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PubMed2002

Role of ATP-sensitive potassium channels in prostaglandin-mediated gastroprotection in the rat.

This study compares the involvement of ATP-sensitive potassium (K(ATP)) channels and prostaglandins in various forms of gastroprotection in the rat. Instillation of 1 ml of 70% ethanol induced severe gastric mucosal damage (lesion index 39 +/- 0.8), which was substantially but not maximally reduced by oral pretreatment with 16,16-dimethyl-prostaglandin (PG) E(2) (75 ng/kg), 20% ethanol (1 ml), sodium salicylate (15 mg/kg), the metal salt lithium chloride (7 mg/kg), the sulfhydryl-blocking agent diethylmaleate (5 mg/kg), and the thiol dimercaprol (10 mg/kg). Administration of indomethacin (20 mg/kg) increased gastric mucosal damage induced by 70% ethanol (lesion index 45 +/- 0.8) and significantly reduced the protective effect of 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The blocker of K(ATP) channels glibenclamide (5-10 mg/kg) significantly antagonized the protective effect of 16,16-dimethyl-PGE(2), 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The inhibition of protection induced by glibenclamide was reversed by pretreatment with the K(ATP) channel activator cromakalim (0.3-0.5 mg/kg). In conclusion, our results indicate a role of K(ATP) channels in the gastroprotective effect of 16,16-dimethyl-PGE(2) and of the other agents tested. Since the protection afforded by these agents is additionally indomethacin-sensitive, it is suggested that under these conditions endogenous prostaglandins act as activators of K(ATP) channels, and this mechanism, at least in part, mediates gastroprotection.

16,16-Dimethylprostaglandin E2↗
PubMed1991

Elemental mercury poisoning.

Three siblings with inhaled elemental mercury toxicity are described, and the signs and symptoms of mercury toxicity, interpretation of mercury concentrations, and management of elemental mercury exposure are reviewed. A 4-year-old girl was admitted to the hospital with a history of fever and increasing irritability, fatigue, malaise, insomnia, headache, anorexia, and ataxia. She was discharged two days later with a diagnosis of acute cerebellar ataxia. During the following 18 days, the child's condition worsened, and she was rehospitalized. Meanwhile her 11-year-old sister was hospitalized for evaluation of fatigue, weakness, lower back pain, and ataxia. The older girl's blood mercury concentration, at 5.5 micrograms/dL, was in the toxic range. Twenty-four-hour urine mercury screening confirmed mercury intoxication in both children. Questioning revealed that the girls' brother had recently spilled 0.5-1 oz of elemental mercury in the house. All family members underwent blood and urine mercury testing. The brother underwent a dimercaprol challenge to determine his tissue mercury burden, which was found to be greater than 2.4 micrograms/dL. The sisters underwent two courses of chelation therapy with dimercaprol. Symptoms persisted in all three children, and they underwent five 10-day cycles of N-acetyl-D,L-penicillamine (NAP) therapy; the youngest underwent a third dimercaprol regimen. All siblings continued NAP chelation therapy because of extensive tissue mercury burden until the results of repeated urine mercury concentration determinations were normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1999

Treatment of mercury intoxication.

The element mercury exists as inorganic, elemental, or organic species. Routes of exposure and toxicity in humans vary according to the species of mercury involved. Treatment of mercury poisoning generally requires the use of sulfhydryl bond-containing chelation agents, including the parenterally administered dimercaprol and its oral congeners. These oral chelators, meso-2,3-dimercaptosuccinic acid and sodium 2,3-dimercapto-1-propanesulfonate, have numerous advantages over dimercaprol, including less toxicity. Although dimercaprol is contraindicated in organic mercury exposures, meso-2,3-dimercaptosuccinic acid and sodium 2,3-dimercapto-1-propanesulfonate may be used to chelate all species of mercury. Recent evidence suggests that their efficacy in organic mercury poisoning is uncertain.

Chelating Agents↗
PubMedDate not supplied

Inhibition of adenylate cyclase by arsenite and cadmium: evidence for a vicinal dithiol requirement.

The effect of sodium arsenite and cadmium chloride on adenylate cyclase activity was examined in turkey erythrocyte membranes. Sodium arsenite was a weak inhibitor of adenylate cyclase -7mM produced only 60% inhibition. Its effect, however, was greatly potentiated by equimolar 2,3 dimercaprol- wherein 0.7 mM sodium arsenite inhibited 100% with an apparent Ki of 0.1 mM. Equimolar mercaptoethanol was less effective in potentiating sodium arsenite inhibition. Thus 0.7mM sodium arsenite in the presence of equimolar mercaptoethanol inhibited adenylate cyclase 56%. Excess 2,3 dimercaprol reversed inhibition by sodium arsenite or cadmium chloride. Sodium arsenite or cadmium chloride inhibited all forms of adenylate cyclase activity tested, including nonhormonal stimulation. Equimolar sodium arsenite and dimercaprol, at concentrations that caused 100% inhibition of adenylate cyclase activity, reduced the binding of the beta-receptor specific ligand iodohydroxybenzylpindolol by less than 15%. These results suggest that turkey erythrocyte membranes contain closely juxtaposed thiol groups and that interaction of such groups with arsenate interferes with the catalytic function of adenulate cyclase.

