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1.
Reprod Toxicol ; 15(6): 673-81, 2001.
Article in English | MEDLINE | ID: mdl-11738520

ABSTRACT

Cadmium and progesterone concentrations were evaluated in term placentas collected from 56 healthy parturients in the city of Zagreb. Concentrations of lead, iron, zinc, and copper in placentas were analyzed. Data collected by questionnaire identified 29 nonsmoking and 27 smoking women. From each placenta, three samples from different locations were taken. Metals were measured by atomic absorption spectrometry. Progesterone was determined by specific radioimmunoassay in homogenized and lyophilized tissue samples after steroid extraction with ethanol. No effect of sample location was found. In placentas of smoking women an increase in cadmium, reduced progesterone and a decrease in iron concentrations were found. Placental copper and zinc concentrations were not altered. In conclusion, the results present new evidence that maternal smoking reduces placental progesterone content and support the established association of smoking with placental cadmium.


Subject(s)
Cadmium/metabolism , Placenta/metabolism , Progesterone/metabolism , Smoking/metabolism , Adult , Birth Weight , Body Height , Cadmium/analysis , Croatia , Female , Humans , Infant, Newborn , Male , Maternal Age , Metals, Heavy/analysis , Metals, Heavy/metabolism , Organ Size , Placenta/chemistry , Pregnancy , Pregnancy, High-Risk , Progesterone/analysis , Surveys and Questionnaires
2.
J Appl Toxicol ; 21(5): 415-6, 2001.
Article in English | MEDLINE | ID: mdl-11746184

ABSTRACT

There is a concern that oral treatment with succimer (meso-2, 3-dimercaptosuccinic acid, DMSA) can promote gastrointestinal lead absorption if not performed in a lead-safe environment. The scope of our investigation was to evaluate the efficacy of oral DMSA treatment during oral lead exposure on tissue lead in suckling rats. Six-day-old Wistar rats of both genders were divided into two groups-untreated (Pb) and treated (Pb + DMSA)-with 10 animals per group. Lead (as acetate) was given orally at a dose of 2 mg kg(-1) body weight day(-1) for eight consecutive days (total dose 16 mg kg(-1), i.e. 0.08 mmol kg(-1)). During this period the treated group received a daily dose of 0.5 mmol DMSA kg(-1) body weight p.o. six times on days 1-3 and 6-8 of the experiment (total dose 3 mmol kg(-1)). Tissue lead was determined by means of atomic absorption spectrometry. The DMSA efficiently reduced the lead concentration in the analysed tissues (carcass, liver, kidneys and brain) by approximately 50% compared with untreated controls. The pups' growth and organ weights were not affected. In conclusion, our results indicate that DMSA is an efficient oral lead chelator in sucklings even if challenged with ongoing lead exposure.


Subject(s)
Chelating Agents/therapeutic use , Lead Poisoning/drug therapy , Organometallic Compounds/pharmacokinetics , Organometallic Compounds/toxicity , Succimer/therapeutic use , Animals , Animals, Suckling , Body Weight/drug effects , Female , Male , Organ Size/drug effects , Rats , Rats, Wistar , Spectrophotometry, Atomic
3.
Pharmacol Toxicol ; 89(6): 326-30, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11903960

ABSTRACT

The effect of calcium supplementation on tissue lead was evaluated in suckling Wistar rats. Such data are not yet available in the literature. The following artificial feeding regimen was used for calcium supplementation: cow's milk by addition of 1%, 3% or 6% Ca as CaHPO(4)x2H(2)O suspension to increase the daily calcium intake about 1.4, 2 or 3 times above control values. Artificial feeding was applied during 7 hr each day for nine consecutive days (from day 6 through 15 after birth). The effect of such treatment on lead absorption and elimination was evaluated in two separate experiments: calcium supplementation during oral lead exposure (as acetate; daily dose 2 mg Pb/kg body wt.; total Pb dose 18 mg/kg body wt.) or after a single intraperitoneal lead administration (5 mg/kg body wt.). At the end of experiments, lead in tissues (liver, kidneys, brain and carcass), and essential elements (Ca, Fe, Zn, Cu) were analysed by atomic absorption spectrometry. Calcium supplementation caused a statistically significant decrease of lead in all tissues of sucklings orally exposed to lead. This decrease was dose-related being about 1.3, 1.5 and 2 times lower in groups supplemented with 1%, 3%, or 6% calcium compared to controls, respectively. Increased calcium intake had no effect on incorporated lead after parenteral lead exposure. Calcium supplementation increased carcass calcium and had no effect on trace elements in tissues, pups' general appearance and body weight gain. It is concluded that higher calcium intake might be a way of efficient reduction of lead absorption during the suckling period.


