Zinc-containing ethanol poisoning antidote and method of treatment with its application

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to zinc-containing antidote of lethal and severe poisonings with ethanol. Claimed antidote represents intramolecular tricyclic complex of triethanolamine with zinc salts of inorganic or organic acids (2, 8, 9-trihydrozincatran), the ratio of triethanolamine to zinc salts being 1:1. Invention also relates to method of treating ethanol poisoning by introduction into organism of zinc-containing antidote in 5 vol.% ethanol in dose range 30-60 mg/kg of body weight.

EFFECT: prevention of lethal outcome in case of ethanol poisoning and reduction of acute toxicity of zinc-containing antidote.

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The invention relates to medicine and aims to create original antidote fatal and severe poisoning with ethyl alcohol.

Known zinc compounds used to reduce the acute toxicity of ethanol, and various disorders caused by its consumption in conditions of experimental biological modeling.

[Rocky AV Reduction voluntary consumption of ethanol under the influence of the drug zinc prolonged action / Avely, Antokhina, Ispolkomskaja, Geo // Bulletin of experimental biology and medicine. - 1992. - T, No. 4. - p.383-385] known antidote to reduce the acute toxicity of ethanol, which is used as the metal powder zinc (50-100 nm).

There is described a method for the treatment of alcohol poisoning by subcutaneous injection of a suspension of finely powdered metallic zinc. It is established that a single subcutaneous injection of the suspension of finely powdered metallic zinc (50-100 nm) in a dose of 5 mg/kg nonlinear rats during voluntary use of aqueous 10% solution of ethanol for 8 months reduces the preference of ethanol in 1-5 days after the administration by 36%, and after 6-14 days by 28%. Creating in the body depot finely powdered metallic zinc may be one of the ways therapeutic the environmental impact on the dependence of the experimental animals from ethanol (prevention of alcoholism).

In [koterov A.N. Reduction of acute toxicity of ethanol drug zinc-metallothionein / Anguelov, Aussagen, Iviliviz // Bulletin of experimental biology and medicine. - 1993. - T, No. 1. - p.36-40; Shilin NM, the Content of substances reacting with 2-thiobarbituric acid in the blood plasma of mice after acute poisoning with ethanol in terms of protection of zinc-metallothionein / Namseling, Anguelov // Bulletin of experimental biology and medicine. - 1995. No. 1. - p.46-49] described the antidote, which is used as the zinc-metallothionein.

There is described a method for the treatment of alcohol poisoning by ingestion intraperitoneally. It is reported that the solution of exogenous purified zinc-metallothionein at a dose of 2 mg/kg in standard buffer, introduced intraperitoneally linear mice with subsequent 10-15 min introduction 32% rectified ethanol in saline solution at a dose of 3000 mg/kg (about 0.5 DL50)binds significantly large amounts of acetaldehyde (a metabolite of ethanol)than other studied proteins - albumin and cytochrome C. This reduces the acute toxicity of ethanol enhances its excretion and accelerates the metabolism.

It is shown that acute alcohol intoxication of animals with ethanol was mainly studied using as an antidote zinc sulfate [Kampov Field WAS Reduced acute toxic the spine of ethanol sulfate zinc / Abinav Field, Avicennia // Bulletin of experimental biology and medicine. - 1989. - C, No. 3. - s-318; Rock V. Protective effect of zinc sulfate in acute alcohol intoxication / Avicennia // Clinical and biological problems of General and forensic psychiatry (Sat. the scientific. papers). The USSR Ministry of health, Institute of General and forensic psychiatry them. Vpostalskogo. - 1988. - p.150-152].

Protective effect of zinc sulfate is also confirmed by nonlinear white mice after receiving them 9900 mg/kg ethanol (DL50) [Kampov Field WAS Reduced acute toxicity of ethanol sulfate zinc / Abinav Field, Avicennia // Bulletin of experimental biology and medicine. - 1989. - C, No. 3. - s-318]. On the model of chronic alcohol intoxication linear mice and rats by ethanol zinc sulfate has immunostimulatory effects [Proskuryakova T.V. evaluation of the effect of zinc sulfate on the performance of the primary immune response in terms of alcohol intoxication / Tverenergo, Vimruntime, Epharma // Experimental and clinical pharmacology. - 1996. - Vol. 59, No. 2. p.47 - 49].

[Rocky AV Prevention of alcohol motivation in rats with zinc sulfate / Avely, Abinav Field // Bulletin of experimental biology and medicine. - 1988. - C, No. 7. - p.56-57] is known to use zinc sulfate for the treatment of alcohol trawl is ment by intraperitoneal administration into the body. Indicated that intraperitoneal injection for 10 days (1 per day) of zinc sulfate at a dose of 50 mcg/kg nonlinear rats that were in the conditions of free choice between water consumption and 15% of ethanol, ethanol consumption decreases as the infusion of the drug, and after its abolition.

