RESUMO
BACKGROUND: Benznidazole and nifurtimox are effective drugs used to treat Chagas' disease; however, their administration in patients in the chronic phase of the disease is still limited, mainly due to their limited efficacy in the later chronic stage of the disease and to the adverse effects related to these drugs. OBJECTIVES: To evaluate the effect of low doses of nanoformulated benznidazole using a chronic model of Trypanosoma cruzi Nicaragua infection in C57BL/6J mice. METHODS: Nanoformulations were administered in two different schemes: one daily dose for 30 days or one dose every 7 days, 13 times. RESULTS: Both treatment schemes showed promising outcomes, such as the elimination of parasitaemia, a reduction in the levels of T. cruzi-specific antibodies and a reduction in T. cruzi-specific IFN-γ-producing cells, as well as an improvement in electrocardiographic alterations and a reduction in inflammation and fibrosis in the heart compared with untreated T. cruzi-infected animals. These results were also compared with those from our previous work on benznidazole administration, which was shown to be effective in the same chronic model. CONCLUSIONS: In this experimental model, intermittently administered benznidazole nanoformulations were as effective as those administered continuously; however, the total dose administered in the intermittent scheme was lower, indicating a promising therapeutic approach to Chagas' disease.
Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Nicarágua , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêuticoRESUMO
Numerous films with a dissolved or dispersed active principle within a polymeric matrix have been described in literature. However, the incorporation of solid crystals into the films may influence several relevant properties. Additionally, it has been reported that different polymeric matrices lead to films presenting a different performance. The aim of this work was to evaluate the effect of the combination of chitosan with carrageenan (κ-, λ-, and ι-) as matrices, and of the miconazole nitrate incorporation method, on the films behavior. Mechanical properties, drug release and antifungal activity were evaluated. The state of the drug in the films was analyzed by different techniques. Films showed a homogeneous surface and a thermal protective effect on the drug. The combination of chitosan and λ-carrageenan leads to films with the highest values of tensile and mucoadhesive strength. Films with solubilized drug displayed slightly higher elongation at break, tensile and mucoadhesive strength and faster drug release than those with suspended miconazole nitrate. However, no differences were found regarding the antifungal activity of the different formulations including time-to-kill curves.
Assuntos
Antifúngicos/administração & dosagem , Carragenina/administração & dosagem , Química Farmacêutica/métodos , Quitosana/administração & dosagem , Miconazol/administração & dosagem , Adesividade , Administração Bucal , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Carragenina/química , Quitosana/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Miconazol/química , Resistência à TraçãoRESUMO
Oral candidiasis is the most common opportunistic infection affecting patients with the human immunodeficiency virus. Miconazole buccal tablets or miconazole gel are approved for the treatment of oropharyngeal candidiasis. However, buccal films present more flexibility and also offer protection for the wounded mucosa, reducing pain. Due to their small size and thickness, buccal films may improve patients' compliance, compared to tablets. Additionally, they may increase the relatively short residence time on the mucosa of oral gels, which are easily removed by saliva. Polymeric films loaded with miconazole nitrate were prepared by a casting/solvent evaporation methodology using chitosan, carbopol, gelatin, gum arabic, and alginate to form the polymeric matrices. The morphology of films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity by differential thermal analysis and X-ray diffraction. Films were characterized in terms of thickness, folding endurance, tensile properties, swelling, adhesiveness, and drug release. Finally, the antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. The more appropriate formulations were those based on chitosan-gelatin and chitosan-carbopol which showed good mechanical properties and adhesiveness, a relative low swelling index, improved drug release, and showed better in vitro activity against Candida cultures than miconazole nitrate raw material. Thus, it will be possible to produce a new pharmaceutical form based on polymeric films containing chitosan and miconazole nitrate, which could be loaded with low drug concentration producing the same therapeutic effect against Candida cultures.
