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The prevention by sulphydryl compounds of the toxicity in the cat of 2,6-dimethoxyphenol and its morpholinopropionyl ester.

1 Intravenous (minus)-2,6-dimethoxyphenyl-2-morpholinopropionate hydrochloride (M&B 16,573) produced anaesthesia of short duration in the mouse, rat, rabbit, cat, dog and monkey. In the cat but not in other species, a severe and usually fatal toxic reaction was seen 1-2 h after administration. 2 This toxic reaction but not the anaesthetic properties of M&B 16,573 was prevented by the intravenous administration of cysteine or N-acetylcysteine. Cysteamine or dimercaprol were ineffective. 3 Intravenous administration of 2,6-dimethoxyphenol or 2,6-dimethoxyquinol in the cat produced a response similar to the delayed toxic effects of M&B 16,573 but not preceded by anaesthesia. The toxic effects of these compounds were prevented by cysteine. 4 Intravenous 4-allyl-2,6-dimethoxyphenyl-2-morpholinopropionate hydrochloride produced anaesthesia in the cat without the delayed toxic effects seen after M&B 16,573. 5 The acute toxicity of 2,6-dimethoxyquinol in mice was reduced by the administration of cysteine or N-acetylcysteine. 6 It is postulated that the delayed effects produced by M&B 16,573 in the cat are due to the formation of 2,6-dimethoxyquinol and 2,6-dimethoxybenzoquinone in this species, the toxicity of the latter being reduced by sulphydryl compounds.

Animals↗

An unusual cause of recurrent abdominal pain.

Abdominal pain is a common complaint with diverse etiologies. We describe an unusual case of recurrent abdominal pain in an adult due to lead poisoning, a condition usually associated with childhood. A previously healthy 42-yr-old man presented with 2 days of severe crampy abdominal pain and a 1-month history of constipation. Physical examination was remarkable for diffuse abdominal pain but peritoneal signs were not present. Blood tests were remarkable for hematocrit of 33 and mean cell volume of 78, with ovalocytes and basophilic stippling on blood smear. Abdominal x-ray showed stool throughout the colon and a nonspecific bowel gas pattern. The patient was treated with intravenous fluids and enemas, and his symptoms resolved within 2 days. Repeat history taking revealed he had been stripping paint from an old Victorian house in the preceding few months. He was discharged after a blood lead level was obtained. Before his clinic appointment he was readmitted 2 days later with recurrent abdominal pain. His blood lead level was elevated at 110 microg/dl (toxic range). After consultation with the Occupational Health and Safety Administration and local poison control service, he was treated with intravenous calcium edetate disodium and intramuscular dimercaprol. He was asymptomatic at discharge, with a level of 56 microg/dl. Two weeks later, a repeat level was elevated at 72 microg/dl, for which he received a 3-wk course of oral dimercaptosuccimer. Subsequent levels were unremarkable, and the patient remains asymptomatic. Abdominal pain secondary to lead poisoning in adults is uncommon. This case highlights the importance of taking a detailed occupational history and appropriately using "routine" blood tests to diagnose a rare condition that presented with a common complaint.

Abdominal Pain↗

Acute arsenic poisoning: absence of polyneuropathy after treatment with 2,3-dimercaptopropanesulphonate (DMPS).

Two men aged 19 and 21 years ingested 1 g and 4 g respectively from 3 kg of a white crystalline powder that they thought was a substance of abuse. It was later identified as almost pure arsenic trioxide. Both had nausea and vomiting and one developed acute renal failure. Each was treated with 2,3-dimercaptopropanesulphonate (DMPS), and made a full recovery with no evidence of prolonged renal or neurological impairment. The DMPS-arsenic complex is probably associated with lower penetration into the CNS and as a consequence treatment with DMPS may result in lower acute and chronic neurotoxicity than treatment with the currently standard recommended chelating agent dimercaprol (British Anti-Lewisite; BAL).

Acute Disease↗

Activation of the alternative pathway of human complement by sulfhydryl compounds of analytic and therapeutic use.

