CHEMICAL IOTERAPEVTYCHESKY MEANS — the pharmaceuticals which are selectively suppressing in a human body development and reproduction of causative agents of infectious diseases and invasions or oppressing proliferation zlokachestvenno of the regenerated cells of an organism or it is irreversible the damaging these cells.
20 century undertaken at a boundary many researchers, including R. Koch, E. Bering, etc., attempts of destruction of causative agents of infectious diseases in an organism of the patient by the principle of «internal disinfection», i.e. by means of chemical substances, the killing microbes in a test tube, were unsuccessful because of the expressed toxic effect of the offered drugs on a macroorganism. Emergence of chemotherapy is connected with a name of P. Ehrlich who laid its scientific foundation. He considered that selective fixing of this drug or products of its transformation on a microorganism shall be a fundamental unit in the mechanism of effect of each chemotherapeutic drug («a magic bullet»). As a theoretical basis of search of chemotherapeutic means P. Ehrlich offered the principle of a chemical variation: creation in their
way of modification of any initial molecule of substances, properties to-rykh change according to replacement of one radicals with others. On this basis he after the long-term researches created the drug «606» (salvarsan) which is killing in an organism of animals and the person of trypanosomes, pale spirochetes and some other pathogenic microorganisms and a little influencing cells of a macroorganism (see. Antisyphilitic means). Then there were other drugs of arsenic — Novarsenolum (see), Myarsenolum (see) etc., having the expressed therapeutic effect at syphilis, a typhinia, a frambeziya, a malignant anthrax and other diseases. In 1907 — 1908 in a wedge, practice the drugs of antimony, at first in the form of the potassium antimonyl tartrat which was widely applied to treatment of leyshmanioz, shistosomoz and other parasitic diseases were administered (see Antiparasitics). Further less toxic drugs of antimony — stibozan and Solusurminum were created (see).
In 1935 — 1936 G. Domagk as chemotherapeutic means offered the first sulfanamide drugs (see) which appeared highly effective remedies inf. the diseases caused by bacteria — pneumococci, streptococci, meningokokka, etc. Quantum leap in creation of chemotherapeutic means and in development of chemotherapy was discovery of penicillin by A. Fleming (1929), and R. Du-bos and R. D. Hotchkiss in 1939 — gramicidin and tyrothricin. In 1940 after development of technology of receiving penicillin by G. Florey and Cheyn (E. V. of Chain) the era of antibiotics (see) — the most effective and the most often applied in a crust, time of chemotherapeutic means began.
As X. villages use various substances of a natural origin — antibiotics (see) and nek-ry alkaloids (see), napr, quinine and emetine, and also synthetic substances from different classes of chemical connections — streptocides (see. Sulfanamide drugs), derivatives of nitrofuran (see Nitrofurans), 8 oxyquinoline, nitroimide-ashes, aminoquinoline, etc.
Due to the basic distinctions between infectious and tumoral processes of X. the villages applied to specific treatment of malignant tumors and leukoses allocate in special group of antineoplastic funds (see).
The main criterion, according to Krom these or those substances carry to X. the page, is their ability to have direct effect on causative agents of the infections and invasions which are in internal environments of a human body. In this regard to X. pages do not carry a vaccine (see), bacteriophages (see), serums (see), gamma-globulins (see Immunoglobulins), and also interferona (see Interferon) and other substances produced by cells of a macroorganism participating in immune responses and thereof exerting indirect impact on life activity of microorganisms. To H.s. do not carry also antimicrobic and antiparasitic substances applied for the purpose of influence on the activators which are localized on a body surface or in the Wednesday surrounding the person i.e. used for an asepsis, antiseptics and disinfection. Such substances make group antiseptic and desinfectants (see. Antiseptic agents, Desinfectants). Unlike H.s. they have no selectivity of action in this connection the majority of antiseptic agents and disinfecting substances has high toxicity for a human body that is the main obstacle for their use as X. page. It especially clearly comes to light during the comparison of a chemotherapeutic index (the relation of the most tolerable dose to minimum effective dose) of X. page and antiseptic agents. At the vast majority of antiseptic agents the chemotherapeutic index is close to unit, and at X. the page — considerably exceeds unit. It follows from this that unlike X. page at antiseptic agents selectivity of action is extremely low or in general is absent. Besides, unlike the antiseptic agents having activity concerning absolute majority of microorganisms, X. pages have rather narrow action spectrum (preferential influence on these or those bacteria, fungal flora, viruses etc.).
