CS200341B1 - Pharmaceutical medicament against poisn by organophosphoric pesticides - Google Patents

Abstract

The present invention relates to a curative antidote of the phosphororganic pesticides which contains atropine sulfate from 1 to 6 mg, ethylbenzatropine chloride from 5 to 12 mg, 4hydroxy-iminomethylpiridyn-1-methyl ester dichloride from 100 to 250 mg, and 1-phenyl-2-methyl-amino-propanol hydrochloride from 5 to 15 mg.

Description

The invention relates to a pharmaceutical composition for the treatment of:. poisoning caused by organophosphorus pesticides.

It is generally known that in the treatment of poisoning caused by organophosphorus pesticides, the poisoned patient is administered chinolitika i сч _г

“СЧ -—— í - СН _г í 1 1 CH -—--- CH— ~ 1 —— ch. “0 ™.

(b) ssasωmlyУ: lhhd ^r rlЬhorrd (beUsa-dethylfaлixюlthhl eete: e dyyeeiiiy ddfenyliocGvV)

200 341

200 341

c) tropacUi (hydrochloride tropineeteiu kyselUiy difluoro bromophenylacetate ') t H _t --- CH

M-CH 3 Ol _- '- - - CH - 1 - ii CH _X

.HC1

(d) benactizine (benzylic acid diethyl ethyl bioethyl ether) hydrochloride

e) aprophene ((diphenylpropionic acid, beea-diethylamine hydrochloride hydrochloride))

200,341 and the like, and the following choiine esterase rectifiers:

f) 2-PjM (pyrldinim-2-aldoximethyl iodide)

1 H-i

(g) ТШЗ-4 (1,3-bifl (pyrldlniiwi-4-alloxin) propaniroromil)

• 0V — CM _Z 2 6y

(h) toxogonin (bifié 4-dxlminodethhlpprlrlriιwal-) meehhPifiterdlchhoril

2СГ.

However, there is currently no reliable and effective commPex pharmaceutical composition for the treatment of people affected by acute poisoning with organophosphorus pesticides. The pharmaceutical compositions of the prior art are based on the fact that they do not eliminate the overall toxic effect of the organophosphorous pesticides, and therefore their application does not achieve a complete cure of acute poisoning by the said pesticides and possibly their poisoning. In addition, in order to achieve at least a partial therapeutic effect of the drug treatment, the known pharmaceutical preparations (in particular atropine) need to be repeatedly injected at short intervals (24 hours).

In addition, the isolated treatment of severe poisoning caused by organophosphorus pesticides by the administration of an organic compound alone does not prevent long-term complications (psychoneuotic disorders, paralysis and the like) from being pulled out.

It is therefore an object of the present invention to provide an effective pharmaceutical composition for the treatment of poisoning caused by organophosphorus pesticides, which has a multi-component structure and which elutes the toxic effect of organophosphorus pesticides in central and peripheral M- and N-. The non-toxic biochemical system of the organism and produced a deblocking effect in the peripheral myoneural structures of the poisoned organism. Such a pharmaceutical preparation is eltoin

200,341 are symptoms of acute poisoning of organo: phosphoxide by pesticides and prevent long-term complications of said poisoning.

SUMMARY OF THE INVENTION The present invention provides a pharmaceutical composition for the prevention of poisoning with organophosphoric peeticides comprising atropine hydrosulfate comprising 1 to 6 mg atropine hydro sulfate, 5 to 12 µg ethyibenzentropine, 100 to 250 µg biu-4-Uydroxiiminomeeyl-pyridyl ether (di) -ethyl ether. and 5-15 mg of 1-phenyl-22-petylenepinolropanol.

These components have the following formula:

a) and arop cHr

CH _r

CH-- AND г 1 N-CH3 1 C.H 1 1 cw ---- CH <

and

* rod) 1

b) ethoxybenzatropine hydrochloride

c) Bis-4-hydroxyiminomethylpyridinium-1-methyl ether dichloride (toxogonine)

CH2-o-icr

d) i-phenyl-22-petyl-pinoprolenol-uydrochuride (ephedrine-ephedrine hydrochloride)

The invention brings the following advantages over the prior art:

(a) the pharmaceutical formulation, in the interior of the above-mentioned cartridges, eliminates to the full extent the toxic effect of pesticide-like pesticides such as

200 341 Phosphdrin (mevinfos) t 2-carbomethoxy-1-methylvinyldimethylphosphate c »I

CH ₃

CH-CO-OCH ^ nevugone (dipterex):

O, O-dimethyl-2,2,2-trichloro-1-oxyethyl phosphate

CH _q O ³ \ p.