Subject(s)
Calcium, Dietary/pharmacology , Intestinal Absorption/drug effects , Lead/pharmacokinetics , Administration, Oral , Animals , Animals, Suckling , Dose-Response Relationship, Drug , Female , Injections, Intraperitoneal , Male , Rats , Rats, Wistar , Tissue Distribution
4.
Pharmacol Toxicol ; 87(4): 179-81, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11097272

ABSTRACT

A higher efficiency of cadmium binding with racemic than with meso-2,3-dimercaptosuccinic acid (rac-DMSA; meso-DMSA) was found in an in vitro speciation model by Fang et al. (1996). This finding has not yet been tested in vivo. This paper presents results on mobilisation of cadmium by meso- and rac-DMSA in rats. Cadmium chloride was administered as the radioactive isotope 109Cd intraperitoneally to all animals. One group was an untreated control and two groups were treated with meso- and rac-DMSA, respectively. Treatment with chelators was applied twice, immediately after 109Cd and 24 hr afterwards intraperitoneally at the dose of 1 mmol/kg, each. Six days later radioactivity was measured in the liver and kidneys. Whole-body counting was carried out on days 1, 2, 3 and 6 of the experiment. At the end of the experiment, both treatments caused a decrease in 109Cd whole-body retention with rac-DMSA being more efficient (decrease from 83% in control to 74% and 64% in groups treated with meso- and rac-DMSA, respectively). The same reduction of 109Cd was obtained by both chelators in the liver (from 57% to about 47%). In the kidney only rac-DMSA produced significant reduction of 109Cd (from 5.3% to 3.5%). In conclusion, these results show modest reduction of cadmium in the body by two isoforms of DMSA with rac-DMSA being slightly more efficient than meso-DMSA.


Subject(s)
Cadmium/metabolism , Chelating Agents/pharmacology , Kidney/drug effects , Liver/drug effects , Succimer/pharmacology , Analysis of Variance , Animals , Cadmium/administration & dosage , Female , Injections, Intraperitoneal , Kidney/metabolism , Liver/metabolism , Rats , Rats, Wistar , Stereoisomerism
5.
Arh Hig Rada Toksikol ; 51(1): 53-60, 2000 Mar.
Article in Croatian | MEDLINE | ID: mdl-11059072

ABSTRACT

Since the antiquity and throughout the Middle Ages, physicians had been observing the harmful effects and the illnesses in people who worked in manufacture and/or mining. They would draw attention to such effects and propose solutions which often entailed improvement of working conditions and environment. The ancient physicians from Varazdin had been familiar with such literature, accepted the ideas thereof, and implemented them in practice. Moreover, they followed-up those who had been exposed to similar harmful effects. Some of their interpretations and understanding do not fall short of the modern perceptions of work-related harmful effects and some seem to be far ahead of their times. The introduction of administrative regulations was gradual; at start rare and related to exposure of certain individuals and later more frequent and comprehensive. Scientific approach to the need for systematic occupational safety has taken root in Croatia ever since World War I. Experts in the field have published important papers on the matter. Varazdin has joined the incentive for health care and protection of the exposed to harmful effects of modern industry and working environment since 1956. Physicians are specialising in occupational medicine. The section of occupational medicine in Varazdin was established within the Institute for Hygiene that later gradually transformed to a well organised unit for occupational health care.


Subject(s)
Occupational Health/history , Occupational Medicine/history , Croatia , History, 17th Century , History, 18th Century , History, 19th Century , History, 20th Century , Humans
6.
Rev Environ Health ; 15(4): 413-9, 2000.
Article in English | MEDLINE | ID: mdl-11199251

