RESUMO

It has been widely described that chronic intake of fructose causes metabolic alterations which can be associated with brain function impairment. In this study, we evaluated the effects of fructose intake on the sleep⁻wake cycle, locomotion, and neurochemical parameters in Wistar rats. The experimental group was fed with 10% fructose in drinking water for five weeks. After treatment, metabolic indicators were quantified in blood. Electroencephalographic recordings were used to evaluate the sleep architecture and the spectral power of frequency bands. Likewise, the locomotor activity and the concentrations of orexin A and monoamines were estimated. Our results show that fructose diet significantly increased the blood levels of glucose, cholesterol, and triglycerides. Fructose modified the sleep⁻wake cycle of rats, increasing the waking duration and conversely decreasing the non-rapid eye movement sleep. Furthermore, these effects were accompanied by increases of the spectral power at different frequency bands. Chronic consumption of fructose caused a slight increase in the locomotor activity as well as an increase of orexin A and dopamine levels in the hypothalamus and brainstem. Specifically, immunoreactivity for orexin A was increased in the ventral tegmental area after the intake of fructose. Our study suggests that fructose induces metabolic changes and stimulates the activity of orexinergic and dopaminergic neurons, which may be responsible for alterations of the sleep⁻wake cycle.

Assuntos

Encéfalo/efeitos dos fármacos , Açúcares da Dieta/farmacologia , Dopamina/metabolismo , Comportamento Alimentar , Frutose/farmacologia , Orexinas/metabolismo , Sono/efeitos dos fármacos , Animais , Glicemia/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Tronco Encefálico/efeitos dos fármacos , Tronco Encefálico/metabolismo , Dieta , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Lipídeos/sangue , Locomoção/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Ratos Wistar , Fases do Sono/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Vigília/efeitos dos fármacos

RESUMO

Protozoan parasites have been one of the most significant public health problems for centuries and several human infections caused by them have massive global impact. Most of the current drugs used to treat these illnesses have been used for decades and have many limitations such as the emergence of drug resistance, severe side-effects, low-to-medium drug efficacy, administration routes, cost, etc. These drugs have been largely neglected as models for drug development because they are majorly used in countries with limited resources and as a consequence with scarce marketing possibilities. Nowadays, there is a pressing need to identify and develop new drug-based antiprotozoan therapies. In an effort to overcome this problem, the main purpose of this study is to develop a QSARs-based ensemble classifier for antiprotozoan drug-like entities from a heterogeneous compounds collection. Here, we use some of the TOMOCOMD-CARDD molecular descriptors and linear discriminant analysis (LDA) to derive individual linear classification functions in order to discriminate between antiprotozoan and non-antiprotozoan compounds as a way to enable the computational screening of virtual combinatorial datasets and/or drugs already approved. Firstly, we construct a wide-spectrum benchmark database comprising of 680 organic chemicals with great structural variability (254 of them antiprotozoan agents and 426 to drugs having other clinical uses). This series of compounds was processed by a k-means cluster analysis in order to design training and predicting sets. In total, seven discriminant functions were obtained, by using the whole set of atom-based linear indices. All the LDA-based QSAR models show accuracies above 85% in the training set and values of Matthews correlation coefficients (C) vary from 0.70 to 0.86. The external validation set shows rather-good global classifications of around 80% (92.05% for best equation). Later, we developed a multi-agent QSAR classification system, in which the individual QSAR outputs are the inputs of the aforementioned fusion approach. Finally, the fusion model was used for the identification of a novel generation of lead-like antiprotozoan compounds by using ligand-based virtual screening of 'available' small molecules (with synthetic feasibility) in our 'in-house' library. A new molecular subsystem (quinoxalinones) was then theoretically selected as a promising lead series, and its derivatives subsequently synthesized, structurally characterized, and experimentally assayed by using in vitro screening that took into consideration a battery of five parasite-based assays. The chemicals 11(12) and 16 are the most active (hits) against apicomplexa (sporozoa) and mastigophora (flagellata) subphylum parasites, respectively. Both compounds depicted good activity in every protozoan in vitro panel and they did not show unspecific cytotoxicity on the host cells. The described technical framework seems to be a promising QSAR-classifier tool for the molecular discovery and development of novel classes of broad-antiprotozoan-spectrum drugs, which may meet the dual challenges posed by drug-resistant parasites and the rapid progression of protozoan illnesses.

