CN101594856A

CN101594856A - Prevention and treatment contain the liquid of alcohol and the medicament and the method for the poisoning that pure succedaneum causes

Info

Publication number: CN101594856A
Application number: CNA2007800492983A
Authority: CN
Inventors: 谢尔盖·米哈伊洛维奇·泽诺维奇
Original assignee: Individual
Current assignee: Valenta Co ltd; Zenovich Sergei Mikhailovich
Priority date: 2006-11-21
Filing date: 2007-11-19
Publication date: 2009-12-02
Anticipated expiration: 2027-11-19
Also published as: EA018359B1; JP2010510307A; CN101594856B; EA200900702A1; KR20090081434A; WO2008063099A1; RU2006140889A

Abstract

The present invention relates to medicine, and can be used for developing medicine and method, it is used for the toxicology practice, and is used at home by the people, to prevent and to reduce the risk of dangerous disease (poisoning that the toxic component in for example pure succedaneum and the alcoholic beverage causes).The present invention is based on the purposes of the known compound of ortho position ethylene dithiol alcohols form.They are used to new purpose, promptly are used to develop medicament, and the character of this medicament can be prevented it, treats the pathological process that is produced by pure succedaneum poisoning or reduced speed.Medicament of the present invention reduces or blocks the pharmacological effect of ethanol and its derivant, and promptly the pathogenesis to the development of poisoning produces direct effect.Described medicament is the most effective when oral administration.Also disclose the test data project, it has proved that medicament of the present invention and prevention method can be widely used in the future, and described method is included in drinks before low quality alcopop and the pure succedaneum and take described medicament afterwards.The quantity that purposes of the present invention makes the poisoning that minimizing causes by succedaneum becomes possibility with the toxic action that reduces the seriousness of poisoning and consume alcopop at home.

Description

Prevention and treatment contain the liquid of alcohol and the medicament and the method for the poisoning that pure succedaneum causes

Technical field

The present invention relates to field of medicaments, and relate to the medicine that is used for the toxicology practice, and also relate to the medicine that is being used as preventive under the family's use alcoholic beverage situation that relates to the poisoning risk comprising.

The poisoning quantity relevant with alcopop (no matter being deliberately to take or accidental taking) that always increases and abuse pure succedaneum and just becoming serious medical treatment and social problem with voluntary use alcoholic beverage.According to official's data, only annual in the Russian Federation just have thousands of people death owing to such poisoning.Usually, medically Deng Ji poisoning case is always by using some poisonous substance and ethanol to cause, and beverage is because its inadequate purification quality, or do not plan to be used as esculent on the whole, usually contains these poisonous substances.Increase alcohol toxicity when known non-ethanol alcohol additive uses in the composition of beverage, described beverage is allowed to consumption usually.

The present invention relates generally to the ways and means that development is used for solving the problem of this area.

Background technology

In order clearly to understand hereinafter, this paper describes the term that uses in the field of the invention.

Alcohols (or alcohol type) is a hydrocarbon derivative, replaces hydrogen atom by hydroxyl (OH) and forms.Term used herein " alcohols " should be understood that the alcohol of any kind of: monoatomic or polyatomic, aliphatic or alicyclic, have the carbochain of any length or any available isomer.This class alcohol also can be represented in term " alcohol ", and it has different functional groups, promptly amino alcohol, halohydrin, sulfo-pure and mild other.

This paper also will discuss the ether of many alcohol, for example cellosolve.

On the whole, according to the disease International Classification (ICD) that The World Health Organization (WHO) accepts, the 10th revision (ICD-10), the poisoning of thinking in the present invention is meant the XIX class, T-51, T-52 group.

Typical poisonous substance (poisoning by its generation will be discussed in the present invention), following specifically material:

1. unary alcohol (alkane alcohols)

Methylol (methanol, carbinol, another name for) CH ₃OH;

According to ICD-10, its toxic action is classified as the T-51.1 group;

Ethyl alcohol (ethanol, ethanol) C ₂H ₅OH; In the present invention, ethanol is not considered to self dependency poisonous substance, but unites with other poisonous substance, and its toxic action is increased and changes especially, and in this case, the poisoning that is caused by ethanol when with other poisonous substance associating is proved to be to be contained by field of the present invention; According to ICD-10, its toxic action is classified as the T-51.0 group;

Propyl group alcohol (normal propyl alcohol, isopropyl alcohol or the third-2 alcohol, or secondary propanol specifically; Isopropyl alcohol, high ethanol (perspirit)) C ₃H ₇OH;

According to ICD-10, its toxic action is classified as the T-51.2 group;

Butyl alcohols (one-level n-butyl alcohol or fourth-1 alcohol, or normal-butyl carbinol; Secondary n-butyl alcohol, or fourth-2 alcohol, one-level isobutanol, the tert-butyl alcohol) C ₄H ₉OH;

According to ICD-10, its toxic action is classified as the T-51.3 group;

Amyl group alcohols (amount to 8 isomers, wherein the most practical is n-pentyl alcohol, or penta-1 alcohol, or the normal-butyl carbinol) C ₅H ₁₁OH;

According to ICD-10, its toxic action is classified as the T-51.3 group.

2. di-alcohols (glycols, alkane glycols):

Ethylene glycol (ethylene glycol-1,2) CH ₂OHCH ₂OH;

Propylene glycol (propylene glycol-1,2) CH ₃CHOHCH ₂OH;

According to ICD-10, its toxic action is classified as the T-52.3 group.

3. polyhydric alcohol:

Tetrahydrofurfuryl alcohol

(oxolane ethanol, tetrahydrofuran base alcohol); CHCHCHC (OH) CH ₂O

Furfural (Furan Aldehydes)

According to ICD-10, its toxic action is classified as the T-51.8 group.

Other toxic action that is suitable for poisonous substance of the present invention is classified as T-51.8 and T-51.9 and T-52 group (all according to ICD-10).

Poisonous substance mentioned above is as follows in the extensive fields of commercial Application:

Methanol is used for coating and varnish industry, also is used for alcoholic acid degeneration.

Ethanol is used to produce alcoholic beverage (and this is the main meaning of this paper) in extensively multiple commodity.

Isopropyl alcohol is used to produce antifreezing agent.Propanol is as the solvent of synthetic resin, quintessence oil etc.

Butanols is used to produce hydraulic fluid, in different organic synthesiss of a lot of industry neutralizations etc. also as solvent.

The one-level n-amyl alcohol is the basis that is called as Alcohols,fusel, and described Alcohols,fusel looks like a kind of oil-based liquid, is the mixture of the distillation end-product of alcoholic culture propagation product.

Tetrahydrofurfuryl alcohol also is used for different organic synthesiss as antigraining agent.

From the viewpoint of chemistry, when using the zymase fermentation, producing ethanol by the culture propagation of sugar is the catalysis multistep sugar decomposition process that forms pure and mild carbon dioxide.In order to guarantee zymic life cycle, with biologically available nitrogen and phosphorus source add the liquid solution (or brewing material (brew)) of being fermented, this certainly leads to some other primary alcohol outside the ethanol: methanol, propanol, isobutanol and isoamyl alcohol, optional active-amyl alcohol (2-methyl butanol-1).Except first kind, they all are collectively referred to as Alcohols,fusel.Except alcohols, in brewing material, together exist the composition of so-called volatility mixture to comprise aldehydes, acids and ethers with ethanol.In fact the fact that is worth believing is, in the distillation and fractional distillation process of the alcohol water blend that produces, is impossible with ethanol water from other alcohols and the complete purification of some other volatility mixture.Simultaneously, the quality of the final ethanol water that is obtained is by quality (its content is few more, and the quality of end-product is high more) and its composition decision of other residual alcohols.In addition, end-product comprises a certain amount of aldehydes that forms simultaneously during the fermentation inevitably.Essential consideration, a lot of alcoholic beverage do not distill (for example medicated beer) after fermentation.

Therefore, should consider, under many circumstances, by certain individual biology being used some simultaneous toxicity mixture and other toxicity mixture and its metabolite that exists with the form of other alcohols, its aldehydes and ethers, take alcoholic beverage and follow the poisoning that causes by ethanol itself and its metabolite.