ABSTRACT

This review relates to possible explanations of the often-observed findings that exposure to certain air pollutants or their mixture results in an increased rate of acute respiratory diseases. Epidemiological investigations have shown that exposure to manganese (MnO2) concentrations only 10 to 50 times higher than the normal urban concentrations of 0.01 to 0.03 microgram/m3 air might have an adverse health effect on respiratory organs. The assumption that one possible mechanism of action could be that manganese at such exposure levels disturbs certain protective functions in the lung--thus making the organism more susceptible to infections--is supported by toxicological studies. In vitro studies have demonstrated the cytotoxic action of manganese, including the inhibition of activities of alveolar macrophages. Animal experiments showed a decrease in resistance toward respiratory infections that were caused by simultaneous exposure to MnO2 and pathogenic bacteria. In cases of combined exposure to gaseous upper respiratory tract irritants and suspended particles, the involvement of adsorption of gaseous compounds on solid particles as carriers has been suggested. The assumption is that through such a mechanism, water-soluble gaseous irritants can be transported deep into air passages, which such irritants normally do not reach. As the adsorption is reversible, the gaseous compounds can later be released from the particles, inducing a local irritating effect in the small airways and alveoli.


Subject(s)
Air Pollutants/adverse effects , Environmental Exposure/adverse effects , Manganese/adverse effects , Respiratory Tract Diseases/chemically induced , Adsorption , Air Pollutants/analysis , Dust/adverse effects , Fluorides/adverse effects , Humans , Incidence , Manganese Compounds/adverse effects , Oxides/adverse effects , Respiratory Tract Diseases/epidemiology , Respiratory Tract Diseases/physiopathology
7.
J Appl Toxicol ; 19(3): 143-7, 1999.
Article in English | MEDLINE | ID: mdl-10362263

ABSTRACT

The very young are more prone to lead poisoning than adults, and the treatment with chelating agents, either as monotherapy or combined treatment, is still a matter of dispute. The purpose of this work was to evaluate the efficiency of three chelating agents administered either as monotherapies or as combined treatments in sucklings. Lead acetate (5 mg Pb kg(-1) i.p.) was administered to the 7-day-old rat pups in eight litters on experimental day 1 and chelating agents on experimental days 2 and 3. Pups were divided into six groups: (1) untreated control; (2) EDTA (calcium disodium ethylendiaminetetraacetate, 0.3 mmol kg(-1) i.p. at 4 p.m.); (3) meso-DMSA (meso-2,3-dimeracaptosuccinic acid, 0.5 mmol kg(-1) p.o. at 10 a.m.); (4) rac-DMSA (racemic-2,3-dimeracaptosuccinic acid, 0.5 mmol kg(-1) p.o. at 10 a.m.); (5) EDTA+meso-DMSA; and (6) EDTA+rac-DMSA. Rats were killed on experimental day 5. Tissue element concentrations were analyzed by atomic absorption spectrometry. Treatment with EDTA did not affect tissue Pb, but it reduced Zn in the carcass and liver. Meso-DMSA reduced Pb in the kidneys and brain, and it did not affect organ essential elements. Rac-DMSA most efficiently reduced Pb concentrations in the carcass, kidneys and brain, but it also reduced Zn and Cu in the liver and Zn in the kidneys. Combined treatments with EDTA never improved the efficiency of either DMSA isoform in decreasing tissue Pb but they did reduce tissue Zn concentrations. All treatments caused the same decrease in the carcass Ca concentrations. The results do not support combined treatment in this age group, which is especially sensitive to trace element deficiencies, and suggest that meso-DMSA might be the treatment of choice in acute lead poisoning in infants.


Subject(s)
Chelating Agents/therapeutic use , Edetic Acid/therapeutic use , Lead Poisoning/prevention & control , Lead/metabolism , Succimer/therapeutic use , Animals , Animals, Suckling , Body Composition/drug effects , Body Weight/drug effects , Brain/drug effects , Brain/metabolism , Calcium/metabolism , Drug Therapy, Combination , Female , Iron/metabolism , Kidney/drug effects , Kidney/metabolism , Lead/toxicity , Lead Poisoning/metabolism , Liver/drug effects , Liver/metabolism , Male , Rats , Rats, Wistar , Stereoisomerism , Succimer/chemistry , Zinc/metabolism
8.
J Appl Toxicol ; 19(3): 211-7, 1999.
Article in English | MEDLINE | ID: mdl-10362273

ABSTRACT

The purpose of this study was to evaluate the direct effect(s) of in vitro cadmium (Cd) exposure on steroidogenesis in rat ovaries during different reproductive states. Sprague-Dawley rats were killed on the day of proestrus, or on gestation day 6 or 16. Ovaries were removed, placed in medium and minced. Culture from each ovary was incubated with Cd2+ ions in concentrations of 0, 100, 500, 1000, 1500, or 2000 microM. One-hour whole-ovary production of progesterone (P4), testosterone and estradiol (E2) in culture medium was evaluated in the absence and presence of human chorionic gonadotropin (hCG) or hCG plus pregnenolone by specific radioimmunoassay. Under in vitro Cd exposure the most affected were productions of P4 and testosterone in proestrus rats and less in pregnant dams, whereas E2 was not affected at all. Cadmium appears to interfere with the ovarian steroidogenic pathway in rats at more than one site.


