I.I. Goriushkin  
  - Alcoholism: what is a pathogenetic treatment? A systemic approach
// Zh Nevrol Psikhiatr Im S S Korsakova. 2006;106(4):90-4. Russian
Горюшкин И.И. -  Алкоголизм: что есть патогенетическое лечение? Cистемный подход ( русский ]

          Key words:    alcohol, alcoholism, ALT, alanine aminotransferases, aspartate aminotransferases, AST, drugs, gamma-glutamyltransferase, GGT, inclination, limiting, medicaments, mentation, metabolism, narcology, narcotic, need, neuroleptics, pathogenesis, pathogenetic treatment, pathology, psychiatry, systemic approach, psychopathology, regulation, therapy, transferases

            Goriushkin I.I. [  - I ask to excuse me for my translation from Russian on English. Later I plan will return to correct ]        ______________________________      

      On the basis of the analysis of data of the literature and own examinations affirms (deductions), that:

    1) treatment of an alcoholism should have the purpose - to help patient to recover; but this purpose cannot be reached if not to aspire to pathogenetic therapy of an alcoholism;

   2) increase in blood of alcoholics of activity of aminotransferases: gamma-glutamyltransferase (GGT) and aspartate aminotransferase (AST), - is itself finding out limiting components of alcoholic pathogenesis;

   3) only such therapy of an alcoholism can be termed pathogenetic in which effect there is a normalisation of levels of aminotransferases: GGT, AST and alanine aminotrasferase (ALT).

    The purpose of treatment of an alcoholism - to help the patient to recover. For achievement of this purpose in the up-to-date manuals on treatment of an alcoholism it is underlined necessity of the solution, at least, three problems [27]:
1) remove of available disturbances in mental and somatic spheres;
2) repressing of inclination to alcohol; and
3) formation and maintenance of the equipment on a sober way of life.

    Certainly, in an ideal treatment should correspond also with a stage of an alcoholism, and with accompanying diseases, and with the years the patient [18]. However the prime should be - the termination of the use of narcotic substance and carrying out of disintoxication, fortifying and boosting actions [24]. For success achievement of the realised consent of the patient on treatment, as well as the peak individualization of therapy, and also - its integrated approach (medicamental therapy + psychotherapy + social rehabilitation, including measures on maintenance of remission and prevention of relapses) [12, 13] is important also.

    For the solution of each of these problems or stages existing approaches can be sectioned on medicamental (with use, for example, neuroleptics for cupping of pathological inclination to alcohol) and not medicamental (for example, with use of psychotherapeutic, reflexotherapeutic and other techniques) [14].

    Though always the most correct select would be - etiotropic (eliminating the causes) and pathogenetic therapy if that, of course, exists.

   The purpose of present article - to designate some problems in treatment of an alcoholism and to offer probable approaches to their solution.

   1. The general-metabolic concept of an alcoholism and possibility of pathogenetic therapy

   Pathogenetic therapy, as is known, - the therapy directed on pathological process and the basic pathogenic factors. Whereas symptomatic therapy is intended only for weakening or liquidation of separate implications of illness (without elimination of the cause). Consequently, only pathogenetic therapy is the present treatment. But for it it is necessary to know pathogenesis.

   From positions of the general-metabolic concept - occurrence of an alcoholism and development of the pathology caused by it, is bound to ability of an organism to adapt for presence of alcohol and yields of its metabolism (to acetic aldehyde, etc.) and, thus, to prolong "normally" to function. By numerous examinations for today it is shown, that the destiny of alcohol in an organism is to the greatest degree bound to synthesis of fatty acids and the lipids, mediated through acetyl-KoA - synthetasal reactions [16, 31, 33]. It is natural, that the alcohol used excessively, excessively activates also a lipide exchange [28]. And, first of all, load those components of a metabolism which immediately participate in transformation and "deposition" of fatty acids which are formed of alcohol.

   In the lipide metabolism, bound to salvaging of ethanol, it is easy to understand cause of "intensity" if to consider, that, for example, in 2 stages of an alcoholism the use of alcohol can reach 1-1,5 l. And more than 40 degree vodkas a day [20, 26]. In recalculation on a calorie it makes from 1600 to 2400 kilocalorie, or 50-70 %% the energy spent by the person for day.

