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Pankaj Chaudhary - One of the best experts on this subject based on the ideXlab platform.
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Lucanthone and Its Derivative Hycanthone Inhibit Apurinic Endonuclease-1 (APE1) by Direct Protein Binding
2016Co-Authors: Mamta D. Naidu, Louis A. Peña, Rakhi Agarwal, Mihaly Mezei, Min Shen, Yuan Liu, Zina Sanchez, Luis Cunha, David M, Pankaj ChaudharyAbstract:Lucanthone and Hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas Hycanthone was pulled out of Phase II trials. Their potential mechanism of action includes DNA intercalation, inhibition of nucleic acid biosyntheses, and inhibition of enzymes like topoisomerases and the dual function base excision repair enzyme apurinic endonuclease 1 (APE1). Lucanthone inhibits the endonuclease activity of APE1, without affecting its redox activity. Our goal was to decipher the precise mechanism of APE1 inhibition as a prerequisite towards development of improved therapeutics that can counteract higher APE1 activity often seen in tumors. The IC50 values for inhibition of APE1 incision of depurinated plasmid DNA by lucanthone and Hycanthone were 5 mM and 80 nM, respectively. The KD values (affinity constants) for APE1, as determined by BIACORE binding studies, were 89 nM for lucanthone/10 nM for Hycanthone. APE1 structures reveal a hydrophobic pocket where hydrophobic small molecules lik
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lucanthone and its derivative Hycanthone inhibit apurinic endonuclease 1 ape1 by direct protein binding
PLOS ONE, 2011Co-Authors: Mamta D. Naidu, Louis A. Peña, Rakhi Agarwal, Luis F Cunha, Mihaly Mezei, Min Shen, David M Wilson, Yuan Liu, Zina Sanchez, Pankaj ChaudharyAbstract:Lucanthone and Hycanthone are thioxanthenone DNA intercalators used in the 1980s as antitumor agents. Lucanthone is in Phase I clinical trial, whereas Hycanthone was pulled out of Phase II trials. Their potential mechanism of action includes DNA intercalation, inhibition of nucleic acid biosyntheses, and inhibition of enzymes like topoisomerases and the dual function base excision repair enzyme apurinic endonuclease 1 (APE1). Lucanthone inhibits the endonuclease activity of APE1, without affecting its redox activity. Our goal was to decipher the precise mechanism of APE1 inhibition as a prerequisite towards development of improved therapeutics that can counteract higher APE1 activity often seen in tumors. The IC50 values for inhibition of APE1 incision of depurinated plasmid DNA by lucanthone and Hycanthone were 5 µM and 80 nM, respectively. The KD values (affinity constants) for APE1, as determined by BIACORE binding studies, were 89 nM for lucanthone/10 nM for Hycanthone. APE1 structures reveal a hydrophobic pocket where hydrophobic small molecules like thioxanthenones can bind, and our modeling studies confirmed such docking. Circular dichroism spectra uncovered change in the helical structure of APE1 in the presence of lucanthone/Hycanthone, and notably, this effect was decreased (Phe266Ala or Phe266Cys or Trp280Leu) or abolished (Phe266Ala/Trp280Ala) when hydrophobic site mutants were employed. Reduced inhibition by lucanthone of the diminished endonuclease activity of hydrophobic mutant proteins (as compared to wild type APE1) supports that binding of lucanthone to the hydrophobic pocket dictates APE1 inhibition. The DNA binding capacity of APE1 was marginally inhibited by lucanthone, and not at all by Hycanthone, supporting our hypothesis that thioxanthenones inhibit APE1, predominantly, by direct interaction. Finally, lucanthone-induced degradation was drastically reduced in the presence of short and long lived free radical scavengers, e.g., TRIS and DMSO, suggesting that the mechanism of APE1 breakdown may involve free radical-induced peptide bond cleavage.
Mello, Maria Luiza S. - One of the best experts on this subject based on the ideXlab platform.
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Nuclear basophilia and anisotropy in cells of mice treated with oxamniquine
Brasil, 2015Co-Authors: Bechara, Ivanira Jose, Mello, Maria Luiza S.Abstract:CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO[No abstract available]Com o objetivo de se estudar a ação da oxamniquine, uma droga utilizada no tratamento da esquistossomose, sobre a cromatina de núcleos de células animais, foram estudados os padrões de basofilia e anisotropia nucleares em hepatócitos, em células do músculo cardíaco e em linfócitos de camundongos adultos jovens. A oxamniquine foi administrada por via oral (436 mg/kg) e preparados foram obtidos após diversos tempos de fornecimento da droga aos animais. Nos núcleos corados com azul de toluidina a pH 4,0, após digestão com RNAse, não se encontrou diferença quanto aos padrões de basofilia e anisotropia comparando-se animais tratados com controles. Demonstrou se assim que as moléculas de oxamniquine não se alojam no interior da dupla hélice do DNA, não alteram a sua conformação helicoidal nem se ligam aos grupos fosfatos livres desta macromolécula, diferindo, portanto, da atuação de outro esquistossomicida, o Hycanthone.Com o objetivo de se estudar a ação da oxamniquine, uma droga utilizada no tratamento da esquistossomose, sobre a cromatina de núcleos de células animais, foram estudados os padrões de basofilia e anisotropia nucleares em hepatócitos, em células do músculo cardíaco e em linfócitos de camundongos adultos jovens. A oxamniquine foi administrada por via oral (436 mg/kg) e preparados foram obtidos após diversos tempos de fornecimento da droga aos animais. Nos núcleos corados com azul de toluidina a pH 4,0, após digestão com RNAse, não se encontrou diferença quanto aos padrões de basofilia e anisotropia comparando-se animais tratados com controles. Demonstrou se assim que as moléculas de oxamniquine não se alojam no interior da dupla hélice do DNA, não alteram a sua conformação helicoidal nem se ligam aos grupos fosfatos livres