Subject(s)
Cadmium/toxicity , Ovary/drug effects , Steroids/biosynthesis , Animals , Chorionic Gonadotropin/pharmacology , Dose-Response Relationship, Drug , Estradiol/biosynthesis , Female , Gestational Age , Humans , Organ Culture Techniques , Ovary/metabolism , Pregnancy , Proestrus/drug effects , Proestrus/metabolism , Progesterone/biosynthesis , Rats , Testosterone/biosynthesis
9.
Arh Hig Rada Toksikol ; 50(3): 327-30, 1999 Sep.
Article in Croatian | MEDLINE | ID: mdl-10649848

ABSTRACT

The review examples of usage of the Latin term magister (master) in various common titles throughout the past, particularly in Croatia. As early as the Roman Empire and until the Middle Ages, the title magister designated various functions and duties, generally denoting authority, higher rank, or a responsible position. The review highlights certain historical events and persons related to the usage of the title magister. Ever since the Middle Ages, the title has specifically denoted various health care professions. The term was used in Latin, as it was the official language in Croatia at the time, for example, m. chirurgiae (master of surgery), m. obstetritiae (master of obstetrics), m. artis occularis (master of the eye-related skills), m. hospitalis (master of the hospice), m. sanitatis (health care master). As an example, the review shows the difference between the titles doctor medicinae and m. obstetritiae according to John the Baptist Lalangue (1743-1799), the official physician of the Varazdin county in the Hapsburg Empire and one of the most prominent figures in the history of health care in Croatia. Lalangue was the author of the first professional medical book in the Croatian language published in 1776 and of several other books in Croatian. The books were meant to teach medical professionals and ordinary people how to improve their health. Beside the title of medical doctor, Lalangue held the title of m. obstetritiae which he earned through additional education. He thought it was essential for a complete health provider to be trained both in general practice and in obstetrics which, at the time, included infant care. Nowadays in Croatia, only persons who are graduate pharmacists use magister pharmaciae as a professional title. The title is otherwise strictly reserved to denote an academic degree between the bachelor's and the doctoral in a particular field. The title magister scientiarum (Master of Science) is achieved upon completion of a postgraduate study and defence of the master's thesis.


Subject(s)
Health Personnel/history , Names , History, 15th Century , History, 16th Century , History, 17th Century , History, Ancient , History, Medieval
10.
Pharmacol Toxicol ; 81(5): 242-4, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9396091

ABSTRACT

Racemic dimercaptosuccinic acid (DMSA) was found more efficient than the meso-isoform in enhancing the removal of mercury in rats. However, racemic-DMSA has recently been found more toxic. The efficiency of combined oral treatment with the two isoforms of DMSA for removal of mercury has now been evaluated. Female albino rats were treated orally for four days with meso- (M) and/or racemic- (R) DMSA (1 mmol/kg each), five days after a single intraperitoneal administration of 203Hg with 0.5 mg HgCl2/kg. The animals were divided into six groups according to the number of treatments with each isomer: control (untreated), 4M, 1R + 3M, 2R + 2M, 3R + 1M, and 4R. Whole body, kidney, liver and brain mercury contents were measured nine days after 203Hg administration. In all treated groups retention in the whole body and kidneys was greatly reduced. The groups treated with racemic-DMSA, regardless of the number of doses, showed a greater removal of mercury than the group treated with meso-DMSA alone (4M). All treatments were less efficient in reducing liver retention, and the brain retention was not affected. It was concluded that even a single application of the more toxic racemic-DMSA during a four-day oral treatment regimen is sufficient to improve the removal by meso-DMSA of mercury from rats.