Adenylyl Cyclase Inhibitors↗
PubMed1993

Sulfhydryl drugs reduce neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse.

Striatal levels of dopamine and its metabolites 3-methoxy-4-hydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA) decreased 7 days after subcutaneous injection of MPTP (20 mg/kg) to the mouse. Striatal GSH contents decreased and GSSG/GSH ratios increased one hour after subcutaneous administration of MPTP. Pretreatments of both cysteamine (200 mg/kg, s.c.) and dimercaprol (20 mg/kg, i.m.) reduced the MPTP-induced decreases in striatal dopamine, DOPAC and HVA, and also prevented the MPTP-induced decreases in GSH levels and increases in GSSG/GSH ratios. On the other hand, injection of cysteamine did not modify the MPTP-induced decreases in striatal levels of dopamine and its metabolites when it was done 2 hours after MPTP administration. Moreover, pretreatment of cysteamine did not affect striatal concentrations of MPP+ in MPTP-treated mice. These results suggest that sulfhydryl drugs such as cysteamine and dimercaprol may reduce neurotoxicity of MPTP probably via changes in redox cycle of glutathione in the brain.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1982

Anti-lewisite activity and stability of meso-dimercaptosuccinic acid and 2,3-dimercapto-1-propanesulfonic acid.

Meso-dimercaptosuccinic acid (DMSA) and the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS) are analogous in chemical structure to dimercaprol (BAL, British Anti-Lewisite). Dimercaprol was among the first therapeutically useful metal chelating agents and was developed originally as an anti-lewisite agent. Either DMSA or DMPS protects rabbits from the lethal systemic action of dichloro(2-chlorovinyl)arsine (29.7 mumols/kg, also known as lewisite. The analogs are active in this respect when given either sc or po. The stability of each of the three dimercapto compounds in distilled H2O, pH 7.0 at 24 degrees, has been examined for seven days. DMSA retained 82% of its mercapto groups, but no titratable mercapto groups remained in the DMPS or BAL solutions. At pH 5.0, however, there was no striking difference in the stability of the three dimercapto compounds (78-87%) over a seven day period. DMSA and DMPS warrant further investigation as water soluble metal binding agents in both in vivo and in vitro experiments.

Administration, Oral↗
PubMed1977

D-penicillamine therapy of acute arsenic poisoning.

Severe poisoning resulting from single ingestions of rodenticides, herbicides, or insecticides containing arsenic have been frequently recognized. We record three cases of solubilized arsenic trioxide poisoning in Navajo Indian children and one case of sodium arsenate ingestion in an infant. One fatality occurred during dimercaprol therapy prior to initiation of therapy with D-penicillamine. Three survivors were treated with 2.3-dimercaprol intramuscularly and with oral D-penicillamine. The use of D-penicillamine in arsenic poisoning has not been generally appreciated. Excretion data from the three children are presented which document the effectiveness of D-penicillamine, administered orally in four daily doses of 25 mg/kg/dose, in the therapy of arsenic intoxication. Excretion data for the trace metals, zinc and copper, during D-penicillamine chelation therapy are also reported.

Acute Disease↗
PubMed1989

Acute lead arsenate poisoning.

Three cases of acute lead arsenate poisoning which occurred in South Australia during a 12 month interval are described. The case reports demonstrate a number of features of the characteristic clinical syndrome which may follow ingestion of lead arsenate. The recommended management is immediate gastric lavage and subsequent chelation therapy with calcium EDTA and dimercaprol. Early gastric lavage may prevent significant lead absorption. However, arsenic acid (produced in the stomach when lead arsenate reacts with hydrochloric acid) is relatively water soluble and prompt gastric lavage is unlikely to prevent extensive arsenic absorption. It remains controversial as to whether chelation with dimercaprol prevents arsenical neuropathy.

Adult↗
PubMed1974

Plasma kinin and kininogen levels in the female rat during the oestrous cycle, pregnancy, parturition and the puerperium.