Uniform conventional classification of X. there is no page. From the practical point of view of X. it is convenient to page to classify taking into account a range of antimicrobic action. On this sign among X. pages can be allocated drugs with preferential antibacterial, antiparasitic, antifungal, antiviral action etc. In turn, in nek-ry of these groups X. pages depending on specifics of use allocate the relevant subgroups. E.g., from among antibacterial X. villages in separate groups allocate antituberculous remedies (see) and antisyphilitic means (see). Antiparasitics
(see) can be conditionally divided on antimalarial (see. Antimalarial means), anti-amoebic, antimecotic (see. Antimecotic means) etc.
Mechanism of action separate X. page various. They can influence various elements of a cell of a microorganism — on a cell wall, a cytoplasmic membrane, the ribosomalny device providing intracellular synthesis of protein, nucleinic to - you and the nek-ry enzymes catalyzing formation of the substances necessary for life activity of cells. So, penicillin (see), cephalosporins (see) and Cycloserinum (see) breaks synthesis of a cell wall of microorganisms. The molecular organization and functions of cytoplasmic membranes are broken by polymyxins (see) and nek-ry antifungal antibiotics of half-yen structure — Amphotericinum In, nystatin, levorinum, etc. Synthesis of protein at the level of ribosomes antibiotics of group of aminoglycosides oppress (see Antibiotics, t. 10, additional materials), levomycetinum (see), tetracyclines (see). Synthesis and functions nucleinic to - t in microorganisms break Rifamycinums (see), griseofulvin (see), Ethambutolum, (see), Chingaminum (see). Ability to influence exchange of DNA nek-ry antiviral means (see), napr, idoksuridin and a vidara-bin have. Row X. the page works by the principle of antimetabolites. So, sulfanamide drugs are competitive antagonists of paraben (see) and replace it in processes of synthesis of the folic acid (see) participating in synthesis of purines and pyrimidines. The mechanism of action of Chloridinum and Trimethoprimum is connected with inhibition of a digidrofolatreduktaza, edges are catalyzed by transformation folic to - you in tetrahydrofolic to - that. Used as X. page drugs of bismuth, napr, biyokhinol (see), Bismoverolum (see) and Pentabismolum (see), compounds of antimony — I salt-surjmin (see), arsenic — Novarsenolum (see), etc., block sulphhydryl groups of various enzymes of microorganisms. Nek-ry X. page from among derivatives of a nit-roimidazol, napr, metronidazole (see) and Tinidazolum, increase the redox potential of cells. Explain these high activity of the specified drugs concerning a number of activators anaerobe bacterias — dysenteric amoebas, lyambliya, trichomonads and asporous anaerobic bacteria.
During creation new X. pages proceed from the following requirements to them: sharp selectivity of antimicrobic effect in doses (a high chemotherapeutic index), non-toxic for the person; slow development of medicinal stability of microorganisms (see); preservation of high activity in different environments of an organism; optimum pharmacokinetic properties (absorption, distribution, allocation) providing accumulation of X. page in the centers of localization of activators in the quantities sufficient for suppression of life activity of microorganisms, etc. Receiving X. the page, completely conforming to all listed requirements, is extremely difficult and seldom feasible task. In this regard the vast majority existing X. the page has these or those shortcomings, to-rye it is necessary to consider in the course of use of separate drugs.
In medical practice of X. villages widely use for causal treatment of patients inf. diseases (see Chemotherapy), and also for prevention of infections (see Chemoprophylaxis) and sanitation of the lindens which are carriers of nek-ry activators.
In the course of use of X. the page is possible development of their side effect (see. Side effects of pharmaceuticals). All caused by X. the page side effects can be divided into three groups: 1) allergic reactions; 2) the reactions connected with direct toxic action of X. page; 3) the reactions connected with their specific (antimicrobic) action.
Like the majority of other medicines X. pages are chemical connections, alien for a human body, and therefore can act as antigens (see). In character caused by X. pages allergic reactions do not differ from the similar reactions caused by any other drugs are similar displays of a medicinal allergy (see). Symptoms of these reactions are characterized by polymorphism — from an itch, urticaria and other medicamentous dermatitis before the heaviest anaphylactic reactions like a Quincke's disease (see Quincke swelled) and an acute anaphylaxis (see). Complications of this group develop at persons, sensibilized to this or that drug. In this regard for their prevention before appointment of X. it is reasonable to page to establish whether there were in the anamnesis of any allergic reactions to the appointed drug or close to it on structure drugs since to substances of a similar chemical structure the cross allergy, napr, to all drugs of group of penicillin, streptocides etc.
of X usually develops. villages, in addition to specific (antimicrobic) activity, have defined organotropnostyo what is the reason of development of the side effects connected with their direct toxic action on separate bodies. Such effects are typical for separate drugs (e.g., ototoxicity of aminoglycosides, the optic neuritis caused by Enteroseptolum, etc.). Degree of their expressiveness and frequency of emergence in many respects depend on doses, ways of introduction and duration of use of drugs.
