CN101594856B - Agent and method for preventing and treating intoxication by alcohol-containing liquids and alcohol substitutes - Google Patents

Abstract

The invention relates to medicine and can be used for developing agents and methods to be used in toxicological practice and by population at home for preventing and reducing risks of dangerous diseases such as intoxication by alcohol substitutes and toxic components of alcoholic beverages. The invention is based on the use of known chemical compounds in the form of vicinal dithioglycoles. They are used for new purposes, namely for developing medicinal agents, the properties of which make it possible to prevent, treat or reduce speed of pathological processes generated by alcohol substitute intoxication. The inventive agents reduce or block the pharmacological effects of alcohols and the derivatives thereof, i.e. produce a direct effect on pathogenetic mechanisms of intoxication development. Said agents are most efficient when perorally administered. Experimental data items proving that the inventive agents and the preventing method, which consists in taking the agents before and after drinking low-quality alcohol-containing beverages and alcohol substitutes, can be widely used in future are also disclosed. The use of the invention makes it possible to reduce the number of intoxication cases produced by substitutes, to decrease the severity of intoxication and the toxic effect of alcoholic beverages consumed at home.

Description

Prevention and treatment are containing the liquid of alcohol and the poisoning medicament that alcohol succedaneum causes

Technical field

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

The poisoning quantity relevant with alcopop (no matter being deliberately to take or accidentally take) to voluntary use alcoholic beverage always increasing and abuse alcohol succedaneum are just becoming serious medical treatment and social problem.According to official's data, only in the Russian Federation, just there is every year thousands due to such poisoning and dead.Conventionally, medically the poisoning case of registration is always by using some poisonous substance and ethanol to cause, and beverage is due to its inadequate purification quality, or do not intend to be used as on the whole esculent, usually contains these poisonous substances.Known non-ethanol alcohol additive increases alcohol toxicity while use in the composition of beverage, described beverage is allowed to consumption conventionally.

The present invention relates generally to the ways and means that develops the problem for solving this area.

Background technology

In order clearly to understand below, herein the term using in the field of the invention is described.

Alcohols (or alcohol type) is hydrocarbon derivative, replaces hydrogen atom form by hydroxyl (OH).Term used herein " alcohols " should be understood to the alcohol of any kind: monoatomic or polyatomic, aliphatic or alicyclic, there is the carbochain of any length or any available isomer.Term " alcohol " also can represent this class alcohol, and it has different functional groups, i.e. amino alcohol, halohydrin, sulfo-alcohol and other.

Also will the ether of many alcohol, for example cellosolve be discussed herein.

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

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

1. unary alcohol (alkane alcohols)

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

According to ICD-10, its toxic action is classified as 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 combines with other poisonous substance, and its toxic action is increased and changes especially, and what in this case, in the time combining with other poisonous substance, caused by ethanol is poisoningly proved to be to be contained by field of the present invention; According to ICD-10, its toxic action is classified as 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 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 T-51.3 group;

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

According to ICD-10, its toxic action is classified as 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 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 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).

Field is as follows the most widely in commercial Application for poisonous substance mentioned above:

Methanol is for coating and varnish industry, also for the degeneration of ethanol.

Ethanol in extensively multiple commodity for the production of alcoholic beverage (and this is main herein meaning).

Isopropyl alcohol is for the production of antifreezing agent.Propanol is as the solvent of synthetic resin, quintessence oil etc.

Butanols is for the production of hydraulic fluid, in different organic synthesiss of a lot of industry neutralization etc. also as solvent.

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 is as antigraining agent, also for different organic synthesiss.

From chemical viewpoint, in the time using zymase fermentation, producing ethanol by sugared culture propagation is the catalysis multistep sugar decomposition process that forms alcohol and carbon dioxide.In order to ensure the life cycle of yeast, by biologically available nitrogen and phosphorus source add the liquid solution (or brewing material (brew)) being fermented, this certainly leads to some other primary alcohol outside ethanol: methanol, propanol, isobutanol and isoamyl alcohol, optional active-amyl alcohol (2-methyl butanol-1).Except the first, they are all 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 producing, is impossible by ethanol water from other alcohols and some other volatility mixture Economical Purification.Meanwhile, the quality of the final ethanol water obtaining is determined by quality (its content is fewer, and the quality of end-product is higher) and its composition of other residual alcohols.In addition, end-product inevitably comprises a certain amount of aldehydes simultaneously forming during the fermentation.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 to some the simultaneous toxicity mixture existing with the form of other alcohols, its aldehydes and ethers and other toxicity mixture and its metabolite, take alcoholic beverage and follow caused by ethanol itself and its metabolite poisoning.

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

the first kind is particularly including following material:

Hydrolysis ethanol and sulphite ethanol (ethanol being produced by the hydrolysis of timber);

Denatured alcohol (industrial alcohols mixing with methanol and aldehydes)

Rough alcohol (through fermentation contain ethanol and Alcohols,fusel: 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 of the additive that contains quintessence oil and/or heterogeneity);

Alcoholic beverage taking ethanol inferior as the doping of basis preparation.