1 Plasma kininogen concentration of the female rat did not change during the oestrous cycle but increased two-fold during gestation. Plasma kininogen did not change during parturition, rose in the first puerperal day and then rapidly declined to non-pregnant levels.2 Free kinin levels in the blood of non-pregnant female rats were low and inconstant. Free kinin was undetectable in the blood of pregnant rats, but was found in four out of ten parturient rats.3 After administration of the kininase inhibitor dimercaprol (30 mg/kg i.p.), free kinin was present in the blood of six parturient rats. Dimercaprol caused appearance of free kinin in the blood of only one out of six non-pregnant rats.4 It appears that the plasma kinin system is activated to a small degree during parturition.

Animals↗
PubMed1991

Respiratory failure and death following acute inhalation of mercury vapor. A clinical and histologic perspective.

A family of four was exposed to toxic levels of mercury vapor while attempting to extract silver from mercury amalgam. All four suffered respiratory failure and subsequent death despite chelation therapy with dimercaprol. Histologic findings at autopsy were similar in all four cases demonstrating a progression of acute lung injury that appeared related to postexposure day survival. There were no clinical signs of extrapulmonary manifestations despite toxic serum mercury levels. Although serum mercury levels decreased in response to the mercury chelating agent dimercaprol, serum levels remained in the toxic range and no clinical response was observed. Acute inhalational exposure to high concentrations of mercury vapor causes pneumonitis that can lead to respiratory failure and death. This continues to be a health hazard in both the workplace and the home environment.

Adult↗
PubMed2002

[Shotgun injury of head and neck: case report].

A 48-year-old male was hit by a shotgun blast from behind while he was hunting. He was only 7 meters away when one of his colleagues pulled the trigger accidentally. About 180 lead pellets penetrated his head and neck. When he was brought to our hospital, he was alert and complained of occipital and nape pain, but had no apparent neurological deficits. We administered 200 mg of dimercaprol immediately and removed 77 pellets by midline suboccipital incision on the next day. Afterwords, we performed four minor operations using a fluoroscope, and removed another 70 pellets by day 29. In addition, we administered a 100 mg x 3 dose of dimercaprol every other week. He was discharged 41 days after the accident without any acute signs of lead poisoning. Though serum lead level did not rise to critical level, EDTA was continued after his discharge to prevent delayed lead poisoning from the retained pellets. Since we seldom encounter this type of patient in Japan, delayed lead poisoning by shotgun injury was discussed with reference to the literature.

Chelating Agents↗
PubMed1983

Studies on the oxygen toxicity after administration of chelate-forming agents in mice.

The influence of the chelating agents CaNa2-EDTA, penicillamine, dimercaprol, unithiol, dithiocarb, aurin tricarboxylic acid, salicylic acid, and acetylsalicylic acid on the toxicity of oxygen at elevated tension was studied in mice. With the possible exception of dimercaprol, no increase in toxic effects of oxygen was observed after administering these chelate-forming agents in the doses used.

Animals↗
PubMed1978

Changes in the hepatic copper conent after treatment with foreign compounds.

The effects of dimercaprol, CaNa2EDTA, D-penicillamine, diethyldithiocarbamate, disulfiram, pyrazole and phenobarbital on the hepatic copper content were studied. Adult male albino rats were given these compounds subcutaneously or intragastrically for 4 or 7 days, and the copper content in the hepatic crude homogenate was measured with an atomic absorption spectrophotometer. The metal chelating compounds dimercaprol, D-penicillamine and diethyldithiocarbamate only slightly decreased the level of copper in the liver. CaNa2 EDTA caused no change in the copper content. A slight decrease was found also after phenobarbital treatment. On the contrary, disulfiram and pyrazole increased the copper content 3- and 2-fold, respectively. It is suggested that the accumulation of copper in the liver is due to the cholestatic action of disulfiram and pyrazole.

Animals↗
PubMed1989

Retention of radiolead by human erythrocytes in vitro.

An in vitro method was developed to assess human erythrocyte lead uptake and release directly, rapidly, and reproducibly; the technique requires small aliquots of blood and uses silicone fluid to separate erythrocytes from their suspending media. Uptake occurred rapidly and was directly related to temperature. Increasing quantities of available elemental lead were associated with increasing absolute quantities but decreasing percentages of uptake. Low values of pH diminished the uptake and enhanced the release of radiolead by erythrocytes, and could be correlated with diminished lead-hemoglobin binding para-Chloromecuribenzoate increased and dithiothreitol inhibited radiolead uptake but neither compound affected lead release, suggesting that sulfhydryl groups are important for lead binding to the erythrocyte. Cyanamide and N-ethylmaleimide did not significantly affect the net uptake or release of radiolead. Calcium disodium EDTA, penicillamine, and dimercaprol significantly reduced lead uptake, although only incubation with dimercaprol resulted in a net removal of lead from erythrocytes. Iron and ceruloplasmin significantly decreased radiolead uptake, but inorganic metal cations other than iron, hyperosmolarity, human serum albumin, cholesterol, and transferrin had no significant effect on uptake or release.