Term " pure succedaneum " (AS) is understood that to allow the unsuitable substitute of the alcoholic beverage consumed.Conditionally, this term can comprise two class beverages: the first kind comprises beverage based on drinkable ethanol (this beverage does not have experience to be enough to obtain the purification process of standard quality), or based on the liquid (being called as " really " succedaneum) of industrial alcohol; Second class comprises and does not contain alcoholic acid or contain the liquid of the mixture of the ethanol of special preparation and other hydro carbons (comprising alcohols and/or its derivant).

The first kind is particularly including following material:

Hydrolysis ethanol and sulphite ethanol (ethanol that produces by the hydrolysis of timber);

Denatured alcohol (with methanol and the blended industrial alcohols of aldehydes)

Rough alcohol (contains ethanol and Alcohols,fusel through fermentation: the distillage of the biomass of propanol, butanols, amylalcohol and other alcohols and its isomer);

Gulong perfume, lotion, other spice and cosmetics liquid (alcoholic solution that contains the additive of quintessence oil and/or heterogeneity);

With ethanol inferior is the adulterated alcoholic beverage of basis preparation.

Polishing liquid (mixture of industrial alcohol and butanols, amylalcohol, chloroform, acetone etc.);

Different liquid (glue class, lacquer etc.).

Second class is particularly including following material:

Alcohol type (comprising ethanol);

Aldehydes, ketone;

The alcohol ethers;

The derivant of the chemical compound that above specifies;

The chemical compound of above stationery body explanation is the industrial liquid of basis preparation.

The feature of the poisoning that AS causes is that converted product biology of the original poison in biology is proved usually has the toxicity stronger than parent compound.Specifically, methanol, ethylene glycol and its ether, pure and mild other of tetrahydrofurfuryl are considered to the lower material of the original toxicity of this class.Material with these character usually is called as easily toxigenous (toxifiable), and described process itself is called as " toxic poisoning ", this means the formation material feasibility more malicious in metabolic process than natural poisonous substance, and the character and the seriousness of its amount influence poisoning in this case.According to alternative terminology, conversion process biology of this natural poisonous substance is known as " lethal is synthetic ".

In the present invention, the term poisonous substance is represented at least a material that is selected from down group:

Alcohol (not being ethanol or ethanol);

01 derivatives;

The alcohol succedaneum,

Poison (or poisoning) be the pathologic state that causes unusually by chemical homeostasis, described chemical homeostasis is caused by the interaction of the toxicant of the different biochemical structures of biology and exogenous origin or endogenous origin unusually.The process of poisoning completely represented in term " poisoning ", it begins development from its very primary symptom, up to the comprehensive clinical module of disease, its content depends on the toxic physiologic function of major receptors, promptly with interactional some biochemical structure of this poisonous substance (poison) selectivity.Different with endointoxication, heterointoxication is commonly called poisoning, and is relevant according to himself metabolism accumulation (self poisoning) in biological with toxicant.

Poisoning as the classification of chemical etiology disease based on 3 guidelines: pathogeny principle, clinical principle and nosonomy principle.

From the viewpoint of pathogeny principle, the poisoning that the present invention discusses:

According to reasons of development, be classified as accidental and/or deliberate;

According to origin, as a principle, be classified as family, be classified as industry more singularly;

Enter biological approach according to poisonous substance and be classified as dosage forms for oral administration, seldom insight is classified as suction, also more singularly-and transdermal delivery;

Origin according to poisonous substance is classified as heterointoxication.

According to the general modfel of development, process and the termination of poisoning, the toxic poisoning of discussing among the present invention can be following poisoning:

Acute, promptly after the toxicant single administration was given biology, clinical poison mode took place with quick and intensive process, rehabilitation or death during termination;

Subacute, promptly after poisonous substance single (or in one period short time several times) was administered to biology, the clinical development of poisoning was carried out in the mode of slowing down, and caused the greater or lesser persistence damage to health;

Chronic, this class poisoning feature is usually with little inferior toxicity dosage, repeatedly, has systemic feature, or the poisonous substance of using intermittently gives biologically, and it follows the symptomatology of its effect that continues and persistent damage to health naturally, and the latter increases and worsens periodically;

Subchronic, such poisoning and chronic poisoning difference are that the persistent period during its poisonous substance is used is shorter, and this is usually to weigh over the week or the moon.

According to the degree of seriousness, the poisoning of this paper discussion can be classified as follows:

Slight, medium serious, serious or lethal.

In the present invention, term " poisoning " is understood that any attainable poisoning that above specifies of being caused by any poisonous substance mentioned above.

The poisoning etiology factor of discussing is alcohols and/or its derivant, or other is with the poisonous substance of toxic concentration accumulation in biological, it can cause chemistry homeostatic unusual, promptly destroy the balance of the natural system of antidotal, described system is intended to the toxicant of biology from multiple origin purified out.

The pathogenesis of the poisoning that alcohols and pure succedaneum (AS) cause is analyzed by following two main aspects:

Toxicokinetics aspect (search the answer of problem, what has taken place poisonous substance in biological);

Toxicodynamics aspect (what has taken place biology under the effect of poisonous substance).

In the framework of toxicokinetics method, illustrate following character:

The physicochemical property of poisonous substance, it determines their behaviors in biological: molecular weight, the dissolubility in water and fat, ionizable ability;

Ability with albumen and some toxic receptor formation valence link;

To entering the explanation of biological approach, the distribution on molecule, cell and organ level;

Transform the biology in biochemical system;

From the excretory pattern of biology.

In the framework of toxicodynamics method, study following character:

The toxigenous effect of poisoning, relevant unusually with the physiologic function of different biochemical structures played the toxicity receptor, and this special symptom by the poisonous substance of discussion shows.

The effect of somatocyte development appears in the system of general biology, its adaptation response to chemical wound (stimulatory function of hypophysis-adrenal system, the shock reaction that blood circulation is concentrated etc.).

In this case, should consider, always take place based on the physiology system that determines as the poisoning of any kind of chemical disease, but with its active result's difference difference, this has obtained its unsuitable pathogenic character.

In the pathogenesis of poisoning, the principal element of following selection is arranged:

1. concentration coefficient, be the molecular concentration of toxicant in the biological media of biology (normally, μ g/ml), it is to instruct sexual factor, because it is relevant with the appearance of clinical symptoms under the toxic concentration of poisonous substance in the blood, and further develops up to potential deadly result relevant under lethasl concentration value (CL) with it.

2. the holdup time of time factor-determine poisonous substance toxicity dose in biological, the speed that it enters and discharges.This factor shows the relation between poisonous substance action time and its toxic action.Determine the kinetics of concentration and time factor, can distinguish the toxigenicity stage and the somatocyte development stage of poisoning, and absorb and the elimination time at the poisonous substance of toxigenicity in the stage.

3. space factor-the determine approach that enters, discharge, and the space of distribution of toxicant, its blood with supply organ and tissue aspect a lot of is relevant.

4. age factor-be reflected at life is hit the degree of different age specificitys biological sensitivity to poisonous substance in the stage, its from the childhood period change significantly to high age, the opposing to toxic action weakens 10 times and more at that time.

5. treatment factor is determined the reaction of biology to the antidotal therapy of enforcement, and this can produce several times of increases of the concentration threshold of the main poisoning symptom of development, and fully shortens the time in toxigenicity stage.

The pathogenesis that research is poisoned is based on following viewpoint: the toxicity receptor is as poisonous substance identification and the ad-hoc location that acts on.

In order to realize biological action, any chemical substance is considered to have at least 2 kinds of specific features: with the affinity and the inherent physical and chemical activity of receptor.

Term " affinity " is understood that the degree of material and acceptor interaction, and this degree is weighed by the tolerance that the speed of dissociating with " material-receptor " complex is inversely proportional to.

The toxic degree of material can be combined and be adjusted the molecule minimum number definition of phase place with important target cell by it.The important herein number that makes deleterious receptor of being not only, and be its importance degree to the vital activity of whole biology.Also importantly form speed, its stability of " poisonous substance-receptor " complex and reverse dissociated ability, it can become than receptor by the more significant factor of the saturated degree of poisonous substance.

Toxic action needn't have strict selectivity, its pair cell generation on the whole.This principle is implemented on a lot of poisonous substances, and wherein common characteristic is that they are not electrolyte.All effects represented in term " non-electrolysis ", and it is directly defined by physicochemical property, for example infusive or make us habit-forming material, and it is the feature of poisonous substance described herein (alcohols).