   The facts of a hypermetabolism of lipids at an alcoholism, fatty infiltration of a liver and another, have led today to representation, that the mechanism of occurrence of an alcoholic pathology is caused, on the one hand, by "deposition" of fatty compounds in a liver, and with another, - the chemical aggressiveness of acetic aldehyde [19] displayed by intensifying of a free-radical oxidising of lipids [30]

   For the correct estimate of a role of those or other factors in pathogenesis of an alcoholism the problem should be considered "is system". In our case it means, that metabolic processes in an organism are not reduced to something, consisting of collection of ferments, substrates, membranes, genomes, and is - system of elements, each of which is built in certain process, in certain interferences and regulationary relations. By such, system examination of biochemical processes in an organism - the problem of regulation, or guidance becomes the main thing. And, according to laws of guidance (regulation in systems) efficiency of functioning of system as a whole is defined only by its limiting components (processes), i.e. - most its "narrow" places.

   Besides, in biological systems, as a rule, limiting components are allocated by [15] controlling functions. And, unlike not limiting, they prove that in reply to any, "sufficient on force" exterior action (drug, the physical factor) or interior activity (exhaust of neuromediates, hormones, etc.), - "find out themselves". In sense, that "is always torn in that place where it is the most thin", and, in our case - "in that place and it is found out".

   The matter is that in an organism by means of regulationary actions there is an activization, first of all, "narrow" components of system (they - "key position", or "pacemaker"). And it allows them to us and to "find out". Moreover, for the purpose of adaptation (including, and to alcohol), in an organism mechanisms of a derepression of sites of the genome responsible for synthesis "de novo" those ferments which could provide "expansion" of these, "narrow" places in a metabolism are started. Actually, it - is good all the known molecular mechanism of adaptation of an organism, whether it be to alcohol, to acetic aldehyde or to something else to another.

    From system examination of this problem also follows, that though at an alcoholism pathological changes can affect many of biochemical processes, - measures on their elimination (pathogenetic therapy) will be the most effective only in the event that they will be referred on restoration of normal functioning, first of all, limiting components of a metabolism and pathogenesis.

   However, from what follows, what exactly aminotransferases: GGT and AST, - which increase of activity occurs at an alcoholism, and are that "narrow", limiting place in pathogenesis of an alcoholism?

   In, earlier publications [6-9], we, just, in details considered the causes and mechanisms of change of activity of aminotransferases: GGT and AST, - in blood of alcoholics of 1st and 2nd stages. From the analysis of own data and data from the literature followed, that changes of activity of these aminotransferases at an alcoholism reflect the changes occurring in general-metabolic processes of an organism. Also that, consequently, behind the phenomenon of a hyperenzymatic of these aminotransferases general-metabolic pathogenetic mechanisms and alcoholic disease disappear.

   Being grounded on these deductions, and also on basic representation about pathogenesis of an alcoholism as process of gradual adaptation of an organism to an accruing intervention of alcohol in a course of general-metabolic processes [11, 22], we assert, that increase in blood serum of alcoholics of activity of aminotransferases (GGT, AST) are that other as limiting components of alcoholic pathogenesis finding out.

   Consequently, if supposition of a limiting role of aminotransferases GGT and AST in general-metabolic processes of alcoholic pathogenesis - is realistic, pathogenetic therapy of an alcoholism and should consist, first of all (or including), in normalisation of levels of activity of these aminotransferases. Moreover, if aforementioned aminotransferases really limit in pathogenesis of an alcoholism the adequate measures guided on normalisation of activity of these aminotransferases should be, in a certain degree, are sufficient and for "recover" from an alcoholism.

   Considering, that level of activity of the ALT in blood serum is a marker of integrity of cellular membranes of hepatocytes - definition of the ALT, in addition to a GGT and AST, - it is possible to consider also as a necessary measure of the objective control over "a biochemical state" the patient, i.e. - and efficiency of made therapy.

   Certainly, all aforesaid does not mean, that at an alcoholism as illnesses do not exist also other, pathogenetically significant components. However, how much these, others - also "are responsible", i.e. - limit alcoholic pathogenesis (instead of it is simple - accompany)?

   Concerning a problem of treatment of an alcoholism as a whole, unconditionally, it is not necessary to forget, that an alcoholism - also socially caused illness or a problem [4, 5]. And for the part of the population costitutionally predisposed to an alcoholism it also, as though, "voluntary" disease (or, unfortunately, employment). And, consequently, without the social equipments on abstention from abusing alcohol and on the healthy way of life which is approved and encouraged (!) with a society, - any pathogenetic treatment is not able to help the solution of a problem an alcoholism.

    2. "Pathogenetic" intervals of GGT, AST and ALT

   Taking into account the aforesaid it is represented, that use of laboratory biochemical methods could promote acceptance of more objective decisions concerning, whether it is necessary to carry this or that medical influence to pathogenetic or to the symptomatic. As, for the stated causes, from symptomatic agents it is impossible to wait for essential and steady changes in level of activity of the above-stated transferases.

