RESUMO
BACKGROUND: Attacks of neuropathic pain, usually abdominal, are characteristic of the acute porphyrias and accompanied by overproduction of heme-precursor molecules, specifically delta-aminolevulinic acid and porphobilinogen. The basis for the acute symptoms in these diseases has been speculative. METHODS: We review genetic acute porphyria, hereditary tyrosinemia, and an acquired condition, lead poisoning. All perturb heme synthesis and present with a similar pain syndrome. RESULTS: Although each of these conditions has characteristic urine biochemistry, all exhibit excess delta-aminolevulinic acid. Moreover, in all, treatment with hemin reduces delta-aminolevulinic acid and relieves symptoms. In contrast, use of recombinant porphobilinogen deaminase to knock down porphobilinogen in acute porphyria was ineffective. CONCLUSIONS: There is now convincing evidence that delta-aminolevulinic acid is the cause of pain in the acute porphyrias. The efficacy of hemin infusion is due mainly, if not entirely, to its inhibition of hepatic delta-aminolevulinic acid synthase-1, the enzyme that catalyzes delta-aminolevulinic acid formation. Delta-aminolevulinic acid synthase-1 is a rational target for additional therapies to control symptoms in acute porphyria.
Assuntos
Ácido Aminolevulínico , Terapia por Quelação/métodos , Heme/biossíntese , Intoxicação por Chumbo , Ayurveda , Porfiria Aguda Intermitente/diagnóstico , Tirosinemias/diagnóstico , Dor Abdominal/etiologia , Dor Abdominal/metabolismo , Adulto , Ácido Aminolevulínico/sangue , Ácido Aminolevulínico/urina , Diagnóstico Diferencial , Feminino , Humanos , Intoxicação por Chumbo/diagnóstico , Intoxicação por Chumbo/etiologia , Intoxicação por Chumbo/metabolismo , Intoxicação por Chumbo/fisiopatologia , Intoxicação por Chumbo/terapia , Neuralgia/etiologia , Neuralgia/metabolismo , Resultado do TratamentoRESUMO
Iron overload in hereditary hemochromatosis and hematologic malignancy has unfavorable effects on morbidity. Herein, 53 children (age 108.4±58.3 mo, 25 girls and 28 boys) with acute myeloblastic and lymphoblastic leukemia, who received 4 different chemotherapy protocols, were evaluated for iron overload throughout chemotherapy. Iron overload arose: (1) before chemotherapy, which was dependent on neither chemotherapy nor packed red blood cell transfusions and (2) after chemotherapy, which was dependent on the duration and nature of chemotherapy and partially on transfusion of packed red blood cells. Iron overload was documented in 75% of patients with a ferritin level >1000 ng/mL, by liver and heart magnetic resonance imaging, and they were administered iron-chelation therapy with success. Three of 10 radiologically iron-overloaded patients were heterozygous for H63D mutation. Aminolevulinic acid and porphobilinogen levels were normal. Light microscopic examination of the bone marrow revealed increased iron granules in erythroblasts, platelets, and megakaryocytes, iron-laden macrophages, free iron in the matrix, dyshematopoiesis, and apoptotic cells. Electron microscopic examination revealed iron-laden secondary lysosomes and autolysosomes in normoblasts and iron-laden primary granules in promyelocytes, irrelevant to the ferritin level, implying autophagia due to chemotherapy as a source of the excess iron. We think that iron overload, which is an important complication of acute leukemia, should be evaluated separately from "transfusion overload," and the management principles specific to leukemia should be implemented.