The most representative feature of the material in the group that this paper considers is the specific film-toxicity-effect that exists film-toxin to cause.The latter's feature is activity of phospholipase to be proved disintegrating of basic liquid-crystal film structure and the result of break (and the cell forfeiture further takes place).

Find that in a lot of research achievements under the poisoning that alkanol and pure succedaneum cause, the direct mechanism of himself film-toxicity-effect or its metabolite is the peroxidating (POL) of lipid.The process of lipid peroxidation cell inner membrance has obtained the feature with the chain reaction of a large amount of cell forfeitures, and described cell forfeiture is the result who exhausts biological natural anti-oxidation system (AOS).

Detoxifcation (detoxifcation), one of the most remarkable mechanism as chemical resistance, it is biochemical and complex that the biophysics reacts in biological, it relates to chemical homeostasis and keeps, this is to guarantee that by some system cooperating performance functions of natural detoxifcation (neutralization of the toxicant of exogenous origin and endogenous origin) described system comprises:

Haematogenic immunity system (blood protein and hemocyte);

Liver detoxification system (MC, as to relate to P-450 enzyme and non-MC) at the composition of the specific enzyme that is used for transforming biology hydrophobic and hydrophilic substance.For the poisonous substance of this paper, this fermentoid is an alcoholdehydrogenase regulating liver-QI acetal dehydrogenase;

Excretory organ system (gastrointestinal tract, kidney, lung and skin).

Be no more than under the situation of certain threshold level at the exogenous and haemoconcentration endogenous cytotoxic material, the normal function of natural antidotal General System rationally reliably will be exogenous with the endogenous cytotoxic material from bioscrubbing.In addition, there is the accumulation of toxicant molecule, and the poison mode development is arranged at the toxicity receptor.The degree of its performance depends on the combination of different factors, under a large amount of situations, it can partly or all sidedly the accumulation with metabolite be relevant, and this is proved has than the remarkable bigger toxicity of natural materials (methanol, ethylene glycol etc.), transforms its biology and carries out along route of intoxication.On the other hand, toxicant to the action intensity of biology in premorbid unusual following increase, describedly be present in main detoxification system part unusually, especially the function (situation toxicity) of liver, kidney and immunity, and for old and old patient, toxicant also increases the action intensity of biology.In this case, develop toxic action being lower than under the toxin blood concentration of threshold value.

Under all surpass the situation of toxicity load threshold level, need be with the system of the natural function of detoxification of performance that mode stimulates or additional maintenance is used to clean quickened.

Antidotal toxicodynamics effect shows that with certain clinical symptoms its content depends on the clinical stages and the selective toxicity of poisonous substance.

In the toxigenicity stage (phase) of acute poisoning, this stage carries out when there is the toxic concentration of poisonous substance in blood, what at first arouse attention is the specific symptoms of disease, and it depends on the pattern and the function of clear and definite toxicity receptor, toxicant and described acceptor interaction.

In the chronic poisoning different, after long-term general physical obstacle, significantly showed specific toxigenicity symptom afterwards with acute poisoning.

The therapeutic treatment of poisoning comprises the specific treatment measure of enforcement of combination, and it is realized in 2 main directions:

1) termination is any further enters, and implement to quicken to discharge toxicant (initiatively antidotal output intent) from biology, and, if possible, by using specific (having Detoxication) pharmacotherapy, implement the quick neutralization of poisonous substance, described treatment reduces the toxicity (toxicokinetics correction) of poisonous substance;

2) pharmacology protects and keeps biological described function, and described biological know-how will experience the damage that toxicant causes, i.e. the symptomatic treatment and the help (toxicodynamics correction) of recovering.

Under some pattern of the poisoning with obvious selective toxicity, the application of special antidote (counterpoison) can influence toxicant or its receptor immediately, reduces its toxicity.

The detoxification of somatocyte development in the stage also relates to the endogenetic toxicosis (endotoxicosis) that elimination develops under the situation of organa parenchymatosum's damage (for example under the situation of acute kidney or hepatic insufficiency).

In the toxic action of alkanol, 2 kinds of compositions are emphasized to specific and nonspecific.

Nonspecific action is relevant with the characteristic of physicochemical property, and is regulated by so-called non-electrolyte effect (being the effect of overall molecule material by the mechanism of existence).The non-electrolyte effect shows as the film fluidization, as a result of, shows its abnormal function.Described alkane alcohols-inherent osmotically active causes the liquid displacement between Different Organs and tissue, the inhibition of platelet aggregation, has developed ARR myocardium to adrenergic sensitization.

The feature of the clinical manifestation that non-electrolyte is poisoned (it relates to described alcohols and its metabolite) is that similar state, the cardiac contractility ability that is in poisoning (or dizzy) weakens and the endocellular metabolism obstacle.

What research was maximum under laboratory and clinical condition is the pattern of ethylism.A series of its brains, liver, the heart and kidney toxic action have been determined, to synapse (synaptotropic) with to the mechanism of the toxic action of film (membranotropic) character.Hereinafter these mechanism will be described briefly, to such an extent as on their basis,, characterize the toxic action of the poisonous substance of this paper consideration after a while by analogy.

Ethanol is by the oxide reductase, promptly by (latter is specific NAD-dependent enzyme) at the hepatocyte cytosol, alcoholdehydrogenase (ADG) in the MEOS of liver (MSES), and by catalase, oxidase and peroxidase oxidation in tissue.Alcoholic acid oxidation causes forming aldehyde, i.e. acetaldehyde.Acetaldehyde is contained liver enzyme (being aldehyde dehydrogenase (the AcDH)) oxidation of FAD, and to form acetic acid (acetic acid), it further generates CO gradually by metabolism ₂And H ₂O.

To the realization of central nervous system's (CNS) toxic effect of ethyl alcohol unusual adjusting, describedly cause by this effect unusually, and in film-action effect, show by functional medium system.Its specific influence to gamma aminobutyric acid (GABA), glutamatergic system changes the permeability and the affinity of film ion channel, changes the function of neurotransmitter system thus.

Transform in the ethanol in biology, produce the recovery form of a large amount of acetaldehyde, acetate and ADG-NADH enzyme.Finally, it is a series of biochemical unusual reasons that caused by alcoholic acid introducing.Under the situation of ethylism, tricarboxylic acid cycle is blocked by acetaldehyde, no longer can utilize acetyl group-coenzyme A, and it causes forming ketone, and changes the synthetic process of fatty acid.According to this basis, the development metabolic acidosis.As everyone knows, a large amount of acetaldehyde cause the respiratory chain mitochondrial function unusual, make its energy function disorder thus.Based on this, form the myocardium dysfunction.

According to our viewpoint, must be pointed out that ADG can catalytic alcohol be converted into the redox reaction of aldehyde, and be not only applicable to ethanol, also be applicable to a lot of other alcohols, at least above it is mentioned those alcohol of so-called intoxicating phenomenon.Another supports that the argument of this reason is the following fact: in the poisoning that many alcohols cause, ethanol is used as special antidote, and its effect is by its competitive inhibition alcoholdehydrogenase and prevent that then the ability of the oxidation of these poisonous substances from explaining.What can classify as this class alcohol is, methanol, carbon chain lengths have aliphatic alcohols, the dihydroxylic alcohols of 5 atoms at the most, with and ether (glycol monoether) with alcohol groups, i.e. those pure and mild its derivants, it is according to typical poisonous substance of the present invention.

Therefore, by those alcoholism that cause (described alcohol is oxidized to its aldehyde by ADG) of described alcohols, observe the quite similar pattern of the toxic effect of described poisonous substance at least.

The cytoplasmic acidosis of the imbalance of cell membrane physicochemical property, alcohol membrane damage that converted product causes biology, growth, imbalance, cell protein and lipid self-dissolving activation of a procedure, abnormalities of sugar/lipid metabolism, the peroxide activation of a procedure of energy process are the characteristic features of specific alcohols effect.On this basis, necrosis and underfed (steatosis) that has developed in the cell of most important organ changes.

Toxic effect of methanol is generally regulated by its metabolite (being formaldehyde and formic acid).Formaldehyde itself is the strongest poisonous substance, and its metabolite also can be disruptive oxidation and the chain of phosphorylation, causes metabolic acidosis, changes the normal processes of a large amount of main biochemical processes.

