DE2549226A1 - AGENT FOR COMBATING MERCURY, LEAD AND CADMIUM POISONING - Google Patents

Description

DIPL-CHEM. DR. VOLKER VOSSIUS PATENT ADVERTISER

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Dr. Ernst A. H. Friedheim Geneva, Switzerland

"Agent for combating mercury, lead and cadmium poisoning"

Priority: November 7, 1974, Switzerland, No. 14 896/74 October 3, 1975, Switzerland, No. 12 871/75

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The present invention relates to an agent for combating mercury, lead and cadmium poisoning. This Agent contains dimercaptosuccinic acid as an active ingredient, which has the formula HOOC-CH (SH) -CH (SH) -COOH and in the form of optical active isomers, as a racemate or in mesoform. The meso form is technically easiest to manufacture and they is readily suitable for the purposes of the present invention. According to the invention, this acid can also be used in the form of its non-toxic salts, in particular their alkali or alkaline earth salts, preferably sodium, potassium, magnesium or calcium alze can be used. Organic salts, for example with diethylamine or methylglucamine, can also be advantageous be used.

It is already known to use dimercaptosuccinic acid in the form of its antimony complex for the treatment of schistosomiasis to be used (Merck Index, page 982).

It is also known to administer heavy metal poisoning such as mercury, lead and cadmium poisoning to treat complex-forming compounds, i.e. heavy metals from the human body through complex formation with remove such connections. Many parameters play an essential role, such as dissociation constants and complex formation constants of heavy metals on the one hand with body components such as proteins and fats, and on the other hand with compounds capable of forming complexes. In addition, there are tolerance, stability in the human body, elimination possibilities, and many other aspects, such as simple production of the active ingredient and easy galenic processing.

Of the very many theoretically possible complex-forming compounds, only very few are practical up to now been applied.

Known complexing agents, which have already been tested for the elimination of heavy metals from the animal body

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are for example D-penicillamine and CaNa _p -edetate. These known complexing agents have certain disadvantages, in particular for the elimination of mercury, lead and cadmium (eg limited effect on the breakdown of the metal branch, accumulation of metal in certain organs), as will be shown below. Mercury, lead and cadmium can accumulate in a wide variety of organs, including the kidneys, liver and brain. It was therefore necessary to find a means which is particularly effective against this form of poisoning, that is, a means which removes mercury, lead and cadmium from the organs mentioned and can then excrete them via physiological excretions. Dimercaptosuccinic acid and its abovementioned salts are surprisingly outstandingly suitable for this purpose. To date, none of the myriad known complexing compounds have been found to be anywhere near equivalent.

Of the very many theoretically possible mercapto compounds or thiols, only very few are practical up to now been applied. BAL (2,3-Dimercapto-lpropanol) seemed to be the most suitable, but the results were disappointing. By replacing the alcohol group in the BAL with a sulfo group, it became a water-soluble one Compound obtained which showed good results in combating organic mercury poisoning. It is however, it is not known how this compound works against methylmercury poisoning. .

With every mercury poisoning, the mercury in the body is gradually converted into methylmercury, which is can accumulate in the kidney, liver and brain. Dimercaptosuccinic acid and its salts mentioned above are surprising ideally suited to excrete mercury in the above-mentioned way. So far none of the countless mercapto resp. Thiol compounds and found only approximately equivalent.

Dimercaptosuccinic acid and its salts can be administered in any pharmaceutical form. Come into question Pills, tablets, capsules, solutions, suppositories, suspensions in oil and retarder forms in general. Soluble non-toxic

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Salts can be administered parenterally, in particular subcutaneously and intramuscularly, in aqueous solution.

An effective detoxification of an acute or chronic with mercury, lead or cadmium or a mercury, lead or Cadmium compound poisoned person can "administer about 1-5 g of dimercaptosuccinic acid daily in doses of each." about 100-1000 mg can be achieved.

The following Table I shows the results obtained with mice poisoned with mercury compounds by treatment with dimercaptosuccinic acid, (DMS) or D-penieillamine (PA) and without treatment. A test group comprised 5 mice, which on the specified days were poisoned or treated with the specified amounts and then slaughtered. In the last column are those in the kidney or the quantities of mercury found in the kidneys, liver and brain in ppm (parts per million).

TABLE I.

Day 1 2 3 4 5 Hg ppm
in kidney kidney liver brain mg / kg 100 100 100
nWkg mg / kg mg / kg 9.8
16.2
30.2 2.0
2.2
5.8 1.1
1.5
1.6 HgCl ₂ 1.0
1.0
1.0 DMS DMS
FATHER
untreated +
+
+ 8.8
9.1
13.2 HgCl ₂ 0.1
0.1
0.1 DMS DMS
PA m
untreated +
+
+ 2.9
4.0
4.6 CH ₃ HgBr 1.0
1.0
1.0 DMS DMS
FATHER
untreated +
+
+

It can be seen from these results that dimercaptosuccinic acid (DMS) is superior.

The DMS used was based on the Owen

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and Sultanbawa, J. Chem. Soc. 1949, 3109.