The local reactions arising owing to direct irritant action of drugs in the field of their introduction, napr, aseptic abscesses and necroses at intramuscular introduction, phlebitis — are among side effects of this group at intravenous administration, dispeptic frustration — at administration of drugs inside. Refer toxic defeats of separate bodies to the same group of complications or fiziol. systems, napr, neurotoxic, hepatotoxic, nephrotoxic reactions, etc.
Neurotoxic reactions can be shown by mental disorders (quinacrine, Cycloserinum, an isoniazid), defeats of the VIII couple of cranial nerves (aminoglycosides, quinine), an optic nerve (Enteroseptolum, quinine, emetine, etam-
butol), polyneurites (an isoniazid, Cycloserinum, a floor to them X of AI. emetine) etc. Nephrotoxic action is typical for aminoglycosides, polymyxins, streptocides, Amphotericinum In, griseofulvin and nek-ry other drugs. Hepatotoxic properties streptocides, Rifamycinums, tetracyclines, Amphotericinum In, erythromycin have izoiia-zid. Streptocides, levomycetinum, Amphotericinum In, Chloridinum can exert negative impact on a hemopoiesis. At persons with inborn insufficiency glyukozo-6-fos-fatdegidrogenazy in erythrocytes nek-ry X. pages (e.g., quinine, Primachinum) can cause hemolitic anemia.
To the side effects connected with antimicrobic action of X. pages, belong dysbacterioses (see), reactions of a bacteriolysis (see the Bacteriolysis), disturbances of vitamin balance and processes of an immunogenesis. Complications of this group meet only at use of X. pages also do not develop under the influence of the other pharmaceuticals which are not possessing antimicrobic action.
Dysbacteriosis develops owing to disturbance under the influence of X. page normal biol. balances of microflora in an organism. E.g., at suppression antibiotics of a broad spectrum of activity of a saprophytic bacterial flora create conditions for overdevelopment of yeast-like fungi and emergence of candidiases. Such complications do not develop at use of X. page with a limited range of antimicrobic action (e.g., synthetic antitubercular drugs — an isoniazid, etc., antimalarial means, griseofulvin and some other drugs).
Reaction of a bacteriolysis, or Endo ksichesky reaction (reaction of Yari-sha — Gertsgeymera), results from bystry death of activators and allocation from them a large amount of endotoxins. It is shown by the fever, fever, plentiful sweating and nek-ry other symptoms reminding manifestations of endocurrent-sichesky shock. This complication can meet at a number of infections (a typhoid, syphilis, a brucellosis, etc.) in an initiation of treatment active X. page in high doses.
The reason of a vitamin deficiency at use of X. the page most often is suppression of life activity of the intestinal microflora synthesizing a number of vitamins by them — Riboflavinum, a pyridoxine, etc. However nek-ry X. pages can cause hypovitaminoses and at the expense of other mechanisms. So, the isoniazid breaks formation of iiridoksal-phosphate and by that promotes development of signs of insufficiency of a pyridoxine.
At vigorous chemotherapy highly active X. page perhaps so bystry suppression of the activator that at the same time sufficient tension of cellular or humoral immunity does not manage to develop. It is one of origins of a recurrence at nek-ry infections — a brucellosis, a typhoid, etc. Besides, nek-ry X. page, napr, levomycetinum, Chingaminum (see) etc., can have a direct immunodepressive effect.
Bibliography: Kassirsky I. A.
Sketches of rational chemotherapy, M., 1951; Clinical pharmacology, under the editorship of V. V. Zakusov, M., 1978; Navaga and S. M. and Fomin I. P N. Rational antibioticotherapia, M., 1982; P l and N e l e with X. X. and X and r and - t about N about in and A. M. By-effects at an antibioticotherapia, M., 1966; Goodman a. Gilman The Pharmacological Basis of Therapeutics, N. Y., 1980, bibliogr.
V. K. Muratov, V. I. Pokrovsky.