In ethylene glycol is poisoned, glyoxalic acid (after the enzymatic conversion first time that relates to ADG) its converted product biology appears in succession, for example; This is single aldehyde, glycolaldehyde (glycole aldehyde) (after the enzymatic conversion second time that relates to ADG), and this is a dialdehyde, is oxalates afterwards, hydroxyacetic acid.Those serial all substances are destroyed the function of tricarboxylic acid cycle enzyme.The aldehydes that occurs is deleterious, and accumulation in biological for a long time, and aldehydes can destroy important biological function in the mode by system.

Ethylene glycol mono-ether experiences approximately uniform metabolic pathway, because its alcohol groups of ADG " attack ", owing to this reason, monoether is converted into relevant aldehyde.According to this point, form glycolic (oxyacetic acid) from ethylene glycol mono-ether, it the cellular metabolism acidosis occurs also causing.Under combined effect, these chemical compounds are regulated the appearance of hypokalemia and hypocalcemia, and homergy and the adenosine triphosphate (ATP) of destroying glucose, lactic acid are synthetic, and destroy the function of a large amount of enzyme systems.

At cellular level, above-described process is thought to develop a series of pathogenic unusual beginnings: homeostasis obstacle (metabolic acidosis, water-electrolyte imbalance, blood coagulation change and other obstacle), and form the secondary syndrome: the inaccessible adnormal respiration of consciousness depression, maincenter and suction, acute cardiac vascular insufficiency, organa parenchymatosum's damage etc.On the basis of the above, developed the process that much has deadly risk.These processes comprise following situation:

Acute respiratory distress (ventilation and substantial function are incomplete);

Circulate poverty-stricken (former with other) because the basis with cardiac contractility ability decline, toxicity cardiomyopathy, hypovolemic (oligemic) shock;

Cerebral disorders;

Organa parenchymatosum's's (liver, kidney, cardiac muscle) damage and dysfunction.

In the clinical module that AS-poisons, select following characteristic symptom:

The toxicity encephalopathy;

Adnormal respiration;

Blood circulation is unusual;

The toxicity hepatopathy;

The toxicity nephropathy;

Homeostasis obstacle (water-electrolyte balance, Acid-Base balance);

Stomach-intestinal obstacle.

These syndromes are described in detail in the following list of references: [source 1:Luzhnikov E.A., people such as Ostapenko Yu.N..“Emergency status under acute poisonings”M.，2001]。Up to now, in the poisoning that methanol according to the present invention, ethylene glycol and its poisonous substance cause, ethanol has been used as special antidote, and uses [source 1, the 155-156 page or leaf] as the competitive inhibitor of alcoholdehydrogenase through intestinal and/or intravenous.This Therapeutic Method has a large amount of shortcomings, because ethanol energy inhibitory enzyme system itself and organa parenchymatosum's function, it faces following demand: continue comprehensive monitoring patient's states, the natural detoxification system ability of patient, premorbid factor, poisoning seriousness, poisoning stage etc.

The objective of the invention is to make effective agent to enter circulation, development with prevention or blocking-up pathological process, or reduce its speed, described pathological process by single and repeatedly, what particularly prolong uses alcopop to cause with systematicness, and described beverage also contains the poisonous substance beyond the ethanol itself.These poisonous substances are present in the beverage as the natural mixture that comes across in the alcohol fermentation preparation process.The toxicity mixture is present in the beverage may also exist some other reasons.In addition, the present invention concentrates on effective ways and medicament is introduced the toxicology practice, prevents and Drug therapy with the poisoning that alcohols and its derivant are caused.

By being designed for medicament through intestinal or parenteral, solved this specified task, described medicament is represented the ortho position dithioglycol of at least a general formula (1), and if desired, together prepares with the carrier of pharmaceutically acceptable carrier or food.Described ortho position dithioglycol is meant the material of following general formula

R ₁(CH ₂) _nCH(SH)CH(SH)(CH ₂) _mR ₂ (1)

R wherein ₁And R ₂Can be independently selected from following groups: (H), (OM '), (COOM '), (SO ₃M '), (O-CH ₂-SO ₃M '), (PO ₃M ₂'), (PO ₂SM ₂'), (PO ₃M "), (PO ₂SM "), symbol M wherein ' expression hydrogen or alkali metal ion, symbol M " the expression alkaline-earth metal ions, wherein m and n are independently selected from 0 to 5 integer.The chemical compound of general formula (1) is that prior art is known.It is described and route of synthesis is listed in, and for example the ChemicalEncyclopedia[source 2: " Chemical Encyclopedia ", M.:SovietEncyclopedia Publishing House, 1990, v.2, the 91-92 page or leaf].Described ortho position dithioglycol (VD) is meant following compounds particularly:

1. dithioglycol (dimercaprol, dimercaptopropanol, BAL, Dimercaprol, Dimercaprol [BAL]), it has following formula:

2.2, the 3-Sodium Dimercapto Sulfonate (" sodium dimercaptopropanesulfonate (Unithiol) ", DMPS), it has following formula:

3.2, the 3-dimercaptosuccinic acid (" dimercaptosuccinic acid ", DMSA), it has following formula:

(4.2-2,3-dimercapto propoxyl group) ethane sulfonic acid sodium (" Oxathiol "), it has following formula:

Ortho position ethylene dithiol alcohols is used as the active medicine of radioprotective, when heavy metal and its chemical compound cause poisoning, when particularly causing poisoning by arsenic, lead, hydrargyrum, also is used as antidote [source 3:Mashkovsky M.D. " Medications ", M., 1993].These are the low molecular compounds with 2 ortho position sulfydryls, because described sulfydryl, they show good capturing ability to heavy metal (comprising radionuclide).

The purposes of these materials is known in the technical field of toxicology practice.When arsenic, bismuth, hydrargyrum, antimony or zinc cause poisoning, dithioglycol (BAL) and 2,3-Sodium Dimercapto Sulfonate (DMPS) is as antidote [source 4:Shiebak V.M., people's " TheFundamentals of Clinical and Analytical Toxicology " (list of references handbook) such as Panchenko L.F., by Tomilin V.V. //professor Moscow edits, 2002, the 46 pages].2,3-Sodium Dimercapto Sulfonate (DMPS), 2,3-dimercaptosuccinic acid (DMSA) and other ortho position dithioglycol (VD) are as the antidote at so-called destructive poisonous substance, and described destructive poisonous substance comprises heavy metallic salt, arsenic and its chemical compound, and the chemical compound of some phosphorus and chlorine.Also known, under the situation that mental disorder alcoholism (alcoholicum), acute alcoholism, narcotic are poisoned, with the Comprehensive Treatment of other antidote combination in, use DMPS (2, the 3-Sodium Dimercapto Sulfonate) [source 3].Known in antidotal therapy as one of its stage, use 2, the 3-Sodium Dimercapto Sulfonate, alleviate fast withdrawal symptom [source 5: " Alcoholism ", by G.V.Morozov, M. edits, Medicina Publishing House, 1985, the 314-321 pages or leaves].Also known in process by the dependence disease that uses ethanol or other psychoactive drug substance to cause, use the development (patent RU 2229291) of VD blocking-up or minimizing pathological process.

The invention provides the purposes that known substance is used for new purpose.

Summary of the invention

The applicant finds first, under known index listed above, behind enteral administration, ortho position ethylene dithiol alcohols (VD) has shown beat all stronger effect, unexpectedly find in addition, after administration, especially behind the oral administration, the ortho position dithioglycol provides new effect, the development that it at first shows blocking-up and/or suppresses pathological process, described pathological process is to be contained alcoholic acid beverage (containing toxic mixture) and/or contained pure beverage (not only contain ethanol as alcohol, and contain pure succedaneum as alcohol) by use to cause.This is listed the character that the people expects discovery and is the basis below effect: ortho position ethylene dithiol alcohols (VD) material of proposition is in vivo in conjunction with the direct metabolite of methanol, ethylene glycol and other unary alcohol and polyalcohols.Because we find this interactional characteristic, this effect is shown very consumingly, and described characteristic is a basic feature of the present invention.

First feature is, the interactional product of VD and specific poisonous substance can not be in cracking under the physiological conditions, and promptly they have chemoresistance.In other words, this reaction is irreversibly carried out in vivo.

Second feature is that for the described pharmacotoxicological effect to biology of significant, basic demonstration, the material (VD) that the present invention is proposed enters liver (fast as far as possible and complete).In order to carry out this effect, fit closely approach be the intestinal administration or, if the latter is prevented from, and equal with it, this drug administration by injection is suitable, it makes specific material access door venous blood flow.Especially by infusion in infusion or other portal vein in the portal vein of VD or through the umbilicus infusion, obtained this effect.