Assuntos
Antifúngicos/química , Adesividade , Química Farmacêutica , Miconazol , Polímeros , Difração de Raios XRESUMO
In this work, chitosan films were prepared by a casting/solvent evaporation methodology using pectin or hydroxypropylmethyl cellulose to form polymeric matrices. Miconazole nitrate, as a model drug, was loaded into such formulations. These polymeric films were characterized in terms of mechanical properties, adhesiveness, and swelling as well as drug release. Besides, the morphology of raw materials and films was investigated by scanning electron microscopy; interactions between polymers were analyzed by infrared spectroscopy and drug crystallinity studied by differential scanning calorimetry and X-ray diffraction. In addition, antifungal activity against cultures of the five most important fungal opportunistic pathogens belonging to Candida genus was investigated. Chitosan:hydroxypropylmethyl cellulose films were found to be the most appropriate formulations in terms of folding endurance, mechanical properties, and adhesiveness. Also, an improvement in the dissolution rate of miconazole nitrate from the films up to 90% compared to the non-loaded drug was observed. The in vitro antifungal activity showed a significant activity of the model drug when it is loaded into chitosan films. These findings suggest that chitosan-based films are a promising approach to deliver miconazole nitrate for the treatment of candidiasis.
Assuntos
Candidíase Bucal/tratamento farmacológico , Quitosana , Sistemas de Liberação de Medicamentos , Derivados da Hipromelose/farmacologia , Miconazol , Adesividade , Administração Bucal , Antidiarreicos/química , Antidiarreicos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Quitosana/química , Quitosana/farmacologia , Composição de Medicamentos , Humanos , Miconazol/química , Miconazol/farmacologia , Microscopia Eletrônica de Varredura/métodos , Pectinas/química , Pectinas/farmacologia , Polímeros/farmacologia , Difração de Raios X/métodosRESUMO
To sustain tumor growth, the cancer cells need to adapt to low levels of oxygen (i.e., hypoxia) in the tumor tissue and to the tumor-associated acidic microenvironment. In this phenomenon, the activation of the sodium/proton exchanger 1 (NHE1) at the plasma membrane and the hypoxia-inducible factor (HIF) are critical for the control of the intracellular pH (pHi) and for hypoxia adaptation, respectively. Interestingly, both of these mechanisms end in sustaining cancer cell proliferation. However, regulatory mechanisms of pHi in human ovary tissue and in malignant ascites are unknown. Additionally, a potential role of NHE1 in the modulation of H(+) efflux in human ovarian cancer cells is unknown. In this review, we discussed the characteristics of tumor microenvironment of primary human ovarian tumors and tumor ascites, in terms of pHi regulatory mechanisms and oxygen level. The findings described in the literature suggest that NHE1 may likely play a role in pHi regulation and cell proliferation in human ovarian cancer, potentially involving HIF2α activation. Since ovarian cancer is the fifth cause of prevalence of women cancer in Chile and is usually of late diagnosis, i.e., when the disease jeopardizes peritoneal cavity and other organs, resulting in reduced patient survival, new efforts are required to improve patient-life span and for a better understanding of the pathophysiology of the disease. The potential advantage of the use of amiloride and amiloride-derivatives for cancer treatment in terms of NHE1 expression and activity is also discussed as a therapeutic approach in human ovarian cancer.
Assuntos
Neoplasias Ovarianas/metabolismo , Animais , Proliferação de Células/fisiologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Oxigênio/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Microambiente Tumoral/fisiologiaRESUMO
Benznidazole (BZL) is the drug of choice for the treatment of Chagas' disease, a neglected parasitic infection. It is poorly soluble in water, which may have a direct impact into its bioavailability. Thus, the aim of this study was to evaluate the impact of stoichiometric and non-stoichiometric BZL-cyclodextrins (CDs) complexes on the bioavailability of BZL. The interaction of BZL with the CDs was investigated using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffractometry (XRD), phase solubility and dissolution studies. The oral bioavailability of BZL from these complexes was examined in rats. Both BZL solubility and dissolution increased by CD complexation. The inclusion complexes were found to improve the dissolution rate of BZL by 4.3-fold in comparison with BZL alone. Complexation of BZL with CDs derivatives increased its plasma concentrations when fed to rats, with AUC0-5 values increasing up to 3.7-fold and Cmax increasing 2.5-fold in comparison with BZL alone. It should be note that a remarkable increase in these parameters was observed in the case of the non-stoichiometric complexes. Thus, these CDs complexes could be used to efficiently deliver BZL in patients suffering from Chagas' disease.