Thiol-containing drugs (dimercaprol, dimercaptopropanesulfonate, captopril, penicillamine, N-acetylcysteine) and the standard reducing agent beta-mercaptoethanol, activate the alternative pathway of complement as shown by in vitro experiments. Depending on the substance tested, at concentrations of 0.5-5 mM, cleavage products of C3 and factor B were demonstrable in serum by immunoelectrophoresis. The regulatory protein factor I proved to be very sensitive to thiols; this observation offers an explanation for the alternative pathway activating effect of these substances. At concentrations of thiols that initiate the alternative pathway, the classical pathway was not or only to a minor extent activated; however, the activity of C2, C5 and one or several of the components C6-9 was directly affected. Alkylation of the thiol group of the compounds tested, abrogated their effects on the complement system.

Alkylation↗

Subinhibitory bismuth-thiols reduce virulence of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a common pathogen in mechanically ventilated patients and produces a wide array of virulence factors. Bismuth-thiols (BTs) are active in vitro against all bacterial lung pathogens, including P. aeruginosa. The objective of these studies was to examine the biochemical and morphologic effects of sublethal BT concentrations on P. aeruginosa and to evaluate virulence in cell culture. Bismuth-dimercaprol, at a fraction of the minimal inhibitory concentration, reduced alginate expression by 67% in P. aeruginosa, whereas subinhibitory bismuth-ethanedithiol (BisEDT) reduced alginate by 92% in P. syringae. BisEDT effects on lipopolysaccharide content and type III secreted cytoxins were examined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Subinhibitory BisEDT reduced cell-associated lipopolysaccharide, and inhibited processing of the secreted cytotoxic protein ExoU. BisEDT-induced outer membrane blebbing and aggregation of cytoplasmic material was noted in electron microscopy. Virulence of P. aeruginosa was assessed by adherence to epithelial cells and sensitivity to serum killing. BisEDT inhibited adherence of P. aeruginosa to 16HBE14o- cells by 28% and to a collagen matrix by 53%. BisEDT-treated bacteria were also 100-fold more sensitive to serum bactericidal activity. In summary, low BT concentrations affect P. aeruginosa in a variety of ways, the combination of which may help prevent or resolve respiratory tract infection.

Bacterial Adhesion↗

Wilson's disease: clinical, genetic and pharmacological findings.

Wilson's disease (WD) is an autosomal recessive disorder characterized by copper accumulation and toxicity in the liver and in other tissues. WD presents with liver disease, neurological or psychiatric disturbances or other less common clinical features. Diagnosis of WD is often difficult and may be formulated through clinical, biochemical, imaging, histochemical and genetic evaluations. Pharmacological approach in WD consists in copper chelating agents such as D-penicillamine, trientine, dimercaprol and tetrathiomolybdate. In 1997 zinc was approved for maintenance therapy of WD by the U.S. FDA. Orthotopic Liver Transplantation is indicated in fulminant hepatic failure, progressive hepatic insufficiency despite therapy, cirrhosis with complications of portal hypertension. However the most appropriate therapy, including OLT, remains controversial in WD and further studies are needed especially in order to differentiate the possibility of specific therapies for different WD phenotypes.

Chelating Agents↗

Mercury poisoning after disc-battery ingestion.

A case is described of a 2-year-old girl who swallowed an alkaline disc battery containing mercuric oxide. Two days after ingestion it disintegrated in the stomach necessitating laparotomy to remove the battery casing and most of its contents. Postoperatively her blood mercury concentration rose to 340 micrograms/l and subsequently she developed small bowel obstruction due to adhesions. She was treated with dimercaprol but blood mercury concentrations did not fall until after a second laparotomy to relieve the obstruction and to remove residual mercury salts from the colon. The corrosive effects of swallowed disc batteries are well documented. The maximum blood concentration of mercury reported in this case is 17 times the 'acceptable level of mercury in the blood' and nearly double the highest level recorded previously after disc-battery ingestion. A policy for management of swallowed batteries is suggested.

Child, Preschool↗

Cysteamine-induced decrease of somatostatin in rat brain synaptosomes in vitro.

