Method for treatment of chronic intoxication with heave metals

FIELD: medicine, toxicology.

SUBSTANCE: treatment is carried out for 2 steps wherein in the first step the preparation xydofone is administrated in the dose 10-20 mg per kg of body mass per 24 h by continuous course for 21-30 days, and in the second step the chelate-forming pharmaceutical preparation with the stability constant 15-20 is administrated in the therapeutic doses by fractional schedule for 2-7 days. Invention promotes to the complete elimination of heavy metal salts from the body due to weakly or strongly fixed ions of heavy metals providing by the successive administration of xydofone and the chelate-forming pharmaceutical preparation, and provides membrane-stabilizing effect on renal tissues that, in turn, prevents arising possible iatrogenic complications. Invention can be used in treatment of chronic intoxication with heavy metals.

EFFECT: improved and enhanced effectiveness of treatment.

3 cl, 2 tbl

 

The invention relates to medicine, in particular to toxicology, and can be used in the treatment of chronic intoxication with heavy metals.

As you know intoxication with heavy metals can be professional and call in the body of the occupational diseases, and may also occur in areas of contamination with salts of heavy metals and cause the so-called ecopathology. Treatment of occupational and environmental pathology has its own specifics, which is that in addition to the generic pharmaceutical medications (symptomatic), you must enter the drugs that are toxic metals and at the same time reducing the severity and manifestation of intoxication. As such drugs, which accelerates the removal of heavy metals in acute and chronic poisoning, medicine used complexing pharmaceuticals (Medmaravis, 2002, 237 S. VIDAL, 2002, 307 S.). The most commonly used for these purposes complexing pharmaceutical drugs, also called chelators, antidotes are: tetatsin (disodium salt of ethylenediaminetetraacetic acid), pentoksil (4-methyl-5-oximetery, DTPA), penicillamine (D-3,3-dimetiltsistein), cuprinol, succimer (dimercaprol)that accelerate the excretion of ions of lead, mercury, antimony, cadmium, cesium and other Data complexing drugs form with metals stable complexes, which are usually soluble in water and in the formation in the body relatively rapidly excreted in the urine.

However, these complexing pharmaceutical drugs can have adverse effects on the body, especially on the function and the parenchyma of the kidneys, even to death. Prolonged use of these drugs may cause excessive excretion of trace elements, allergic reactions, reduce the level of calcium in the blood, disorders of the gastrointestinal tract. In addition, soluble complexes with titatinum can be absorbed from the gastrointestinal tract, increasing intoxication, and therefore this drug is often used with intravenous administration. The most vulnerable organs in acute and chronic poisoning with heavy metals are the kidneys, as it is excreted through the kidneys, the basic amount entering the body of heavy metal ions (food, water, air). The most toxic of the heavy metals are Pb, Cd, Hg, Cr, and As.

In experiments and in clinical trials it was shown that prolonged intake of small doses of these metals in the body leads to damage of the epithelium of the proximal tubules of the nephron, the violation of their functions and to forerunnerle jade (Furness W.R., Rainbow P.S.// Heavy metals in the marine enviroment// CRC Press Inc. Boca Raton, Florida, 1990; Kahan E., Derazne E., Rosenboim J. Adverse health effects in workers exposed to cadmium// Amer.J.Ind.Med., 1992, v.21, No.4, p.527-537; Leonard A., R.R. Lauwerys// Carcinogenecity and mutagenecity of cromium/ Mutant Res., 1980, 76, p.227-239; M. Wilhelm, Lomberk J., Kouras Century// the Dietary intakes of As, Cd, Pb and Hg by german children// Int. Congress Envirom.Med, 1994, p.208-215; Weden R.P.// Environmental renal disease: Pb, Cd and Balkan nephropathy// Kidney Int., Suppl. 1991, v.34, p.84-88).

In view of these disadvantages of the known drugs continues the search for new efficient low-toxic drugs for the treatment of chronic intoxication with heavy metals in occupational and egiptologicheskih States. Such low-toxic effective drug is a pharmaceutical preparation xidian (K+, Na+ salt oxyethylenenitrilo acid). This medication is used to treat disorders of calcium metabolism, for the treatment of exonerate (hematuria, interstitial unshaven) in children from the region that has been contaminated by salts of heavy metals (cadmium, lead, chromium, arsenic) (Trukhina O.N., Abstract. Kida. Diss., M., 1993, 23 C.). For removing heavy metals xidian appoint a rate of 10 mg/kg of body weight per day. However, the application of one califona related to the category of soft complexing agents /Kmouth5-10/, well-known scheme is not enough to eliminate the maximum amount of heavy metals and does not completely eliminate all of the prize is like intoxication. For these purposes the drug succimer with different trade names (Chemet, dimercaprol, produced by Johnson and Johnson, USA). Succimer is mainly used in acute poisoning with heavy metals (mercury, lead, cadmium, chromium) in a dose of 200-300 mg per day.