Assuntos
Células da Medula Óssea , Medula Óssea , Hemocromatose , Quelantes de Ferro/administração & dosagem , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Ácido Aminolevulínico/sangue , Medula Óssea/metabolismo , Medula Óssea/ultraestrutura , Células da Medula Óssea/metabolismo , Células da Medula Óssea/ultraestrutura , Criança , Feminino , Ferritinas/sangue , Hemocromatose/sangue , Hemocromatose/complicações , Hemocromatose/tratamento farmacológico , Hemocromatose/genética , Hemocromatose/patologia , Humanos , Ferro/sangue , Quelantes de Ferro/efeitos adversos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Masculino , Mutação de Sentido Incorreto , Porfobilinogênio/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
BACKGROUND: In most industrialized countries, occupational lead poisoning has become increasingly rare, however this metal remains a serious health hazard in the rest of the world. REPORT OF CASES: We observedfour male patients (aged 35 / 54 years) who had suffered recurrent abdominal pain due to recent lead exposure (for 7 to 13 months) in two Chinese battery recycling plants. On their return to Italy, three of them presented normocytic, normochromic anaemia. The diagnosis was confirmed by high lead levels in the blood and urine, decreased erythrocyte delta-aminolevulinic acid dehydratase (ALA-D), raised erythrocyte zinc protoporphyrin (ZP), and elevated urinary excretion of b-aminolevulinic acid (ALA-U) and porphyrins. Chelation with EDTA resulted in increased urinary lead excretion, improvement of the clinical picture, decreased ZP, and progressive normalization of the other lead biomarkers (Pb-B, ALA-D, ALA-U, urinary porphyrins). CONCLUSIONS: Temporary work in developing countries may result in imported lead poisoning. Differential diagnosis of this unusual condition requires careful medical history collection and specific toxicological analysis. Preventive measures for workers going abroad are needed.
Assuntos
Intoxicação por Chumbo/diagnóstico , Intoxicação por Chumbo/prevenção & controle , Doenças Profissionais/diagnóstico , Doenças Profissionais/prevenção & controle , Exposição Ocupacional/prevenção & controle , Dor Abdominal/induzido quimicamente , Adulto , Ácido Aminolevulínico/sangue , Ácido Aminolevulínico/urina , Anemia/induzido quimicamente , Biomarcadores/sangue , Biomarcadores/urina , Quelantes/uso terapêutico , Terapia por Quelação/métodos , China , Países em Desenvolvimento , Diagnóstico Diferencial , Ácido Edético/uso terapêutico , Humanos , Itália , Chumbo/sangue , Chumbo/urina , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/tratamento farmacológico , Intoxicação por Chumbo/urina , Masculino , Anamnese , Metalurgia , Pessoa de Meia-Idade , Doenças Profissionais/sangue , Doenças Profissionais/tratamento farmacológico , Doenças Profissionais/urina , Exposição Ocupacional/efeitos adversos , Protoporfirinas/sangue , Protoporfirinas/urina , Reciclagem , Resultado do TratamentoRESUMO
Severe acute lead intoxications are rare and are associated with accidental or purposeful ingestion. There were only few cases of severe to fatal poisonings reported in literature in children. We report a case of acute lead intoxication in a child with extremely high lead blood level of 20.4 micromol/L (422.7 microg/dL), who was treated with chelation and in whom significant organ dysfunction did not develop. Documented significant high level above 3.37 micromol/L (corresponding to 70 microg/dL) in this patient persisted for approximately 24 h. Adequate, single or combined chelatation therapy in early phase of acute lead poisoning is essential for the further patient's outcome.