Liquid for polishing (mixture of industrial alcohol and butanols, amylalcohol, chloroform, acetone etc.);

Different liquid (glue class, paint etc.).

equations of The Second Kind is particularly including following material:

Alcohol type (comprising ethanol);

Aldehydes, ketone;

Alcohol ethers;

The derivant of the compound above illustrating;

The compound that above literary composition illustrates is the industrial liquid of basis preparation.

The poisoning feature that AS causes is that converted product biology of the original poison in biology is proved conventionally has the toxicity stronger than parent compound.Specifically, methanol, ethylene glycol and its ether, tetrahydrofurfuryl alcohol and other are considered to the lower material of the original toxicity of this class.The material with these character is usually called as easily toxigenous (toxifiable), and described process itself is called as " toxic poisoning ", this means the formation material feasibility more malicious than natural poisonous substance in metabolic process, and its amount affects poisoning character and seriousness 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, term poisonous substance represents that at least one is selected from the material of lower group:

Alcohol (not being ethanol or ethanol);

01 derivatives;

Alcohol succedaneum,

Poisoning (or poisoning) is the pathologic state extremely being caused by chemical homeostasis, and described chemical homeostasis is caused by the interaction of the toxicant of biological different biochemical structures and exogenous origin or endogenous origin extremely.Term " poisoning " represents poisoning process completely, it starts development from its very original symptom, until the comprehensive clinical module of disease, its content depends on the physiologic function of the toxicity of major receptors, with interactional some biochemical structure of this poisonous substance (poison) selectivity.Different from endointoxication, heterointoxication is commonly called poisoning, relevant according to himself accumulation (self poisoning) of metabolism in biology with toxicant.

The poisoning classification as chemical etiology disease is taking 3 guidelines as basis: pathogeny principle, clinical principle and nosonomy principle.

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

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

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

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

Be classified as heterointoxication according to the origin of poisonous substance.

According to the general modfel of poisoning development, process and termination, the toxic poisoning of discussing in the present invention can be poisoning as follows:

Acute,, after toxicant single administration is to biology, clinical poison mode is to occur with quick and strong process, rehabilitation or death when termination;

Subacute, be administered to after biology at poisonous substance single (or within one period of short time several times), poisoning clinical development is carried out in the mode of slowing down, and causes greater or lesser to healthy persistence damage;

Chronic, the poisoning feature of this class is conventionally with little inferior toxicity dosage, repeatedly, there is Systematic Features, or intermittently use poisonous substance to biological, it follows its lasting effect and the lasting symptomatology to healthy damage 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, this conventionally with week or month over weigh.

According to the degree of seriousness, poisoning can being classified as follows of discussing herein:

Slight, medium serious, serious or lethal.

In the present invention, term " poisoning " is understood to any illustrate attainable poisoning being caused by any poisonous substance mentioned above 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 abnormal, the balance of destroying the natural system of removing toxic substances, described system is intended to biology to purify out from the toxicant of multiple origin.

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

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

Toxicodynamics aspect (what has occurred 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 biology: molecular weight, the dissolubility in water and fat, ionizable ability;

Form the ability of valence link with the receptor of albumen and some toxicity;

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

Transform the biology in biochemical system;

From the pattern of biology excretion.

In the framework of toxicodynamics method, study following character:

Poisoning toxigenous effect, extremely relevant from the physiologic function of different biochemical structures, plays toxicity receptor, and this special symptom by the poisonous substance of discussing shows.

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

In this case, should consider, always occurs as basis taking physiology's system of determining as any type of chemical disease poisoning, the still difference with the difference of its active result, this has obtained its unsuitable pathogenic character.

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

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

2. time factor-the determine holdup time of poisonous substance toxicity dose in biology, 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 poisoning generation toxicity stage and somatocyte development stage, and absorb and the elimination time at the poisonous substance producing in the toxicity stage.

3. space factor-determine the approach that enters, discharges, and the space of distribution of toxicant, it is relevant to the blood of supplying with Organ and tissue aspect a lot.

4. age factor-reaction is hit in the different Age-specific stages degree of the biological sensitivity to poisonous substance in life, its from childhood period change significantly to high age, at that time the opposing of toxic action is weakened to 10 times and more.

5. treatment factor, determines the biological reaction to the antidotal therapy of implementing, and this can produce several times of increases of the concentration threshold of the main poisoning symptom of development, and fully shortens the time that produces the toxicity stage.

Study poisoning pathogenesis using following viewpoint as basis: toxicity receptor is as the ad-hoc location of poisonous substance identification and effect.

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

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

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

Toxic action needn't have strict selectivity, and it can occur cell on the whole.This principle is implemented on a lot of poisonous substances, and wherein common characteristic is that they are not electrolyte.Term " non-electrolysis " represents all effects, and it is directly defined by physicochemical property, and for example infusive or make us addicted material, it is the feature of poisonous substance described herein (alcohols).

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

In a lot of research achievements, find, cause at alkanol and alcohol succedaneum poisoning under, 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 of the chain reaction of losing with a large amount of cells, and it is the result that exhausts biological natural anti-oxidation system (AOS) that described cell is lost.

