RESUMO
Heavy metals have received great attention as environmental pollutants mainly because once introduced in the biological cycle they are incorporated in the food chain. Especially the mercury toxicity due to a diversity of effects caused by different chemical species should be emphasized. Heavy metal intoxication has been treated with chelating agents such as 2,3-dimercapto-1-propanol (BAL). However, the efficacy of this treatment is questionable due to the lack of specific effect on the toxic metal. The present study examined the effects of HgCl2 exposure (five doses of 5.0 mg/kg between ages 8 to 12 days) on physiological parameters, on porphobilinogen synthase activity, and on mercury content in liver, kidneys and brain from suckling rats. The effect of BAL (one dose of 12.5-75 mg/kg) applied 24 hr after mercury intoxication on these parameters was also investigated. The results demonstrate that HgCl2 intoxication induced a decrease of corporal weight gain as well as brain weight and an increase in renal weight. The inhibition of porphobilinogen synthase from liver and kidney, is still significant and was not modified by subsequent BAL treatment. However, BAL altered two effects induced by mercury: increase in death percentage and decrease in mercury contents in liver and kidney. The increase of mortality induced by mercury was not promoted by metal redistribution to brain nor by the increase of porphobilinogen synthase inhibition induced by metal. More investigations are necessary to determine if the different effects of BAL on intoxication by metals are possibly related to other tissues and/or if the probable metal-chelating complex formed is more toxic than the metal itself.
Assuntos
Dimercaprol/farmacocinética , Rim/química , Fígado/química , Cloreto de Mercúrio/farmacocinética , Mercúrio/antagonistas & inibidores , Sintase do Porfobilinogênio/farmacocinética , Animais , Animais Recém-Nascidos/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Química Encefálica , Morte , Dimercaprol/administração & dosagem , Dimercaprol/efeitos adversos , Esquema de Medicação , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Injeções Subcutâneas , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cloreto de Mercúrio/administração & dosagem , Cloreto de Mercúrio/antagonistas & inibidores , Mercúrio/química , Tamanho do Órgão/efeitos dos fármacos , Sintase do Porfobilinogênio/efeitos dos fármacos , Sintase do Porfobilinogênio/metabolismo , Ratos , Ratos Wistar , Aumento de Peso/efeitos dos fármacosAssuntos
Dimercaprol/administração & dosagem , Succímero/administração & dosagem , Unitiol/administração & dosagem , Ácido Aminolevulínico/antagonistas & inibidores , Ácido Aminolevulínico/química , Animais , Química Encefálica/efeitos dos fármacos , Dimercaprol/farmacocinética , Dimercaprol/toxicidade , Epilepsia Tônico-Clônica/induzido quimicamente , Injeções Subcutâneas , Rim/química , Rim/efeitos dos fármacos , Fígado/química , Fígado/efeitos dos fármacos , Masculino , Camundongos , Succímero/farmacocinética , Succímero/toxicidade , Compostos de Sulfidrila/química , Fatores de Tempo , Testes de Toxicidade Aguda/métodos , Unitiol/farmacocinética , Unitiol/toxicidade , Zinco/químicaRESUMO
Dimercaprol is a compound used in the treatment of mercury intoxication, however with low therapeutic efficacy. It is assumed that dimercaprol acts by reactivating target sulfhydryl-containing proteins. In the present investigation we studied the inhibitory effect of mercuric chloride treatment (3 days with 2.3 or 4.6 mg/kg HgCl2, sc) in mice on cerebral, renal and hepatic delta-aminolevulinate dehydratase (ALA-D) activity, and a possible reversal of the effect of mercury by dimercaprol (0.25 mmol/kg, 24 hr after the last mercury injection). Mercuric chloride did not inhibit cerebral ALA-D at the doses injected. Dimercaprol treatment did not restore the normal enzyme activity of the liver after the 25% inhibition caused by 4.6 mg/kg HgCl2. In the kidney, dimercaprol enhanced the inhibitory effect of 4.6 mg/kg mercuric chloride (from 35% after mercury treatment alone to 65% after mercury plus dimercaprol treatment). Mercury content increased in kidney after exposure to 2.3 or 4.6 mg/kg and the levels attained were higher than in any other organ Mercury accumulated in liver only after exposure to 4.6 mg/kg HgCl2, and dimercaprol further increased mercury deposition. Dimercaprol treatment also increased the levels of mercury in brain of animals exposed to 4.6 mg/kg HgCl2 The enzymes from all sources presented similar sensitivity to the combined effect of HgCl2 and dimercaprol in vitro. In the absence of preincubation, 0-500 muM dimercaprol potentiated the inhibitory effect of HgCl2 on ALA-D activity. In the presence of preincubation, and 100 and 250 muM dimercaprol enhanced ALA-D sensitivity to mercury, whereas 500 muM dimercaprol partially protected the enzyme from mercury inhibition. Dimercaprol (500 muM) inhibited renal and hepatic ALA-D when preincubated with the enzymes. These data suggested that the dimercaprol-Hg complex may have a more toxic effect on ALA-D activity than Hg2+. Furthermore, the present data show that dimercaprol did not acts by reactivating mercury-inhibited sulfhydryl-containing ALA-D, and that indeed it may have an inhibitory effect per se depending on the tissue.
