■ Sodium Dextran Sulfate Amount of Table 4 Toxic Substances Antidote Dose ■ (■/Kg) (~/9) Number of Test Animals Number of Lives Number of Deaths ■ Sodium Dextran Sulfate jIS Table Amount of green vegetables - amount Sodium 200 Comte 90 Ichi: / (#! 2000
10 8 2 ・Sodium Table 6 Toxic Substances: t Antidote from poison administration Antidote ■ Trial
Experiment 200 30 p, o, (200
9) 11 3 8200
30 p, o, (9 in 2000"!i'/)
11 6 5+1. v, (6oI11f/Kr) ■ Dextran sodium sulfate is used as the antidote.

p90. indicates oral administration, i, v indicates intravenous injection (tail vein).

Nine-fold test using mice: 4-week-old aaY strain mice (weight, weight 18-209) were used. Food was removed 24 hours before administration and fed again 6 hours after administration.

After oral administration of baraquos dichloride 200119i per 11 kg of body weight to mice, 0.10°20.
Once after 30 and 60 minutes, dextran sodium sulfate (
An amount giving 200 Omq per Ikg of body weight was orally administered. Eleven mice were used in each group.

The survival rate on the 7th day after administration is as follows.

Time (minutes) Survival rate (-) ■ The survival rate of mice to which no dextran sulfate sodium was administered was O.

Detoxification test using mice: 4-week-old aaY strain mice (weight 18-209) were used. Food was removed 24 hours before administration and fed again 6 hours after administration.

Immediately after oral administration of 200 g of baraquat dichlorite per body weight IKf to mice, sodium chondroitin sulfate was added in an amount of 9010 times the amount of baraquat dichlorite.The survival rate on the 7th day after administration was 70-80 g. Ta.

(Example 1) Dextran sodium sulfate (nw 9. sulfuric acid content 18.0%, intrinsic viscosity 0.028) bulk powder 209 was prepared using f# water to a total amount of 1 ton and 100 gg. This product costs 250 to 500 per dose for initial or mild poisoning due to bipyridylium π quaternary salt! l1l (about 100
01NI/Kl) Oral administration is recommended.

(Example 2) Dextran sodium sulfate (nm 9. Sulfuric acid content 18
．． 0, intrinsic viscosity 0.028) Bulk powder 609 was prepared in a total amount of 100 mg using purified water.This product is 150 to 100 mg per dose for severe poisoning caused by bipyridylium π quaternary salt.
It is recommended to take 350ak (approximately 2000aP/Kl) orally.

(Example 3) Sodium dextran sulfate (n-9, sulfur content 5.
8%) Bulk powder 3001119 was purified by 5 me KF l'J using purified water. This product is used in conjunction with oral administration to treat poisoning caused by bipyridylium π quaternary salt.
An intravenous injection of 5 to 10 srj (30 aP/Kf to 9 in 60 srj) per dose is recommended.

Claims (1)

[Claims] Bipyridylium IV, which is characterized by containing polysaccharide sulfate or its ester salt as an active ingredient.
An antidote for the treatment of poisoning with class cation salts.