The mechanism of somatostatin depletion induced by cysteamine [2-mercaptoethylamine (CySH)] was studied in isolated nerve endings (synaptosomes) from rat brain in vitro. A dose-dependent reduction of somatostatin-like immunoreactivity (SLI) was observed which reached its maximal extent (41%) at a concentration of 300 microM CySH after 1-5 min. There was no release of somatostatin into the incubation medium. CySH at concentrations of up to 10 mM did not interfere in the RIA. Among a variety of compounds, structurally related to CySH 4-aminothiophenol, 2-aminothiophenol and N,N-dimethylaminothiol exhibited the highest efficacy in decreasing somatostatin (60%, 50%, 30%, respectively, at 10 mM and 10 min). The disulfide form of CySH cystamine and dimercaprol resulted in about 15% reduction after 10-min incubation, whereas taurine, alanine, cysteine, and mercaptoethanol were inactive. A saturable, sodium-dependent uptake process was found for the disulfide form of [35S]CySH cystamine [Michaelis-Menten constant (Km) = 18.6 microM, maximum velocity (Vmax) = 2.3 nmol/mg protein X 3 min) which was inhibited by cysteine (87% at 1 mM). [35S]CySH, at concentrations of 20 microM or less, was not stable in buffer solution. It underwent considerable nonenzymatic conversion into its dimeric form (60% at 37 C and 3 min), however it exhibited the same kinetic data for its uptake. Size exclusion HPLC of purified hypothalamic synaptosomes revealed a major SLI peak coeluting with synthetic somatostatin-14 and two minor peaks representing somatostatin-28 and a 13,000 mol wt protein. The three molecular forms of somatostatin were reduced to varied extent by CySH (somatostatin-14 by about 70%, somatostatin-28 by 15%, and the high mol wt form by 30%). Our experiments suggest that high affinity uptake of CySH may precede its action in decreasing somatostatin levels. Increased release or inhibition of synthesis of somatostatin have been excluded as possible mechanisms. It is suggested that SLI is equally affected in nerve endings and in perikarya.

Animals↗

Severe lead poisoning in pregnancy.

BACKGROUND: Lead freely crosses the placenta. Consequently, gestational lead poisoning is not only harmful to the woman but also to the developing fetus, invariably producing congenital lead poisoning. The scope and consequences of severe lead poisoning in pregnancy (blood lead level > or =45 microg/dL) have not been well characterized. METHODS: We reviewed our experience in the management of women with severe gestational lead poisoning. Additionally, we reviewed the literature on this disorder in an effort to identify patterns in etiology and outcome. RESULTS: Over a 3-year period treatment was provided to 7 severely lead-poisoned women. A 25-year review of the medical literature identified an additional 8 cases. Among these 15 women, 70% were Hispanic, all of whom developed lead poisoning from the ingestion of soil, clay, or pottery ("tierra"). Other sources of lead poisoning were paint chip ingestion (n = 2), household renovation, and use of a complementary-alternative medication (bone meal). Lead poisoning was discovered in the third trimester in 12 (86%) subjects after the women presented with subtle but characteristic findings of severe lead poisoning, including malaise, anemia, or basophilic stippling on blood smear; one woman was identified when she presented after a generalized seizure, having a blood lead level of 104 microg/dL. Five women received chelation therapy during pregnancy with CaNa(2) EDTA, dimercaprol, or succimer. At delivery mean maternal blood lead level was 55 microg/dL, whereas mean neonatal lead level was 74 microg/dL (P =.009). Thirteen neonates underwent chelation, all within the first 28 days of life. No infant in the current series had an identifiable birth defect. CONCLUSIONS: On the basis of this experience we conclude that severe lead poisoning in pregnant women has the following characteristics: 1) it most often occurs because of intentional pica, 2) its presenting features are subtle, often consisting only of malaise and anemia, and 3) blood lead levels in the neonate are higher than simultaneous maternal lead levels.

Female↗

Strategies for safe and effective therapeutic measures for chronic arsenic and lead poisoning.