CH 3 O 4 a

AND

OH

Cl

Cl

C tinoxt 2-methylthioethyldimethylphosphothionate, and any toxic symptoms of functional disorders of the central and peripheral 1- and N-cholinergic system of the organism;

(b) the pharmaceutical composition of the invention, when administered intramuscularly, rapidly and efficiently eliminates all symptoms of acute poisoning of organophosphorus pesticides and ensures 100% survival of persons poisoned by absolutely lethal doses of organophosphorus pesticides (1 to 1.5 LDiqq); the healing effect occurs immediately in the first moments after injection;

c) administration of the pharmaceutical composition according to the invention achieves complete cure of the poisoned persons even with a single unrepeated injection (only in some cases it is necessary to repeat this application);

d) application of the pharmaceutical composition according to the invention avoids long-term complications after poisoning with organophosphorus pesticides;

e) The liquid pharmaceutical composition containing the above ingredients is stable to sterilization and storage.

The liquid pharmaceutical formulation is filled into ampoules or single-use syringe containers and is mainly administered intramuscularly.

In the following, several exemplary embodiments of the pharmaceutical compositions of the present invention will be set forth.

Example 1

Composition of the pharmaceutical preparation and atropine hydrosulfate1 mg ethylbenztropine hydrochloride5 mg bis- [4-hydroxyiminomethylpyridinium-1 *]

-methyl} ether dichloride 100 mg 1-phenyl-2-methylaminopropanol5 mg

It is recommended to use this preparation for the treatment of mild or initial form of poisoning. The liquid preparation (1.5-2 ml) is injected intra-muscularly with a disposable syringe.

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Example 2

Pharmaceutical Composition 2 Atropine Hydrochloride3 mg Ethyltoenztropine Hydrochloride6 mg Bia R-4-Hydroxyiminomethylliumidin-1-Methyl] Ether Dichloride 150 mg

1-phenyl-2-methylaminopropanol10 mg

It is recommended to use a pharmaceutical composition of the above composition for the treatment of moderate or severe poisoning. Liquid product (x 2ml), stored in a glass ampoule and protective glass, is injected intremuscularly by medical staff ·

Example 3

Composition of the pharmaceutical preparation:

β-tripinhydrosulphate6 mg ethilbenztropine hydrochloride12 mg bis- 4 4-hydroxylInvinylmethylpulidium-1-methyl-1-methyl-250 mg 1-phenyl-22-m (methylamivopropavol15 mg

It is recommended that the composition of the aforementioned composition be used in the treatment of a particularly convective stage of organophosphorus pesticide poisoning. A liquid composition (x 5 stored in a glass ampoule of protective stained glass) is applied intravenously or intrevenously to diseased personnel.

In the following part of the description, the results of the pharmacological-toxicological toxicology-related electrophysiological studies obtained with the application of the pharmaceutical preparation according to the invention will be presented.

The following table 1 shows the therapeutic index values obtained when the pharmaceutical composition of the invention is applied to white rats in acute nengon and fosdrin poisoning.

Table 1

Type of organophosphorus LDcjo v · ^ / kg (not LD50 in ^ / kg ^ o ' Therapeutic index pesticide product applied application preparation- (TI) according to the invention according to the invention Nevugon 370 1320 3.57 Posdrin 0.42 4.8 11.42

Table 2 illustrates the efficacy of the pharmaceutical composition of the invention applied to white rats poisoned by increasing numbers of lethal doses of phosphate (fossirin was injected). The composition of the invention was injected intramuscularly 15 minutes before rat intoxication. neutralizes 114 LD ^ q phosphate ·

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Table 2

The dose of the preparation according to the invention Dose of phosphdrin expressed in LD ^ q Number of theater animals From them survived it died 0.2 ml / 100 g 60 10 10 0 0.2 ml / 100 g 80 10 10 0 0.2 ml / 100 g 100 ALIGN! 10 6 4 0.2 ml / 100 g 120 10 6 4 0.2 ml / 100 g 140 10 0 10 0.2 ml / 100 g 160 10 0 10

The following Table 3 illustrates the efficacy of the pharmaceutical composition of the invention applied to white crystals and acute poisoning by increasing doses of nevugon (which was injected intramuscularly). The preparation was injected intramuscularly 15 minutes prior to rat intoxication. The results show that the composition neutralizes 9,4 LD ^ ₀ nevugonu.

