RU2285523C2 - Method for treatment of chronic intoxication with heave metals - Google Patents

Abstract

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

Description

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, heavy metal intoxication can be professional and cause occupational pathology in the human body, and can also occur in places of contamination with heavy metal salts and cause the so-called ecopathology. Treatment of occupational pathology and ecopathology has its own specificity, which consists in the fact that in addition to the use of general pharmacological drugs (symptomatic), it is necessary to introduce drugs that eliminate toxic metals and at the same time reduce the severity of the course and the manifestation of intoxication. Complex-forming pharmaceuticals are used in medicine as such drugs that accelerate the excretion of heavy metals in acute and chronic poisoning (M.D. Mashkovsky, 2002, 237 pp. VIDAL, 2002, 307 pp.). The most used complexing pharmaceutical preparations for these purposes, otherwise called chelators, antidotes, are: tetacin (disodium salt of ethylenediaminetetraacetic acid), pentoxyl (4-methyl-5-hydroxymethyluracil, DTPA), penicillamine (D-3,3-dimethylcysteine) , succimer (trimercaptol), which help to accelerate the excretion of lead, mercury, antimony, cadmium, cesium, etc. ions from the body. These complexing drugs form stable complexes with metals that are usually well soluble in water and the formation of the body relatively quickly excreted in the urine.

However, these complexing pharmaceutical preparations can have an adverse effect on the body, especially on the function and parenchyma of the kidneys, even fatal. Long-term use of these drugs can cause excessive elimination of trace elements from the body, allergic reactions, lower levels of calcium in the blood, and disorders of the gastrointestinal tract. In addition, soluble complexes with tetacin can be absorbed from the gastrointestinal tract, increasing intoxication, and therefore this drug is often used by intravenous administration. The most vulnerable organs in acute and chronic heavy metal poisoning are the kidneys, since it is through the kidneys that the main amount of heavy metal ions entering the body is excreted (food, water, air). The most toxic of heavy metals are Pb, Cd, Hg, Cr, As.

In the experiment and in clinical conditions, it was found that prolonged intake of small doses of these metals in the body leads to damage to the epithelium of the proximal tubules of the nephron, impaired function and the formation of interstitial nephritis (Furness WR, Rainbow PS // 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, N4, p. 527-537; Leonard A., Lauwerys RR // Carcinogenecity and mutagenecity of cromium / Mutant Res., 1980, 76, p. 227-239; Wilhelm M., Lomberk J., Kouras V. // Dietary intakes of As, Cd, Pb and Hg by german children // Int. Congress Envirom.Med, 1994, p.208-215; Weden RP // Environmental renal disease: Pb, Cd and Balkan nephropathy // Kidney Int., Suppl. 1991, v. 34, p. 84-88).

In connection with these shortcomings of known drugs, the search continues for new effective low-toxic drugs for the treatment of chronic intoxication with heavy metals in occupational and ecopathological conditions. Such low-toxic effective drugs include the pharmaceutical preparation xidifon (K +, Na + hydroxyethylidene bisphosphonic acid salt). This drug is used to treat disorders of calcium metabolism, for the treatment of econephropathy (hematuria, interstitial nebritis) in children from a region contaminated with salts of heavy metals (cadmium, lead, chromium, arsenic) (Trukhina O.N., Abstract of Cand. Diss., M., 1993, 23 pp.). To remove heavy metals, xidiphone is prescribed at the rate of 10 mg / kg weight per day. However, the use of one xidifon, which belongs to the category of soft complexing agents / To _mouth 5-10 /, according to the known scheme is not enough to eliminate the maximum amount of heavy metals and does not completely eliminate all signs of intoxication. For the same purposes, the drug succimer is used, which has other trade names (Chemet, trimercaptol, manufactured by Johnson and Johnson, USA). Succimer is used mainly in acute poisoning with heavy metals (mercury, lead, cadmium, chromium) in a dose of 200-300 mg per day.

