RESUMO
Magnetic nanoparticles can be used in different areas of biology. It is therefore important to know the effects of such nanomaterials on germline cells as they may traverse the blood-testis barrier. This work aimed to evaluate the response of bull sperm after exposure to a magnetic fluid containing DMSA-coated maghemite nanoparticles (MNP-DMSA) in order to determine nanotoxicity. Bull sperm was incubated with MNP-DMSA at final concentrations of 0.06, 0.03 or 0.015 mg Fe/mL. Sperm kinetics, plasma membrane integrity and acrosome reaction were evaluated over a 4 h incubation period. The sperm cells were also evaluated by transmission electron microscopy. Exposure of bull sperm to MNP-DMSA did not affect sperm kinetics or integrity. Neither ultrastructural damage of sperm cells nor uptake of nanoparticles by the spermatozoa was observed. In conclusion, MNP-DMSA does not affect sperm function or structure under the conditions tested.
Assuntos
Compostos Férricos/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Espermatozoides/efeitos dos fármacos , Succímero/administração & dosagem , Animais , Bovinos , Membrana Celular/efeitos dos fármacos , Compostos Férricos/química , Masculino , Nanopartículas Metálicas/química , Microscopia Eletrônica de Transmissão , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Espermatozoides/ultraestrutura , Succímero/químicaRESUMO
Magnetic nanoparticles can be used for numerous in vitro and in vivo applications. However, since uptake by the reticuloendothelial system represents an obstacle for the achievement of nanoparticle diagnostic and therapeutic goals, the aim of the present study was to evaluate the uptake of dimercaptosuccinic acid coated magnetic nanoparticles by reticuloendothelial system phagocytic cells present in lymph nodes, spleen, and liver tissue and how the presence of these particles could have an impact on the morphology of these organs in capuchin monkeys (Sapajus spp.). Animals were intravenously injected with dimercaptosuccinic acid coated magnetic nanoparticles and euthanized 12 hours and 90 days post-injection. Organs were processed by transmission electron microscopy and histological techniques. Samples of spleen and lymph nodes showed no morphological changes. Nevertheless, liver samples collected 90 days post-administration showed slight morphological alteration in space of Disse. Moreover, morphometrical analysis of hepatic mitochondria was performed, suggesting a clear positive correlation between mitochondrial area and dimercaptosuccinic acid coated magnetic nanoparticles administration time. The present results are directly relevant to current safety considerations in clinical diagnostic and therapeutic uses of magnetic nanoparticles.
Assuntos
Magnetismo , Sistema Fagocitário Mononuclear/anatomia & histologia , Nanopartículas , Succímero/administração & dosagem , Animais , Cebus , Fígado/anatomia & histologia , Fígado/ultraestrutura , Linfonodos/anatomia & histologia , Linfonodos/ultraestrutura , Microscopia Eletrônica de Transmissão , Mitocôndrias Hepáticas , Sistema Fagocitário Mononuclear/ultraestrutura , Baço/anatomia & histologia , Baço/ultraestruturaRESUMO
Introduction: mercury is a heavy metal widely dispersed in nature, occurring in three chemical forms. Exposure to mercury at work sites and even at home may be clinically significant. Objective: to update the knowledge about the risks of this toxic element. Case report: the case of a teenager and his family poisoned by elemental mercury is reported. The diagnostic process was difficult, mainly due to an initial presumption of probable infectious etiology, unavailability of key anamnestic data and unusual clinical behavior, with signs and symptoms of multisystem compromise (neurological, hepatic, renal and dermatological compromise). Discussion: the study was based on literature review of various clinical presentations regarding this poisoning and its management, emphasizing the need for dimercaptosuccinic acid chelator. As a major public health problem, the importance of education and implementation of public policies to have a mercury-free environment is discussed.
