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We report a case of cupric sulfate intoxication in a child who had a serum copper level of 1,650 mug/100 ml. His course was accompanied by hemolytic anemia and renal tubular damage. We review the pathophysiology of copper metabolism and intoxication. We also review modes of therapy, with specific reference to the initial approach, using dimercaprol (BAL) and edetic acid rather than penicillamine.
Phenylmercury acetate (PMA), which not only causes an elevation of sister chromatid exchanges (SCEs) but also induces high frequency of endoreduplication in human lymphocytes, may be genotoxic to humans. The major aim of our study was to investigate the effects of germanium oxide (GeO2), D-penicillamine (D-PA), dimercaprol (BAL), and diltiazem (DTM) on PMA-induced genotoxicity as quantified by SCEs. All concentrations of the four chemical compounds tested alone did not induce genotoxicity in cultured human lymphocytes. However, GeO2 significantly inhibited PMA-induced genotoxicity in a concentration-dependent manner. Similarly, D-PA at concentrations of 3 microM and 10 microM, and BAL at a concentration of 30 microM produced the antigenotoxic effects. In addition, GeO2 (1.5 microM) significantly reversed an increase of endoreduplication frequency caused by PMA. In a cell cycle kinetic study, GeO2 (0.5-5.0 microM) reversed the inhibition of PMA on the proliferating rate index (PRI) of lymphocytes. On the contrary, both D-PA and DTM at concentrations of 30-300 microM markedly potentiated PMA-induced inhibition of PRI. These findings show that GeO2, D-PA and BAL could antagonize PMA-induced genotoxicity, and GeO2 appears to be the most effective.
Exposure to mercury can cause serious multiorgan damage affecting the central nervous system, kidneys, liver, lungs, spleen, bone marrow, and skin. At the end of the summer of 1999, the accidental leakage of 4 liters of mercury from a container into the waterway canals resulted in mass exposure to elemental mercury among the residents of a building block of a residential area of the city of Shiraz, in the south of Iran. One hundred and eleven individuals who experienced exposure to elemental mercury were investigated. Twenty-four-hour measurement of the urine mercury level-revealed a toxic level of more than 20 microg/L in 6 children and 3 adults (including a pregnant woman). Despite normal physical and laboratory (CBC, renal and liver function tests, and urinalysis) findings, dimercaprol was prescribed. One month later during the course of the follow-up the urine mercury level in 6 patients, including the pregnant woman from the same family, was found to be again at a toxic level. The pregnant mother from the same family aborted her fetus; however, due to the lack of equipment for measuring the serum mercury level, it was not possible to confirm the relation between the mercury toxicity and the abortion. This family had kept mercury in their kitchen against health workers' instructions. The attractive physical and chemical properties of mercury could explain the continuity of exposure and poisoning in these 6 cases. It is concluded that prophylactic therapy in the presence of toxic levels of mercury, despite the presence of an asymptomatic state in exposed residents, is effective in preventing the development of signs and symptoms, though instruction of high-risk cases is the best way to combat it.
Base-catalyzed transesterification of acyl lipids with methanol in the presence of trimethylsulfonium hydroxide (TMSH) is an easy and convenient method for the preparation of fatty acid methyl esters for gas chromatography (GC) analyses. Free fatty acids are converted to fatty acid methyl esters by the pyrolytic reaction with TMSH as well. We have found that lipids and other compounds containing thiol groups are also converted easily to the corresponding methyl sulfides (methyl thioethers) by the pyrolytic reaction with TMSH occurring in the injector of the gas chromatograph. For example, alkane thiols such as dodecane thiol and octadecane thiol are converted to the corresponding alkyl methyl sulfides, whereas bis(methylthio) derivatives are formed from alpha,omega-alkane dithiols, e.g., 1,8-octanedithiol, and from 2,3-dimercaptopropan-1-ol (dimercaprol). Furthermore, 3beta-mercaptocholest-5-ene (thiocholesterol) is converted to 3-methylthiocholest-5-ene by the same reaction. The S-methylation reactions which finally lead to the corresponding methylthio derivatives of lipids and other compounds with thiol groups may be of diagnostic value for the structural analysis of such compounds by GC and GC/mass spectrometry.