A similar effect of both drugs on the excretion of heavy metals was established: after 7 days of treatment, children from the contaminated region with eco-nephropathy noted an increase in urinary excretion of arsenic, chromium, antimony, cadmium, more pronounced when using a succimer. However, in children who received one succimer, pathological changes in the urine remained, in contrast to patients who received one xidiphone (Trukhina O.N., Avtoref.kand.diss., M., 1993, 23 pp.).

Thus, the use for one purpose of one xidiphone, which belongs to the category of “soft” complexing agents (K _mouth 5-10), in some cases may be insufficient to eliminate the maximum amount of heavy metal and eliminate signs of intoxication, and the use of only a succimer is possible only in short courses and undesirable long-term use due to side effects on liver function, etc. To eliminate the above drawbacks, increase the effectiveness of treatment and reduce the risk of complications in the treatment of chronic heavy metal intoxication in patients with occupational pathology and ecopathology, a method has been developed for the treatment of heavy metal intoxication by phasing in the patient first with xidiphone and then with a short intermittent course of a complexing pharmaceutical with a stability constant at the level of resistance 15-20, according to the following scheme: xidiphon is introduced in the form of a 2% solution at the rate of 10-20 mg per kg of mass for of 21-30 days, and then followed by intermittent administered in therapeutic doses of complexing pharmaceutical formulation a stability constant at 15-20 for 2-7 days. The duration of treatment within the specified limits depends on the clinical manifestations of intoxication. As a complexing pharmaceutical preparation with a high complexation constant (15-20), such preparations as succimer, tetacin, pentacin, penicillamine are used, which does not limit the use of other strong complexing agents according to the new scheme (in 2 stages). An essential feature of the new method for the treatment of chronic heavy metal intoxication in patients with occupational pathology and ecopathology is a certain sequence of administration of previously used drugs, which allows a course of treatment of chronic heavy metal toxicity with a minimal side effect, while reducing the dose and duration of taking strong complexing agents that have sufficiently strong side effects effects. To illustrate the efficacy and safety of a new method of treatment that reduces the risk of complications compared with a single-stage continuous method of treating chronic intoxication with heavy metals, examples are described that describe the new method, and for comparison, known methods of treatment with only xidiphone and only a strong complexing agent on the example of a succimer. The use of a complex-forming pharmaceutical preparation with a low stability constant - xidiphone, the so-called “soft” complexing agent in vivo and / or in vitro at the first stage, provides the removal of weakly fixed heavy metal ions, and also provides a membrane-stabilizing effect on the kidney tissue, which is confirmed by additional studies, proving the eliminating effect of xidiphon on lead ions fixed on protein molecules placed on silicon substrates after incubation in creates acetic acid lead.

A Ce-ATPase-based film deposited on a silicon substrate together with a phospholipid is used as a model system. Using the method of standing x-ray waves and using an atomic force microscope, the location of lead ions on organic molecules (enzyme phospholipid) was determined before and after incubation with lead, as well as after the eliminating effect of xidiphone. The method is based on the simultaneous measurement of x-ray reflection and the intensity of the output of fluorescent radiation arising from inelastic scattering of x-rays. The method used makes it possible to directly determine the location of heavy metal ions inside a molecular film. Xidiphon was found to efficiently remove labile bound lead ions fixed by Ca-ATPase functional (SH) groups during pre-incubation in a solution of acetic acid lead. In places of stronger binding (the active center of Ca-ATPase molecules), lead ions were inaccessible to the action of the bisphosphonate. The research results also show that after preliminary incubation of Ca-ATPase with xidiphon, lead ions do not integrate into protein molecules. The results obtained allow us to conclude that the use of xidiphone bisphosphonate provides massive, but not complete removal of lead ions, fixation on Ca-ATPase molecules. Due to its complexing properties, xidiphone removes easily fixed lead ions by binding them to water-soluble chelate complexes, which are then removed by subsequent washing of the sample. In places of stronger binding (the active center of the Ca-ATPase molecule, located at the lower boundary of the film), lead ions are inaccessible to the action of xidiphon, which necessitates the use of stronger complexons in the second stage.

An additional positive effect of xidiphone was revealed: it turned out that a protein incubated with xidiphone and subsequently immobilized on a silicon substrate coated with a DPPE phospholipid monolayer does not bind lead, which is possibly due to the screening (protective) effect of xidiphone molecules attached to the protein molecule.