Exposure to toxic metals remains a widespread occupational and environmental problem in world. There have been a number of reports in the recent past suggesting an incidence of childhood lead poisoning and chronic arsenic poisoning due to contaminated drinking water in many areas of West Bengal in India and Bangladesh has become a national calamity. Low level metal exposure in humans is caused by air, food and water intake. Lead and arsenic generally interferes with a number of body functions such as the central nervous system (CNS), the haematopoietic system, liver and kidneys. Over the past few decades there has been growing awareness and concern that the toxic biochemical and functional effects are occurring at a lower level of metal exposure than those that produce overt clinical and pathological signs and symptoms. Despite many years of research, we are still far from an effective treatment of chronic plumbism and arsenicosis. Medical treatment of acute and chronic lead and arsenic toxicity is furnished by chelating agents. Chelating agents are organic compounds capable of linking together metal ions to form complex ring-like structures called chelates. They have been used clinically as antidotes for acute and chronic poisoning. 2, 3-dimercaprol (BAL) has long been the mainstay of chelation therapy for lead or arsenic poisoning. Meso 2, 3, -dimercaptosuccinic acid (DMSA) has been tried successfully in animals as well as in a few cases of human lead and arsenic poisoning. DMSA could be a safe and effective method for treating lead or arsenic poisoning, but one of the major disadvantages of chelation with DMSA has been its inability to remove lead from the intracellular sites because of its lipophobic nature. Further, it does not provide protection in terms of clinical/ biochemical recovery. A new trend in chelation therapy is to use combined treatment. This includes the use of structurally different chelators or a combination of an adjuvant and a chelator to provide better clinical/biochemical recovery in addition to lead mobilization. The present review article attempts to provide update information about the current strategies being adopted for a safe, effective and specific treatment for two major toxic metals or metalloid.

Animals↗

Acute mercury poisoning by intentional ingestion of mercuric chloride.

A 26-year-old woman ingested 0.9 g of mercuric chloride in a suicide attempt and developed hematemesis, melena and acute renal failure. Anuria persisted for 14 days. She was treated by plasma exchange, hemodialysis and peritoneal dialysis in combination with continued dimercaprol chelation. While hemodialysis was ineffective in removing the mercury, plasma exchange effectively eliminated mercury. After two plasma exchange therapies, mercury concentration in the blood decreased linearly on a log scale with half-lives of 23.1 days for whole blood and 19.1 days for plasma, using first-order kinetics. One month after ingestion, renal function recovered to normal as judged by serum creatine and blood urea nitrogen levels, although the beta 2-microglobulin level in urine was still elevated. At a follow-up examination four months later, renal function was found to be completely normal. This indicates that the renal damage caused by acute mercuric chloride poisoning may not be permanent.

Adult↗

Lead toxicity and chelation therapy.

PURPOSE: Common sources of lead exposure, the primary clinical effects of lead toxicity, and current recommendations for managing lead toxicity, including chelation therapy, are reviewed. SUMMARY: Common sources of lead exposure in children and adults include industrial and mining activities, paint, dust, soil, water, air, the workplace, food, trinkets, ethnic folk remedies, and cosmetics. The absorption and biological fate of lead are affected by a variety of factors, including an individual's nutritional status, health, and age. Children with a blood lead concentration of >10 microg/dL and adults with a blood lead concentration of > or = 45 mug/dL should undergo further evaluation. Symptoms and time to onset of symptoms postexposure may vary, and it can be difficult to identify the early, subtle neurologic effects of lead toxicity. The classic symptoms of lead toxicity generally correlate with blood lead concentrations of 25-50 microg/dL in children and 40-60 microg/dL in adults. Management of lead toxicity requires extensive risk assessment and caregiver education. Chelation is generally not indicated for adults with blood lead concentrations of < 45 microg/dL because of the potential risk of adverse drug events and concerns about remobilized lead, and chelation for children with blood lead concentrations of < 45 microg/dL remains controversial. Dimercaprol, edetate calcium disodium, and succimer are the three agents primarily used for chelation. CONCLUSION: Lead toxicity remains a significant public health concern. Elimination of elevated blood lead levels in children can be accomplished by educating appropriate health care providers and caregivers, recognizing potential lead sources, and adopting aggressive prevention and case management measures.

Adult↗

Thallium toxicity and the role of Prussian blue in therapy.