The 3rd feature (additional feature) be, if this class poisonous substance as deutero-aldehyde of alcohol and the reaction of water solublity ortho position dithioglycol, product also becomes water misciblely then, obtains the ability that together is discharged from by kidney and urine.This is 3 atoms and more carbochain for length, is very important, because from propionic aldehyde, and the poorly water-soluble of these aldehydes, and it reduces with the chain length increase.Based on this behavior, medicament and method as this paper proposes except these are the medicament and method of antidote Drug therapy, have become effective antidotal active agents and method; They not only quicken poisonous substance and eliminate, and can carry out the drainage of poisonous substance by kidney.For the drainage of ketone, identical process is real.Relate to kidney in the poisonous substance discharge process influences the concentration coefficient of pathogenesis with having superiority.

The 4th feature also is additional feature, and be as follows: because its suitable physicochemical property, alcohols has easily overcome organizes the hematogenous barrier, and is distributed in organ and tissue very equably.Then, therein, alcohols experience biotransformation, the phase I is converted into aldehydes.Aldehydes is bigger than alcohols toxicity, has stronger reactivity.The end group of aldehydes and plasma protein and hemocyte, enzyme and the reaction of other key element change their function (immunity thus, hemostasis, breathing, CNS, cardiac muscle, energy function and much other function be affected).In other words, the toxicity receptor of aldehydes more significantly than alcohols.Different with alcohols, aldehydes is proved to be to be organized in the haematogenous obstacle obviously poorlyer etc. overcoming, and it causes their accumulation in those organs and tissue, pure metabolism beginning (being the phase I of pure oxidation) in described organ and tissue.Simultaneously, under the effect of liver enzyme-aldehyde dehydrogenase, formoxy-ization takes place.In view of mentioned above, in organ outside liver and the tissue, any further formoxy-ization is prevented from, and this has aggravated the exposure (time factor) and the toxic action of aldehydes.This problem itself shows in the people who belongs to yellow's ethnic group in acute especially mode, because they have the aldehyde dehydrogenase activity of the reduction that is predetermined in the heredity.Can find the new solution of this problem according to the application of medicament of the present invention and method.Significantly, make enter liver according to active substance of the present invention (VD) after, the combination of aldehyde takes place.This causes the changes in balance in " alcohol-aldehyde " reversible reaction.So according to Le Chatelier principle, system is by strengthening pure oxidation and reducing its concentration in liver subsequently, to its reaction.According to identical principle, this cause alcohol from other organ and tissue further flow out with and flow into liver, to recover concentration.Be held if be present in the VD of liver, then the amount of the new aldehyde that is obtained by the pure oxidation that flows into liver is by combination once more, and this circulation repeats to take place.Therefore, use material according to the present invention and reduced the toxicity load at all organs and tissue because these materials promote poisonous substances from extremely important organ with organize rapid drainage.According to the viewpoint of poisoning pathogenesis, coming into effect this class Drug therapy as quickly as possible is important thing.According to the present invention, enter the circulation defending party to the application described herein who realizes under the condition of liver at maintenance active substance (VD) and be called " biological alcohol-aldehyde detoxifcation circulation " (CAAD).Point out that also CAAD also realizes by preventative VD administration.Therefore, CAAD produces useful influence to the time factor and the space factor of poisoning pathogenesis.

Therefore, the applicant has found the new pharmacological activity of a class of ortho position ethylene dithiol alcohols, be that they can make biology from alcohols and the detoxifcation of its metabolite in vivo, known described alcohols and its metabolite are strong poisonous substances, for example methanol and formaldehyde, propanol, butanols and amylalcohol and aldehyde thereof, di-alcohols and its aldehyde and monoether, and binary aldehydes, and on this basis, in the poison, utilize them in these as special antidote (first basic feature).Second basic feature according to the purposes of this new purpose is the medication of ortho position dithioglycol, according to this method, must guarantee that it is fully final and enter liver fast, because initial in this organ just toxicant metabolism and its poisoning take place.In the case, best solution is through enteral administration, but when status of patient needs, pointed out with drug administration to portal venous flow or through the umbilicus administration with together carry out through enteral administration, or use drug administration replaced through enteral administration to portal venous flow or through the mode of umbilicus administration.Based on this, the applicant provides medicament and the method that is used to prevent the poisoning that caused by the poisonous substance that above describes in detail with Drug therapy.

The explanation of technical result

Below, characterize by group, list effect, it obtains by medicament and the method (being technical result) that is illustrated, at first, its use with the typical poisonous substance that contains in the alcoholic solution that is intended to family's use is relevant, or relevant with the abuse alcopop, described beverage also contains toxic mixture, and the use of the poisonous substance of considering with this paper is relevant.

The 1st group: the toxicokinetics correction treatment

The chemical bond poisonous substance;

Prevent poisonous substance and toxic receptors bind;

Quickening poisonous substance and/or its toxic metabolites drains from biology;

Quickening poisonous substance drains from its organ that occupies and tissue (brain, lung etc.);

Prevent the poisoning of natural poisonous substance;

Increase poisonous substance or its metabolite and according to the water-soluble of the product of the active substance of medicament of the present invention;

Reduce the alcohol toxicity that the existence by one or more poisonous substances in the pure succedaneum causes;

Improving poisonous substance drains;

Prevention or reduce toxic effect to the effect of respiratory chain mitochondrion.

The 2nd group: the toxicodynamics correction treatment

Recover organa parenchymatosum's function;

Recover the function of neurotransmitter system;

Recover the CNS function;

Recover the energy function of cell.

The 3rd group: prevention

Prevention may enter the appearance or the development of the acute or subacute poisoning that causes in the biological process by poisonous substance at it;

Prevention is being used the appearance of the inferior chronic or chronic poisoning that causes in the process that contains pure liquid or pure succedaneum repeatedly or regularly or is being reduced its speed of development, and described liquid contains the poisonous substance of inferior toxicity dosage;

The seriousness of the poisoning of minimizing under the situation that poisonous substance may be taken in;

Increase the toxic threshold level that concentrates;

Influence concentration coefficient to reduce the toxic concentration value;

Reduce amount of poisons in the brain to such an extent as to influence concentration coefficient;

Reduce poisonous substance and expose (time factor);

Reduce biological sensitivity to poisonous substance;

In the process of its premorbid damage, strengthen liver and kidney function of detoxification (reducing situation toxicity);

Reduce the risk of endotoxin shock appearance and the seriousness of development.

Because the applicant has found the new property of general formula (1) chemical compound, another aspect of the present invention be take at least a according to poisonous substance of the present invention after, use at least a ortho position dithioglycol as the pre-anti-poisoning generation or the medicament of development.This purpose is new, because it is not based on the antioxidant properties of known detoxifcation, these materials.Relate to that to use VD also be new as the purpose of the active agents of preparation medicine, described medicament is mixed with dosage form or non-dosage form, is used to prevent or poisoning that Drug therapy is caused by poisonous substance according to the present invention.This class medicine can be represented compositions, and also comprises other active component.For the form of preparation, they can be to be used to ingest or the liquid or solid medicine of parenteral.

The ortho position dithioglycol can stop the destructive process of biomembranous free radical, and specifically, they protect myelinic ozone layer to avoid damage, protection hepatocyte, blood vessel and brain structure.On the basis of the above behavior of the ortho position ethylene dithiol alcohols of explanation, its administration can be blocked or lower cardiac muscular tissue, pancreas, vascular system, CNS and other organs of biology and the damaging action of system.

Ortho position ethylene dithiol alcohols is relevant with the pharmacological effect of using poisonous substance to these and other effects of described process, allows the appearance of those effects, and described effect is enumerated above, and represents the technical result of claimed technical scheme.

According to the present invention, the toxic action of using poisonous substance shows as the organ of a lot of biologies and the influence of system, and promptly these toxic actions cause beginning simultaneously or activating a considerable amount of pathological processes.Under the situation of the character of considering ortho position ethylene dithiol alcohols mentioned above or behavior, can infer that the latter has wholesome effect to this class pathological process of entire quantity, but this influence can be shown or realize, although simultaneously, have performance in various degree.Its influence is at first depended on its residing stage to the performance degree of particular pathologies process.The generation of some process can be blocked by the preventive administration according to medicine of the present invention, and the pathological process that other have begun can be suppressed by using these medicines.To the performance of particular pathologies process influence, the toxic action of using as poisonous substance is regulated, and also depends on strategy, toxicity load and other factors of dosage according to medicament of the present invention, individual body and other characteristics, drug administration.