The invention is illustrated by the results of specific studies below on the example of the total sequential use of complexing pharmaceutical preparations: xidiphon (a “soft” complexing agent) and succimer (a “strong” complexing agent) - (in vivo) in children with eco-nephropathy from a region contaminated with heavy metal salts.

Xidiphon and succimer were used in different groups of sick children with standard course treatment periods, including for xidiphon within 21, 30 days, and for succimer within no more than 7 days (within 2, 4, 7 days). To compare the effectiveness of the 2-stage treatment method with the consecutive use of xidifon and suzimer, as well as the 1-stage method of using complex-forming pharmaceutical preparations, studies were conducted of the dynamics of excretion of heavy metals in each individual case, shown in Table 1.

Table 1.
Dynamics of excretion of heavy metals in urine in children with econaphropathy with succimer and xidiphone for 7 days. Drug groups Arsenic, μg / L Chromium, mcg / l Antimony, mcg / l Cadmium μg / L Xidiphon before lay down. 0 1.1 ± 0.1 0.2 ± 0.0 0.01 ± 0.001 (n = 20) after lying down. 1.1 ± 0.1 2.2 ± 0.1 0.5 ± 0.1 0.01 ± 0.001 Succimer to lay down. 3.5 ± 0.1 1.8 ± 0.2 0.5 ± 0.1 0.01 ± 0.001 (n = 20) after lying down. 13.2 ± 1.2 3.6 ± 0.3 1.0 ± 0.1 0.02 ± 0.001 p 1-2 <0.001 <0.001 <0.001 > 0.05 p 3-4 <0.001 <0.001 <0.001 <0.001

When studying the excretion of metals with urine in dynamics on days 2, 4, 7 of treatment, when it was shown that the largest amount of heavy metals, including lead and chromium, was released on the second day after the start of treatment, a more pronounced effect was observed with the use of a succimer. Subsequently, the elimination of heavy metals decreased to normal or to initial values.

A characteristic effect is observed in the group of children (16) receiving xidiphone for 21 and 30 days. At the beginning of the treatment process, there is an increase in the elimination of lead, chromium and aluminum (second and fourth days of treatment). By the end of treatment, there is no increased excretion of both heavy and essential (iron, copper, zinc) metals in the urine. The appointment of a succimer in this group of children for 4 days in a therapeutic dose leads to a significant increase in the excretion of arsenic, chromium, lead, aluminum and a moderate increase in zinc excretion on the second day after taking the succimer, and a decrease in the excretion of these elements on the fourth day of treatment, which indicates additional mobilization firmly fixed heavy metal ions in the second stage of treatment with complexing pharmaceutical preparations (see table 2).

Table 2.
Excretion of elements with urine using a two-stage method for the use of complexing pharmaceutical preparations. Metals Mg Cr Si Cu As Pb Zn Al Fe Preparations Xidiphone 11.0 0.8 1.9 next 0 0.3 0.15 4,5 0.1 21 days of treatment 30 days of treatment 17.0 1,1 2,4 next 0 0.5 0.29 7.0 0.2 Stage I Succimer 2 stages 31,0 2,53 4.7 0.04 1,1 1.7 0.43 10.8 0.41 2 day of treatment 4th day of treatment 23.0 1.35 3.2 next 0,03 1,0 0.3 6.5 0.3 7 day of treatment 13.0 0.5 2,5 next next 0,03 next 3,7 0.01

Claims (3)

1. A method of treating chronic intoxication with heavy metals by introducing complex-forming pharmaceutical preparations into the patient’s body, characterized in that the treatment is carried out in 2 stages, and at the first stage, the drug xidiphone is administered at a rate of 10-20 mg per 1 kg for 21-30 days mass per day, and at the second stage, a complex-forming pharmaceutical preparation with a stability constant of 15-20 is administered in therapeutic doses in a fractional course for 2-7 days. 2. The method according to claim 1, characterized in that the succimer is preferably administered as a complexing pharmaceutical preparation at the 2nd stage. 3. The method according to claim 1, characterized in that the course of treatment is repeated after 3-4 months.