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We describe a case with neurologic disease manifested as encephalopathy, generalized muscle fasciculations, and peripheral neuropathy occurring in a patient treated with therapeutic doses of gold for presumed rheumatoid arthritis. The illness remitted promptly during chelation therapy with dimercaprol (BAL). A review of the limited experience in the literature with the central nervous system toxicity of gold is given.
A 31 year-old inhabitant of French Guiana was prescribed mercuric iodide per os for two and a half months. Shortly before the end of the treatment he developed fasciculations in the trunk and particularly the lower limb muscles, distal painful paresthesias with vasomotor disorders, episodes of excessive perspiration and palmoplantar erythema, moderate fluctuating hypertension, progressive loss of weight and irritability with insomnia. Clinical and electrical signs of neuropathy were lacking. The clinical picture was that of Morvan's fibrillary chorea with acrodynia, the conditions of onset strongly suggesting a mercurial intoxication. Blood and particularly urine mercury levels were elevated. Administration of dimercaprol (BAL) considerably increased urinary excretion of mercury and there was progressive improvement and finally recovery after two months of BAL treatment. This case exemplifies the possible co-existence of fibrillary chorea and acrodynia. Whereas in many cases of fibrillary chorea a precise etiology cannot be determined, the affection can be induced by mercury as by gold administration. The fact that cases of fibrillary chorea due to mercury poisoning are rarely reported may be the result of individual patient hypersensitivity or particular metabolic absorption and excretion features of mercury. This case cannot be included within the continuous activity syndrome of muscle fibers described by Isaacs, since muscle contractures were absent and there was associated acrodynia. Moreover, there was no latent polyneuropathy, in spite of the intense fasciculations. It must be concluded, therefore, that in spite of its rarity fibrillary chorea should keep its semiologic autonomy.
This paper reviews the recently discovered role of sulfhydryls and early vascular injury in the pathogenesis of acute gastric mucosal injury. In the rat ethanol caused a dose-dependent decrease in nonprotein sulfhydryl concentration in the gastric mucosa within 1-5 min following an intragastric dose. These biochemical changes were accompanied by increased vascular permeability in the glandular stomach as revealed by the measurement of extravasated Evans blue injected i.v. prior to the administration of ethanol. Morphologic evidence of vascular injury was provided by labelling of damaged blood vessels in the stomach following the i.v. administration of colloidal particles in the form of india ink or monastral blue. The functional and structural damage to capillaries and venules in the glandular stomach was also maximal within 1-6 min after 1 ml of 75 or 100% ethanol given orally. Pretreatment with sulfhydryl (SH) containing drugs (e.g., L-cysteine, N-acetyl-L-cysteine, cysteamine, dimercaprol) or prostaglandin (PG) F2 beta prevented the ethanol-induced increase in vascular permeability, the labelling of blood vessels with vascular tracers, and the subsequent haemorrhagic erosions. The desquamation of superficial epithelial cells, however, was not markedly modified by either SH or PG compounds. This organoprotective effect of SH and PG drugs was virtually counteracted in adrenalectomized rats that exhibited "vascular fragility". Glucocorticoid treatment restored the response of adrenalectomized animals. Thus, a SH- and glucocorticoid-sensitive early vascular injury seems to be of major significance in the pathogenesis of haemorrhagic gastric erosions and SH-containing compounds represent a new group of cytoprotective or organoprotective agents.
A 58-year-old laboratory-glassware manufacturer was referred to hospital because of coarse "tremor" of the upper extremities of 16-months-duration. Examination showed severe intention and action myoclonus, confirmed by electromyographic recording, slight memory impairment but was otherwise normal. Mercury levels were high in blood and urine (not in CSF) and, as other causes of myoclonus were excluded, inorganic mercury poisoning, was diagnosed. Only slight unilateral intention tremor persisted after dimercaprol treatment. Inhalation of mercury vapor was the mode of contamination. Myoclonus is the hallmark of severe inorganic mercury intoxication, the main clinical and pathological aspects of which are briefly discussed.
We successfully adapted the dimercaprol (BAL) tributyrate-5,5'-dithiobis(2-nitrobenzoic acid) method (J. Biochem. 81: 361, 1977) for assay of lipase in human serum to a discrete analyzer (the TBA 880) (I) or a continuous-flow analyzer (AutoAnalyzer, Type II) (II). In both, BAL-tributyrate is used as substrate, in combination with serum esterase inhibitors and a chromogenic reagent for the SH group of the liberated BAL. Serum lipase activities of patients with pancreatic diseases, measured at 90 or 40 samples per hour by I or II, respectively, correlated well with those measured by the corresponding manual method or by Kaplan's radioassay (Anal. Biochem. 33: 213, 1970). The correlation coefficients were all greater than 0.95, and the coefficients of variation were less than 8%, showing the practical usefulness of these procedures.
Two persons, exposed to high concentration of mercury vapour in their home developed a few hours later febrile illness with interstitial pneumonitis and mercurial stomatitis. Symptomatic treatment was associated with dimercaprol (BAL) and steroïds; an alveolar washing was performed to remove non-absorbed mercury in the respiratory three which seems to be responsible for the observed inflammatory reaction and, sometimes, the delayed development of fibrosis. A review of the literature revealed that such intoxications had been previously described in about 20 cases. Prognosis depends on the severity of the pulmonary lesions. Fatalities have been described in 9 cases (10%); in 8 cases the victims were young children or old people. An acute gingivo-stomatitis is generally observed. The onset of mercurial encephalopathy is an uncommon feature. Renal disturbances are exceptionally described and always mild. There is no correlation between the clinical condition of the patient and the levels of mercury in the urine.