Thallium salts have been used as medicinal agents, as key ingredients in a variety of manufacturing processes, and as a potent rodenticide. Additionally, environmental concerns are growing, as thallium is a waste product of coal combustion and the manufacturing of cement. Thallium salts are rapidly and nearly completely absorbed by virtually all routes, with gastrointestinal exposure being the most common route to produce toxicity. Thallium enters cells by a unique process governed by its similarity in charge and ionic radius to potassium. Although the exact mechanism of toxicity has not been established, thallium interferes with energy production at essential steps in glycolysis, the Krebs cycle, and oxidative phosphorylation. Additional effects include inhibition of sodium-potassium-adenosine triphosphatase and binding to sulfhydryl groups. The major manifestations of toxicity consist of a rapidly progressive, ascending, extremely painful sensory neuropathy and alopecia. Unlike exposure to most metal salts, gastrointestinal symptoms of thallium toxicity are relatively minor, and constipation is more characteristic than diarrhoea. Many other findings such as an autonomic neuropathy, cranial nerve abnormalities, altered mental status, motor weakness, cardiac, hepatic, and renal effects are described, but are less specific. Thallium also crosses the placenta freely and produces abnormalities in animals as well as fetal demise, overt toxicity and congenital abnormalities in humans. There are no controlled trials of treatments in thallium-poisoned patients. Thus, the literature is predominated by very small animal studies and case reports with very limited data. Strong evidence speaks against the use of traditional metal chelators such as dimercaprol (British Anti-Lewisite) and penicillamine, and the latter may cause redistribution of thallium into the central nervous system. Likewise, forced potassium diuresis appears harmful. The use of single- or multiple-dose activated charcoal is supported by in vitro binding experiments and some animal data, and charcoal haemoperfusion may be a useful adjunct. Multiple animal studies give evidence for enhanced elimination and improved survival with Prussian blue. Unfortunately, despite the fact that many humans have been treated with Prussian blue, the data presented are insufficient to comment definitively on its efficacy. However, Prussian blue's safety profile is superior to that of other proposed therapies and it should be considered the drug of choice in acute thallium poisoning. Public health efforts should focus on greater restrictions on access to, and use of, thallium salts.

Animals↗

Chelators as antidotes of metal toxicity: therapeutic and experimental aspects.

The effects of chelating drugs used clinically as antidotes to metal toxicity are reviewed. Human exposure to a number of metals such as lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium, arsenic, chromium, nickel and platinum may lead to toxic effects, which are different for each metal. Similarly the pharmacokinetic data, clinical use and adverse effects of most of the chelating drugs used in human metal poisoning are also different for each chelating drug. The chelating drugs with worldwide application are dimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-D-penicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa(2)EDTA), calcium trisodium or zinc trisodium diethylenetriaminepentaacetate (CaNa(3)DTPA, ZnNa(3)DTPA), deferoxamine (DFO), deferiprone (L1), triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). Several new synthetic homologues and experimental chelating agents have been designed and tested in vivo for their metal binding effects. These include three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTA and DTPA), the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA) and the carbodithioates. Many factors have been shown to affect the efficacy of the chelation treatment in metal poisoning. Within this context it has been shown in experiments using young and adult animals that metal toxicity and chelation effects could be influenced by age. These findings may have a bearing in the design of new therapeutic chelation protocols for metal toxicity.

Age Factors↗

[Arterial hypertension due to mercury intoxication with clinical and laboratorial syndrome simulating pheochromocytoma].

A 17-year-old boy was admitted to hospital because of severe hypertension (200/130 mmHg), headache, irritability, sweating, etc. Initial biochemical tests suggested pheochromocytoma, being treated with nifedipina, clonidina and propranolol. On reporting exposure to mercury vapour, he underwent twenty-four-hour urine screening and measurement of blood mercury which confirmed intoxication. The patient received courses of chelation therapy with dimercaprol (BAL) and penicillamine with remission of symptoms and normalisation of hypertension after 2 months. This case is relevant to current practice regarding similarity between mercury intoxication and hypertension secondary to pheochromocytoma.