The influence of pH and angiotensinase inhibitors on the in vitro generation of angiotensin I during PRA measurements has been investigated. PRA values obtained at pH 5.7 are higher than those obtained at pH 7.4. At pH 5.7, values obtained using diisopropylfluorophosphate (DRP 9 mM) as an angiotensinase inhibitor are higher than values obtained with a mixture of dimercaprol (BAL, 1.6 mM) and hydroxyquinoline (8-OHQ, 3 to 4 mM). Since the two methods for inhibiting angiotensinase are completely and equally efficient, it is suggested that these inhibitors might interfere with the renin angiotensinogen reaction. Significant correlations are observed between the PRA values obtained by the different methods which have been studied. Using an incubation pH of 5.7, and BAL and 8-OH quinoline as angiotensinase inhibitors, the distribution of PRA values in a population of 124 hospitalized hypertensive patients ingesting a normal sodium diet had been studied, and it has been demonstrated that the sensitivity of this method of measurement can detect small changes in PRA in patients with low renin activity.
Data on 598 patients with Trypanosoma brucei gambiense sleeping sickness, with abnormal cerebrospinal fluid (CSF) and treated with melarsoprol, were reviewed to determine risk factors for drug-induced encephalopathy. The incidence of melarsoprol-induced encephalopathy was increased in patients with trypanosomes present in the CSF, in patients with a high CSF lymphocyte count, and among patients in whom no trypanosomes were found in either the blood or the lymph node aspirate. Among patients with trypanosomes in the CSF, the risk of encephalopathy was similar whether or not they also had trypanosomes seen in the haemolymphatic system. Dimercaprol, a heavy metal chelator, did not reduce the case-fatality rate of patients with encephalopathy. These observations and others are compatible with the hypothesis that an immune phenomenon is involved in the pathogenesis of melarsoprol-induced encephalopathy. Whether the basic mechanism relates to deposits of immune complexes in the central nervous system or to the release of trypanosomal antigens which subsequently bind to brain cells and attract antibodies or T lymphocytes, the rapidity with which trypanosomal antigens are released may be critical, and very aggressive therapeutic schemes may result in higher toxicity, especially in patients with an impaired blood-brain barrier.
This paper reviews the incidence of, and risk factors for, drug-induced encephalopathy and mortality (from all causes) during treatment with melarsoprol of 1083 patients with Trypanosoma brucei gambiense sleeping sickness in Nioki hospital (Zaire) between 1983 and 1990. Sixty-four patients (5.9%) developed encephalopathy and 62 (5.7%) died: 43 from reactive encephalopathy and 19 from other causes. Univariate and multivariate analyses showed that the administration of prednisolone reduced significantly the incidence of encephalopathy and mortality during treatment, especially in patients with trypanosomes observed in the cerebrospinal fluid (CSF) and/or with a CSF white blood cell (WBC) count of 100 or more per mm3. The risk of encephalopathy was associated more strongly with the CSF WBC count than with the presence of CSF trypanosomes. In the subgroup of patients with a CSF WBC count of 100 or more mm3, changing the melarsoprol regimen to 3 series of 3 injections instead of 3 series of 4 injections halved the mortality rate during treatment. Treatment of patients who do develop reactive encephalopathy with the heavy metal chelator dimercaprol, in addition to intravenous steroids and anticonvulsants, may be harmful. The data suggest that a further reduction of the total dose of melarsoprol may decrease toxicity without jeopardizing efficacy.
The effect of the chelating agent dimercaprol (BAL) on the embryotoxic and teratogenic effects of arsenite (As3+) was determined. BAL (sc, 30 mg/kg) was administered to pregnant CD-1 mice, either 8 and 4 hr prior to or 4 and 8 hr after a 12-mg/kg ip dose of arsenite; other females received a single sc injection of 60 mg/kg BAL concurrently with the arsenite. Treatments were given on Gestation Day 9 or 12 (copulation plug = Day 1). Controls received sc corn oil or ip H2O, with or without arsenite or BAL. Arsenite treatment caused gross and skeletal malformations and prenatal deaths, while controls were unaffected. When BAL was given prior to arsenite on Day 9, incidences of prenatal mortality and skeletal malformation were significantly diminished, and on Day 12, BAL protected against fetocidal effects of arsenite when given concurrently with the arsenite. No other significant protective effects against arsenite toxicity were seen due to BAL; however, concurrent BAL treatment on Day 9 appeared to result in decreased fetal mortality and a decline in skeletal malformations. BAL given following arsenite on Day 9 afforded no significant protection against the arsenic, although an apparent decrease in gross and skeletal malformations was suggestive of such an effect. According to these results, BAL is unlikely to have a practical beneficial effect on the arsenite exposed conceptus, because it must be administered prior to the teratogen (or perhaps simultaneously with it) to be effective.