Assuntos
Antídotos/uso terapêutico , Carvão Vegetal/uso terapêutico , Quelantes/uso terapêutico , Ácido Edético/uso terapêutico , Intoxicação por Chumbo/terapia , Nitratos/intoxicação , Doença Aguda , Adolescente , Ácido Aminolevulínico/sangue , Feminino , Humanos , Chumbo/metabolismo , Intoxicação por Chumbo/metabolismo , Nitratos/metabolismo , Tentativa de Suicídio , Irrigação Terapêutica , Resultado do TratamentoRESUMO
The dose dependent effects of monoisoamyl and monomethyl esters of meso 2,3-dimercaptosuccinic acid (DMSA) (0.1, 0.3 and 0.5 mmol kg(-1), intraperitoneally (i.p.) once daily for 5 days) to offset the characteristic biochemical, immunological, oxidative stress consequences and DNA damage (based on DNA fragmentation and comet assay) following sub-chronic administration of gallium arsenide and the mobilization of gallium and arsenic were examined. The effects of these chelators alone in normal animals too were examined on above-mentioned variables. Male Wistar rats were exposed to 10 mg kg(-1), GaAs, orally once daily for 12 weeks and were administered DMSA or two of its monoesters (monoisoamyl or monomethyl) for 5 consecutive days. DMSA was used as a positive control. DMSA and its derivatives, when given alone, generally have no adverse effects on various parameters. After 5 days of chelation therapy in GaAs pre-exposed rats, MiADMSA was most effective in the reduction of inhibited blood delta-aminolevulinic acid dehydratase (ALAD) activity and zinc protoporphyrin level while, all three chelators effectively reduced urinary ALA excretion, compared to GaAs alone exposed rats. MiADMSA was also effective, particularly at a dose of 0.3 mmol kg(-1), in enhancing the inhibited hepatic transaminase activities. Parameters indicative of oxidative stress responded less favorably to the chelation therapy, however, three chelators significantly restored the altered immunological variables. MiADMSA was relatively more effective than the other two chelators. GaAs produced significant DNA damage in the liver and kidneys and the chelation treatment had moderate but significant influence in reducing DNA damage. All three chelators significantly reduced arsenic concentration and, however, MiADMSA was more effective than the other two chelators in depleting arsenic concentration from blood and other soft tissues. A dose of 0.3 mmol kg(-1) was found to be relatively better than the other two doses examined. Gallium contents of blood and soft tissues remained uninfluenced by the chelation therapy. Significant loss of copper after MiADMSA administration, however, is of concern and requires further exploration. Additionally, further studies are required for the choice of appropriate dose, duration of treatment and possible toxic/side effects. Keeping in view the promising role of MiADMSA in the treatment of GaAs poisoning, these data will be needed for the registration of this chelating agent as licensed drug for the treatment of gallium arsenide intoxication.
Assuntos
Antídotos/uso terapêutico , Intoxicação por Arsênico/tratamento farmacológico , Quelantes/uso terapêutico , Gálio/intoxicação , Succímero/análogos & derivados , Succímero/uso terapêutico , Ácido Aminolevulínico/sangue , Animais , Antídotos/administração & dosagem , Intoxicação por Arsênico/metabolismo , Arsenicais/sangue , Biomarcadores/análise , Quelantes/administração & dosagem , Terapia por Quelação , Ensaio Cometa , Fragmentação do DNA/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gálio/sangue , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Protoporfirinas/sangue , Ratos , Ratos Wistar , Succímero/administração & dosagem , Resultado do TratamentoRESUMO
In 123 Croatian men with no occupational exposure to metals, the influence of cadmium on reproductive parameters was examined after adjusting for age, smoking, alcohol, and biomarkers of lead, copper, zinc, and selenium. The following variables were measured: blood cadmium (BCd), blood lead (BPb), activity of delta-aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin, serum copper (SCu), serum zinc (SZn), serum selenium (SSe), activity of glutathione peroxidase (GPx) in blood, testis size, semen quality (including sperm concentration, motility, viability, and morphology), indicators in seminal fluid (the lactate dehydrogenase isoenzyme LDH-C4, fructose, zinc, acid phosphatase, and citric acid), and hormones in serum (follicle-stimulating hormone--FSH, luteinizing hormone, prolactin, testosterone, and estradiol). The median and range BCd values were 2.94 (0.49-11.93) microg/L in 61 smokers and 0.59 (0.20-3.71) microg/L in 62 nonsmokers (p < 0.0001). Smoking habits (cigarettes/day) highly significantly correlated with BCd (p < 0.0001). After adjusting for potential confounding variables by multiple regression, BCd was significantly associated with a decrease in testis size (p < 0.03) and an increase in serum estradiol (p < 0.005), FSH (p < 0.03), and testosterone (p < 0.04). Smoking was significantly associated with a decrease in serum prolactin (p < 0.006) and LDH-C4 in seminal fluid (p < 0.03). Several reproductive parameters were significantly associated with BPb and ALAD, biomarkers of lead, and/or with SCu, SZn, SSe, and GPx. The necessity of controlling for various metals, and other potential confounders when assessing the influence of a particular metal on reproductive function in men, is emphasized.