The applicant has been found that when the dosage forms for oral administration medicament, above the effect that has superiority on Shuo Ming the physiology is proved to be with strong especially degree.As if to enter some characteristic of the high-speed and described material of liver and liver enzyme interacting relevant with active substance for this phenomenon.This more inapparent effect also can be observed at topical and the inhalation-type drug administration by oral mucosa, nose.

Above Shuo Ming effect has been expanded the character of known up to now ortho position ethylene dithiol alcohols significantly.Their known detoxicating activities are used to reduce the acute situation of giving up, and promptly are used for the treatment of the people by the alcoholism influence.With 2, the 3-Sodium Dimercapto Sulfonate is treated mental disorder alcoholism to the patient, and described patient suffers from original (the 3rd) alcoholism of clinical stages, and the feature of described clinical stages is the appearance of serious spirituality obstacle.Known antioxidant activity has also replenished the new ability of ortho position ethylene dithiol alcohols well.The applicant has been found that ortho position ethylene dithiol alcohols can alleviate the be still drank after a night seriousness of (or alcohol withdrawal syndrome) situation of domestic levels before, and its hint is used alcoholic acid harmful result, and it appears at second day that uses behind the ethanol.This effect causes (patent RU 2157647C1 number, 2000) to the activity of acetaldehyde in vivo by VD.At present, based on newfound effect in test, it can be asserted that the effect of ortho position ethylene dithiol alcohols (as active substance) shows by their administration, it takes place discretely with the fact of using AS, for example by several weeks (Drug therapy process) or a couple of days before taking in AS, or a few hours during in preventive administration show.At other poisonous substances identical phenomenon is arranged.Importantly, notice that the applicant has determined the effect of the pathogenetic common contact of the poisoning that ortho position ethylene dithiol alcohols causes the metabolite by alcohols and its Different Origin.

Therefore, have reason very much the known properties of ortho position ethylene dithiol alcohols and the synergism of the character that above illustrates are reached a conclusion, it allows for new purpose, recommends its application.

The medicament forms of the medicament that proposes can comprise and being suitable for through enteral administration, particularly oral administration, by probe administration, nose administration, part (comprising) administration by oral mucosa, or by suction or the form by drug administration by injection through cheek and Sublingual.The medicament that proposes can have the solution form that is used for drug administration by injection.In this case, mix with suitable liquid component by the active substance that will propose, and carry out its administration down, thereby prepare infusion solution the auxiliary of related preparation equipment according to the present invention.Pharmaceutical preparation can be represented compositions, and the form of the administration unit that can disperse easily provides, any method preparation of can the pharmaceutics field knowing.All these method of pharmacy comprise active substance and liquid-carrier or broken solid carrier or their both (if desired) the blended steps of fine powder, and step subsequently is, product are molded into the shape of expectation, if this needs.

The pharmaceutical preparation that is suitable for oral administration can show as the form of discrete unit, for example tablet, capsule, cachet, and they contain the active component of preliminary recipe quantity separately; Or show as powder or particulate form; Or show as the form of solution, suspension or emulsion.Active component can also show as the form of bolus or paste, or exists with its pure form, does not promptly contain carrier.The tablet and the capsule that are used for oral administration except additional physiology goes up activated composition, also can contain common received additive, for example adhesive, filler, lubricity material, fluffer (fluffer), wettability material.Push or pressing mold with described form by optional and one or more additional compositions, can prepare tablet.In suitable machine, can be the active component of free-flowing form by extruding, for example, prepare compressed tablets with the powder or the granule of optional approach and adhesive, lubricity material, inert diluent, lubricant, surfactant or dispersant.On suitable machine, by the mixture (by the moistening mixture of inert liquid diluent) of mould-casting powder compound, the preparation molded tablet.Can use according to method well known in the art shell coated tablet.Liquid oral medicine can be the form of aqueous for example or oily suspensions, solution, emulsion, syrup or elixir, maybe can show as the form of water before use or the blended dryed product of other appropriate solvent.These liquid preparations except the additional physiologically active composition of introducing, also can contain common received additive, for example suspending agent, non-aqueous solvent (it can comprise edible oil), flavoring additive, aromatic, coloring agent or antiseptic.Can choose the form that preparation is above enumerated wantonly, with provide the active substance that wherein contains slowly or the drainage of control.

Be intended to by the oral mucosa topical, for example comprise and containing at its correctives substrate (carbohydrate for example by form through cheek or sublingual administration approach, for example sucrose, arabic gum or Tragacanth) in the lozenge of active component, and the pastille that in substrate, contains active component, described substrate is for example gelatin, glycerol, carbohydrate, arabic gum etc.For the intranasal administration of active substance of explanation above, operable form is that for example aerosol maybe can become the powder or the drop of powder.These drops can use or non-aqueous substrate make, it also contains one or more dispersants, solubilizing agent or suspending agent.Liquid aersol is convenient to being packaged to be from pressurization.For inhalation, chemical compound according to the present invention be convenient to from the insufflator that is used to prepare aerosol spray, suction-type pressurized package or other easily device obtain.Packing under pressure can contain suitable propellant, for example dichlorodifluoromethane, Arcton 11, carbon dioxide or other suitable gas.For the aerocolloidal situation under pressure, provide spraying by the valve that uses the amount of supplying metering, thereby determine dosage unit.

Selectively, for giving can use the form of dry powder powder mixture according to material of the present invention by sucking or being blown into, the powder mixture of active substance and relevant Powdered substrate for example, described substrate is for example lactose, starch, Talcum.The form that powdered composition can show as single dose exists, and for example capsule, cartridge case, gelatin or cohesiveness plaster packing can be introduced described powder by inhaler or insufflator from above-mentioned form.

If desired, use above-described form, it is suitable for providing the lasting release of active component.

Also can contain one or more other active component according to drug agents of the present invention, its interpolation, as principle, be used to strengthen the effect of the material that proposes by the present invention, with and can be used to the composition that obtains to add and according to the synergism of chemical compound of the present invention.The active component that adds can be to be selected from following composition: vitamin, previtamin, vitamin derivative, organic acid, organic acid derivatives, lipid, the last activated peptide of physiology, aminoacid, amino acid derivativges, enzyme, enzyme derivative, enzyme precursor, coenzyme, coenzyme derivant, coenzyme precursors, carbohydrate, mineral, metal ion source, albumen and its mixture.For example, add aminoacid and have superiority, it is a neurotransmitter, for example glycine, γ-An Jidingsuan (GABA).Add metal ion source and have superiority because by methanol, ethylene glycol and much the poisoning that causes of other poisonous substances destroy water-electrolyte balance, cause hypocalcemia, cause that thus muscle rigidity shrinks.In this case, add divalent metal ion source and also have superiority, because some in them, for example magnesium, calcium, manganese play a significant role in enzyme catalysis, and it constitutes the part that coenzymatic composite divides.The shortage of calcium (as the regulator of a lot of processes), as noted above, with and metabolism toxicity suppress to quicken the development of a lot of pathological processes.As the additive that has superiority in medicament composition according to the present invention also can be the source of lipid; phospholipid particularly; for example lecithin, glycolipid; other liver protection things; vitamin particularly, for example alpha-tocopherol, its precursor, its derivant, the last activated peptide of physiology; neuropeptide for example, and much other physiologys known in the art go up activated material.

Be appreciated that the composition of partly enumerating except above, can comprise other compositions, medicament according to medicament of the present invention, it is considered to conventional in this application, and is used to the form of the special medicament of discussing of this paper.For example, the medicine that is used for oral administration can contain correctives or structure-formation agent.Especially, what relate to poisoning prevention significantly can be mixed with medicament forms or non-medicament forms according to medicament of the present invention, for example is mixed with food product form, particularly beverage.

The preferred form that contains fractionated dose is the form of active substance according to the present invention that contains effective dose, and is as mentioned below, or contains the form of the described dosage of suitable part.