The conditioned flavor-aversion paradigm was used to assess the toxicity of acutely administered cadmium and the interaction of cadmium with the heavy-metal chelating agents dimercaprol (BAL) and dimercaptosuccinic acid (DMSA). Shortly after consuming saccharin, rats received ip administration of cadmium either alone or in combination with sc administration of BAL or DMSA. Three days later they were given the choice between consuming saccharin or water, and saccharin preferences were recorded. When compared to rats receiving either nothing or the vehicle, rats receiving cadmium displayed significant reductions in saccharin preference (i.e., conditioned flavor aversions). BAL and DMSA were also capable of producing conditioned flavor aversions when given alone. Rats receiving cadmium in combination with either BAL or DMSA displayed significant, but not complete attenuations of conditioned flavor aversions when compared to the flavor aversions of rats receiving cadmium alone. Chelator-induced blockade of cadmium-induced flavor-aversion conditioning was not obtained when BAL or DMSA administration was delayed by 4 hr. Attenuation of cadmium-induced aversions by BAL and DMSA extends earlier findings of an attenuation of lead-induced flavor-aversion conditioning by these complexing agents, and thus demonstrates further the utility of the flavor-aversion conditioning paradigm in characterizing metal-chelator interactions.
Four chelating agents that have been used most commonly for the treatment of humans intoxicated with lead, mercury, arsenic or other heavy metals and metalloids are reviewed as to their advantages, disadvantages, metabolism and specificity. Of these, CaNa2EDTA and dimercaprol (British anti-lewisite, BAL) are becoming outmoded and can be expected to be replaced by meso-2,3-dimercaptosuccinic acid (DMSA, succimer) for treatment of lead intoxication and by the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS, Dimaval) for treating lead, mercury or arsenic intoxication. Meso-2,3-DMSA and DMPS are biotransformed differently in humans. More than 90% of the DMSA excreted in the urine is found in the form of a mixed disulfide in which each of the sulfur atoms of DMSA is in disulfide linkage with an L-cysteine molecule. After DMPS administration, however, acyclic and cyclic disulfides of DMPS are found in the urine. The Dimaval-mercury challenge test holds great promise as a diagnostic test for mercury exposure, especially for low level mercurialism. Urinary mercury after Dimaval challenge may be a better biomarker of low level mercurialism than unchallenged urinary mercury excretion.
Rats given calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA), diethylenetriaminepentaacetic acid (DTPA), dimercaprol, p-aminosalicylic acid (PAS), or d-penicillamine (penicillamine) i.p. for 7 successive days showed a significant decrease in the activity of hepatic microsomal benzphetamine N-demethylase. There was no appreciable change in the microsomal cytochrome P-450 concentration. In vitro incubation of the chelating drugs with liver microsomes isolated from rats pre-treated with phenobarbital caused no significant loss of the hemoprotein. The decreased rate of benzphetamine metabolism in microsomal preparations from rats, pretreated with the chelating drugs, may be attributed partly to hepatic depletion of essential trace elements by the chelating drugs.