Removing toxic substances (removing toxic substances), as one of the most remarkable mechanism of chemical resistance, it is complex biochemical in biological and biophysics's reaction, it relates to chemical homeostasis and maintains, this is to be guaranteed by some system cooperating performance functions of natural removing toxic substances (neutralization of the toxicant of exogenous origin and endogenous origin), and described system comprises:

Haematogenic immunity system (blood protein and hemocyte);

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

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

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

All exceed toxicity load threshold level in the situation that, need to the mode of accelerating stimulate or additional maintenance for the system of the clean natural function of detoxification of performance.

The toxicodynamics effect of removing toxic substances is with certain clinical symptoms demonstration, and its content depends on clinical stages and the selective toxicity of poisonous substance.

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

In the chronic poisoning different from acute poisoning, after long-term general physical obstacle, significantly showed afterwards the specific signs of toxicity that produces.

Poisoning therapeutic treatment comprises that the enforcement of combination specifically treats measure, and it is realized in 2 main directions:

1) stop anyly further entering, and implement from biological accelerated release in vitro toxicant (the initiatively output intent of removing toxic substances), and, if possible, by applying specific (thering is Detoxication) pharmacotherapy, implement the quick neutralization of poisonous substance, described treatment reduces the toxicity (toxicokinetics correction) of poisonous substance;

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

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

Detoxification in the somatocyte development stage also relates to eliminates the endogenetic toxicosis (endotoxicosis) developing organa parenchymatosum damage (for example, in acute kidney or hepatic insufficiency in the situation that) in the situation that.

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

Nonspecific action is relevant with the characteristic of physicochemical property, and is regulated by so-called non-electrolyte effect (being that overall molecule material is by the effect of the mechanism of existence).Non-electrolyte effect shows as film fluidization, as a result of, shows its abnormal function.Described alkane alcohols-intrinsic 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 poisoning clinical manifestation of non-electrolyte (it relates to described alcohols and its metabolite) is that similar state, cardiac contractility ability in poisoning (or dizzy) weakens and endocellular metabolism obstacle.

Under laboratory and clinical condition, most study is the pattern of ethylism.A series of its brains, liver, the heart and Nephrotoxicity are determined, to Synaptic (synaptotropic) with to the mechanism of the toxic action of film (membranotropic) character.To briefly describe hereinafter these mechanism, to such an extent as on their basis, by analogy, characterize after a while the toxic action of the poisonous substance of considering herein.

Ethanol passes through SOD, by (the latter is specific NAD-dependent enzyme) at hepatocyte cytosol, alcoholdehydrogenase (ADG) in the MEOS (MSES) of liver, and by the catalase in tissue, oxidase and peroxidase oxidation.The oxidation of ethanol causes forming aldehyde, i.e. acetaldehyde.Liver enzyme (being aldehyde dehydrogenase (the AcDH)) oxidation that acetaldehyde is contained FAD, to form acetic acid (acetic acid), it further generates CO gradually by metabolism ₂and H ₂o.

The realization of the toxic effect of ethyl alcohol to central nervous system (CNS) is by the abnormal adjusting of functional medium system, describedly extremely caused by this effect, and shows in film-action effect.Its specifically impact on gamma aminobutyric acid (GABA), glutamatergic system changes permeability and the affinity of film ion channel, changes thus the function of neurotransmitter system.

In biology ethanol conversion, produce the recovery form of a large amount of acetaldehyde, acetate and ADG-NADH enzyme.Finally, it is the abnormal reasons of a series of biochemistry that caused by the introducing of ethanol.The in the situation that 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, development metabolic acidosis.As everyone knows, a large amount of acetaldehyde causes respiratory chain mitochondrial function abnormal, thus can dysfunction.Based on this, form 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, be also applicable to a lot of other alcohols, it is mentioned those alcohol of so-called intoxicating phenomenon at least above.Another supports that the argument of this reason is following truth: cause at many alcohols poisoning in, ethanol is used as special antidote, its effect is by its competitive inhibition alcoholdehydrogenase and then prevent that the ability of the oxidation of these poisonous substances from explaining.Can classify as this class alcohol, methanol, carbon chain lengths have aliphatic alcohols, the dihydroxylic alcohols of 5 atoms at the most, with and there is the ether (glycol monoether) of alcohol groups, i.e. those alcohol and its derivant, 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 imbalance of cell membrane physicochemical property, the alcohol membrane damage that converted product causes biology, the cytoplasmic acidosis of 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, the necrosis and underfed (steatosis) that have developed in the cell of most important organ change.

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

Ethylene glycol mono-ether experiences approximately uniform metabolic pathway, because its alcohol groups of ADG " attack ", due to this reason, monoether is converted into relevant aldehyde.According to this point, form glycolic (oxyacetic acid) from ethylene glycol mono-ether, there is also causing cellular metabolism acidosis in it.Under combined effect, these compounds regulate 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 abnormal beginnings: homeostasis obstacle (metabolic acidosis, water-electrolyte imbalance, blood coagulation change and other obstacle), and form 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 much with lethal risk.These processes comprise following situation:

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

Circulate poverty-stricken (former because basis with other 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 poisoning clinical module of AS-, select following characteristic symptom:

Toxicity encephalopathy;

Adnormal respiration;

Blood circulation is abnormal;

Toxicity hepatopathy;

Toxicity nephropathy;

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

Stomach-intestinal obstacle.