Experimentally studied the effect of introducing an aqueous solution of sulphate of zinc during acute alcohol intoxication linear and nonlinear mice [Rock AV Protective action of zinc sulfate in acute alcohol intoxication / Avicennia // Clinical and biological problems of General and forensic psychiatry (Sat. the scientific. papers). The USSR Ministry of health, Institute of General and forensic psychiatry them. Vpostalskogo. - 1988. - p.150-152]. Zinc sulfate at a dose of 3 mg/kg, animals received 30 and 90 min prior to the introduction of a 25% aqueous solution of ethanol at a dose of 5500 mg/kg, shortens the duration of ethanol narcosis 1.7-2.6 times, but increases the mortality 31.7 and 41% (p<0,01), respectively. With the introduction of zinc sulfate nonlinear mice-males at a dose of 0.07 mg/kg duration of ethanol anesthesia decreases (46,5±2,6 min compared to 70.2±4,8 min in controls; p<0,001), and the introduction of ethanol toxic dose 9200 mg/kg mortality decreased by 21.1% (p<0,05). Intraperitoneal administration to mice of lines W/6 and DBA/2 zinc sulfate at a dose of 0.07 mg/kg 15 minutes after received the I narcotic doses of ethanol (4600 and 5800 mg/kg) exerts a different influence on the duration of ethanol narcosis. So, the mice W/6 the length of the lateral position in the experimental group decreased significantly and totaled 135.6±14,0 mins of 177.8±12,2 min in controls; p<0,01). In mice of the DBA/2 remained unchanged. In addition, in mice these lines detected the difference in the activity of metallothionen in the blood under the action of ethanol in drug dose. If intact mice of both lines of activity zinkevicius carbonic anhydrase was not different, the animals line DBA/2, which after the introduction of ethanol was administered zinc sulfate, it sharply increased compared to controls (p<0,001). The catalase activity in the intact animals of both strains was similar, whereas the introduction of zinc sulfate on the background of ethanol increased this indicator W/6, but did not change in DBA/2.

[Rocky AV Protective action of zinc sulfate in acute alcohol intoxication / Avicennia // Clinical and biological problems of General and forensic psychiatry (Sat. the scientific. papers). The USSR Ministry of health, Institute of General and forensic psychiatry them. Vpostalskogo. - 1988. - p.150-152] it is also known to use as an antidote zinc sulfate.

There is described a method for the treatment of alcohol poisoning. It is shown that zinc sulfate, entered mice DBA/2, at a dose of 0.07 mg/kg 15 minutes after they receive DL50(9900 mg/kg), reduces mortality compared with the control at 25%. Who is you, this is to some extent associated with increased activity zinkevicius carbonic anhydrase, which, in turn, significantly affects acid-base balance and respiration.

When determining the influence of sulphate of zinc toxicity in experimental animals ethanol was used nonlinear white mice and rats, which is experimentally more correctly.

Together theoretical material closest (prototype) of the compound for the treatment of ethanol poisoning is zinc sulfate, and the closest (prototype) method of treatment of poisoning with ethanol is injected into the body zinc antidote. This is due primarily to the fact that zinc sulfate, and the patented antidote belong to the same class of chemical compounds (salts), and are composed of zinc.

The General disadvantage of zinc-containing substances, discussed above, is that they reduce, but 100% not exclude death by poisoning with ethanol, and the preparation of finely powdered zinc is complex. The high toxicity of zinc sulfate. It sredneseriynoe dose for mice is 1891 mg/kg [CIT. on The Physical and Theoretical Chemistry Laboratory Oxford University. - http://msds.chem.ox.ac.uk/ZI/zinc_sulfate_monohydrate.html].

The common tasks group of inventions is to develop synthetic is automatic readily available zinc treatment for fatal or severe ethanol poisoning, with the aim of expanding the range simplest way to obtain an effective drug, not shown in the treatment of side effects.

The technical result of a group of inventions is to prevent death by poisoning with ethanol and the reduction of acute toxicity of zinc antidote.

Eliminate these drawbacks and achieve the claimed technical result from implementation of the zinc-containing antidote ethanol poisoning reach due to the fact that the antidote is a 2,8,9-digitalnature - intramolecular tricyclic complex of Tris(2-hydroxyethyl)amine (triethanolamine) with zinc salts of inorganic or organic acids corresponding to formula (CH2CH2OH)3N·ZnX2or (CH2CH2OH)3N·ZnY, where X is a monobasic anion, and Y is the anion dibasic acid.