Has a similar effect of both drugs on the excretion of heavy metals: after 7 days of treatment in children from the contaminated region with econephropathy marked increase in excretion with urine arsenic, chromium, antimony, cadmium, more pronounced when using succimer. However, in children receiving one succimer remained pathological changes in the urine, in contrast to patients receiving one xidian (Trukhina O.N., Autoreponders., M., 1993, 23 C.).

Thus, the use for these purposes, one califona classified as "soft" complexing agents (Kmouth5-10), in some cases, may not be sufficient to eliminate the maximum number of heavy metal and the elimination of signs of intoxication, and use only succimer only possible short courses and undesirable long-term use because of side effects on liver function, etc. To eliminate the above disadvantages, improve patient outcomes and reduce the risk of complications in the treatment of chronic intoxication with heavy metal is lame in patients with occupational diseases and ecopathology developed a method for the treatment of intoxication by heavy metals phased introduction into a patient first califona, and then intermittent short course complexing a pharmaceutical preparation with a stability constant of at 15-20, according to the following scheme: introducing xidian in the form of 2%solution at a rate of 10-20 mg per kg of body weight within 21-30 days and then subsequent intermittent course administered in therapeutic doses complexing pharmaceutical drug with the stability constant of 15-20 within 2-7 days. The duration of treatment in these limits depends on the clinical manifestations of intoxication. As complexing pharmaceutical preparation with a high complexation constant (15-20) used drugs such as succimer, tetatsin pentatsin, penicillamine, which does not limit the use of other strong complexing agents in the new scheme (in 2 stages). The essential feature of the new method of treatment of chronic intoxication with heavy metals in patients with occupational diseases and ecopathology is a specific sequence of introduction of previously used drugs, allowing fewer side effects to treatment of chronic intoxication with heavy metals, reducing the dose and duration of reception of strong complexing agents having a strong enough side effects. To illustrate the effectiveness and safety of a new JV is soba treatment, reducing the risk of complications compared with one-stage continuous method for the treatment of chronic intoxication with heavy metals, examples, describing the new method, and to compare the known methods of treatment only califona and only the strong complexing agents for example succimer. The use of complexing a pharmaceutical preparation with a low stability constant of - califona, the so-called "soft" komleksoobrazovateli in vivo and/or in vitro in the first stage, ensures that the removal of poorly fixed ions of heavy metals, and also provides a stabilizing effect on renal tissue, which is confirmed by additional studies proving eliminating the effect of califona ions of lead, attached to protein molecules placed on a silicon substrate after incubating them in a solution of acetic acid lead.

As a model system used film-based CE-ATPase deposited on a silicon substrate together with the phospholipid. By the method of x-ray standing waves and using the atomic force microscope to identify the location of lead ions on organic molecules (enzyme-phospholipid) before and after incubation with lead, and after eliminating actions califona. The method is based on the simultaneous measurement of rents Nevskogo reflection and output intensity of the fluorescent radiation, occur in the inelastic scattering of x-rays. The method used allows to directly determine the location of heavy metal ions inside the molecular film. Found that xidian effectively removes labile associated ions of lead, fixed functional (SH-) groups of CA-ATPase in the process of inactivated in a solution of acetic acid lead. In places that are more durable binding (active center of the molecule of CA-ATPase) of lead ions was not available for the action of bisphosphonates. The research results also show that after pre-incubation of CA-ATPase with califona of lead ions are not embedded in the protein molecule. The obtained results allow to conclude that the use of bisphosphonates califona provides massive, but not complete removal of lead ions, the fixation of the molecules of CA-ATPase. Due to its complexing properties xidian removes easily fixed of lead ions by binding them into water-soluble chelate complexes, which are then removed followed by washing of the sample. In places that are more durable binding (active center of the molecule of CA-ATPase located at the bottom of the film) of lead ions unavailable for califona that necessitates the use of more powerful chelating agents on the second this is that is

Identified additional positive effect of califona: it turned out that the protein proskurovsky with califona and further immobilized on a silicon substrate covered by a monolayer of phospholipid DPPE, tie a lead that may be due to screening (shielding) effect attached to the protein molecule molecules califona.