In order to reach recommended target, according to the present invention, above Shuo Ming the medicament that contains the effective dose active component can be by oral or different approach easily with dosage 0.1 to 250mg/kg (every kg of patient body weight) introducing every day.General adult's the common scope of dosage level every day be about 5mg to about 10g, normally at littler about 50mg extremely in the scope of about 2g, most preferred scope is from 100 to 1000mg every days.Tablet or other forms of the medicament that provides with the form of discrete unit are used for it is convenient, can contain under this dosage effectively amount, or a plurality of amount, for example contain 50mg to 1000mg, are generally about unit of 200 to 500mg.

Introduce according to pharmacy optimization per os of the present invention, adopt accurate dosage and respectively, described dosages of substance should give according to application specifications or expert's recommendation.But the actual dosage that uses depends on several factors, and it comprises sex, age, body weight, risk factor, situation that the poisonous substance picked-up causes, individual body and spiritual neurological characteristic etc.When the time of determining to use medicament and persistent period (speed), should note the factor of identical type.Can recommend the form administration of medicament with process, when it can be prescribed before may using alcopop, it relates to the risk or the harm of poisoning, and/or poisonous substance enters other biological possible approach (breathing, suck), or in using this class beverage (or make poisonous substance enter biology by other modes) back certain time interval, or before using and afterwards, or contain in the different combination of beverage of Toxic in use.According to this point, adjusting gives the moment of medicament and uses above cited can partly the making up each other with other possible choices of using the time relationship between the moment of alcopop or AS or other poisonous substances.

For parenteral, use the infusion agent of special preparation usually.For its preparation, active substance according to the present invention is mixed with appropriate solvent.Can use the water of special adjusting as this solvent.

Hereinafter the embodiment of Xian Shiing has illustrated essence of the present invention, but the scope of invention of requirement for restriction protection not.

Embodiment 1. sodium dimercaptopropanesulfonate tablets

Mix 25g sodium dimercaptopropanesulfonate (powdered substance), 5g lactose, 10g aerosil, 30g starch, 5g sodium starch glycolate, 5g magnesium stearate, 1g calcium pantothenate, 7g folic acid, moistening gained mixture, fully stir, homogenize and tabletting obtain the 0.5g tablet.

Tablet formulation

The instant capsule that embodiment 2. usefulness are particles filled, it comprises:

Composition	mg
Composition	mg	Dimercaptopropanol, BAL	50
Dimercaptosuccinic acid	50	Dimercaptopropanol, BAL	50
Dimercaptosuccinic acid	50	Sodium dimercaptopropanesulfonate	100
Succinic acid	100	Sodium dimercaptopropanesulfonate	100
Succinic acid	100	Calcium citrate	100
Lecithin	50	Calcium citrate	100
Lecithin	50	Magnesium oxide	50
Pyridoxine hydrochloride	20	Magnesium oxide	50

Make granule according to known technology in pharmacology's technology.

The application that is used for above-described purpose has adopted laboratory animal to detect.The applicant initiatively studies the detoxifcation behavior (using sodium dimercaptopropanesulfonate as an example) of ortho position ethylene dithiol alcohols.

It is that the male rat of the Wistar-100 strain of 150-250g carries out that the experimental section of 3. work of embodiment adopts initial body weight.These animals are raised under the artificial lighting condition of (12 hours every days), and free contact standard mixed feed and water.

These animals are divided into 4 groups (3 experimental grouies, 1 matched group).Each group all detected biochemical physiochemical indice before experimentizing: triglyceride, liver enzyme: alanine aminotransferase of peroxide procedural strength (AlAT) or serum glutamic pyruvic transminase (SGPT) and aspartate aminotransferase (AsAT) index-TBA-positive products (detecting) with thiobarbituric acid, and the index of biological antioxidant system: uric acid, vitamin E, A; The SH group.

In first experimental group (EG1), under the situation that does not have prevention also not have to handle, animal is poisoned; In one hour, these animals are used placebo with the form of gelatine capsule.In second experimental group (EG2), in poisoning preceding 1 hour, with the amount of the sodium dimercaptopropanesulfonate in the gelatine capsule with the every kg body weight of 150mg, per os gave these animals.In the 3rd experimental group (EG3), after poisoning in half an hour, described animal is used the sodium dimercaptopropanesulfonate in the capsule of same amount.

For obtaining the acute poisoning that methanol causes, give rat with 1ml dosage per os and single with methanol aqueous solution.

The zoopery result shows, lipid peroxidation end-product in the blood plasma of poisoning rat (EG1), and (EG2 EG3) has clear and definite difference to the concentration numerical value of TBA-positive compound aspect increase than the sodium dimercaptopropanesulfonate administration group of the same period.The content of main endogenous antioxidant-vitamin E of EG1 rat, A, SH group obviously reduces.The relatively demonstration of the amplitude chart of all three treated animals, the violent reduction of Vitamin E levels appears in the animal of only accepting methanol and placebo.The animal of accepting sodium dimercaptopropanesulfonate and methanol simultaneously maintains the meansigma methods of vitamin E on the level of values of control groups.At other endogenous antioxidants: observe identical pattern in the variation of vitamin A and SH group.

Also proved, the enzyme labelling thing to damaging hepatocellular activity (AlAT, AsAT) in EG1 apparently higher than the group of accepting sodium dimercaptopropanesulfonate.To the relatively demonstration of the biochemical indicator of EG2 and EG3, accept the EG2 treated animal of sodium dimercaptopropanesulfonate, from the survival significantly better of poisoning as preventive measure.This also shows when observing animal, its behavior and reaction.

Check that in back 12 days of poisoning the result according to the animal tissue of ethics biology criterion sacrificed by decapitation shows, maximum damage takes place in EG1 animal tissue.In lung tissue, be clear that focus infiltration, alveolar membranes thicken and the edema due to disorder of QI position.In cardiac muscle, observe the strong hyperemia of endocardium blood vessel, the fragmentation of individual fibers.In liver, observe hepatocellular granularly and drip the malnutrition of shape, the strong hyperemia of central vein, there is beam (beam) structure of two garland cellss, diffusion.Kidney is changed influences minimum, observes the hyperemia of some blood vessels and the moderate change in the brain layer.

For the EG3 animal, in tissue, observe similar variation, it is more not obvious that these change performance: liver is more complete, has kept girder construction; Malnutrition in the myocardial cell changes more not obvious; There is not the edema due to disorder of QI position in the lung.It is minimum as changing in the tissue of the EG2 animal of preventive measure to accept sodium dimercaptopropanesulfonate.In liver, under the situation of central vein hyperemia, hepatocyte is more complete, although also observe granular malnutrition.In lung, there is the focus infiltration.In cardiac muscular tissue, exist the myocyte to consume.

The result that research is learned by this test organization allows effect is drawn as drawing a conclusion: the acute poisoning that the ortho position dithiols causes methanol has shown therapeutic and preventative character.

It is the male rat of the Wistar-100 strain of 150-250g that the experimental section of 4. researchs of embodiment adopts initial body weight.These animals are raised under the artificial lighting condition of (12 hours every days), and free contact standard mixed feed and water.

These animals are divided into 4 groups (3 experimental grouies, 1 matched group).Each group all detected biochemical physiochemical indice before beginning experiment: triglyceride, liver enzyme: the alanine aminotransferase of peroxide procedural strength (AlAT), serum glutamic pyruvic transminase (SGPT) and aspartate aminotransferase (AsAT) index-TBA-positive products (detecting) with thiobarbituric acid, alkali phosphatase, and the index of biological antioxidant system: uric acid, vitamin E, A; The SH group.

In first experimental group (EG1), under the situation that does not have prevention also not have to handle, animal is poisoned; In one hour, these animals are used placebo with the gelatine capsule form.In second experimental group (EG2), in poisoning preceding 1 hour, with the amount of the sodium dimercaptopropanesulfonate in the gelatine capsule with the every kg body weight of 150mg, per os gave these animals.In the 3rd experimental group (EG3), in back 30 minutes of poisoning, also these animals are used sodium dimercaptopropanesulfonate in the capsule.

For obtaining the acute poisoning that ethylene glycol causes, give rat with 1ml dosage per os and single with glycol water.