Introducción: el mercurio es un metal pesado ampliamente distribuido en el medio ambiente, en sus tres formas químicas. La exposición a dicho metal en recintos laborales e incluso en el hogar, puede llegar a ser clínicamente significativa. Objetivo: actualizar el conocimiento acerca de los riesgos de este tóxico. Caso clínico: se presenta el caso clínico de un adolescente y su familia intoxicados por mercurio elemental, cuyo proceso diagnóstico fue difícil, principalmente por la presunción inicial de una probable etiología infecciosa, falta de disponibilidad de datos anamnésticos claves y el inusual comportamiento clínico, con signos y síntomas de compromiso multisistémico (neurológico, hepático, renal y dermatológico). Discusión: se revisa la literatura en relación a las diversas formas de presentación clínica de esta intoxicación y su manejo, destacando la utilidad del quelante ácido dimercaptosuccínico. Por ser un importante problema de salud pública, se destaca la trascendencia de la educación e implementación de políticas públicas por un ambiente libre de mercurio.
Assuntos
Humanos , Masculino , Adolescente , Intoxicação por Mercúrio/diagnóstico , Intoxicação por Mercúrio/tratamento farmacológico , Exposição Ambiental , Intoxicação por Mercúrio/etiologia , Mercúrio/efeitos adversos , Quelantes/administração & dosagem , Succímero/administração & dosagemRESUMO
Magnetic nanoparticles surface-covered with meso-2,3-dimercaptosuccinic acid (MNPs-DMSA) constitute a promising approach for tissue- and cell-targeted delivery of therapeutic drugs in the lung. However, they can also induce a transient transendothelial migration of leukocytes in the organ as a side effect after endovenous administration of MNPs-DMSA. We demonstrated that monocytes/macrophages constitute the main subpopulation of leukocytes involved in this process. Our recent research found that MNPs-DMSA up-regulated the mRNA expression of E-, L- and P-selectin and macrophage-1 antigen, and increased concentration of tumor necrosis factor-α in lung, in a time dependent manner. The critical relevance of the ß2 integrin-dependent pathway in leukocyte transmigration elicited by MNPs-DMSA was demonstrated by use of knockout mice. Our work characterizes mechanisms of the pro-inflammatory effects of MNPs-DMSA in the lung, and identifies ß2 integrin-targeted interventions as promising strategies to reduce pulmonary side effects of MNPs-DMSA during biomedical applications. In addition, MNPs-DMSA could be used as modulators of lung immune response.
Assuntos
Leucócitos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nanopartículas de Magnetita/administração & dosagem , Succímero/administração & dosagem , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Animais , Antígenos CD18/metabolismo , Leucócitos/metabolismo , Antígeno de Macrófago 1/efeitos dos fármacos , Antígeno de Macrófago 1/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Selectina-P/efeitos dos fármacos , Selectina-P/metabolismo , Succímero/química , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We studied the expression pattern of cell adhesion molecules associated to transendothelial migration of leukocytes in different lung's vascular compartments after administration of a magnetic fluid sample containing maghemite nanoparticles surface-coated with meso-2,3-dimercaptosuccinic acid. The analyses were conducted in mice 4 and 12 h after endovenous administration of the magnetic fluid in control mice. Firstly, the migratory activity of leukocytes after magnetic fluid surface-coated with meso-2,3-dimercaptosuccinic acid administration was confirmed using broncho-alveolar lavage and light microscopy. Then, the expression of cell adhesion molecules in the lung's vascular compartments was investigated by immunofluorescence microscopy of frozen sections, using antibodies against L-selectin, P-selectin, E-selectin, macrophage antigen-1, and leukocyte function associated antigen-1. L- and P-selectin showed similar pattern of expression in the pulmonary vasculature in animals treated with magnetic fluid and in the control group. In contrast, macrophage antigen-1 and leukocyte function associated antigen-1 were found in capillary only in animals treated with magnetic fluid surface-coated with meso-2,3-dimercaptosuccinic acid administration. In addition, after magnetic fluid administration E-selectin was found in post-capillary sites. Our findings demonstrated that magnetic fluid surface-coated with meso-2,3-dimercaptosuccinic acid administration exhibits modulation effects on expression patterns of E-selectin, macrophage antigen-1, and leukocyte function associated antigen-1 in the lung's vascular compartments. These findings are very important in a strategy to reduce the potential toxicity of magnetic fluid surface-coated with meso-2,3-dimercaptosuccinic acid administration for medical applications.