English Abstract↗

Cysteine analogues potentiate glucose-induced insulin release in vitro.

In rat pancreatic islets, cysteine analogues, including glutathione, acetylcysteine, cysteamine, D-penicillamine, L-cysteine ethyl ester, and cysteine-potentiated glucose (11.1 mM) induced insulin secretion in a concentration-dependent manner. Their maximal effects were similar and occurred at approximately 0.05, 0.05, 0.1, 0.5, 1.0, 1.0 mM, respectively. At substimulatory glucose levels (2.8 mM), insulin release was not affected by these compounds. In contrast, thiol compounds, structurally different from cysteine and its analogues, such as mesna, tiopronin, meso-2,3-dimercaptosuccinic acid (DMSA), dimercaprol (BAL), beta-thio-D-glucose, as well as those cysteine analogues that lack a free-thiol group, including L-cystine, cystamine, D-penicillamine disulfide, S-carbocysteine, and S-carbamoyl-L-cysteine, did not enhance insulin release at stimulatory glucose levels (11.1 mM); cystine (5 mM) was inhibitory. These in vitro data indicate that among the thiols tested here, only cysteine and its analogues potentiate glucose-induced insulin secretion, whereas thiols that are structurally not related to cysteine do not. This suggests that a cysteine moiety in the molecule is necessary for the insulinotropic effect. For their synergistic action to glucose, the availability of a sulfhydryl group is also a prerequisite. The maximal synergistic action is similar for all cysteine analogues tested, whereas the potency of action is different, suggesting similarity in the mechanism of action but differences in the affinity to the secretory system.

Acetylcysteine↗

Putative cocaine receptor in striatum is a glycoprotein with active thiol function.

Dopamine transporters of bovine and rat striata were identified by their specific [3H]cocaine binding and cocaine-sensitive [3H]dopamine [( 3H]DA) uptake. Both binding and uptake functions of bovine striatal transporters were potentiated by lectins. Concanavalin A (Con A) increased the velocity but did not change the affinity of the transporter for DA; however, it increased its affinity for cocaine without changing the number of binding sites. This suggests that the DA transporter is a glycoprotein and that Con A action on it produces conformational changes. Inorganic and organic mercury reagents inhibited both [3H]DA uptake and [3H]cocaine binding, though they were all more potent inhibitors of the former. n-Ethylmaleimide inhibited [3H]DA uptake totally but [3H]cocaine binding only partially. Also, n-pyrene maleimide had differential effects on uptake and binding, inhibiting uptake and potentiating binding. [3H]DA uptake was not affected by mercaptoethanol up to 100 mM, whereas [3H]cocaine binding was inhibited by concentrations above 10 mM. On the other hand, both uptake and binding were fairly sensitive to dimercaprol (less than 1 mM). The effects of all these sulfhydryl reagents suggest that the DA transporter has one or more thiol group(s) important for both binding and uptake activities. The Ellman reagent and dithiopyridine were effective inhibitors of uptake and binding only at fairly high concentration (greater than 10 mM). Loss of activity after treatment with the dithio reagents may be a result of reduction of a disulfide bond, which may affect the transporter conformation.

4-Chloromercuribenzenesulfonate↗

Hemodialysis in a patient with acute mercuric cyanide intoxication. Concentrations of mercury in blood, dialysate, urine, vomitus, and feces.

The effectiveness of hemodialysis in removing mercury was examined in a 14-year-old boy with acute renal failure due to intoxication by 1.5 gm of mercuric cyanide. Mercury concentrations in blood, dialysate, urine, vomitus, and feces were measured. In some materials, the total mercury and the "free" mercury (inorganic and weakly bound) were determined separately. With the first hemodialysis, 1.4 mg of mercury was removed, but this amount decreased rapidly with subsequent dialyses. Fecal mercury excretion, on the other hand, was approximately 1 mg daily during the first two weeks. Excretion of mercury in urine did not exceed 126 microgram/day even during the polyuric phase. Losses in vomitus were insignificant. It is concluded that hemodialysis is of little use in elimination of mercury, even if performed after administration of dimercaprol.

Acute Kidney Injury↗