The invention is illustrated by the following results of specific studies on the example of total consistent application of complexing pharmaceutical drugs: califona (soft complexing agents) and succimer ("strong" complexing agents) - (in vivo) in children with econephropathy from the region that has been contaminated by salts of heavy metals.

Califon and succimer applied in different groups of patients children with the standard course duration of treatment, including for califona within 21 30 days, and for succimer within not more than 7 days (for 2, 4, and 7 days). To compare the effectiveness of 2-stage treatment with the consistent application of califona and sucker, and 1-pass method complexing pharmaceuticals were studies of the dynamics of excretion of heavy metals in each case, reflected in table 1.

Table 1.

Dynamics of excretion of heavy metals in urine in children with ecoproperty when applying succimer and califona within 7 days.
Drug groupArsenic, ág/lChromium, ug/lAntimony, ug/lCadmium, ug/l
Xidian to Leche.01,1±0,10,2±0,00,01±0,001
(n=20) after Leche.1,1±0,12,2±0,10,5±0,10,01±0,001
Succimer to Leche.3,5±0,11,8±0,20,5±0,10,01±0,001
(n=20) after Leche.13,2±1,23,6±0,31,0±0,10,02±0,001
p 1-2<0,001<0,001<0,001>0,05
p 3-4<0,001<0,001<0,001<0,001

In the study of the excretion of metals with urine in the dynamics of 2, 4, and 7 days of treatment, when it is shown that the largest number of heavy metals, including lead and chromium, were allocated on the second day after the start of treatment, a more pronounced effect was observed when applying succimer. Further elimination of heavy metals, smijalasia norm or baseline values.

The typical effect is observed in the group of children (16), the receiving xidian for 21 and 30 days. At the beginning of the treatment process is an increase in the elimination of lead, chromium and aluminum (the second and fourth days of treatment). By the end of the treatment has not been excessive in both heavy and essential (iron, copper, zinc) metals in the urine. The purpose of this group of children succimer for 4 days in a therapeutic dose causes a significant increase in excretion of arsenic, chromium, lead, aluminum and moderate increase in the excretion of zinc on the second day after receiving succimer, and reduced excretion of these elements on the fourth day of treatment, which suggests additional mobilization firmly fixed ions of heavy metals on the second stage of treatment complexing pharmaceutical drugs (see table 2).

Table 2.

Excretion of elements with urine when using a two-step application method complexing pharmaceuticals.
MetalsMgCrSiCuAsPbZnAlFe
Drugs
Xidian11,00,81,9CL.00,30,154,50,1
the 21-day treatment
30 days of treatmentof 17.01,12,4CL.00,50,297,00,2
Stage I
Succimer,
phase 231,02,53the 4.70,041,11,70,4310,80,41
day 2 of treatment
4 day treatment23,01,353,2CL.0,031,00,36,50,3
7 day treatment13,00,52,5CL.CL.0,03CL.3,70,01

1. The method of treatment of chronic intoxication with heavy metals introduction into a patient complexing pharmaceutical preparations, characterized in that the treatment is carried out in 2 stages, and the first step in a continuous course within 21-30 days to introduce the drug xidian at the rate of 10-20 mg per 1 kg of body weight per day, and in the second phase, fractional-rate within 2-7 days is administered in therapeutic doses complexing pharmaceutical drug with the stability constant of 15-20.

2. The method according to claim 1, characterized in that as a complexing pharmaceutical drug on the 2nd stage is preferably introduced succimer.

3. The method according to claim 1, characterized in that the treatment is repeated after 3-4 months.



 

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EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

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12 cl, 5 tbl, 9 dwg

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EFFECT: enhanced effectiveness of treatment.

1 tbl

FIELD: veterinary.

SUBSTANCE: claimed preparation contains (mass %): disodium or dipotassium salt of ethylenediamine-N,N'-disuccinic acid 15.0-35.0; iron (III) 0.6-4.0; manganese (II) 0.5-2.5; copper (II) 0.05-0.25; zinc (II) 0.3-2.5; cobalt (II) 0.005-0.05; selenium (IV) 0.01-0.03; iodine (I) 0.03-0.08; vitamins: A 0.006-1.2; D3 0.00006-0.0015; E 0.1-3.5; B1 0.005-0.2; B2 0.01-0.25; B3 0.02-0.03; B4 5.5-20.0; B5 0.04-1.4; B6 0.005-1.2; and balance: water.

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6 cl, 6 tbl

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