Assuntos
Moléculas de Adesão Celular/metabolismo , Compostos Férricos/química , Leucócitos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nanopartículas/administração & dosagem , Succímero/farmacologia , Animais , Movimento Celular , Compostos Férricos/síntese química , Leucócitos/citologia , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/ultraestrutura , Magnetismo , Masculino , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Succímero/administração & dosagemRESUMO
OBJECTIVES: The present study reports on the preparation and testing of a desoxycholate amphotericin B (D-AMB) sustained delivery system based on poly(lactic-co-glycolic acid) (PLGA) and dimercaptosuccinic acid (DMSA) polymeric blends (Nano-D-AMB) aimed at reducing the number of AMB administrations required to treat mycosis. METHODS: BALB/c mice were infected with the yeast Paracoccidioides brasiliensis intravenously to mimic the chronic form of paracoccidioidomycosis. At 30 days post-infection, the animals were treated with Nano-D-AMB [6 mg/kg of encapsulated D-AMB, intraperitoneally (ip), interval of 72 h] or D-AMB (2 mg/kg, ip, interval of 24 h). Drug efficacy was investigated by the fungal burden recovery from tissues. Toxicity was assessed by renal and hepatic biochemical parameters, physical appearance of the animals and haematological investigation. The control groups used were non-infected and the infected mice mock treated with PBS. RESULTS: Nano-D-AMB presented results comparable to free D-AMB, with a marked antifungal efficacy. The Nano-D-AMB-treated group presented lower loss of body weight and absence of stress sign (piloerection and hypotrichosis) observed after D-AMB treatment. No renal [blood urea nitrogen (BUN), creatinine] or hepatic (pyruvic and oxalacetic glutamic transaminases) biochemical abnormalities were found. The micronucleus assay showed no significant differences in both the micronucleus frequency and percentage of polychromatic erythrocytes for Nano-D-AMB, indicating the absence of genotoxicity and cytotoxic effects. CONCLUSIONS: The D-AMB-coated PLGA-DMSA nanoparticle showed antifungal efficacy, fewer undesirable effects and a favourable extended dosing interval. Nano-D-AMB comprises an AMB formulation able to lessen the number of drug administrations. Further studies would elucidate whether Nano-D-AMB would be useful to treat systemic fungal infections such as paracoccidioidomycosis, candidiasis, aspergillosis and cryptococcosis.
Assuntos
Anfotericina B/uso terapêutico , Ácido Desoxicólico/uso terapêutico , Ácido Láctico/uso terapêutico , Nanopartículas/uso terapêutico , Paracoccidioides/efeitos dos fármacos , Paracoccidioidomicose/tratamento farmacológico , Ácido Poliglicólico/uso terapêutico , Succímero/uso terapêutico , Anfotericina B/administração & dosagem , Anfotericina B/efeitos adversos , Animais , Peso Corporal , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Medula Óssea/fisiologia , Contagem de Colônia Microbiana , Ácido Desoxicólico/administração & dosagem , Ácido Desoxicólico/efeitos adversos , Combinação de Medicamentos , Feminino , Rim/efeitos dos fármacos , Rim/fisiologia , Ácido Láctico/administração & dosagem , Ácido Láctico/efeitos adversos , Fígado/efeitos dos fármacos , Fígado/microbiologia , Fígado/fisiologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/efeitos adversos , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/efeitos adversos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Succímero/administração & dosagem , Succímero/efeitos adversos , Resultado do TratamentoAssuntos
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
Acute effects of cadmium in mice testes were evaluated. Animals received a single dose of CdCl2 (2.5 mg/kg or 5 mg/kg, intraperitoneally) and a number of toxicological parameters in mice testes were examined such as delta-aminolevulinic acid dehydratase (delta-ALA-D) activity, lipid peroxidation, hemoglobin content and components of the antioxidant defenses (superoxide dismutase (SOD) activity and ascorbic acid concentration). Furthermore, a possible protective effect of meso-2,3-dimercaptosuccinic acid (DMSA) and diphenyl diselenide (PhSe)2 are studied. The results demonstrated inhibition of delta-ALA-D and SOD activities, reduction in ascorbic acid, increase of lipid peroxidation induced by cadmium, indicating testes damage. DMSA (400 micromol/Kg) and (PhSe)2 (100 micromol/Kg) protected inhibitory effect of 2.5 mg/kg CdCl2 on delta-ALA-D and restored the increase of TBARS levels. Otherwise, (PhSe)2 treatment was effective in reducing the increase of TBARS levels induced by 5 mg/kg CdCl2, whereas DMSA and (PhSe)2, in combination, were ineffective in reducing TBARS level. However, these compounds alone or in combination, were unable to protect SOD activity and to improve ascorbic acid levels near to the normal value. The use of combined therapy (DMSA plus (PhSe)2) not proved be better than the monotherapy, in improving toxicological parameters evaluated in this model of testicular damage induced by cadmium.