   In the resulted table we present diagnostic intervals of levels of activity of transferases: GGT, AST and ALT, - in blood serum of the alcoholics, received in earlier researches [21-23]. Which, from our point of view, can be offered for an estimation of a pathogenetic orientation of made therapy of an alcoholism, as well as its efficiency.

   The specified intervals represent arithmetic-mean values - the "M" which are paying off for each of ferments in concrete laboratory on group "practically healthy", irrespective of particularly used method.

   The table: Diagnostic intervals of GGT, AST and ALT [21-23]

      State of health:

     Diagnostic intervals in "M"

    Alcoholism is not present, "is practically healthy"

    GGT  0,2 - 1,6
    AST  0,4 - 1,5
    ALT  0,3 - 1,9

    Alcoholism, 1 stage

    GGT >  1,6
    AST  0,6 - 1,8
    ALT  0,7 - 1,9

    Alcoholism, 2 stage

    GGT >  2,4
    AST >  1,8
    ALT  0,9 - 2,2

    Alcoholism, 3 stage

    GGT >  0,2
    AST >  1,8
    ALT >  2,2

    Pathology of a liver (fatty infiltration)

    AST / ALT >  1,7

    Pathology of a liver (cirrhosis, necrosis, active cytolysis; owing to an infectious hepatitis, toxicomania; their combinations to an alcoholism)

    AST / ALT
(as a rule)  < 1

     M -
arithmetic-mean value of activity of ferments in ME (international units), calculated on group "healthy";

     AST / ALT - a ratio

   As is known, group "practically healthy" receive in public to some extent "free from illnesses". It is quite clear, that if cases will get to group of "practically healthy" persons of "household drunkenness" or the initial stages of disease by an alcoholism, use of biochemical parametres of "such normal" (for the purpose of an estimation of efficiency and a pathogenetic orientation of therapy of an alcoholism) can turn out and unproductive.

   Decrease of activity of transferases can be observed and is simple from the termination of the use of alcohol, that - is natural. On the one hand, it will be testifies to a pathogenetic orientation of the most such measure, as the termination of the use of alcohol. On the other hand, it will testify that the alcoholic hepatitis decreases also. Certainly, there will be it only in the event that the chosen treatment for cupping of an abstinence and a measure of detoxicating will be adequate to an alcoholic pathology. If decrease of activity of transferases in blood does not occur, two causes can be fault to it, at least: continuation of the use of alcohol "secretly" or inadequate medical influence.

   For example, it is known, that teturam (disulfiram, antabus), in due time widely used for treatment of an alcoholism, could not only worsen a current of an alcoholic hepatitis but also cause disturbances in a condition of cardiovascular system. Not speaking already - about possibility of occurrence of such complications, as a teturammy hepatitis or a teturammy psychosis [26].

   Confirming to inadequacy of similar schemas of treatment of an alcoholism and expediency of use of transferases as criterion of this inadequacy the facts testify also - at use of the yielded schemas of treatment level of transferases the long time remains raised [34].

   Certainly, at use of transferases for an estimation of a pathogenetic orientation of schemas applied in narcology treatment, it is possible to face and a pathology accompanying an alcoholism. For example, with an acute virus hepatitis (which, as is known, as accompanied by increase of activity of transferases). How correctly to interpret results of changes of activity of transferases in these cases?

   But, first, at entering of the patient in a hospital, even only with suspicion on an alcoholism or any other hepathologic disease differential diagnostics of diseases of a liver, as is known, is obligatoryly made. For what others are used also - laboratory, anamnestic and clinical methods. Secondly, treatment of virus hepatitises, as well as other diseases accompanying an alcoholism, not is, generally, a prerogative of the doctor-expert in narcology. Here again hardly it will be possible to do without the help of the therapist, the gastroenterologist, the hepatologist or the endocrinologist?! Though and - together with the expert in narcology.

   But, even at presence at the alcoholic of an accompanying pathology already fact of absence of normalisation of transferases - will be, that less, "objectively" to testify about not sufficient adequacy of used schemas of treatment. And at such patient, nosologicaly, after all "not absolutely" an alcoholism, and its combination to a virus hepatitis. And it, you see, special disease, anyway, from its metabolic "support". What will demand from the doctor of more creative approach and, perhaps, not absolutely traditional schemas of treatment?!

   Though, on the other hand, likely, it would be not absolutely correct to offer us - definition of transferases in blood at alcoholics - as panacea or replacement to everything existing at the disposal of experts for this purpose, an arsenal of methods and agents. It is thought, that it and is obvious.

    3. And what with neuroleptics?

   All above-stated is based by us on representation about general-metabolic mechanisms of increase in blood of activity of transferases (GGT, AST and ALT) and more has been with deep arguments already considered in our early publications (see, [6,8-11]).