These syndromes are described in detail in following list of references: [source 1:Luzhnikov E.A., the people such as Ostapenko Yu.N..“Emergency status under acute poisonings”M.，2001]。Up to now, cause at methanol according to the present invention, ethylene glycol and its poisonous substance poisoning in, ethanol has been used as special antidote, and uses [source 1, the 155-156 page] 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 object of the invention is to make effective agent to enter circulation, with the development of prevention or blocking-up pathological process, or reduce its speed, described pathological process by single and repeatedly, what particularly extend uses alcopop to cause with systematicness, and described beverage also contains the poisonous substance beyond ethanol itself.These poisonous substances are present in beverage as the natural mixture coming across in alcohol fermentation preparation process.Toxicity mixture is present in beverage may also there are some other reasons.In addition, the present invention concentrates on effective ways and medicament is introduced to toxicology practice, with poisoning the prevention and Drug therapy that alcohols and its derivant are caused.

By being designed for the medicament through intestinal or parenteral, solve the task of this appointment, described medicament represents the ortho position dithioglycol of at least one general formula (1), and if need, together prepares with the carrier of pharmaceutically acceptable carrier or food.Described ortho position dithioglycol refers to the material of following general formula

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

Wherein R 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 "), wherein symbol M ' represent hydrogen or alkali metal ion, symbol M " and represent alkaline-earth metal ions, wherein m and n are independently selected from 0 to 5 integer.The compound of general formula (1) is that prior art is known.It is described and route of synthesis is listed in, for example ChemicalEncyclopedia[source 2: " Chemical Encyclopedia ", M.:SovietEncyclopedia Publishing House, 1990, v.2,91-92 page].Described ortho position dithioglycol (VD) refers to following compounds particularly:

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

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

3.2,3-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 medicine of radioprotective activity, when heavy metal and its compound cause poisoningly, is particularly caused when poisoning by arsenic, lead, hydrargyrum, also as antidote [source 3:Mashkovsky M.D. " Medications ", M., 1993].These are the low molecular compounds with 2 ortho position sulfydryls, and due to 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 when 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., edited by Tomilin V.V. //professor Moscow, 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 for so-called destructive poisonous substance, described destructive poisonous substance comprises heavy metallic salt, arsenic and its compound, and the compound of some phosphorus and chlorine.Also known, in the situation that mental disorder alcoholism (alcoholicum), acute alcoholism, narcotic are poisoning, with the Comprehensive Treatment of other antidote combination in, use DMPS (DMPS) [source 3].Known in the antidotal therapy as one of its stage, use DMPS, alleviate fast withdrawal symptom [source 5: " Alcoholism ", by G.V.Morozov, M. edits, Medicina Publishing House, 1985, the 314-321 pages].Also known in the process of the dependence disease by using 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 of known substance for new object.

Summary of the invention

Applicant finds first, under known index listed above, after enteral administration, ortho position ethylene dithiol alcohols (VD) has shown beat all stronger effect, have been surprisingly found that in addition, after administration, especially after oral administration, ortho position dithioglycol provides new effect, the development that first it show blocking-up and/or suppress pathological process, described pathological process is by using the beverage (containing toxic mixture) containing ethanol and/or causing containing the beverage (not only contain ethanol as alcohol, and contain alcohol succedaneum as alcohol) of alcohol.The character of the unexpected discovery of the following row of this effect be basic: 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 basic feature of the present invention.

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

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

The 3rd feature (additional feature) be, if this class poisonous substance reacts with water solublity ortho position dithioglycol as the derivative aldehyde of alcohol, then product also becomes water misciblely, obtains the ability being together 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 increases and reduces with chain length.Based on this behavior, as medicament in this paper and method, except these are the medicament and method of antidote Drug therapy, become active agents and the method for effective removing toxic substances; They not only accelerate poisonous substance and eliminate, and can carry out by kidney the excretion of poisonous substance.For the excretion of ketone, identical process is real.In poisonous substance discharge process, relate to kidney affects the concentration coefficient of pathogenesis with having superiority.