Table 3

Dose of the dose Dose of nevugon Number of animals tested Of which according to the invention expressed in LD ™ ^9, survivors have died

0.2 ml / 100 g 2 10 10 0 0.2 ml / 100 g 4 10 10 0 0.2 ml / 100 g 6 10 10 0 0.2 ml / 100 g 6 10 8 2 0.2 ml / 100 g 10 10 4 6 0.2 ml / 100 g 12 10 0 Ю Following table 4 illustrates the therapeutic effect of the composition of the invention (0.5 ml / kg at intramuscular injection) in the treatment of acute dog poisoning Fosdrin (1.2 mg / kg at intra-

muccular application).

Table 4 Serious lip numbers teatozví- Symptoms of friction, miofibrillation (min, aek) after poisoning Excessive saliva production (min / sec) Conv. (Min, sec) Symptoms after administration according to the invention Convolution disappears (min, sec) The animal stands on its own feet (min, sec) 1 1 * 00 ” 5'00 7'00 1'30 3'10 2 5 * 00 « 7'00 7 * 00 2 * 00 7 * 00 3 3 * 00 5'15 ^й 5'15 2 * 00 4 * 40 4 3 * 00 4'00 5 * 30 2 * 10 4 * 00 WITH 2'30 5 * 00 7 * 00 1'15 V 4 * 00 ? frame.value 3 * 00 5'15 6'21 1'45 4 * 34

200,341 β

The following Table 5 illustrates the therapeutic efficacy of the pharmaceutical composition of the invention (U, 5 ml / kg in intramuscular injection) in the treatment of acute dog poisoning with 1.5 LD ^ qq nevugen (300 mg / kg intramuscular injection!).

Table 5

number of test animal Symptoms of poisoning Konnvu.se (min, sec) symptoms after administration of the invention Tremor, miofibrilaoe (min, sec) Excessive saliva production (min _r sec) Koonuuse disappears (mln, sec) the animal stands on its feet (minnsek). 1 18 '00 19 '00 29 '00 2 * 00 Apr '00 2 18'00 18 '00 30'00 2'30 5'00 3 17 '00 17 '00 30'00 Jan '30 3'00 4 25'00 20 '00 25 '00 1 * 30 3 * 00 5 20 * 00 20 '00 25 '00 Jan '50 » 5 '00 Pním.hodnota 19 * 36 19 '00 27 '48 1'52 Apr '00

The following Table 6 shows the 'drug comparison' of a pharmaceutical composition of the invention with that of a combination of etropine and oxime reactivators of cholinesterase 2PAM (pralidoxime) and TM-4 (dipyroxime) administered by intramuscular injection in acute phosphdrin poisoning.

Table 6

Type and dose of poison Type and dose of antibody Number of test animals Of which Fatigue (%) survived it died Foedrin 2LD5 _O - 10 0 10 100 ALIGN! Foedrin Atropine (9 in / kg) 2 LD ₅ q 2-PAM (30 mg / kg) 10 2 8 80 Fosdrin Atropine (9 mg / kg) ^2LD 5 ^O tm-4 (30m: / kg) 10 4 6 60 Foedrin 2 LD ₅ q Dooin (0.2 ml / 100 g) 10 10 0 0 Foedrin Dooin (0.2 ml / 100 g) 10 10 0 0 io ld ₅₀

Table 7 illustrates the therapeutic efficacy of atropine and the pharmaceutical composition of the invention in the treatment of acute nevugon poisoning.

Table 7

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C. Poison Dose (mg / kg) Type of antibody Dose of protoplasts (ml / 100g Number) test. · Animals of which —Width (%) survived it died 1 500 - - 10 0 10 100 ALIGN! 2 500 Atropine 0.15 10 7 3 30 3 500 According to the invention 0.15 10 10 0 0 4 700 Atropine 0.15 10 4 6 60 5 700 According to the invention 0.15 10 10 0 0

Claims (1)

A pharmaceutical preparation of poisoning with organophosphorus pesticides, comprising etropinhydrooutphate, characterized in that it contains 1 to 6 mg of Uydrooutphate, 5 to 12 mg of ethylbenztropine, 100 to 250 mg of bi- 4-hydroxyynmomethytypyridrnium- (1) -methyl-ether-richlorirt and 5 to 15 mg. mg of 1-phenyl-2-ethyl-aminopropaeal.