Assuntos
Derivados de Benzeno/farmacologia , Cádmio/toxicidade , Quelantes/farmacologia , Compostos Organosselênicos/farmacologia , Succímero/farmacologia , Testículo/efeitos dos fármacos , Testículo/patologia , Animais , Derivados de Benzeno/administração & dosagem , Quelantes/administração & dosagem , Hemoglobinas/análise , Peroxidação de Lipídeos , Masculino , Camundongos , Compostos Organosselênicos/administração & dosagem , Sintase do Porfobilinogênio/análise , Sintase do Porfobilinogênio/farmacologia , Succímero/administração & dosagem , Superóxido Dismutase/farmacologiaRESUMO
The authors studied children in Andean villages contaminated by a lead-glazing cottage industry. Mean blood lead (PbB) level in 35 exposed children, aged 3-14 years, a year before treatment, at the time of initiation of a comprehensive lead education and prevention program, was 53.4 microg/dL. PbB levels immediately before and three weeks after a ten-day regimen of succimer treatment of the 35 children were 43.4 microg/dL and 34.3 microg/dL, respectively, showing a 21% reduction and a significant difference between means (t = 5.09, p = 0.0001). PbB levels of the same children a year before treatment and immediately pre-treatment were also significantly different (t = 10.59, p = 0.0001). Thus, a ten-day course of succimer chelation effectively reduced PbB in children with moderate to severe Pb intoxication, and the education and prevention program, initiated with parents, health care providers, and educators, also contributed significantly to reducing PbB.
Assuntos
Quelantes/uso terapêutico , Intoxicação do Sistema Nervoso por Chumbo na Infância/tratamento farmacológico , Exposição Ocupacional/efeitos adversos , Succímero/uso terapêutico , Adolescente , Cerâmica , Quelantes/administração & dosagem , Terapia por Quelação , Criança , Pré-Escolar , Equador/epidemiologia , Humanos , Chumbo/sangue , Intoxicação do Sistema Nervoso por Chumbo na Infância/epidemiologia , Exposição Ocupacional/prevenção & controle , Pediatria , Succímero/administração & dosagemRESUMO
The uptake of the rhenium-188 (188Re(V)-DMSA) complex of dimercaptosuccinic acid by cervical carcinoma cells in nude mice was evaluated. The pharmacokinetics and dosimetry calculations in normal rats were also evaluated. The images obtained in mice did not show significant accumulation in metabolic organs and the biodistribution studies showed that 3.52 +/- 0.76% of the injected activity per gram (n = 4) was taken up by the tumor. This percentage produces a cumulated activity of 35.63 +/- 8.40 MBq h and an equivalent dose per injected activity of 260 +/- 8.91 mSv/MBq. Pharmacokinetics and dosimetry of the 1887e(V)-DMSA complex indicate that this radiopharmaceutical could be evaluated in patients with soft tissue tumors, since the risk of radiation damage to the kidney or red bone marrow could not be an obstacle for its application in therapeutic nuclear medicine.