The 4th feature, is also additional feature, as follows: due to its suitable physicochemical property, alcohols has easily overcome Tissue Blood originality barrier, and is distributed in very equably Organ and tissue.Then, therein, alcohols experience biotransformation, the first stage is converted into aldehydes.Aldehydes is larger than alcohols toxicity, has stronger reactivity.Aldehydes reacts with end group and hemocyte, enzyme and other key element of plasma protein, changes their function (immunity thus, hemostasis, breathing, CNS, cardiac muscle, energy function and much other function are affected).In other words, more significantly than alcohols of the toxicity receptor of aldehydes.Different from alcohols, aldehydes is proved to be overcoming in the sexual disorders of Tissue Blood source obviously poorlyer etc., and it causes them in those Organ and tissues, to accumulate, and alcohol metabolism starts (being the first stage of alcohol oxidation) in described Organ and tissue.Meanwhile, under the effect of liver enzyme-aldehyde dehydrogenase, there is formoxy-.In view of mentioned above, in the Organ and tissue outside liver, any further formoxy-is prevented from, and this has aggravated 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 predetermining in heredity.Can find the new solution of this problem according to the application of medicament of the present invention and method.Significantly, enter after liver according to active substance of the present invention (VD) making, the combination of aldehyde occurs.This causes the changes in balance in " alcohol-aldehyde " reversible reaction.So according to Le Chatelier principle, system is by strengthening alcohol oxidation and reducing its concentration in liver subsequently, to its reaction.According to identical principle, this causes alcohol further to flow out with and flow into liver from other Organ and tissue, to recover concentration.Be kept if be present in the VD of liver, the amount that is oxidized by the alcohol that flows into liver the new aldehyde obtaining is by combination again, and this is cycled to repeat generation.Therefore, apply material according to the present invention and on all Organ and tissues, reduced toxicity load, because these materials promote poisonous substance from extremely important Organ and tissue rapid drainage.According to the viewpoint of poisoning induced Anttdisease Mechanism, coming into effect as quickly as possible this class Drug therapy is important thing.According to the present invention, enter at maintenance active substance (VD) the circulation defending party to the application described herein who realizes under the condition of liver and be called " biological alcohol-aldehyde removing toxic substances circulation " (CAAD).Also point out, CAAD also realizes by preventative VD administration.Therefore, time factor and the space factor of CAAD to poisoning pathogenesis produces beneficial effect.

Therefore, 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 removing toxic substances 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 poison, utilize them as special antidote (the first basic feature) in these.Be the medication of ortho position dithioglycol according to the second basic feature of the purposes of this new object, according to the method, must guarantee that it finally completely also enters liver fast, because it is poisoning with it that toxicant metabolism occurs at first just in this organ.In the case, best solution is through enteral administration, but in the time that status of patient needs, pointed out by drug administration to portal venous flow or through 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, applicant provides the poisoning medicament and the method that are caused by poisonous substance detailed above with Drug therapy for preventing.

The explanation of technical result

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

The 1st group: toxicokinetics correction treatment

Chemical bond poisonous substance;

Prevent the receptors bind of poisonous substance and toxicity;

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

Accelerate Organ and tissue (brain, the lung etc.) excretion that poisonous substance occupies from it;

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 being caused by the existence of one or more poisonous substances in alcohol succedaneum;

Improve poisonous substance excretion;

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

The 2nd group: toxicodynamics correction treatment

Recover organa parenchymatosum's function;

Recover the function of neurotransmitter system;

Recover CNS function;

Recover the energy function of cell.

The 3rd group: prevention

Appearance or development that prevention may enter at it acute or subacute poisoning causing in biological process by poisonous substance;

The appearance of the chronic or chronic poisoning in Asia that prevention causes in using repeatedly or regularly containing the liquid of alcohol or the process of alcohol succedaneum or reduce its speed of development, the poisonous substance that described liquid contains inferior toxicity dosage;

Reduce the poisoning seriousness in the situation that poisonous substance may be taken in;

Increase the threshold level of the toxicity that concentrates;

Affect concentration coefficient to reduce toxic concentration value;

Affect concentration coefficient to such an extent as to reduce the amount of poisons in brain;

Reduce poisonous substance and expose (time factor);

Reduce the 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 applicant has found the new property of general formula (1) compound, another aspect of the present invention is to take at least one according to after poisonous substance of the present invention, applying the medicament of at least one ortho position dithioglycol as generation or the development of preventing poisoning.This object is new, because it is not taking the antioxidant properties of known removing toxic substances, these materials as basis.Relate to that to use VD be also new as the object of the active agents of preparing medicine, described medicament is mixed with dosage form or non-dosage form, for preventing or that Drug therapy is caused by poisonous substance according to the present invention is poisoning.This class medicine can represent compositions, and also comprises other active component.For the form of preparation, they can be for ingesting or the liquid or solid medicine of parenteral.

Ortho position dithioglycol can stop the process that biomembranous free radical destroys, and specifically, they protect myelinic ozone layer to avoid damage, protection hepatocyte, blood vessel and brain structure.On the basis of the behavior of ortho position explained above ethylene dithiol alcohols, its administration can be blocked or lower cardiac muscular tissue, pancreas, vascular system, CNS and biological other organs 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 organ on a lot of biologies and the impact of system, and these toxic actions cause starting simultaneously or activating a considerable amount of pathological processes.In the case of considering the character or behavior of ortho position ethylene dithiol alcohols mentioned above, can infer that the latter has wholesome effect to this class pathological process of entire quantity, but this impact can be shown or realize, although simultaneously, there is performance in various degree.First its impact depends 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 started can be suppressed by using these medicines.On the performance impact of particular pathologies process, as poisonous substance use toxic action regulated, also depend on according to strategy, toxicity load and other factors of the dosage of medicament of the present invention, individual body and other characteristics, drug administration.

Applicant has been found that the effect having superiority on physiology explained above is proved to be with strong especially degree in the time of oral administration medicament.This phenomenon seems that to enter the high-speed and described material of liver relevant with some characteristic of liver enzyme interacting with active substance.This more inapparent effect also can be observed at the topical by oral mucosa, nose and inhalation-type drug administration.