The ratio of Tris(2-hydroxyethyl)amine(triethanolamine) with zinc salts of inorganic or organic acids is 1:1.

Comparative analysis of the prototype and patent-pending antidote to poisoning with ethanol shows that they are zinc-containing compounds.

A distinctive feature of patentable antidote to poisoning with ethanol is that it is with the battle 2,8,9-digitalnature - intramolecular tricyclic complex of Tris(2-hydroxyethyl)amine(triethanolamine) with zinc salts of inorganic or organic acids. The ratio of Tris(2-hydroxyethyl)amine(triethanolamine) with zinc salts of inorganic or organic acids is 1:1.

Eliminate these drawbacks and to achieve a technical result from the implementation of the method of treatment of ethanol poisoning by ingestion of zinc-containing antidote reach that antidote, representing 2,8,9-digitalnature - intramolecular tricyclic complex of Tris(2-hydroxyethyl)amine (triethanolamine) with zinc salts of inorganic or organic acids, are introduced into the organism intragastrically.

The ratio of Tris(2-hydroxyethyl)amine(triethanolamine) with zinc salts of inorganic or organic acids is 1:1, and the antidote is administered in the range of doses of 30-60 mg/kg of body weight. Before the introduction of the antidote is dissolved in 5% vol. the ethanol under heating.

Comparative analysis of the prototype and patent-pending method of treatment of poisoning with ethanol shows that total is the introduction into the body zinc antidote.

A distinctive feature of the method of treatment of poisoning with ethanol is that the antidote representing 2,8,9-digitalnature - vnutrimolekulyarnim the th tricyclic complex of Tris(2-hydroxyethyl)amine(triethanolamine) with zinc salts of inorganic or organic acids, injected into the body intragastrically.

The ratio of Tris(2-hydroxyethyl)amine(triethanolamine) with zinc salts of inorganic or organic acids is 1:1, and the antidote is administered in the range of doses of 30-60 mg/kg of body weight. Before the introduction of the antidote is dissolved in 5% vol. the ethanol under heating.

The essence of the invention and the possibility of its realization is illustrated by the following examples of synthesis of the claimed zinc antidote and treatment of ethanol poisoning with its use on the model of lethal or severe intoxication.

Example 1. Getting the antidote "Citronen"

A mixture of 21.9 g of zinc acetate and 14.9 g of triethanolamine in 80 ml absolute ethanol is heated under stirring until complete dissolution. The hot solution is filtered and leave at room temperature until complete precipitation, and then filtered and repeatedly washed with ethanol and then ether and dried in vacuum. Get a 32.6 g (98%) intramolecular tricyclic triethanolamine complex with zinc acetate in a ratio of 1:1 in the form of a white powder with TPL=142-143°C. Found, %: C - 35,87; N - 6,50; N - 4,48; Zn - 19,47. Brutto-formula - C10H21O7NZn. Calculated, %: C - 36,10; N - 6,37; N - 4,21; Zn - 19,65.

Example 2. Obtaining complex based on a zinc salt of ortho-resocialise acid

The mixture 16,62 g ortho-BAP is exucuse acid and 4,07 g of zinc oxide in 150 ml of benzene is heated under reflux with stirring for 8 hours The precipitate is filtered and washed with ether. Received 19 g (96%) of the zinc salt of ortho-resocialise acid in the form of a colourless powder with TPL- Of 180.5-181°C. Found, %: C - 54,37; N - 4,53; Zn - 16,40.

The mixture 19,79 g of zinc salt of ortho-resocialise acid and 7,46 g of triethanolamine in 150 ml absolute methanol is heated under stirring for 5 hours After removal of the solvent in vacuo the residue was washed with ether and dried in vacuum. The yield was 25 g (91,7%) intramolecular tricyclic triethanolamine complex with zinc salt of ortho-resocialise acid in the ratio of 1:1 with TPL=104-105°C. Found, %: C - 52,56; N - 6,17; N - 3,00; Zn - 12,05. Brutto-formula - C24H33O9NZn., %: 52,89; N - 6,11; N - 2.57 M; Zn - 12,00.

Example 3. Obtaining complex on the basis of zinc chloride

Analogously to example 1 with the difference that instead of zinc acetate taking 6.8 g of zinc chloride. Received 18,95 g (87.3 per cent) intramolecular tricyclic triethanolamine complex with zinc chloride in a ratio of 1:1 with TPL=227-228°C. Found, %: C - 32,90; N - 7,40; N - 6,57; Cl - 15,9; Zn - 15,78. Brutto-formula - C12H30O6N2Cl2Zn. Calculated, %: C - 33,16; N - Of 6.96; N-6,45; Cl - To 16.31; Zn - 15,04.