In rats the sinusoidal glutathione (GSH) carrier transports GSH bidirectionally, and its activity is influenced by the thiol-disulfide status; the Vmax of sinusoidal GSH efflux was increased by dithiothreitol (DTT) and decreased by cystine. In the present work we examined the specificity and directionality of the thiol effect. Using in situ perfused livers, we found that 1 mM DTT and other dithiols, including 1,2-ethanedithiol, 1,3-propanedithiol, and 1,4-butanedithiol, stimulated sinusoidal GSH efflux by 200-500% but dihydrothioctic acid, which is negatively charged, had no effect. Uncharged or positively charged monothiols (2 mM), such as dimercaprol, monothioglycerol, 2-mercaptoethanol, 3-mercapto-2-butanol, 1-mercapto-2-propanol, and cysteamine, also exerted a stimulatory effect on sinusoidal GSH efflux. In contrast, monothiols containing a negatively charged substituent, such as penicillamine, captopril, N-acetylcysteine, mercaptopropionylglycine, mercaptoethanesulfonic acid, mercaptoacetic acid, and mercaptopropionic acid, had no effect. The thiol moiety was essential for activity, inasmuch as ethanol, propanol, propanediol, and glycerol had no effect on sinusoidal GSH efflux. The effect of DTT or cystine pretreatment (2 mM or 0.5 mM, respectively, for 30 min) on GSH uptake was then examined using cultured rat hepatocytes. The linear rate of [35S]GSH uptake and the concentration dependence were measured after cells were pretreated with acivicin (0.5 mM, for 15 min) and buthionine sulfoximine (10 mM, 15 min), to prevent breakdown and resynthesis of GSH from precursors, respectively. Uptake buffer also contained 20 mM alpha-(methylamino)isobutyric acid and 20 mM threonine (inhibitors of amino acid transport systems A and ASC, respectively), to prevent uptake of cysteine. Pretreatment with DTT decreased the Vmax of GSH uptake by approximately 50% (control Vmax value, 24 nmol/10(6) cells/30 min), whereas the Km remained unaffected (approximately 8 mM). Cystine pretreatment had no influence on GSH uptake but inhibited efflux. In conclusion, the presence of at least one thiol group and the absence of negative charge are required to stimulate sinusoidal GSH efflux. The direction of GSH transport is modulated by the thiol-disulfide status, so that thiol reduction changes the GSH transporter from a bidirectional GSH transporter into a preferentially unidirectional (outward) transporter by inhibiting uptake while stimulating efflux and thiol oxidation favors inward transport by inhibiting only efflux.
A 17 year-old boy was admitted to the hospital because of severe hypertension (200/130 mmHg), headache, irritability, and sweating. Initial biochemical tests suggested pheochromocytoma, being treated with nifedipine, clonidine and propranolol. However, with report of exposure to mercury vapor, twenty-four-hour urine screening and measurement of blood mercury confirmed intoxication. The patient underwent courses of chelation therapy with dimercaprol (BAL) and penicillamine with remission of symptoms and normalization of blood pressure after 2 months. This case has relevance for current practice reflecting similarity between mercury intoxication and hypertension secondary to pheochromocytoma.
Five heavy metal antagonists were compared for their specificity of chelating action against copper (CuCl, CuCl2) and iron (FeCl2, FeCl3). ESR spectroscopy showed that both copper and iron significantly enhanced the radical intensity of ascorbate and sodium 5,6-benzylidene-L-ascorbate (SBA). Equimolar concentrations of dimercaprol efficiently chelated all these metals, thus significantly reducing their stimulation effects. On the other hand, the chelating action of penicillamine, ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid was limited to CuCl and CuCl2 whereas deferoxamine mesylate (DFO) was a specific iron chelator. The cytotoxic activity of sodium ascorbate was augmented by DFO, but diminished by FeCl3. The simultaneous addition of DFO and FeCl3 counteracted each other, thus neutralizing their individual effects. The cytotoxic activity of both sodium ascorbate and SBA was significantly enhanced by CuCl2 and this stimulation effect of CuCl2 was effectively chelated by DTPA. The present study demonstrates the specificity of the chelating action of these five antagonists, suggesting the possible application of these different types of antagonists for the prevention of the pathogenic diseases catalyzed by the corresponding metals.
We show that N-acetylcysteine (NAC) has the ability to cause statistically significant diminishment in the in vitro formation of irreversibly sickled cells (ISCs) at concentrations greater than 250 micromol/L. Other antioxidants, approved for human use (cysteamine, succimer, dimercaprol), were not efficacious. NAC had the ability to cause statistically significant conversion of ISCs formed in vivo back to the biconcave shape. NAC was also shown to reduce the formation of dense cells and increase the available thiols in beta-actin. We showed that diminishing reduced glutathione (GSH), by treatment with 1-chloro-2,4-dinitrobenzene, resulted in increased dense cells. We conclude the NAC blocks dense cell formation and ISC formation by targeting channels involved in cellular dehydration and beta-actin, respectively. The efficacy of NAC is probably due to its combined antioxidant activity and ability to increase intracellular GSH.
A striking reduction in serum arsenic level was achieved after four hours of hemodialysis in a patient with acute arsenic intoxication and transient renal failure. Quantitative dialysance of arsenic and a comparison of daily urinary excretion of arsenic with amount removed by dialysis suggested that hemodialysis is indicated in the treatment of acute arsenic intoxication if there is concomitant renal failure. In the presence of normal renal function, supportive measures, including dimercaprol (BAL in Oil) therapy, constitute the best available treatment.
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