Assuntos
Cádmio/sangue , Fertilidade , Sêmen/fisiologia , Contagem de Espermatozoides , Adulto , Ácido Aminolevulínico/sangue , Biomarcadores , Cádmio/metabolismo , Cobre/sangue , Croácia , Estradiol/metabolismo , Glutationa Peroxidase/sangue , Humanos , Infertilidade Masculina , Chumbo/sangue , Masculino , Pessoa de Meia-Idade , Protoporfirinas/sangue , Análise de Regressão , Selênio/sangue , Fumar , Motilidade dos Espermatozoides , Fatores de Tempo , Zinco/sangueRESUMO
OBJECTIVE: To evaluate the effects of arsenic (III) exposure on porphyrin metabolism and the central nervous system supplemented with data on the effect of hepatic and renal tissues of rats and guinea pigs. METHODS: Rats and guinea pigs were exposed to 10 or 25 ppm arsenic in drinking water for 16 weeks. RESULTS: Following chronic arsenic (III) exposure, delta-aminolevulinic acid dehydratase activity in blood showed a significant reduction as did the total cell counts (RBC and WBC) and reduced glutathione with increased urinary delta-aminolevulinic acid. Zinc protoporphyrin, a sensitive indicator of iron deficiency and impairment of heme biosynthesis, showed a significant increase in arsenic exposure. The hepatic delta-aminolevulinic acid dehydratase and delta-aminolevulinic acid synthetase activity increased in chronic arsenic (III) exposure in rats and guinea pigs. Significant changes in the steady-state level of three major neurotransmitters, dopamine, norepinephrine, and 5-hydroxytryptamine, and monoamine oxidase were observed following chronic arsenic (III) exposure. CONCLUSION: At low doses (10 and 25 ppm in drinking water), the effects of arsenic on hematopoietic indices and whole-brain neurotransmitter concentrations were more prominent in guinea pigs than in rats with some variability in the dose response.
Assuntos
Arsenitos/toxicidade , Encéfalo/efeitos dos fármacos , Sistema Hematopoético/efeitos dos fármacos , Compostos de Sódio/toxicidade , 5-Aminolevulinato Sintetase/metabolismo , Ácido Aminolevulínico/sangue , Ácido Aminolevulínico/urina , Animais , Arsenitos/farmacocinética , Monoaminas Biogênicas/metabolismo , Contagem de Células Sanguíneas , Células Sanguíneas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Líquidos , Glutationa/sangue , Cobaias , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Sintase do Porfobilinogênio/sangue , Protoporfirinas/sangue , Ratos , Compostos de Sódio/farmacocinética , Abastecimento de ÁguaRESUMO
Thirty-five (five groups with seven animals each) male albino rats (initial average weight = 44 g) were fed phytate-rich diets (analysed phytic acid concentration = 6.9 g/kg) based on maize and soy bean meal (5 g Ca, 3 g P, 1.2 g Mg, 23 mg Zn, 10 mg Pb, 5 mg Cd/kg diet). Experimental diets were supplemented with 0, 2, 4, 6 and 8 g calcium from CaCO3 per kg. The supplementation of increasing amounts of calcium resulted in a dose-dependent decrease in the apparent absorption of phosphorus. Furthermore, apparent zinc absorption and femur zinc concentration were moderately decreased due to the calcium supplementation. Kidney Cd concentration was significantly lower in rats that were fed the high calcium diets in comparison with the control animals. Femur lead concentration and hepatic delta-aminolevulinic acid dehydratase, which are known to be sensitive parameters of lead accumulation remained unchanged by the different dietary treatments. Magnesium absorption as well as liver and plasma zinc concentration and activity of plasma alkaline phosphatase were also unaffected. Although calcium supplementation may lead to a decrease in the accumulation of certain heavy metals such as cadmium, the carry-over of lead was not affected under the given experimental conditions. Furthermore, calcium-phytate-zinc interactions may adversely affect zinc bioavailability in growing rats.