   At the same time, there are numerous facts of that neuromediator and neuroendocrinal systems of a brain are involved in an alcoholism [29,32]. Not casually, thereupon, to changes in the catecholaminny neuromediation, result ining to occurrence of "vicious circle" of hyperfunctioning of dopaminergic structures of a brain by a number of researchers the role of a neurochemical basis of pathological inclination of the person to alcohol [2,12] is taken away.

   Certainly, studying of neurochemical bases of inclination to alcohol is important. However considering a problem of treatment of an alcoholism from positions of systems approach, it is represented, that most "weak component" in pathogenesis, and, consequently, and "target" for pathogenetic treatment should be and general-metabolic processes of a metabolism, immediately or mediationly participating in transformation of alcohol. And as they are most active in a liver, that, in any sense an alcoholism - mainly chronic intoxicationful hepathologic disease.

   At more late stage of development of the alcoholic pathology accompanied, as is known, is more narrow and the expressed psychopathologic symptomatic: a tremens, an alcoholic hallucinosis, an alcoholic encephalopathy (a polyneurotic psychosis, encephalopathy Gaje-Vernike), etc., - psychopathologic problems for an alcoholism become quite actual.

   On the other hand, in activity "narcotized itself" a brain, it is possible and not to see any serious mental pathology. As is known, the brain carries out integration and management of activity of all systems of an organism. And, in case of abusing alcohol, the brain, probably, only "fairly" carries out the reserving: provides satisfaction of needs of an organism. However, now it is new need, continuation of the use of alcohol. But, in physiologic relation, inclination to alcohol has few differences from other, alimentary inclinations [25].

   At the same time, inclination of biological need to satisfaction something - a natural, normal condition. Whether there can be it "pathological"? Likely, can, if it, for example, too strong, or too weak. As well as - in case of full absence of inclination at objectively existing need. But, whether it is probable, in principle, - "distortion" of inclination? That is satisfaction of in what there is no need. Such system, in principle, should not be capable to survive, and, consequently, and to exist.

   Therefore, whether correctly the inclination caused by need to alcohol, to narcotic substances to carry obligatoryly to a category of the pathological? In what, actually, a pathology? After all if there is an addiction on alcohol, means exists in alcohol and need. And inclination - only implication of this need. From biological positions inclination (whether to alcohol, whether to a narcotic or to an opposite sex) - only the vital attribute referring an organism on realisation actualise at present of need. It is the fact.

   In a basis and such, absolutely not so medical, and the social phenomena as criminality (the criminal world), is probably, also lays satisfaction, let and "antisocial", but - needs. Certainly, at desire also it is all it is possible to try to "treat". And, then why, is probably not to try to treat and, say, pathological character of the "pathological" person?! A word - all that from us does not suit someone. Whether only what tomorrow and we not begin not suit someone will be received from this?

   Consequently, more correctly, likely, not to treat it, and socially to control. I.e. - to stipulate socially, stating an estimation to acts, behaviour: punishing or encouraging, condemning or uplifting. Certainly, it is a question of normal, sane individuals, without a genetic predisposition to harmful and self-blasting habits.

   Consequently, has put all that the need for narcotic substances is socially unacceptable need. But, it is unacceptable - excessive need. Therefore as moderated, whether it be drunkenness or a tobacco smoking, you see, does not meet while any serious social counteraction (if only in words).

   However, if the alcoholic pathology can come so far, that change in general-metabolic processes (their disturbance) is available to hope with the help only psychotropic drugs (for example, neuroleptics, tranquilizers) or neurotrops (for example, naltrexone) to solve at least a part of the psychosomatic problems caused by it, - hardly can be convince.

   The matter is that already existing agents for treatment of pathological inclination (and them today more than 150) if have the an effect only in the course of their reception. After the termination - inclination to alcohol, as a rule, arises again [26]. But other result, from application of symptomatic agents of treatment, likely, hardly followed and to expect.

   Certainly, refusal of use of neuroleptics does not mean, simultaneously, refusal and of a psychological and social readaptation of the alcoholic - for the purpose of "reprogramming" of its consciousness which still remains filled with alcoholic senses and valuable orientations [3].

   Insufficient efficiency of purely psychotropic treatment admits today also psychiatrists. For this reason today even more often it is possible to meet on pages of scientific medical editions of attempt to solve a problem of "congestion" psychotropic drugs of patients not only narcological a profile, but also psychiatric [17]. For example, by means of use of such nonconventional method, as a pyrotherapy (a controllable fervescence). By the way, shown high performance even in case of postabstinent therapeutic resistance of pathological inclination to alcohol [1].


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