We investigated the effects of dimercaprol (BAL), meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-1-propanesulphonic acid (DMPS) on human blood delta-aminolevulinate dehydratase (delta-ALA-D) activity, the most reliable indicator of lead intoxication in humans, in the presence of lead in vitro. Furthermore, we studied the effects of the chelating agents, administered subcutaneously, on delta-ALA-D activity in blood and tissues of mice submitted to sub-acute lead exposure (50 mg/kg for 15 consecutive days, subcutaneously). In vitro results demonstrated that human blood delta-ALA-D activity was significantly inhibited (62%) by lead acetate. Lead acetate (1-1000 microM) pre-incubated with human blood increased the inhibitory potency of this compound on delta-ALA-D when compared to the assay without pre-incubation (89%). Chelating agents caused a marked potentiation of delta-ALA-D inhibition induced by lead, in vitro. One of the most notable observations in the present study was the correspondence between in vitro and ex vivo effects. In fact, BAL and DMPS increase the inhibitory effect of lead on delta-ALA-D activity from mice blood. The complexes formed (lead and chelators) were more inhibitory than lead alone in kidney and liver enzyme activity, ex vivo.
The corneal copper content was measured by X-ray excitation spectrometry in two controls and in seven patients with Wilson's disease. Patients who were treated irregularly or not treated at all showed a high corneal copper content. Those who were adequately treated had low levels, comparable to the controls. In one case the corneal copper content declined 45%, after a course of dimercaprol. The corneal copper measured showed no correlation with the slit-lamp appearance of the Kayser-Fleischer ring. It is suggested that non-invasive X-ray excitation spectrometry can provide a fast and reliable method for the early diagnosis of Wilson's disease and for the objective evaluation of the efficacy of the treatment of this disease.
A 16-month-old boy ingested liquid zinc chloride/ammonium chloride soldering flux. He developed severe local burns, metabolic acidosis, hepatic damage, hyperamylasemia, lethargy, and hypertension. Peak measured plasma zinc was 1,199 micrograms/dL. Because of persistent signs of systemic toxicity, he was chelated with dimercaprol (BAL) and EDTA. Although clinical improvement was noted coincident with the initiation of chelation, there was no apparent increase in urinary zinc excretion. Scarring in the gastric antrum necessitated an antrectomy. The child recovered without other apparent complications.
Ca2+ is involved in the regulation of a variety of physiological processes, but a persistent increase in free cytosolic Ca2+ concentrations may contribute to cell injury. Dimercaprol (BAL) is a compound used in the treatment of mercury intoxication, but presents low therapeutic efficacy. The molecular mechanism responsible for the BAL toxicity is poorly known. In the present study, the effect of BAL and inorganic and organic mercury on Ca2+ transport by Ca2+-ATPases located in the sarco/endoplasmic reticulum of fast-skeletal muscle and brain was examined. Ca2+ uptake by brain and fast-skeletal muscle microsomes was inhibited in a dose-dependent manner by Hg2+. The calculated IC50 for Ca2+ uptake inhibition by HgCl2 was 1.05+/-0.09 microM (n = 8) for brain and 0.72+/-0.06 microM (n = 9) for muscle. The difference was significant at p < 0.01 (data expressed as mean +/- SD). At a low concentration (1 microM), 2,3-dimer-captopropanol had no effect on Ca2+ uptake by brain or muscle vesicles and did not abolish the inhibition caused by Hg2+. A high concentration of BAL (1 mM) nearly abolished the inhibition caused by 1.75 microM HgCl2 or 6 microM CH3HgCl in skeletal muscle. Surprisingly, at intermediate concentrations (40-100 microM) BAL partially inhibited Ca2+ transport in brain but had no effect on muscle. Furthermore, ATP hydrolysis by brain or muscle microsomes was not inhibited by BAL. These results suggest that in brain microsomes BAL affects in a different way Ca2+ transport and ATP hydrolysis. The increase in BAL concentration observed after toxic administration of this compound to experimental animals may contribute to deregulate Ca2+ homoeostasis and, consequently, to the neurotoxicity of BAL.