Assuntos
Cálcio da Dieta/farmacologia , Suplementos Nutricionais/efeitos adversos , Ácido Fítico/metabolismo , Fosfatase Alcalina/sangue , Ácido Aminolevulínico/sangue , Ração Animal , Animais , Cádmio/análise , Cálcio/análise , Cálcio da Dieta/administração & dosagem , Cálcio da Dieta/efeitos adversos , Fêmur/química , Hemoglobinas/análise , Rim/química , Chumbo/análise , Fígado/química , Magnésio/análise , Masculino , Fósforo/análise , Ratos , Ratos Wistar , Zinco/análiseRESUMO
Blood lead levels observed in the general population of Venice and the surrounding area are reported for the period between 1976 and 1992. A time dependent decrease of blood lead levels is evident and parallels the step wise decrease of lead levels in gasoline which took place between 1981 and 1991. The observed lowering time trend of blood lead levels could possibly be ascribed, perhaps not negligibly, to technological improvements, the development of new analytical procedures and the continuous practice of quality control.
Assuntos
Exposição Ambiental , Chumbo/sangue , Adolescente , Adulto , Idoso , Poluentes Atmosféricos/análise , Ácido Aminolevulínico/sangue , Criança , Pré-Escolar , Monitoramento Ambiental , Monitoramento Epidemiológico , Feminino , Gasolina/análise , Humanos , Itália/epidemiologia , Chumbo/efeitos adversos , Chumbo/análise , Intoxicação por Chumbo/epidemiologia , Intoxicação por Chumbo/prevenção & controle , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Programas Nacionais de Saúde , Vigilância da População , Estudos de Amostragem , Emissões de Veículos/análiseRESUMO
Effect of different concentrations of selenium (Se) on heme biosynthesis was studied at different developmental stages of chick embryo. The first rate limiting enzyme ALA-synthase (ALA-S; E.C.2.3-1.37) activity was enhanced by selenium, while hepatic and blood ALA-dehydratase activity (ALA-d; E.C.3.2.1.24) was decreased. Hepatic and blood free-sulfhydryl (-SH) group contents were significantly decreased by Se. Further, hepatic aminolevulinic acid (ALA) and total blood porphyrin levels were enhanced and hepatic heme levels were depleted by selenium exposure. Heme biosynthesis was maximally inhibited in the E4 (4th day injected embryos) when compared to later periods.
Assuntos
5-Aminolevulinato Sintetase/metabolismo , Inibidores Enzimáticos/farmacologia , Heme/biossíntese , Sintase do Porfobilinogênio/antagonistas & inibidores , Selênio/farmacologia , Ácido Aminolevulínico/sangue , Ácido Aminolevulínico/metabolismo , Animais , Embrião de Galinha , Dactinomicina/farmacologia , Fígado/efeitos dos fármacos , Fígado/embriologia , Fígado/enzimologia , Fígado/metabolismo , Porfirinas/sangue , Porfirinas/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Compostos de Sulfidrila/análise , Compostos de Sulfidrila/sangue , Compostos de Sulfidrila/metabolismo , Fatores de TempoRESUMO
1. The therapeutic ability of Ca disodium EDTA and meso 2,3-dimercaptosuccinic acid (DMSA) was studied, both individually and when given in combination, in reducing lead concentration in blood and other soft tissues, and in restoring lead induced altered biochemical variables in acute lead intoxicated rats. 2. Combined treatment with the above two chelating agents was more beneficial in reducing blood and hepatic lead compared to treatment with these drugs alone. Kidney lead concentration however, remained high following combined treatment, indicating the possibility of extra renal burden following treatment. 3. Lead sensitive biochemical variables also responded more favourably to combined treatment than treatment with these drugs alone. However, clinical biochemical indices indicate caution regarding the use of this new treatment regimen, and further investigation is required.