The authenticity of the chemical structure of the drugs confirmed by elemental analysis and NMR spectroscopy.

Example 4. The treatment of poisoning with ethanol using pre is Arata "Citronen"

Pharmacological experiments were performed on 30 nonlinear white rats-males weighing 180-220 g Animals were divided into 5 containing 6 rats groups: 1 - control; 2 - zinc antidote (Citrinin") was administered intraperitoneally 30 min prior to the introduction of ethanol; 3 - the antidote was administered intragastrically for 30 min prior to the introduction of ethanol; 4 - the antidote was administered intragastrically 30 min after injection of ethanol; 5 - the antidote was administered intragastrically through 1 hour after administration of ethanol. Ethanol poisoning was simulated by intragastric administration probe at a dose of DL50(9000-12000 mg/kg), which in terms of animal weight of 200 g is 7.2 ml of 40% vol. of ethanol. Antidote dose of 50 mg/kg dissolved in 5% vol. ethanol when heated and introduced into the body in the form of an aqueous-alcohol solution using a metal probe once.

Intragastric preparation in the body of clinical signs of irritation of the gastrointestinal tract were observed. At the same time in a group, where the antidote was administered to the animals intraperitoneally, almost immediately after the injection, marked a distinct irritation of the peritoneum, the lateral region of the abdomen frantically strained, animals showed anxiety. Monitoring the dynamics of death of the animals was carried out within 14 days. It does not reveal a single case of death of the animals received and DIDOT, while in the control group were killed 75% of the animals.

Example No. 5. The toxicity study "Tetrimino"

Toxicity Tetrimino" studied in nonlinear white mice and rats. It is established that the average lethal dose when injected into the stomach DL50are 5167±1000 mg/kg (mouse) and 5500±1250 mg/kg (rat). According to the American classification of medicinal substances (Hodge and Sterner) citrinin has a 5-th degree of toxicity and relates to the practical non-toxic medicines. According to GOST 12.1.007-76 (SSBT Harmful substances. Classification and General safety requirements "Citronen" refers to the 4th class of hazard (low hazard). Compared with this, the toxicity of zinc sulfate, the use of which has been studied previously, several times higher (DL50for mice 1891 mg/kg) [CIT. on The Physical and Theoretical Chemistry Laboratory Oxford University. - http://msds.chem.ox.ac.uk/ZI/zinc_sulfate_monohydrate.html].

As follows from the above review of the prior art, zinc antidote, its structure, methods of preparation and use are brand new and original, which indicates that the patentability of the invention. Declared the antidote, the method of its production and use are not derived from the famous still of information, that the proposed solutions are not obvious for specialists and inventive.

From Britanie allows you to extend the range of a simple method for producing effective drugs, used for the treatment of fatal or severe ethanol poisoning. However, he does not show side effects. The proposed antidote shows strong detoxifying action and quickly removes animals from the state of alcohol intoxication.

Practical test "Tetrimino" in the treatment of fatal or severe ethanol poisoning has allowed to prove experimentally that it is synthetically easily accessible, the original remedy. therapeutic effect of the drug is based on the total manifestation of the properties of the cation and anion of the drug: the main antioxidant effect zikatanov cation [N(CH2CH2OH3)3Zn]2+and the anion X-or Y2-shows additional therapeutic effect or remains inert.

1. Zinc antidote ethanol poisoning, characterized in that the antidote is an intramolecular tricyclic triethanolamine complex with zinc salts of inorganic or organic acids.

2. Zinc antidote according to claim 1, characterized in that the ratio of triethanolamine and zinc salts in the complex is 1:1.

3. Zinc antidote according to claim 1, wherein the safener is applied in the form of an aqueous-alcohol solution.

4. Zinc antidote according to claim 1, from which causesa fact, that dose of the antidote is 30-60 mg/kg of body weight.

5. The method of treatment of ethanol poisoning by ingestion of zinc-containing antidote, characterized in that the injected antidote representing intramolecular tricyclic triethanolamine complex with zinc salts, inorganic or organic acids.

6. The method of treatment of poisoning with ethanol according to claim 5, characterized in that the ratio of triethanolamine and zinc salts in the complex is 1:1.

7. The method of treatment of poisoning with ethanol according to claim 5, characterized in that the antidote is introduced into the body in the form of a water-alcohol solution, which is obtained by dissolving an antidote to 5%vol. -ethanol.

8. The method of treatment of poisoning with ethanol according to claim 5, characterized in that the antidote is administered at a dose of 30-60 mg/kg of body weight.

9. The method of treatment of poisoning with ethanol according to claim 5, characterized in that the antidote is administered intragastrically.



 

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