Assuntos
Ciclodextrinas/química , Ciclodextrinas/farmacocinética , Nitroimidazóis/química , Nitroimidazóis/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Ciclodextrinas/administração & dosagem , Cinética , Masculino , Nitroimidazóis/administração & dosagem , Ratos , Solubilidade , Termogravimetria , Difração de Raios XRESUMO
The protozoan parasite most frequently associated with diarrhoea worldwide is Giardia intestinalis. In 2005, a study was initiated to identify the genotypes of this parasite infecting children in the Argentinian provinces of Buenos Aires, Mendoza and Chaco, and to explore the associations between the genotype detected in a child, the characteristics of the child's household and the child's clinical presentation. Overall, 998 children (504 boys and 494 girls) aged between 2-14 years, with or without symptoms, were enrolled. The G. intestinalis in 94 of the 117 stool samples found positive for the parasite by microscopy were successfully genotyped by PCR. Seventy-seven of the children were found to be infected with genotype B only and 14 with genotype AII only, three children being found to have mixed (AII and B) infections. Only genotype B was detected in children from rural areas (P<0·05) and most Giardia detected in children from households with a piped water supply were also of this genotype (P<0·05). The other household characteristics investigated (quality of building, history of flooding, type of sanitation, level of overcrowding, and presence/absence of pet dogs) had no significant effect on the genotype distribution. Children infected with genotype AII were significantly younger than those infected with genotype B (P<0·05) and there was a significant positive association between infection with genotype B and abdominal pain (P<0·05). Diarrhoea was not, however, found to be significantly associated with genotype-AII or genotype-B infection. This is the first published report on the Giardia genotypes circulating in the provinces of Mendoza and Chaco. The results indicate the importance of asymptomatic children in the transmission of Giardia among the young.
Assuntos
Giardia lamblia/genética , Giardíase/epidemiologia , Adolescente , Argentina/epidemiologia , Criança , Pré-Escolar , Fezes/parasitologia , Feminino , Genótipo , Giardia lamblia/classificação , Giardia lamblia/isolamento & purificação , Giardíase/parasitologia , Giardíase/transmissão , Humanos , Masculino , Prevalência , Características de Residência/estatística & dados numéricos , Fatores de Risco , Saúde da População Rural/estatística & dados numéricos , Saúde da População Urbana/estatística & dados numéricos , Abastecimento de ÁguaRESUMO
Human endothelial dysfunction is a common feature in many diseases of pregnancy, such as gestational diabetes (GD). Metabolic changes include abnormal synthesis of nitric oxide (NO) and abnormal membrane transport of l-arginine and adenosine in primary cultures of human umbilical vein (HUVEC, macrovascular) and placental microvillus (hPMEC, microvascular) endothelial cells. These alterations are associated with modifications in the expression and activity of endothelial (eNOS) and inducible (iNOS) NO synthases, respectively, an effect that is maintained at least up to passage 5 in culture. HUVEC and hPMEC exhibit expression and activity of the human cationic amino acid transporter 1 (hCAT-1), equilibrative nucleoside transporters 1 (hENT1) and hENT2, as well as the corresponding SLC7A1, SLC29A1 and SLC29A2 gene promoter activities. Altered gene expression results from increased NO level, protein kinase C, mitogen-activated protein kinases, and hCHOP-C/EBPα transcription factor activation. Reduced ENT-mediated adenosine transport in GD is associated with stimulation of the l-arginine/NO pathway, and mainly due to reduced expression and activity of hENT1. In addition, hENT2 activity seems able to restore the reduced adenosine transport in GD. Additionally, insulin exerts a differential modulation of endothelial cells from macrocirculation compared with microcirculation, possibly due to expression of different insulin receptor isoforms. It is suggested that a common functional characteristic leading to changes in the bioavailability of adenosine and metabolism of l-arginine is evidenced by human fetal micro and macrovascular endothelium in GD.