The following experiments show the effectiveness of meso-dimercaptosuccinic acid (DMS), D-penicillamine (PA) and CaNa ₃ -edetate (EDTA) against lead and cadmium poisoning in guinea pigs and mice.
A. Lead poisoning in guinea pigs

Three groups of two guinea pigs each were treated as follows:
Day 1-5 Groups I, II and III: 10 mg / kg lead acetate daily

Day 6-8 Group I:
Day 6-8 Group II:
Day 6-8 group "III:

(as a 0.1 l aqueous solution) intramuscularly per animal

250 mg / kg DMS IM daily per animal daily 250 mg / kg PA i.m. per animal no treatment

Day 9 groups I, II and III: no treatment Day 10 groups I, II and III: chloroformation, cardiac puncture,

Autopsy.

The same organs in each group were combined, homogenized and dried at 110 ° C. to constant weight. The lead content was determined in aliquots of the dried material by flameless atomic absorption.

The lead concentrations found in the liver, brain and blood are given in the following table II in % of the lead concentrations that were determined in the untreated control animals * In addition, the absolute lead concentrations that were found in the control animals are given in nanograms / gram dry matter »

TABLE II brain blood liver 100 # $ 100 Control animals $ 100 3.3 0.68) (absolute values in ng / g 50.8 49.5 # 33 # treated with DMS 18.4 <£ £ 87.6 53 # treated with PA 38 pounds

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You can see that guinea pigs with

Lead acetate have been treated, DMS and PA lower the lead concentration in the liver, brain and blood, but DMS is much more effective than PA.
B. Lead poisoning in mice

Four groups of five white mice each were treated as follows:

Day 1-5 each group: daily 10 mg / kg lead acetate (as 0.1 $ lge

aqueous solution) intramuscularly per animal

Day 6-7 Each group: break

Day 8-10 Group I: 10 mg / kg DMS i.m. daily per animal Day 8-10 Group II: daily 10 mg / kg PA i.m. per animal day 8-10 Group III: daily 10 mg / kg EDTA i.m. per animal Day 8-10 Group IV: no treatment Day 10-12 each group: break

Day 13 each group: chloroformation, autopsy.

The same organs in each group were combined, homogenized and ^{dried at HO 0} C to constant weight. The lead content was determined in aliquots of the dried material by flameless atomic absorption.

In the following Table III the results are shown in the same way as in Table II.

TABLE III

Liver kidney brain

Control animals $ 100 $ 100 $ 100 (absolute values in ng / g 51 91 8.0 treated with DMS $ 33.3 $ 43.9 $ 42.5 treated with PA $ 92.1 $ 118.7 $ 102.5 treated with EDTA $ 88.2 $ 79.1 $ 47.5

Under the given test conditions, it was found that DMS and EDTA poisoned the lead content in with lead acetate Degrade mice, with DMS outperforming EDTA. The lead reduction achieved with EDTA is caused by DMS in the liver and kidney roughly doubled and improved by $ 10 in the brain. PA

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causes only a slight decrease in the liver and an increase in the lead content in the kidneys and brain. C. Cadmium poisoning in mice

Four groups of five white mice each were treated as follows:

Day 1-5 each group: daily 10 mg / kg cadmium chloride (as

0, l ^ ige aqueous solution) intramuscularly per animal

Day 6-7 each group: break

Day 8-10 Group I: 100 mg / kg DMS IM daily per animal Day 8-10 Group II: 100 mg / kg PA i.m. daily per animal day 8-10 Group III: daily 100 mg / kg EDTA i.m. per animal Day 8-10 Group IV: no treatment Day 10-12 each group: break

Day 13 each group: chloroformation, autopsy.

Blood was taken by cardiac puncture and the same organs of each group were combined, homogenized and dried to constant weight ^{at 110 ° C.} The lead content was determined in aliquots of the dried material by flameless atomic absorption.

In the following Table IV the results are given in the same manner as in Table II.

TABLE IV

Control animals

(absolute values in ng / g treated with DMS treated with PA

treated with EDTA $ 85 75, i

In mice poisoned with cadmium chloride, only DMS in all three organs examined (liver, Kidney and brain) significantly reduces the cadmlum content. PAhat less effect in the liver and brain and no effect in the kidney. EDTA has little effect on the liver and kidneys, none in the brain.

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liver kidney brain ioo £ 100 # $ 100 48.5 31.0 2.8) $ 53.6 38, 7 # 35.1 % $ 72.0 1005g 60.7 %

For the treatment of mercury, lead and

Cadmium poisoning in humans comes in daily doses of about 1-5 g of dimercaptosuccinic acid, possibly not in the form toxic salts, in question, whereby these daily doses can be divided into individual doses of about IQO to 1000 mg each. Any known galenic form can be used as the form of administration Question.

The funds are not only used to reduce the mercury, cadmium and lead content in those who have already been poisoned Persons. They can also be used prophylactically for people who, professionally or otherwise, are at risk of mercury, Are exposed to cadmium and lead poisoning.

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Claims (2)

Claims 1. Medicinal products to combat mercury, lead and cadmium poisoning, consisting of dimercaptosuccinic acid or its salt with a base and usual carriers and / or diluents and / or auxiliaries. 2. Medicinal preparations according to claim 1, characterized in that that the salt of dimercaptosuccinic acid is an alkali or alkaline earth metal salt or the salt of an organic base, in particular of diethylamine or glucamine. 609820/1018