Subject(s)
Chelating Agents/administration & dosage , Mercury/analysis , Succimer/administration & dosage , Animals , Body Burden , Brain/metabolism , Female , Kidney/metabolism , Liver/metabolism , Mercury/metabolism , Mercury/toxicity , Rats , Rats, Wistar , Stereoisomerism , Succimer/metabolism
11.
Pharmacol Toxicol ; 80(4): 182-6, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9140137

ABSTRACT

Comparison of the racemic and meso forms of 2,3-dimercaptosuccinic acid (DMSA) in lead mobilization from lead-loaded albino Wistar rats demonstrates that the racemic form is significantly more effective in reducing femur lead levels. After four oral doses at 0.5 mmol/kg, femur lead levels were reduced to 87% of control values by meso-DMSA and to 50% of control levels by rac-DMSA. Similarly, when the dose was increased to 1.0 mmol/kg, femur lead levels were reduced to 69% of control levels by meso-DMSA and to 45% of control levels by rac-DMSA. A similar pattern was found for renal lead levels. Brain lead concentrations were significantly lower in treated groups than in control groups, but no differences were found between rac- and meso-DMSA. Rac-DMSA is more soluble than meso-DMSA in acetonitrile, ethyl acetate, and ethyl ether. The partition coefficient of rac-DMSA in the n-octanol/water system was found to be about 2.8. These results indicate that rac-DMSA deserves further attention as a possible substitute for meso-DMSA.


Subject(s)
Lead/metabolism , Succimer/pharmacology , Animals , Body Weight/drug effects , Brain Chemistry/drug effects , Female , Femur/chemistry , Kidney/chemistry , Lead/analysis , Liver/chemistry , Rats , Rats, Wistar , Stereoisomerism
12.
J Appl Toxicol ; 17(1): 71-4, 1997.
Article in English | MEDLINE | ID: mdl-9048230

ABSTRACT

The efficiency of racemic-2,3-dimercaptosuccinic acid (rac-DMSA) compared with meso-2,3-dimercaptosuccinic acid (meso-DMSA) in mobilizing inorganic mercury was evaluated in female rats. Chelators were administered orally at a dose of 0.5, 1.0 or 2.0 mmol kg-1 on four consecutive days, 5 days after a single intraperitoneal 203Hg injection (with 0.5 mg HgCl2 kg-1). Both chelators reduced 203Hg retention in whole body and kidney and at higher doses also in the liver. Racemic-DMSA was more efficient at lower dose levels and equal to meso-DMSA at the highest dose level. Kidney retention decreased after rac-DMSA to 27, 10 and 10% of controls and after meso-DMSA to 68, 39 and 10% of control values at the 0.5, 1.0 and 2.0 mmol kg-1 dose level, respectively. Since meso-DMSA is already approved for human use, its stereoisomeric form, rac-DMSA, deserves further attention for treatment of mercury poisoning.


Subject(s)
Chelating Agents/pharmacology , Mercury/metabolism , Succimer/pharmacology , Administration, Oral , Animals , Body Burden , Female , Kidney/drug effects , Kidney/metabolism , Rats , Rats, Wistar , Stereoisomerism
13.
Arh Hig Rada Toksikol ; 48(3): 307-17, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9501633

ABSTRACT

Following the idea of interrelated role of epidemiology and toxicology in risk assessment and dose response evaluation, this paper presents certain experiences from the authors' studies of health effects of environmental exposure to lead and manganese. Epidemiologic observations of adverse effects on female reproductive integrity in a lead smeltery area agree with the experimental data. Animal studies show that the adverse reproductive effects in females are time and dose-related, and reversible after exposure has ceased. Field studies show that effects of manganese on the respiratory system in a polluted region are dose, age and season-related. Cytotoxic effects of manganese, including the inhibitory effect on alveolar macrophages described in in vitro studies on mammalian cells confirm the epidemiologic observations. Authors conclude that in the process of risk assessment, toxicology and epidemiology have to act together. Available human data should be combined with experimental findings and data on the mechanism of toxic action.