The zoopery result shows, lipid peroxidation end-product in the blood plasma of poisoning rat (EG1), and (EG2 EG3) has clear and definite difference to the concentration numerical value of TBA-positive compound aspect increase than the sodium dimercaptopropanesulfonate administration group of the same period.The content of main endogenous antioxidant-vitamin E of EG1 rat, A, SH group obviously reduces.The relatively demonstration of the amplitude chart of all three treated animals, the violent reduction of Vitamin E levels appears in the animal of only accepting ethylene glycol and placebo.The animal of accepting sodium dimercaptopropanesulfonate and ethylene glycol simultaneously maintains the meansigma methods of vitamin E on the numerical value level of matched group.At other endogenous antioxidants: also observe identical pattern in the variation of vitamin A and SH group.The alkaline phosphatase enzyme level of EG1 animal raises.

Also proved, the enzyme labelling thing to damaging hepatocellular activity (AlAT, AsAT) in EG1 apparently higher than the group of accepting sodium dimercaptopropanesulfonate.To the relatively demonstration of the biochemical indicator of EG2 and EG3, accept the EG2 animal of sodium dimercaptopropanesulfonate, from the survival significantly better of poisoning as preventive measure.The described index of control animals is proved to be stable.

Check that in back 12 days of poisoning the result according to the animal tissue of ethics biology criterion sacrificed by decapitation shows, exists maximum damage in EG1 animal tissue.In lung tissue, be clear that focus infiltration, alveolar membranes thicken and isolating edema due to disorder of QI position.In cardiac muscle, strong hyperemia and the dystrophic of observing blood vessel change.In liver, observe hepatocellular granular and drip the malnutrition of shape, the strong hyperemia of central vein, the girder construction of non-a large amount of diffusions.In kidney, small intestinal and pancreas, do not observe visible variation.

For the EG3 animal, in tissue, to observe similar variation, but compare with the EG1 group, it is more not obvious that these change performance: liver keeps more completely, has kept girder construction; Malnutrition in the myocardial cell changes more not obvious; Although observe individual myocyte's hypertrophy, there is not the edema due to disorder of QI position in the lung, although alveolar membranes thickens yet.It is minimum as changing in the tissue of the EG2 animal of preventive measure to accept sodium dimercaptopropanesulfonate.In liver, under the strong congested situation of central vein, hepatocyte keeps more completely, although also observe granular malnutrition.In lung, there is the focus infiltration.In cardiac muscular tissue, exist the myocyte to consume.

This test allows effect is drawn as drawing a conclusion to the result of Histological research of animal tissue: the acute poisoning that the ortho position dithiols causes ethylene glycol has shown therapeutic and preventative character.

Claims

1. the ortho position dithioglycol of at least a general formula (1) is used for the treatment of the purposes of the poisoning that is caused by at least a toxic component that contains pure liquid and/or pure succedaneum,

R ₁(CH ₂) _nCH(SH)CH(SH)(CH ₂) _mR ₂(1)

R wherein ₁And R ₂Can be independently selected from following groups: (H), (OM '), (COOM '), (SO ₃M '), (O-CH ₂-SO ₃M '), (PO ₃M ₂'), (PO ₂SM ₂'), (PO ₃M "), (PO ₂SM "), symbol M wherein ' expression hydrogen or alkali metal ion, symbol M " the expression alkaline-earth metal ions, wherein m and n are independently selected from 0 to 5 integer.

2. according to the purposes of claim 1, it is characterized in that in intestinal and/or portal vein infusion or give the ortho position dithioglycol of at least a general formula (1) through the umbilicus infusion.

3. according to the purposes of claim 1, it is characterized in that when treating the poisoning that is caused by at least a toxic component that contains pure liquid and/or pure succedaneum, the ortho position dithioglycol of at least a general formula (1) is as special antidote.

4. according to the purposes of claim 3, it is characterized in that in intestinal and/or portal vein infusion or give the ortho position dithioglycol of at least a general formula (1) through the umbilicus infusion.

5. according to claim 1,2,3 and 4 each purposes, it guarantees to obtain at least aly to proofread and correct relevant effect with the poisoning toxicodynamics, and it is selected from:

Recover organa parenchymatosum's function;

Recover the function of neurotransmitter system;

Recover central nervous system's (CNS) function;

Recover the energy function of cell;

And/or guarantee to obtain at least aly to proofread and correct relevant effect with the poisoning toxicokinetics, it is selected from:

The chemical bond poisonous substance;

Prevent poisonous substance and toxic acceptor interaction;

Prevent the poisoning of natural poisonous substance;

Improving poisonous substance drains;

The prevention or reduce bringing into play the toxic effect of mitochondrial respiratory chain effect.

6. the ortho position dithioglycol of at least a general formula (1) is used to prevent the purposes of the poisoning that at least a toxic component by liquid that contains alcohol and/or pure succedaneum causes.

7. according to the purposes of claim 6, it is characterized in that giving the ortho position dithioglycol of the general formula (1) of at least a claim 1 through intestinal.

8. according to the purposes of claim 6, it is characterized in that the special antidote of the poisoning that the ortho position dithioglycol of the general formula (1) of at least a claim 1 is caused by at least a toxic component of liquid that contains alcohol and/or pure succedaneum as prevention.

9. purposes according to Claim 8 is characterized in that giving through intestinal the ortho position dithioglycol of at least a general formula (1).

10. according to claim 6,7,8 and 9 each purposes, it guarantees to obtain the relevant effect of risk at least a and that poison and occur, and it is selected from:

Reduce the seriousness of the poisoning in the process that may use poisonous substance;

Increase the toxic threshold level that concentrates;

Influence concentration coefficient to reduce the toxicity that concentrates;

Reduce poisonous substance and expose (time factor);

Reduce biological sensitivity to poisonous substance;

11. the method for the poisoning that prevention is caused by the liquid that contains alcohol and/or at least a toxic component of pure succedaneum, it comprises the ortho position dithioglycol that gives at least a general formula (1) of claim 1 through intestinal.

12. the method for the poisoning that Drug therapy is caused by the liquid that contains alcohol and/or at least a toxic component of pure succedaneum, it comprises the ortho position dithioglycol that gives the general formula (1) of at least a claim 1 through intestinal.

13. the method for the poisoning that Drug therapy is caused by the liquid that contains alcohol and/or at least a toxic component of pure succedaneum, it comprises the ortho position dithioglycol that gives the general formula (1) of at least a claim 1 through intestinal and parenteral.

14. the method for the poisoning that Drug therapy is caused by the liquid that contains alcohol and/or at least a toxic component of pure succedaneum, it comprises that parenteral gives the ortho position dithioglycol of the general formula of at least a claim 1 (1).

15. according to the method that claim 13 and 14 each Drug therapys are poisoned, it comprises that the ortho position dithioglycol with the general formula of at least a claim 1 (1) is administered in portal vein and/or the umbilical vein, promptly comprises in the portal vein infusion or through the umbilicus infusion.

16., wherein realize by using peroral dosage form through enteral administration according to claim 11,12 and 13 each methods.

17., wherein realize by probe through enteral administration according to claim 12 and 13 each methods.

18. according to each the method for Drug therapy of claim 12 to 17, wherein further realize it by detoxifcation measure complex known in the art, described measure is that toxicokinetics is proofreaied and correct and/or toxicodynamics is proofreaied and correct.

19. the medicament of the poisoning that prevention is caused by the liquid that contains alcohol and/or at least a toxic component of pure succedaneum, it comprises at least a active component, it is characterized in that as at least a active component, described medicament contains the ortho position dithioglycol of the general formula (1) of claim 1.

20., it is characterized in that described medicament is formulated into the form that is suitable for oral administration according to the medicament of claim 19.

21., it is characterized in that described medicament is mixed with dosage form or non-dosage form according to the medicament of claim 20.

22. the medicament of the poisoning that Drug therapy is caused by the liquid that contains alcohol and/or at least a toxic component of pure succedaneum, it comprises at least a active component, it is characterized in that as at least a active component, described medicament contains the ortho position dithioglycol of the general formula (1) of claim 1.

23., it is characterized in that described medicament is formulated into the form that is suitable for oral administration according to the medicament of claim 22.

24., it is characterized in that described medicament is formulated into solid drug forms or liquid medicine form according to claim 22 and 23 each medicaments.

25. according to each medicament of claim 19 to 24, it additionally contains at least a following active substance that is selected from: vitamin, previtamin, vitamin derivative, organic acid, organic acid derivatives, lipid, the last activated peptide of physiology, aminoacid, amino acid derivativges, enzyme, enzyme derivative, enzyme precursor, coenzyme, coenzyme derivant, coenzyme precursors, carbohydrate, mineral, metal ion source, albumen and its mixture.