Assuntos
Diabetes Gestacional/fisiopatologia , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Microvasos/fisiopatologia , Placenta/irrigação sanguínea , Placenta/fisiopatologia , Diabetes Gestacional/metabolismo , Endotélio Vascular/citologia , Feminino , Humanos , Microvasos/citologia , Microvasos/metabolismo , Placenta/citologia , Placenta/metabolismo , GravidezRESUMO
Extracellular adenosine removal is via human equilibrative nucleoside transporters 1 (hENT1) and 2 (hENT2) in the endothelium, thus regulating adenosine-induced revascularization and angiogenesis. Since human endothelial progenitor cells (hEPCs) promote revascularization, we hypothesize differential expression of nucleoside transporters in hEPCs. hEPCs were cultured 3 (hEPC-3d) or 14 (hEPC-14d) days. RT-PCR for prominin 1, CD34, octamer-4, kinase insert domain receptor, oxidized low-density lipoprotein (lectin-like) receptor 1 and tyrosine endothelial kinase was used to evaluate phenotypic differentiation. Flow cytometry was used to estimate CD34(+)/KDR(-) (non-differentiated), CD34(-)/KDR(+) (differentiated) or CD34(+)/KDR(+) (mixed) cell populations. Adenosine transport was measured in absence or presence of sodium, S-(4-nitrobenzyl)-6-thio-inosine (NBTI, 1-10 µM), inosine, hypoxanthine or guanine (0.1-5 mM), hENTs protein abundance by western blot, and hENTs, hCNT1, hCNT2 and hCNT3 mRNA expression by real time RT-PCR. hEPC-3d cells were CD34(+)/KDR(-) compared with hEPC-14d cells that were CD34(-)/KDR(+). hEPC-3d cells exhibit hENT1-like adenosine transport (NBTI-sensitive, Na(+)-independent), which is absent in hEPC-14d cells. hEPC-14d cells exhibit two transport components: component 1 (NBTI insensitive, Na(+)-independent) and component 2 (NBTI insensitive, Na(+)-dependent, Hill coefficient â¼1.8), the latter resembling CNT3-like transport. hEPC-3d cells express hENT1 protein and mRNA, which is reduced (â¼90%) in hEPC-14d cells, but instead only hCNT3 mRNA is expressed in this cell type. hENT2, hCNT1 and hCNT2 were undetectable in hEPCs. Thus, hEPCs exhibit a differential expression of hENT1 and hCNT3 functional nucleoside transporters, which could be related with its differentiation stage.
Assuntos
Células Endoteliais/fisiologia , Transportador Equilibrativo 1 de Nucleosídeo/biossíntese , Transportador Equilibrativo 2 de Nucleosídeo/biossíntese , Células-Tronco/fisiologia , Adenosina/metabolismo , Transporte Biológico , Western Blotting , Diferenciação Celular/fisiologia , Células Endoteliais/metabolismo , Transportador Equilibrativo 1 de Nucleosídeo/genética , Transportador Equilibrativo 2 de Nucleosídeo/genética , Humanos , Cinética , RNA/química , RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/metabolismo , Tioinosina/análogos & derivados , Tioinosina/farmacologiaRESUMO
Primary epiploic appendagitis is a very rare condition that results from acute inflammation of an epiploic appendix. Clinical presentation is non-specific, and many times can mimic acute abdomen. When the diagnosis of epiploic appendagitis is made, conservative treatment must be initiated to avoid unnecessary surgery. We report three cases of acute epiploic appendagitis which were diagnosed by imaging and were managed conservatively with good clinical outcome.