RESUMO
The development and use of nanomaterials are increasing significantly. Among nanomaterials, carbon nanotubes are of particular interest due to its distinctive physicochemical properties. This material composed of sheets of graphite has very high thermal conductivity, metallic-type electrical conductivity, stiffness, toughness and unique ability to bond to itself in an extended network with extraordinary strength. Its application in the industry is continuously growing, which could lead to the accumulation in the environment and a consequent impact on both humans and ecosystems. Considering that environmental systems are dynamic, it is difficult to predict the risks associated with the release of nanomaterials to the environment. Bioindicators are useful tools as primary signals of environmental risk, and their responses reveal the organism and ecosystem health. In the present study, we evaluated the impact of multi-walled carbon nanotubes with different dimensions and agglomeration pattern on zebrafish embryo and larvae; mainly, studies were focused on physiological and behavioral responses. In embryos, measurements were hatching rate, morphology changes, and viability. In larvae, locomotor activity, heart rate, innate inflammatory response, general and tissue-specific morphology were measured. MWCNT-S (short, wide and mostly dispersed) caused depression of the locomotor activity of larvae, indicating an alteration of the central nervous system, and depression of neutrophil migration activity. MWCNT-L (long, thin and agglomerated) caused malformations during larval development, a decrease of neutrophil migration and alteration of cardiac rhythm. Results obtained for both carbon nanotubes were different, highlighting the importance of dimensions of the same nanomaterial, and also the kind of agglomeration and shape adopted, for the toxic effects on organisms.
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Epilepsy is a neurological disorder treated with antiepileptic drugs (AEDs). Since AEDs are administered in women in childbearing age, it is critical to study if drugs are capable of inducing developmental toxicity. Along the bibliography available, there is no research comparing teratogenicity and anticonvulsant effect within the same study. In the present study, we evaluated the teratogenic and anticonvulsant effects of six different AEDs: carbamazepine, levetiracetam, lamotrigine, phenobarbital, phenytoin and valproic acid. Zebrafish was the selected animal model because of its small size, rapid external development and similar neurophysiology to mammals. Zebrafish embryo and larvae were exposed to AEDs. Embryo development was monitored by their hatching and morphology. In larvae, locomotor activity was measured as a parameter of neurotoxicity. Finally, anticonvulsant effect was determined after exposure to AEDs in zebrafish larvae treated with the proconvulsant drug pentylenetetrazole. Our results suggest that lamotrigine and phenytoin could be suitable non-teratogenic and efficient anticonvulsant options for epilepsy treatment.
Assuntos
Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos , Larva/efeitos dos fármacos , Teratogênese/efeitos dos fármacos , Peixe-Zebra/embriologia , Animais , Anticonvulsivantes/toxicidade , Avaliação Pré-Clínica de MedicamentosRESUMO
In recent years, the use of commercial nanoparticles in different industry and health fields has increased exponentially. However, the uncontrolled application of nanoparticles might present a potential risk to the environment and health. Toxicity of these nanoparticles is usually evaluated by a fast screening assay in zebrafish (Danio rerio). The use of this vertebrate animal model has grown due to its small size, great adaptability, high fertilization rate and fast external development of transparent embryos. In this review, we describe the toxicity of different micro- and nanoparticles (carbon nanotubes, dendrimers, emulsions, liposomes, metal nanoparticles, and solid lipid nanoparticles) associated to their biophysical properties using this model. The main biophysical properties studied are size, charge and surface potential due to their impact on the environment and health effects. The review also discusses the correlation of the effects of the different nanoparticles on zebrafish. Special focus is made on morphological abnormalities, altered development and abnormal behavior. The last part of the review debates changes that should be made in future directions in order to improve the use of the zebrafish model to assess nanotoxicity.
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Cytotoxicity of sulfadiazine (SDZ) complexed with PAMAM dendrimers of fourth generation (SDZ-DG4) determined by MTT assay and LDH leakage, was reduced on covered (with mucins) but not on nude (without mucins) Caco-2 cell line. SDZ-DG4 adsorption and uptake on nude and covered Caco-2 cells, determined by flow cytometry and fluorescence confocal microscopy indicated that positively charged DG4 remained electrostatically attracted to the negatively charged mucins macromolecules. Hence, the in vivo accession of cationic dendrimers to epithelial cells could partly be impaired by their entrapment into mucins. This fact could account for an in vivo decreased cytotoxicity. Besides this finding, when orally administered to Wistar rats, no differences in SDZ biodistribution were found between SDZ-DG4 and free SDZ. However, when intravenously administered at 1.5 mg SDZ per kg body weight, Cmax for free SDZ was 0.7+/-0.2 microg vs. 2.7+/-0.4 microg/ml for SDZ-DG4, whereas AUC0-3 for free SDZ was 0.8+/-0.6 microg/h ml vs. 5.2+/-2 microg/h ml for SDZ-DG4. SDZ-DG4 initial volume distribution (Vd) was 2.6-fold lower than for free SDZ. Remarkably, 3 h upon SDZ-DG4 administration, SDZ concentration in muscle and in brain were 17- and 10-fold higher, respectively, than those achieved with free SDZ.