Subject(s)
Environmental Exposure , Lead/adverse effects , Manganese/adverse effects , Abortion, Spontaneous/chemically induced , Animals , Female , Health Policy , Humans , Lead/toxicity , Manganese Poisoning , Pregnancy , Public Health Practice , Rats , Reproduction/drug effects , Respiratory Tract Diseases/chemically induced
14.
Arh Hig Rada Toksikol ; 48(3): 335-43, 1997 Sep.
Article in Croatian | MEDLINE | ID: mdl-9501636

ABSTRACT

The paper presents particulars on damaging effects of work on human health drawn from the first professional medical book published in the Croatian language. Most official documents and papers of the 18th century were written in Latin. Originally, the subject book, Medicina Ruralis, was also written in Latin and subsequently translated to Croatian. It was published in 1776, in the city of Varazdin, Croatian capital at the time. The author was John the Baptist Lalangue, the viceroy's physician and the official physician of the Varazdin county, during the rule of Hapsburg archduchess Maria Theresa. The paper attempts to show to what extent does the Lalangue's book reflect the first ideas and recommendations related to occupational diseases, particularly those described in the capital work of Ramazzini who was acknowledged as "the father of occupational health". Such ideas developed with the progress of the Industrial Revolution at the end of 17th century. In his book, Lalangue considers hard, physical work the major cause of diseases in population he observed and cured in his everyday practice. He gave detailed recommendations for physicians on how to get professional history data of the patient. Furthermore, Lalangue's book introduces the first ideas as to the professional rehabilitation of diseased persons. The paper concludes that Lalangue's ideas represent the origins of modern occupational health on Croatian territory, and emphasises the significance of such ideas appearing soon after their occurrence in other industrially more developed European countries.


Subject(s)
Occupational Diseases/history , Belgium , Croatia , History, 18th Century , Humans
15.
Arh Hig Rada Toksikol ; 47(3): 245-59, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8989890

ABSTRACT

Experimental studies in laboratories in Croatia and U.S.A. were conducted on female rats exposed to lead or cadmium to evaluate effects on the female reproductive integrity. The health condition of the offspring and relationship with essential elements were also evaluated. By using simple biomarkers of reproductive effects it was found that subchronic oral exposure to lead (1500-5500 ppm) or cadmium (50 ppm) during pregnancy and lactation decreased pup body weight, and that lead also decreased pup viability. Acute exposure to cadmium (3 or 5 mg/kg body weight s.c.) in vivo suppressed serum concentrations of progesterone and estradiol depending on the reproductive stage. Organ accumulations of lead or cadmium were accompanied by changes in the concentrations of iron and zinc in both mother and pups. Future research should focus on the effects of metals on endocrine disruption in the ovary and placenta, and on concomitant interaction of toxic and essential metals in mother and offspring.


Subject(s)
Cadmium/toxicity , Fetus/drug effects , Lead/toxicity , Pregnancy, Animal/drug effects , Trace Elements/metabolism , Animals , Birth Weight/drug effects , Estradiol/biosynthesis , Female , Litter Size/drug effects , Ovary/drug effects , Ovary/metabolism , Pregnancy , Progesterone/biosynthesis , Rats , Rats, Sprague-Dawley , Rats, Wistar
16.
Chem Res Toxicol ; 9(6): 965-9, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8870983

ABSTRACT

Three meso-2,3-dimercaptosuccinic acid mono-N-alkylamides (meso-RNHCOCH(SH)CH(SH)-COOH, where R = CHMe2, Mi-PDMA; CH2CHMe2, Mi-BDMA; and CH2CH2CHMe2, Mi-ADMA), were prepared via a synthetic route using the sulfhydryl-protected anhydride. 2,2-Dimethyl-1,3-dithiolane-4,5-cis-dicarboxylic acid anhydride was opened up with 1 mol of corresponding amine to give the SH-protected monoamide. Subsequent deblocking of the vicinal dithiol functionality was accomplished by conversion of the dithiolane into the mercury complex followed by reaction with H2S to give the target molecule. The potential utility of these compounds in chronic cadmium intoxication was examined by evaluation of their cadmium mobilizing efficacy in vivo in cadmium-loaded female albino rats using sodium N-benzyl-D-glucamine-N-carbodithioate (BGDTC) as the standard drug. Compared to BGDTC, the new compounds were, except at the highest dosage studied, equally or more effective in decreasing retention of hepatic cadmium, while mostly less effective in decreasing renal cadmium. The greatest reductions were obtained with Mi-BDMS at 4 x 1.5 mmol/kg, where liver and kidney cadmium levels were reduced to 12% and 59% of control levels, while at the same dosage BGDTC induced a reduction to 50% and 13% of control levels. The order of the efficacy of the monoamides as hepatic cadmium mobilizing agents was found to be Mi-PDMA > Mi-BDMA > Mi-ADMA. However, the isopropyl analog, though very effective at reducing hepatic cadmium at a low dosage, was found to be more toxic than the isobutyl and isoamyl monoamides. While the new compounds were shown to be effective cadmium mobilizing agents, the specific compounds examined did not possess optimized structures in terms of the balance between effectiveness and toxicity.