Chelating Agents↗
PubMed2006

Persistent conjunctivitis associated with drinking arsenic-contaminated water.

PURPOSE: The aim of this study was to report on 2 cases of bilateral chronic conjunctivitis that were associated with the drinking of arsenic-contaminated underground water for a long time. DESIGN: Interventional case reports comprised the study. METHODS: This study was a review of clinical data and laboratory investigations. RESULTS: Papillary conjunctivitis developed in 2 members of a family who has been drinking underground water for 15 years. There were severe dermatological changes, including hyperkeratosis, on palms and soles, hypo- and hyperpigmented lesions (rain-drop) on the abdomen, chest, and back. Arsenic levels estimated in the nails and hair of both patients were very high. The arsenic level of the drinking water was above the permissible limit. Histopathological examination of conjunctival tissue confirmed the inflammatory response of a papillary type; however, an arsenic estimation in conjunctival tissue was not possible. There were no inclusions of bodies in conjunctival smears stained with hematoxylin and eosin (H&E) stain. There was no response to the usual treatment for papillary conjunctivitis, which only subsided, along with a regression of dermatological changes, when patients were treated with the chelating agent, dimercaprol, and multivitamin preparations, as well as no longer drinking the contaminated water. CONCLUSIONS: This is a rare association and, to the best of our knowledge, the first report of successful treatment with dimercarpol. The source of arsenic was contaminated underground drinking water (from a deep tube-well). The pathophysiology is thought to be the result of an inflammatory response caused by accumulated arsenic in local tissues. Papillary conjunctivitis and dermatological changes can be successfully managed with dimercaprol and multivitamins. Further studies are required to find out the possible link between the papillary response of conjunctiva and arsenic accumulation within the body.

Adolescent↗
PubMed2005

Microarray analysis of mouse ear tissue exposed to bis-(2-chloroethyl) sulfide: gene expression profiles correlate with treatment efficacy and an established clinical endpoint.

Bis-(2-chloroethyl) sulfide (sulfur mustard; SM) is a potent alkylating agent. Three treatment compounds have been shown to limit SM damage in the mouse ear vesicant model: dimercaprol, octyl homovanillamide, and indomethacin. Microarrays were used to determine gene expression profiles of biopsies taken from mouse ears after exposure to SM in the presence or absence of treatment compounds. Mouse ears were topically exposed to SM alone or were pretreated for 15 min with a treatment compound and then exposed to SM. Ear tissue was harvested 24 h after exposure for ear weight determination, the endpoint used to evaluate treatment compound efficacy. RNA extracted from the tissues was used to generate microarray probes for gene expression profiling of therapeutic responses. Principal component analysis of the gene expression data revealed partitioning of the samples based on treatment compound and SM exposure. Patterns of gene responses to the treatment compounds were indicative of exposure condition and were phenotypically anchored to ear weight. Pretreatment with indomethacin, the least effective treatment compound, produced ear weights close to those treated with SM alone. Ear weights from animals pretreated with dimercaprol or octyl homovanillamide were more closely associated with exposure to vehicle alone. Correlation coefficients between gene expression level and ear weight revealed genes involved in mediating responses to both SM exposure and treatment compounds. These data provide a basis for elucidating the mechanisms of response to SM and drug treatment and also provide a basis for developing strategies to accelerate development of effective SM medical countermeasures.

Administration, Topical↗
PubMed1975

Arsenic poisoning in childhood. An unusual case report with special notes on therapy with penicillamine.

An unusual care of arsenic ingestion involving five children is reported, which involved the process of sublimation. As2O3 was inadvertently heated in a charcoal barbecue, and the meat cooked thereon was contaminated. It is possible that the sublimation may have potentiated the toxicity of the usually mildly toxic, relatively unsoluble As2O3. Penicillamine was used in the latter part of the therapy in three cases after initial dimercaprol, and the clinical effect of penicillamine was particularly dramatic in one case in which dimercaprol discontinuation had been accompanied by recurrent symptoms. Remarks on the mode of action of penicillamine are made. More work needs to be done to establish the possible role of penicillamine in arsenic poisoning.

Adolescent↗
PubMed1976

Clinical observations on treatment of alkylmercury poisoning in hospital patients.

Twenty-six patients suffering from methylmercury poisoning were treated by different therapeutic regimes. Seven received penicillamine or N-acetyl-d-L-penicillamine, 10 were treated with dimercaprol sulfonate and 9, who could not be treated, were given a placebo and were used as controls. Penicillamine, N-acetyl-d-L-penicillamine, and dimercaprol sulfonate reduced the blood level of mercury and increased its urinary excretion. No appreciable clinical improvement was noticed among the severe or very severe cases, while mild or moderate cases improved clinically irrespective of the treatment given.

Adolescent↗