Effect explained above has been expanded the character of known ortho position ethylene dithiol alcohols up to now significantly.Their known detoxicating activities are used for reducing acute withdrawal situation, are used for the treatment of the people who is affected by alcoholism.Patient is treated to mental disorder alcoholism with DMPS, the alcoholism of original (the 3rd) clinical stages that described patient suffers from, the feature of described clinical stages is the appearance of serious spirituality obstacle.Known antioxidant activity has also supplemented the new ability of ortho position ethylene dithiol alcohols well.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 harmful result of ethanol, and it appears at second day that uses after ethanol.This effect causes (No. 2157647C1st, patent RU, 2000) to the activity of acetaldehyde in vivo by VD.At present, taking newfound effect in test as basis, it can be asserted that the effect of ortho position ethylene dithiol alcohols (as active substance) shows by their administration, it occurs discretely with the fact that uses AS, for example pass through several weeks (Drug therapy process) or a couple of days before absorption AS, or in during a few hours, preventive administration shows.There is identical phenomenon for other poisonous substances.Importantly, notice that applicant has determined the effect of ortho position ethylene dithiol alcohols to the poisoning pathogenetic common contact being caused by the metabolite of alcohols and its Different Origin.

Therefore, have reason very much known properties to ortho position ethylene dithiol alcohols and the synergism of character explained above to reach a conclusion, it allows for new object, recommends its application.

The medicament forms of medicament proposing can comprise and being suitable for through enteral administration, particularly oral administration, by probe administration, nose administration, by part (comprising through cheek and the Sublingual) administration of oral mucosa, or by sucking or by the form of drug administration by injection.The medicament proposing can have the solution form for drug administration by injection.In this case, by the active substance proposing according to the present invention is mixed with suitable liquid component, and carry out its administration under relevant Preparation equipment auxiliary, thereby prepare infusion solution.Pharmaceutical preparation can represent compositions, and the form of administration unit that can be discrete easily provides, any method preparation of can pharmaceutics field knowing.All these method of pharmacy comprise the step that active substance and liquid-carrier or the broken solid carrier of fine powder or their both (if needs) are mixed, and step is subsequently product to be 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 the form of powder or granule; 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, not containing carrier.For the Tablet and Capsula of oral administration, except the upper activated composition of additional physiology, 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 by extruding the active component of free-flowing form, for example, with powder or the granule of optional approach and adhesive, lubricity material, inert diluent, lubricant, surfactant or dispersant, prepare compressed tablets.On suitable machine, by the mixture (by the moistening mixture of inert liquid diluent) of mould-casting powder compound, prepare molded tablet.Can use according to method well known in the art shell coated tablet.Liquid oral medicine can be the form of for example aqueous or oily suspensions, solution, emulsion, syrup or elixir, maybe can show as the form of the dryed product of water before use or other suitable 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), taste masking additive, aromatic, coloring agent or antiseptic.Can the optional system standby form of above enumerating, with provide the active substance that wherein contains slowly or the excretion of controlling.

Be intended to by oral mucosa topical, for example for example contain, at its correctives substrate (carbohydrate by comprising through the form of cheek or sublingual administration approach, for example sucrose, arabic gum or Tragacanth) in the lozenge of active component, and in substrate, containing the pastille of active component, described substrate is such as gelatin, glycerol, carbohydrate, arabic gum etc.For the intranasal administration of active substance explained above, operable form is powder or the drop that for example aerosol maybe can become 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, compound according to the present invention be convenient to from the insufflator for the preparation of aerosol spray, suction-type pressurized package or other easily device obtain.Packaging under pressure can contain suitable propellant, for example dichlorodifluoromethane, Arcton 11, carbon dioxide or other suitable gas.For the aerocolloidal situation under pressure, the valve of supplying the amount of metering by use provides spraying, thereby determines dosage unit.

Selectively, for giving, according to material of the present invention, can use the form of dry powder powder mixture by sucking or being blown into, the powder mixture of for example active substance and relevant Powdered substrate, 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 packaging, can introduce described powder by inhaler or insufflator from above-mentioned form.

If needed, use above-described form, it is suitable for providing the sustained 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, for strengthening the effect of the material being proposed by the present invention, with and can be used for obtaining the composition of interpolation and according to the synergism of compound of the present invention.The active component adding can be to be selected from following composition: vitamin, previtamin, vitamin derivative, organic acid, organic acid derivatives, lipid, the upper 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 to have superiority, it is neurotransmitter, for example glycine, γ-aminobutyric acid (GABA).Add metal ion source to have superiority, because of for by methanol, ethylene glycol and poisoning destruction water-electrolyte balance that much other poisonous substances cause, cause hypocalcemia, cause that thus muscle rigidity shrinks.In this case, add divalent metal ion source also to have superiority, because some in them, for example magnesium, calcium, manganese play a significant role in enzyme catalysis, and it forms 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 accelerate the development of a lot of pathological processes.Also can be the source of lipid as the additive having superiority in medicament composition according to the present invention; particularly phospholipid; for example lecithin, glycolipid; other liver protection things; particularly vitamin, for example alpha-tocopherol, its precursor, its derivant, the upper activated peptide of physiology; for example neuropeptide, and much other physiologys known in the art go up activated material.