Assuntos
Anti-Infecciosos/farmacocinética , Encéfalo/metabolismo , Músculo Esquelético/metabolismo , Sulfadiazina/farmacocinética , Administração Oral , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/toxicidade , Materiais Biocompatíveis , Sobrevivência Celular/efeitos dos fármacos , Dendrímeros , Células Epiteliais/metabolismo , Excipientes , Fibroblastos/metabolismo , Citometria de Fluxo , Hemólise/efeitos dos fármacos , Humanos , Técnicas In Vitro , Injeções Intravenosas , Macrófagos/metabolismo , Microscopia Confocal , Mucinas/metabolismo , Poliaminas , Ratos , Ratos Wistar , Sulfadiazina/administração & dosagem , Sulfadiazina/toxicidade , Distribuição TecidualRESUMO
The high doses of sulfadiazine (SDZ), used in synergistic combination with pyrimethamine, are mainly responsible for severe side effects and discontinuation of toxoplasmosis treatments. In the search for new strategies that improve the efficacy of treatments with reduced doses of SDZ, we have determined the performance of cationic G4 (DG4) and anionic G4.5 (DG4.5) poly(amidoamine) (PAMAM) dendrimers to act as SDZ nanocarriers. Both dendrimers could efficiently load SDZ (SDZ-DG4 and SDZ-DG4.5) up to a ratio of 30 molecules SDZ per dendrimer molecule. The MTT assay on Vero and J774 cells showed no cytotoxicity for DG4.5 and its SDZ complex incubated between 0.03 and 33 microM of dendrimer concentration. On the other hand, DG4 and its SDZ complex resulted cytotoxic when incubated at dendrimer concentrations higher than 3.3 microM. Finally, complexes and empty dendrimers were in vitro tested against Vero cells infected with RH strain of Toxoplasma gondii along 4h of treatment. For SDZ-DG4.5 and DG4.5 to cause an infection decrease between 25 and 40%, respectively, a dendrimer concentration of 33 microM was required; however, SDZ-DG4 produced the highest infection decrease of 60% at 0.03 microM. These preliminary results, achieved with nanomolar doses of SDZ-DG4 as unique active principle, point to this complex as a suitable potential candidate for antitoxoplasmic therapy.
Assuntos
Cátions/química , Sulfadiazina/farmacologia , Toxoplasmose/tratamento farmacológico , Animais , Membrana Celular/metabolismo , Sobrevivência Celular , Chlorocebus aethiops , Dendrímeros , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Humanos , Poliaminas/química , Solubilidade , Sulfadiazina/química , Sais de Tetrazólio/farmacologia , Tiazóis/farmacologia , Toxoplasma/metabolismo , Células VeroRESUMO
With the aim of investigating if delivery of benznidazole (BNZ) to liver could be increased by incorporating the drug in multilamellar liposomes, single bolus of free BNZ or liposomal BNZ formulations (MLV-BNZ) composed of HSPC:DSPG:Chol 2:1:2 (mol/mol/mol) at 0.7% (w/w) drug/total lipid ratio, were injected by intramuscular (i.m.), subcutaneous (s.c.) and intravenous (i.v.) routes, at 0.2 mg BNZ/kg, in rats. The resulting blood concentrations were followed along 9 h post-injection (p.i.) and drug accumulation in liver was determined after 4 and 9 h p.i. Only upon i.v. injection of MLV-BNZ, a threefold higher BNZ accumulation in liver was obtained, together with blood BNZ concentrations of 1.1 microg/ml (30% lower than the blood BNZ concentration achieved upon i.v. administration of free drug) occurred 4 h p.i. However, such increased liver uptake of BNZ, raised twice a week had no effect on parasitaemia levels of mice infected with the RA strain of Trypanosoma cruzi. Our results indicate that the relationship between increased selectivity for an infected tissue and therapeutic effect is not always straightforward, at least for the MLV-BNZ regimen used in the present study.