Assuntos
Compostos Organometálicos/farmacocinética , Radioisótopos/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Rênio/farmacocinética , Succímero/farmacocinética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/radioterapia , Animais , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Nus , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/uso terapêutico , Doses de Radiação , Radioisótopos/administração & dosagem , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/uso terapêutico , Ratos , Ratos Wistar , Rênio/administração & dosagem , Rênio/uso terapêutico , Succímero/administração & dosagem , Succímero/uso terapêutico , Distribuição TecidualRESUMO
La intoxicación con plomo sigue siendo una causa de importancia no despreciable de una serie de síndromes que principalmente afectan a los niños, y que pocas veces se sugiere como agente etiológico. A continuación descutiremos los aspectos más importante de este tipo de intoxicación, elementos para poder sospecharla y esquemas de tratamiento sugeridos por el Centro de Información Toxicológica UC (CITUC)
Assuntos
Humanos , Intoxicação por Chumbo/diagnóstico , Exposição Ambiental , Intoxicação por Chumbo/tratamento farmacológico , Intoxicação por Chumbo/fisiopatologia , Succímero/administração & dosagem , Succímero/efeitos adversos , Sintomas ToxicológicosRESUMO
The dimercaptosuccinic acid (DMSA) renal scan is a method for assessing kidney function. Indications for DMSA scanning in children with urinary tract infection (UTI), as well as timing, have changed. Pitfalls in interpreting DMSA scans include: (1) acute pyelonephritis (APN), (2) tubular dysfunction, (3) hypertension, (4) use of captopril in patients with renovascular hypertension and (5) duplex kidneys. Interpretation of DMSA scans in children with UTI vary according to timing and clinical setting. During the course of a febrile UTI a DMSA scan may reveal a normal kidney, APN or a non-functioning, small and/or ectopic kidney. In the absence of UTI (up to 6 months) in children with vesicoureteric reflux a DMSA scan may indicate a normal kidney, renal scarring (reflux nephropathy), occult duplex kidney and allows the progression of scarring and hypertrophy of normal areas of the kidney to be followed anatomically. The DMSA renal scan in now the most reliable test for the diagnosis of APN. The transient abnormalities due to APN can occur in normal or scarred kidneys. Lesions due to reflux nephropathy (defined as a defect in the renal outline or contraction of the whole kidney) are permanent. Intravenous urography reveals renal abnormalities later than the DMSA scan. If abnormalities are seen on a DMSA scan performed during the course of APN it is impossible to predict the outcome: they can progress to permanent scarring or heal completely. An abnormal DMSA scan during a febrile UTI allows the identification of children at risk of developing renal scars. These children should be carefully investigated, maintained on long-term quimioprophylaxis and followed.
Assuntos
Compostos de Organotecnécio , Succímero , Infecções Urinárias/diagnóstico por imagem , Doença Aguda , Animais , Criança , Cicatriz/diagnóstico por imagem , Cicatriz/microbiologia , Humanos , Injeções Intravenosas , Rim/metabolismo , Rim/patologia , Nefropatias/diagnóstico por imagem , Nefropatias/microbiologia , Compostos de Organotecnécio/administração & dosagem , Compostos de Organotecnécio/metabolismo , Pielonefrite/diagnóstico por imagem , Pielonefrite/microbiologia , Cintilografia , Succímero/administração & dosagem , Succímero/metabolismo , Ácido Dimercaptossuccínico Tecnécio Tc 99m , Urografia/métodos , Refluxo Vesicoureteral/diagnóstico por imagem , Refluxo Vesicoureteral/microbiologiaRESUMO
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
2,3-Dimercaptosuccinic acid (DMSA) is an orally effective orphan drug that is more specific and has a wider therapeutic index than other currently available drugs used for lead intoxication. Its investigational use in the United States has been limited to the treatment of men with occupational plumbism. Twenty-one children with blood lead concentrations of 31 to 49 micrograms/dl, who also had a positive calcium disodium edetate (CaNa2EDTA) mobilization test result, were hospitalized for 7 days. Fifteen children were randomly assigned to three groups that received either 350, 700, or 1050 mg/m2/day, respectively, of DMSA in three divided doses daily. A fourth group of six children received conventional treatment with 1000 mg/m2/day of intravenously administered CaNa2EDTA in two divided doses daily. The 1050 mg/m2/day dose of DMSA was significantly more effective than lower doses of DMSA or intravenously administered CaNa2EDTA in reducing blood lead levels and restoring erythrocyte delta-aminolevulinic acid dehydratase activity. Intravenously administered CaNa2EDTA significantly increased the urinary excretion of several essential minerals (zinc, copper, iron, and calcium), whereas DMSA did not. The DMSA was well tolerated and appears extremely promising as a drug that will simplify the management of childhood lead poisoning.