1. The effects of the non-selective cyclo-oxygenase (COX) inhibitor indomethacin and the selective COX-2 inhibitors, N-[2-(cyclohexyloxy)-4-nitrophenyl] methanesulphonamide (NS-398), 5-methanesulphonamido-6-(2,4-difluorothio-phenyl)-1-indan one (L-745,337) and 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-furanone (DFU), on the protection induced by the mild irritant 20% ethanol were investigated in the rat stomach. 2. Instillation of 20% ethanol (1 ml, p.o.) effectively protected against gastric mucosal injury induced by subsequent instillation of 70% or 96% ethanol (1 ml, p.o.). 3. Oral administration of indomethacin (1.25-20 mg kg[-1]) dose-dependently counteracted the protective effect of 20% ethanol (ID50: 3.5 mg kg[-1]). 4. Likewise, NS-398 (0.1-1 mg kg[-1]), L-745,337 (0.2-2 mg kg[-1]) and DFU (0.02-0.2 mg kg[-1]) inhibited the protective effect of 20% ethanol in a dose-dependent manner with ID50 values of 0.3 mg kg(-1), 0.4 mg kg(-1) and 0.06 mg kg(-1), respectively. 5. Inhibition of mild irritant-induced protection was also found when NS-398 (1 mg kg[-1]) was administered s.c. or when 96% ethanol was used to damage the mucosa. 6. Pretreatment with 16,16-dimethyl-prostaglandin (PG)E2 at 4 ng kg(-1), a dose that did not protect against ethanol (70%)-induced mucosal damage when given alone, completely reversed the effect of the selective COX-2 inhibitors on the mild irritant-induced protection. 7. Pretreatment with dexamethasone (3 mg kg(-1), 24 and 2 h before instillation of 20% ethanol) did not affect the protective activity of the mild irritant, indicating that enzyme induction is not involved. 8. Indomethacin (20 mg kg(-1), p.o.) did not prevent the protection conferred by sodium salicylate (100 mg kg[-1]), dimercaprol (30 microg kg[-1]), iodoacetamide (50 mg kg[-1]) and lithium (20 mg kg[-1]). Likewise, the protective effect of these agents was not counteracted by NS-398 (1 mg kg(-1), p.o.). 9. Whereas indomethacin (20 mg kg(-1), p.o.) near-maximally inhibited gastric mucosal formation of PGE2, 6-keto-PGF1alpha and thromboxane (TX) B2 as well as platelet TXB2 release, the selective COX-2 inhibitors were ineffective. 10. The findings show that selective COX-2 inhibitors, although lacking in ulcerogenic activity, prevent the protection conferred by a mild irritant. Prostaglandis generated by a constitutive COX-2 could thus contribute to physiological functions involved in gastric homeostasis, although at present a non-COX-2-related mechanism underlying the effect of the selective COX-2 inhibitors tested on mild irritant-induced protection cannot be completely excluded.
The main application of the radioimmunoassay for angiotensin I is the measurement of plasma renin activity (PRA). Methods published for the measurement of PRA differ in many details and make the comparison of results difficult. This paper deals with some of the problems. 1. The radioactive labelling of angiotensin I using chloramine-T requires the purification of the labelled peptide. A method applying both anion exchange chromatography and gel filtration is described. It resulted in tracer angiotensins of very reproducible characteristics. 2. For the measurement of PRA, the pH of the plasma has to be adjusted prior to the incubation. The adjustment to the physiologic pH of 7.4 is recommended. 0.1 volume of a concentrated buffer controlled the pH during a three hours incubation without diluting the plasma too much. 3. At pH 7.4, EDTA, dimercaprol, and 8-hydroxyquinoline were found to inhibit converting enzyme and angiotensinases better than EDTA and DFP and should therefore be used as inhibiting agents. 4. Nonspecific cross reaction of antisera are the cause of the blank values when angiotensin I is measured in unextracted plasma. The problem of subtraction of a blank may be minimized by the selection of an antiserum of high specificity which shows no or only little nonspecific cross reaction. Lor or unmeasurable blank values will result.
In the German Federal Republic it has recently become known that generalised disorders of chronic mercury poisoning (loss of weight, stomatitis, hearing and sensory loss, emotional disturbances) have accompanied the cardinal signs of nail discolouration and loss of hair. The mercury content of nails in such patients was extremely high (1720 mg/l). The urinary level of mercury after dimercaprol injection was 1.97 mg/l, about 400 times above the upper limit of normal (0.005 mg/l). The poisoning was apparently caused by the use of mercury-containing bleaches (about 5% and 6% Hg) which do not require prescription and are marketed without any statement about composition or possible side-effects. The cases are a warning against uncontrolled use of external application of mercury-containing preparations.