Assuntos
Antídotos/farmacologia , Dimercaprol/farmacologia , Cloreto de Mercúrio/toxicidade , Mercúrio/metabolismo , Sintase do Porfobilinogênio/metabolismo , Análise de Variância , Animais , Antídotos/administração & dosagem , Antídotos/toxicidade , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Dimercaprol/administração & dosagem , Dimercaprol/toxicidade , Injeções Subcutâneas , Rim/efeitos dos fármacos , Rim/enzimologia , Dose Letal Mediana , Fígado/efeitos dos fármacos , Fígado/enzimologia , Cloreto de Mercúrio/administração & dosagem , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Distribuição TecidualRESUMO
We examined the efficacy and safety of meso-2,3-dimercaptosuccinic acid (DMSA) in children with markedly elevated blood lead (BPb) concentrations. Among 19 children with BPb concentrations of 50 to 69 micrograms/dl (2.41 to 3.33 mumol/L) who received a 5-day inpatient oral course of DMSA (1050 mg/m2 per day), the mean BPb concentration decreased by 61%; in four who received calcium disodium ethylenediaminetetraacetic acid (CaNa2EDTA) (1000 mg/m2 per day intravenously), it decreased by 45% (p less than 0.0007). Urinary lead excretion was comparable in both groups. Treatment with DMSA was more effective than treatment with CaNa2EDTA in restoring metabolic activity to the heme pathway and was well tolerated even among nine patients who received concomitant iron supplementation and two who had homozygous deficiency of glucose-6-phosphate dehydrogenase. On discharge, these 19 children received either no chelation therapy or DMSA, 350 or 700 mg/m2 per day for 14 days on an outpatient basis. After 14 days the mean BPb values for the no-chelation, low-DMSA, and high-DMSA groups were 73%, 66%, and 50% of the pretreatment values, respectively. We conclude that a 5-day oral course of DMSA is effective in the treatment of children with severe lead poisoning. In addition, on an outpatient basis the administration of DMSA, 700 mg/m2 per day, is capable of delaying the typical rebound in BPb values and should ultimately reduce the need for repeated hospitalizations.
Assuntos
Intoxicação por Chumbo/tratamento farmacológico , Succímero/uso terapêutico , Administração Oral , Assistência Ambulatorial , Ácido Aminolevulínico/urina , Cálcio/urina , Quelantes/administração & dosagem , Quelantes/uso terapêutico , Criança , Pré-Escolar , Dimercaprol/administração & dosagem , Dimercaprol/uso terapêutico , Ácido Edético/administração & dosagem , Ácido Edético/uso terapêutico , Eritrócitos/enzimologia , Seguimentos , Humanos , Lactente , Injeções Intravenosas , Chumbo/sangue , Chumbo/urina , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/urina , Sintase do Porfobilinogênio/sangue , Segurança , Succímero/administração & dosagem , Zinco/urinaRESUMO
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.