Assuntos

Antiprotozoários/farmacologia , Quinoxalinas/síntese química , Ciclização , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Quinoxalinas/química

RESUMO

Compound 1-methyl-7-nitro-4-(5-(piperidin-1-yl)pentyl)-3,4-dihydroquinoxalin-2(1H)-one (VAM2-6) was evaluated against a blood-induced infection with chloroquine-sensitive Plasmodium yoelii yoelii lethal strain in CD1 mice in a 4-day test scheme. LD50 of the compound was 56.51 mg/kg and LD10 was 20.58 mg/kg (taken as the highest dose). Animals were treated by oral gavage of 20, 10, and 5 mg/kg. Mice in the untreated control group showed a progressively increasing parasitemia leading to mouse death on 6 days post-infection; in this group, all mice showed parasites in the blood on the fifth day of sampling; the mean parasitemia on that day was 19.4%. A 4-day dosage of 20 mg/kg of VAM2-6 showed a 97% chemosuppression of total parasitemia on the fifth day, a 28 days survival time, and 20% of cured animals. A 4-day dosage of 10 and 5 mg/kg showed 85 and 37%, respectively, chemosuppression of total parasitemia on the fifth day; but all mice died from days 6 to 9 post-infection with increasing parasitemia. Mice treated with chloroquine at 5 mg/kg survived during the experiment. The results obtained in this study showed that the infection outcome of P. yoelii yoelii-infected mice is affected by VAM2-6 compound by slowing down the parasite replication, retarding the patency time, and increasing their survival time. Although compound VAM2-6 was active at higher doses than chloroquine, these results leaves a door open to the study of its structure in order to improve its antimalarial activity.

Assuntos

Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Plasmodium yoelii/efeitos dos fármacos , Quinoxalinas/uso terapêutico , Administração Oral , Animais , Bioensaio , Modelos Animais de Doenças , Masculino , Camundongos , Análise de Sobrevida , Resultado do Tratamento

RESUMO

Blackwater fever (BWF) is the term used to designate the occurrence of hemoglobin pigments in the urine of patients infected with malaria parasites. BWF is more often associated with Plasmodium falciparum infection in man. The pathogenesis of BWF has not been explained satisfactorily. In the present study, the clinical and pathological observations made upon CD1 mice infected with Plasmodium yoelii yoelii lethal strain with clinical signs of hemoglobinuria and acute renal failure were evaluated. From the 40 P. yoelii yoelii-infected mice, 14 presented hemoglobinuria. In the observations, it was emphasized that hemoglobinuria occurred in the animals 1-2 days before they die. At 6 days post-infection, infected hemoglobinuric mice (HM) exhibited clinical signs such as dark red urine, apnea, and evident oliguria and hematuria; urine microscopical examination showed very few red blood cells. The entire non hemoglobinuric infected mice had a high parasitemia preceding the time of death, while the HM parasitemia was just detectable. In HM, marked hepatosplenomegaly, anemia, and renal and hepatic dysfunction were observed with the blood chemistry analysis at 6 days post-infection. Severe renal lesions were demonstrated in histopathological and scanning electron microscopy samples. Occlusion and necrosis of convoluted tubules were the main lesions found. The conditions required for the experimental production of hemoglobinuria in CD1 mouse infected by P. yoelii yoelii is still unknown. The clinical picture of a BWF, like in our rodents, was produced exclusively by the interaction between the parasite and its host. Results showed that hemoglobinuria in CD1 mice infected with P. yoelii yoelii and BWF in man infected with P. falciparum are similar in their pathogenesis.

Assuntos

Febre Hemoglobinúrica/patologia , Plasmodium yoelii/patogenicidade , Animais , Febre Hemoglobinúrica/parasitologia , Modelos Animais de Doenças , Hemoglobinúria/parasitologia , Hemoglobinúria/patologia , Histocitoquímica , Rim/patologia , Masculino , Camundongos , Microscopia Eletrônica de Varredura , Parasitemia/parasitologia , Parasitemia/patologia , Fatores de Tempo , Urina/química , Urina/citologia

RESUMO

The damage to the tegument of 3-week-old Fasciola hepatica was evaluated by scanning electron microscopy (SEM) following treatment with the 5-chloro-2-methylthio-6-(1-naphtyloxy)-1H-benzimidazole (called compound alpha) in its natural host. For the present study, flukes were raised in pelibuey sheep infected orally with metacercariae of F. hepatica; the parasites were recovered from the liver of the sacrificed sheep after 6, 12 and 24 h of treatment with compound alpha. At 6 h of treatment, the flukes showed some lesions on the ventral surface of the anterior region, such as a swollen tegument and blebs. At 12 h after treatment, the specimens showed structural disorganization and spine loss in the ventral anterior region. The tegument of the flukes treated for 24 h was completely lost in some areas of the ventral surface, leaving an exposed basal lamina. The tegument of immature F. hepatica might be a target organ for compound alpha to exert its fasciolicide effect.