Subject(s)
Amides/chemical synthesis , Cadmium/analysis , Chelating Agents/chemical synthesis , Chelating Agents/toxicity , Succimer/chemical synthesis , Animals , Brain/metabolism , Cadmium/administration & dosage , Cadmium/toxicity , Chelating Agents/administration & dosage , Female , Kidney/metabolism , Liver/metabolism , Rats , Rats, Inbred Strains , Sorbitol/administration & dosage , Sorbitol/analogs & derivatives , Structure-Activity Relationship , Succimer/analogs & derivatives , Succimer/toxicity , Thiocarbamates/administration & dosage
17.
J Appl Toxicol ; 16(2): 157-8, 1996.
Article in English | MEDLINE | ID: mdl-8935791

ABSTRACT

The cadmium mobilizing efficiency of a combined treatment with a novel cadmium chelating agent disodium N,N'-bis(D-glucosyl)-1,9-nonanediamine-N,N'-biscarbodithioate++ + (C9G2DTC) and with sodium N-benzyl-D-glucamine-N-carbodithioate (BGDTC) was evaluated in albino rats. They received 109Cd intraperitoneally once and 1 week later chelation therapy six times over 12 days at 2-day intervals. The treatment groups were: 1, control; 2, BGDTC six times; 3, C9G2DTC six times; 4, C9G2DTC three times followed by BGDTC three times; 5, C9G2DTC twice followed by BGDTC four times; 6, C9G2DTC once followed by BGDTC five times. The radioactivity in liver, kidney and brain was determined 19 days after 109Cd administration. Results were expressed as a percentage of the 109Cd dose and differences were analyzed by Duncan's multiple range test (P < 0.05). Treatment with C9G2DTC resulted in higher Cd reduction in the liver and lower in the kidney than with BGDTC, which is in agreement with our previous findings. Combined treatment resulted in a greater reduction of Cd in the liver and kidney than by using either chelating agent alone, irrespective of the number of C9G2DTC or BGDTC treatments, and without causing redistribution to the brain. The important aspect of this work is that C9G2DTC--the novel cadmium chelating agent which is extremely efficient in reducing Cd liver deposits and about three times more toxic than BGDTC--has to be used only once at the beginning of the treatment to obtain optimal reduction of aged organ cadmium deposits.


Subject(s)
Cadmium Chloride/metabolism , Chelating Agents/pharmacology , Glucosides/pharmacology , Kidney/metabolism , Liver/metabolism , Sorbitol/analogs & derivatives , Thiocarbamates/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Cadmium Chloride/administration & dosage , Cadmium Radioisotopes , Drug Synergism , Female , Kidney/drug effects , Liver/drug effects , Rats , Rats, Wistar , Sorbitol/pharmacology
18.
Arh Hig Rada Toksikol ; 47(1): 1-8, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8768442

ABSTRACT

The aim of this study was to investigate possible correlations between chronic, recurrent lead poisoning, renal function and immune response. The study involved 74 patients with a history of at least one lead poisoning. Fifty-three patients were occupationally poisoned, and 21 were poisoned accidentally after consumption of alcohol beverages or food from lead glazed pottery. In all patients glomerular filtration rate (GFR) was determined by measuring creatinine and DTPA clearances, and T- and B-lymphocytes were assessed as indicators of cellular and humoral immunity. A significant negative correlation was found between the number of past lead poisonings indicating increased lead body burden, and both creatinine and DTPA clearances. There was a significant positive correlation between the number of poisonings and the percentage of B-lymphocytes (r = 0.31; P < 0.05), and no correlation at all with the T-lymphocyte count. Our results show that chronic, recurrent lead poisoning with a consequently increasing lead body burden can cause an impairment in renal function and a concomitant stimulation of humoral immunity.