Be appreciated that except the composition that above part is enumerated, 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 herein.For example, can contain correctives or structure-forming agent for the medicine of oral administration.Especially, what relate to significantly poisoning prevention can be mixed with medicament forms or non-medicament forms according to medicament of the present invention, for example, be 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, as mentioned below, or containing the suitable form of the described dosage of part.

In order to reach recommended target, according to the present invention, the medicament that contains effective dose active component explained above can be introduced with every daily dose 0.1 to 250mg/kg (every kg of patient body weight) by oral or different approach easily.General adult's the common scope of every dosage level be about 5mg to about 10g, normally at less approximately 50mg to the scope of about 2g, most preferred scope is from 100 to 1000mg every days.The tablet of the medicament providing with the form of discrete unit or other forms, easy to use for it, can contain under this dosage and effectively measure, or multiple amount, for example contain 50mg to 1000mg, be generally approximately 200 units 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 using depends on several factors, it comprises that sex, age, body weight, risk factor, poisonous substance absorb the situation causing, individual body and spiritual neurological characteristic etc.Determining while using time of medicament and persistent period (speed), should note the factor of identical type.Can recommend the form administration of medicament with process, in the time that it can be prescribed before may using alcopop, it relates to poisoning risk or harm, and/or poisonous substance enters other biological possible approach (breathing, suck), or using after this class beverage (or making by other means poisonous substance enter biology) in certain time interval, or before using and afterwards, or in the different combination using containing the beverage of Toxic.According to this point, regulate and give the moment of medicament and use using the cited of time relationship between the moment above and can partly combining each other with other possible choices of alcopop or AS or other poisonous substances.

For parenteral, conventionally use the infusion agent of special preparation.For its preparation, by active substance according to the present invention and suitable solvent.Can use the water of special adjusting as this solvent.

The embodiment below showing has illustrated essence of the present invention, but does not limit the scope of claimed invention.

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 0.5g tablet.

Tablet formulation

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

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

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

Application for above-described object has adopted laboratory animal to detect.The initiatively removing toxic substances behavior to ortho position ethylene dithiol alcohols of applicant (using sodium dimercaptopropanesulfonate as an example) is studied.

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 contact free standard mixed feed and water.

These animals are divided into 4 groups (3 experimental grouies, 1 matched group).Each group is all detected biochemical physiochemical indice before testing: triglyceride, liver enzyme: the alanine aminotransferase (AlAT) of peroxide procedural strength 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; SH group.

In the first experimental group (EG1), in the situation that prevention is not processed yet, make animal poisoning; In one hour, these animals are used to the placebo with the form of gelatine capsule.In the second experimental group (EG2), at poisoning first 1 hour, the amount by the sodium dimercaptopropanesulfonate in gelatine capsule with the every kg body weight of 150mg, per os gives these animals.In the 3rd experimental group (EG3), within poisoning rear half an hour, described animal is used to the sodium dimercaptopropanesulfonate in the capsule of same amount.

The acute poisoning causing for obtaining methanol, gives rat by methanol aqueous solution with 1ml dosage per os and single.

Results of animal shows, end product of lipid hyperoxygen in the blood plasma of poisoning rat (EG1), and the concentration numerical value of TBA-positive compound is having clear and definite difference compared with the sodium dimercaptopropanesulfonate administration group (EG2, EG3) of the same period aspect increase.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 simultaneously accepting sodium dimercaptopropanesulfonate and methanol maintains the meansigma methods of vitamin E in 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, enzyme labelling thing to damaging hepatocellular activity (AlAT, AsAT) in EG1 apparently higher than the group of accepting sodium dimercaptopropanesulfonate.The relatively demonstration of the biochemical indicator to EG2 and EG3, accepts the EG2 treated animal of sodium dimercaptopropanesulfonate as preventive measure, from poisoning survival significantly better.This also shows in the time observing animal, its behavior and reaction.

In poisoning latter 12 days, check according to the result of the animal tissue of ethics biology criterion sacrificed by decapitation and show, maximum damage occurs in EG1 animal tissue.In lung tissue, be clear that focus infiltrates, alveolar membranes thickens and 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, the strong hyperemia of central vein of shape, there is beam (beam) structure of two garland cellss, diffusion.What kidney was changed affects minimum, observes the moderate change in hyperemia and the brain layer of some blood vessels.

For EG3 animal, in tissue, observe similar variation, it is more not obvious that these change performance: liver is more complete, has retained girder construction; Malnutrition in myocardial cell changes more not obvious; In lung, there is no edema due to disorder of QI position.Accept sodium dimercaptopropanesulfonate minimum as changing in the tissue of the EG2 animal of preventive measure.In liver, the in the situation that of central vein hyperemia, hepatocyte is more complete, although also observe granular malnutrition.In lung, exist focus to infiltrate.In cardiac muscular tissue, exist myocyte to consume.

The result that research is learned by this test organization allows effect to draw the following conclusions: the acute poisoning that 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 contact free standard mixed feed and water.

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

In the first experimental group (EG1), in the situation that prevention is not processed yet, make animal poisoning; In one hour, these animals are used to the placebo with gelatine capsule form.In the second experimental group (EG2), at poisoning first 1 hour, the amount by the sodium dimercaptopropanesulfonate in gelatine capsule with the every kg body weight of 150mg, per os gives these animals.In the 3rd experimental group (EG3), in poisoning latter 30 minutes, also these animals are used to the sodium dimercaptopropanesulfonate in capsule.