Assuntos

Anti-Helmínticos/farmacologia , Epiderme/efeitos dos fármacos , Fasciola hepatica/efeitos dos fármacos , Imidazóis/farmacologia , Naftalenos/farmacologia , Doenças dos Ovinos/parasitologia , Animais , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/uso terapêutico , Epiderme/ultraestrutura , Fasciola hepatica/crescimento & desenvolvimento , Fasciola hepatica/ultraestrutura , Fasciolíase/tratamento farmacológico , Fasciolíase/parasitologia , Fasciolíase/veterinária , Imidazóis/administração & dosagem , Imidazóis/uso terapêutico , Masculino , Microscopia Eletrônica de Varredura , Naftalenos/administração & dosagem , Naftalenos/uso terapêutico , Doenças dos Ovinos/tratamento farmacológico , Fatores de Tempo

RESUMO

Our objective was to determine by scanning electron microscopy the structural changes in the tegument of adult Fasciola hepatica after treatment with 5-chloro-2-methylthio-6-(1-naphtyloxy)-1 H-benzimidazole, called compound alpha, and its active metabolite sulphoxide, under in vitro and in vivo conditions. For the in vitro studies, flukes from sheep were exposed to 40 mg/l of compound alpha-sulphoxide over different incubation times. Flukes for the in vivo studies were raised in sheep treated orally with compound alpha and killed at different times post-treatment. Non-treated controls were included for each time of incubation. The results showed lesions after 6 h of treatment, such as swelling and furrows. At 12 h, the spines appeared to be surrounded by the tegument. At 24 h the tegument in some areas showed an exposed basal lamina. These changes became more severe as the incubation periods of the treated flukes increased. Compound alpha exerts a significant effect on the tegument of F. hepatica.

Assuntos

Anti-Helmínticos , Epiderme/efeitos dos fármacos , Fasciola hepatica/efeitos dos fármacos , Fasciolíase/veterinária , Imidazóis , Naftalenos , Sulfóxidos/farmacologia , Animais , Anti-Helmínticos/metabolismo , Anti-Helmínticos/farmacologia , Anti-Helmínticos/uso terapêutico , Epiderme/ultraestrutura , Fasciola hepatica/ultraestrutura , Fasciolíase/tratamento farmacológico , Imidazóis/metabolismo , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Masculino , Microscopia Eletrônica de Varredura/veterinária , Naftalenos/metabolismo , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Doenças dos Ovinos/parasitologia

RESUMO

Objetivo: Identificar si la presencia de fondo coroideo sin miopía modifica la proporción de retinopatía en pacientes diabéticos.Material y métodos: Se realizó una revisión retrospectiva de los pacientes diabéticos valorados oftalmoscópicamente por primera vez, de septiembre de 1998 a noviembre de 1999 y se comparó la proporción de retinopatía diabética en pacientes con fondo coroideo (grupo 1) y sin él (grupo 2). Se evaluó el tiempo de evolución de la diabetes y la presencia de retinopatía diabética. Las diferencias encontradas se analizaron mediante x2. Resultados: se evaluaron 621 pacientes, de los cuales 138 (22 por ciento) presentaban fondo coroideo. La proporción de pacientes con retinopatía diabética fue significativamente menor (p = 0.00) en el grupo 1 que en el 2, diferencia que se mantuvo al ajustar los grupos por tiempo de evolución de la diabetes en forma acumulada.Discusión: La presencia de fondo coroideo se asoció a una menor proporción de pacientes con retinopatía diabética y a aparición más tardía. En los pacientes con fondo coroideo las manifestaciones de retinopatía diabética podrían tener una expresión diferente, y no ser representativas del estado sistémico de afección microvascular.

Assuntos

Humanos , Masculino , Feminino , Corioide , Retinopatia Diabética , Diabetes Mellitus , Fundo de Olho

RESUMO

Se investigó por el método de inmunofluorescencia directa la presencia de IgM, IgG IgA, C3 en biopsias de piel de 304 pacientes con distintas enferemdades del tejido conectivo. Se analizó los resultados obtenidos, se realizó la correlación clínico patológica y se revisó la bibliografía con respecto a: lupus discoide crónico, enfermedad superpuesta del tejido conectivo, LES y Artritis reumatoidea. En los resultados se menciona especialmente el test de Banda para lupus que fue positivo en piel lesionada en el 100 por ciento de casos de lupus discoide crónico. En piel clinicamente sana del borde cubital de la mano izquierda el test de banda fue positiva en: 89 por ciento de pacientes con enfermedad superpuesta del tejido conectivo, 57 por ciento de LES y 7,6 por ciento de artritis reumatoidea. El mayor número depacientes con lupus y test de banda positivo presentaron signos de actividad de enfermedad. Se encontró signos clínicos de lesión renal con mayor frecuencia en pacientes con test de banda positivo con respecto a los pacientes negativos. Se encontró test de banda positivo y anticuerpos antinucleares fijos en pacientes con enfermedad del tejido conectivo superpuesta y en pacientes con lupus eritematoso sistémico

Assuntos

Humanos , Masculino , Feminino , Adulto , Tecido Conjuntivo/patologia , Lúpus Eritematoso Discoide/diagnóstico