Subject(s)
Glomerular Filtration Rate , Lead Poisoning/physiopathology , Adult , Aged , Chronic Disease , Humans , Immunity, Cellular , Lead Poisoning/immunology , Middle Aged
19.
Chem Res Toxicol ; 9(1): 313-7, 1996.
Article in English | MEDLINE | ID: mdl-8924610

ABSTRACT

Four novel cadmium-chelating agents N,N'di(D-glucosyl)alkanediamine-N,N'-bis(carbodithioates) 4a-e were prepared as disodium salts of the general formula (CH2)n[N(CS2Na)CH2(CHOH)4CH2OH]2, where n = 7, 8, 10, and 12. They were synthesized by the reductive coupling of 2 mol of alpha-D-(+)-glucose (1) with 1 mol of the corresponding alkanediamines 2a-e followed by reaction with CS2 in a basic medium. The elemental analyses of the Cd complexes 5a, b, d, and e prepared revealed that these bis(carbodithioates) form 1:1 complexes with Cd2+. The in vivo cadmium-mobilizing efficacy of three of the new chelators (4a, b, and d) was determined in rats pretreated ip with CdCl2.H2O containing 2 microCi of 109Cd (74 kBq), and comparable data were obtained on a previously reported member of this series (4c, n = 9), and with BGDTC (sodium N-benzyl-D-glucamine-N-carbodithioate, 6), all given once at 1.0 mmol/kg ip. The compound with n = 12 (4e, C12G2DTC) proved to be too toxic in the preliminary study and was not evaluated further. A single injection of the 4a, b, and d caused a reduction in Cd levels of the whole body to ca. 50% and liver to ca. 12% of control levels. Comparable experimental data on BGDTC resulted in a reduction of whole-body cadmium to only 78% of the control levels and a reduction in liver cadmium to only 56% of control. After one and six injections at the same dosage, the new chelators (4a, b, and d) and C9G2DTC (4c, n = 9) significantly surpassed BGDTC for whole-body and liver Cd depletion but caused only a very modest depletion of renal Cd. While these compounds were designed to allow the two dithiocarbamate groups to coordinate to the same Cd2+ in vivo, the data do not prove that the two > NCS2Na groups bind to the same cadmium ion in vivo. The very rapid reduction in liver cadmium levels following only a single injection indicates that these -2 anions rapidly gain access to intracellular hepatic sites by some transport system.


Subject(s)
Cadmium/pharmacokinetics , Chelating Agents/pharmacokinetics , Thiocarbamates/pharmacokinetics , Animals , Cadmium/toxicity , Cadmium Radioisotopes/pharmacokinetics , Female , Liver/chemistry , Liver/drug effects , Molecular Weight , Rats , Rats, Wistar , Sorbitol/analogs & derivatives , Sorbitol/pharmacokinetics , Structure-Activity Relationship
20.
Pharmacol Toxicol ; 77(3): 216-8, 1995 Sep.
Article in English | MEDLINE | ID: mdl-8884886

ABSTRACT

Two monoesters of meso-2,3-dimercaptosuccinic acid (DMSA), monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) and mono-n-hexyl meso-2,3-dimercaptosuccinate (Mn-HDMS) were compared to DMSA in their efficiency to mobilize 203Hg in mercury-laden suckling rats. Seven-day-old pups were given 203Hg (18.5 kBq) with a dose of 0.5 mg Hg/kg/day as HgCl2 for five days. Seven days after the beginning of Hg loading a ten-day oral treatment with DMSA, Mi-ADMS, or Mn-HDMS was administered at a dose of 0.25 mmol/kg/day. At the end of experiment, radioactivity was measured in the whole body, liver, both kidneys, and brain. Monoesters of DMSA were superior to DMSA in decreasing body and organ Hg retention. The highest reduction in comparison to controls in groups treated with DMSA, Mi-ADMS, or Mn-HDMS occurred in the kidneys (48%, 97%, and 96%), followed by reduction in the liver (24%, 84%, and 83%), and in the brain (8%, 23%, and 23%, respectively). For both, Mi-ADMS and Mn-HDMS, the reductions in the whole body and organs were significantly greater than in controls or DMSA-treated rats. No difference between the efficiency of the two DMSA-monoesters was found.


Subject(s)
Chelating Agents/pharmacology , Mercury/metabolism , Succimer/analogs & derivatives , Administration, Oral , Animals , Animals, Suckling , Brain/metabolism , Female , Isotope Labeling , Kidney/metabolism , Liver/metabolism , Male , Rats , Rats, Wistar , Succimer/pharmacology , Tissue Distribution
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