The acute poisoning causing for obtaining ethylene glycol, gives rat by glycol water with 1ml dosage per os and single.

Results of animal shows, end product of lipid hyperoxygen in the blood plasma of poisoning rat (EG1), and the concentration numerical value of TBA-positive compound is having clear and definite difference compared with the sodium dimercaptopropanesulfonate administration group (EG2, EG3) of the same period aspect increase.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 simultaneously accepting sodium dimercaptopropanesulfonate and ethylene glycol maintains the meansigma methods of vitamin E in 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, enzyme labelling thing to damaging hepatocellular activity (AlAT, AsAT) in EG1 apparently higher than the group of accepting sodium dimercaptopropanesulfonate.The relatively demonstration of the biochemical indicator to EG2 and EG3, accepts the EG2 animal of sodium dimercaptopropanesulfonate as preventive measure, from poisoning survival significantly better.The described index of control animals is proved to be stable.

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

For EG3 animal, in tissue, observe similar variation, but compared with EG1 group, it is more not obvious that these change performance: liver keeps more completely, has retained girder construction; Malnutrition in myocardial cell changes more not obvious; Although observe individual myocyte's hypertrophy, in lung, there is no edema due to disorder of QI position, although alveolar membranes thickens yet.Accept sodium dimercaptopropanesulfonate minimum as changing in the tissue of the EG2 animal of preventive measure.In liver, the in the situation that of the strong hyperemia of central vein, hepatocyte keeps more completely, although also observe granular malnutrition.In lung, exist focus to infiltrate.In cardiac muscular tissue, exist myocyte to consume.

This test allows effect to draw the following conclusions to Histological research's result of animal tissue: the acute poisoning that ortho position dithiols causes ethylene glycol has shown therapeutic and preventative character.

Claims (13)

1. the sodium dimercaptopropanesulfonate of following formula is in the purposes of preparing in medicine,

Wherein said medicine is used for the treatment of caused by least one toxic component poisoning, and described toxic component is selected from methanol and ethylene glycol.

2. according to the purposes of claim 1, it is characterized in that in intestinal and/or portal vein infusion or give described medicine through umbilicus infusion.

3. according to the purposes of claim 1, it is characterized in that described medicine is used as special antidote in the time treating caused by described at least one toxic component poisoning.

4. according to the purposes of claim 3, it is characterized in that in intestinal and/or portal vein infusion or give described medicine through umbilicus infusion.

5. according to the purposes of claim 2 and 4 any one, wherein saidly realize by application peroral dosage form through intestinal.

6. according to the purposes of claim 2 and 4 any one, wherein saidly realize by probe through intestinal.

7. according to the purposes of claim 1,2,3 and 4 any one, it guarantees to obtain at least one and the positively related effect in poisoning toxicodynamics school, and it is selected from:

-recovery organa parenchymatosum's function;

The function of-recovery neurotransmitter system;

-recovery central nervous system's function;

The energy function of-recovery cell;

And/or guarantee to obtain at least one and the positively related effect in poisoning toxicokinetics school, it is selected from:

-chemical bond poisonous substance;

-prevent the acceptor interaction of poisonous substance and toxicity;

-acceleration poisonous substance and/or its toxic metabolites are drained from biology;

The Organ and tissue excretion that-acceleration poisonous substance occupies from it;

-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 caused by the existence of one or more poisonous substances in alcohol succedaneum;

-improve poisonous substance to drain;

-prevent or reduce the toxic effect to bringing into play mitochondrial respiratory chain effect.

8. the sodium dimercaptopropanesulfonate of following formula is in the purposes of preparing in medicine,

Wherein said medicine is poisoning for what prevent to be caused by least one toxic component, and described toxic component is selected from methanol and ethylene glycol.

9. purposes according to Claim 8, is characterized in that giving described medicine through intestinal.

10. according to the purposes of claim 9, it is characterized in that described medicine is used as the poisoning special antidote that prevention is caused by described at least one toxic component.

11. according to the purposes of claim 10, it is characterized in that giving described medicine through intestinal.

12. according to the purposes of claim 9 and 11 any one, and wherein said is to realize by application peroral dosage form through intestinal.

13. according to Claim 8, the purposes of 9,10 and 11 any one, it guarantees to obtain at least one effect relevant to the risk of poisoning appearance, it is selected from:

Appearance or development that prevention may enter at it acute or subacute poisoning causing in biological process by poisonous substance;

The appearance of the chronic or chronic poisoning in Asia that prevention causes in using repeatedly or regularly containing the liquid of alcohol or the process of alcohol succedaneum or reduce its speed of development, the poisonous substance that described liquid contains inferior toxicity dosage;

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

Increase the threshold level of the toxicity that concentrates;

Affect concentration coefficient to reduce the toxicity that concentrates;

Affect concentration coefficient to such an extent as to reduce the amount of poisons in brain;

Reducing poisonous substance exposes;

Reduce the biological sensitivity to poisonous substance;

In the process of its premorbid damage, strengthen liver and kidney function of detoxification;

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