desta macromolécula, diferindo, portanto, da atuação de outro esquistossomicida, o Hycanthone.2613137CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOsem informaçãoWith the aim of evaluating the effect of oxamniquine, a drug used in the clinical trials of schistosomiasis mansoni, on chromatin of animal cell nuclei, the patterns of nuclear basophilia and anisotropy were determined for hepatocytes, cardiac miocytes, and lymphocytes of young adult mice. The animals received the oxamniquine orally in a single dose of 436 mg/kg. Cell preparations were obtained at various times after the administration of the drug. The nuclei were subjected to RNAse digestion and stained with a toluidine blue solution at pH 4.0. No difference was found when comparing the patterns of nuclear basophilia and anisotropy of treated animals with those of untreated controls. It was demonstrated that the oxamniquine molecules do not penetrate the interior of the DNA double helix, neither do they alter the helical conformation of this nucleic acid. Furthermore, the oxamniquine molecules do not attach themselves to the free phosphate groups of the DNA. Therefore, this drug does not affect the DNA of the animal chromatin, differing from another schistosomicide, Hycanthone.With the aim of evaluating the effect of oxamniquine, a drug used in the clinical trials of schistosomiasis mansoni, on chromatin of animal cell nuclei, the patterns of nuclear basophilia and anisotropy were determined for hepatocytes, cardiac miocytes, and lymphocytes of young adult mice. The animals received the oxamniquine orally in a single dose of 436 mg/kg. Cell preparations were obtained at various times after the administration of the drug. The nuclei were subjected to RNAse digestion and stained with a toluidine blue solution at pH 4.0. No difference was found when comparing the patterns of nuclear basophilia and anisotropy of treated animals with those of untreated controls. It was demonstrated that the oxamniquine molecules do not penetrate the interior of the DNA double helix, neither do they alter the helical conformation of this nucleic acid. Furthermore, the oxamniquine molecules do not attach themselves to the free phosphate groups of the DNA. Therefore, this drug does not affect the DNA of the animal chromatin, differing from another schistosomicide, Hycanthone
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Nuclear basophilia and anisotropy in cells of mice treated with oxamniquine
Instituto de Medicina Tropical, 2015Co-Authors: Bechara, Ivanira Jose, Mello, Maria Luiza S.Abstract:With the aim of evaluating the effect of oxamniquine, a drug used in the clinical trials of schistosomiasis mansoni, on chromatin of animal cell nuclei, the patterns of nuclear basophilia and anisotropy were determined for hepatocytes, cardiac miocytes, and lymphocytes of young adult mice. The animals received the oxamniquine orally in a single dose of 436 mg/kg. Cell preparations were obtained at various times after the administration of the drug. The nuclei were subjected to RNAse digestion and stained with a toluidine blue solution at pH 4.0. No difference was found when comparing the patterns of nuclear basophilia and anisotropy of treated animals with those of untreated controls. It was demonstrated that the oxamniquine molecules do not penetrate the interior of the DNA double helix, neither do they alter the helical conformation of this nucleic acid. Furthermore, the oxamniquine molecules do not attach themselves to the free phosphate groups of the DNA. Therefore, this drug does not affect the DNA of the animal chromatin, differing from another schistosomicide, Hycanthone.Com o objetivo de se estudar a ação da oxamniquine, uma droga utilizada no tratamento da esquistossomose, sobre a cromatina de núcleos de células animais, foram estudados os padrões de basofilia e anisotropia nucleares em hepatócitos, em células do músculo cardíaco e em linfócitos de camundongos adultos jovens. A oxamniquine foi administrada por via oral (436 mg/kg) e preparados foram obtidos após diversos tempos de fornecimento da droga aos animais. Nos núcleos corados com azul de toluidina a pH 4,0, após digestão com RNAse, não se encontrou diferença quanto aos padrões de basofilia e anisotropia comparando-se animais tratados com controles. Demonstrou se assim que as moléculas de oxamniquine não se alojam no interior da dupla hélice do DNA, não alteram a sua conformação helicoidal nem se ligam aos grupos fosfatos livres desta macromolécula, diferindo, portanto, da atuação de outro esquistossomicida, o Hycanthone
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Nuclear basophilia and anisotropy in cells of mice treated with oxamniquine
Instituto de Medicina Tropical, 2015Co-Authors: Bechara, Ivanira Jose, Mello, Maria Luiza S.Abstract:With the aim of evaluating the effect of oxamniquine, a drug used in the clinical trials of schistosomiasis mansoni, on chromatin of animal cell nuclei, the patterns of nuclear basophilia and anisotropy were determined for hepatocytes, cardiac miocytes, and lymphocytes of young adult mice. The animals received the oxamniquine orally in a single dose of 436 mg/kg. Cell preparations were obtained at various times after the administration of the drug. The nuclei were subjected to RNAse digestion and stained with a toluidine blue solution at pH 4.0. No difference was found when comparing the patterns of nuclear basophilia and anisotropy of treated animals with those of untreated controls. It was demonstrated that the oxamniquine molecules do not penetrate the interior of the DNA double helix, neither do they alter the helical conformation of this nucleic acid. Furthermore, the oxamniquine molecules do not attach themselves to the free phosphate groups of the DNA. Therefore, this drug does not affect the DNA of the animal chromatin, differing from another schistosomicide, Hycanthone.Com o objetivo de se estudar a ação da oxamniquine, uma droga utilizada no tratamento da esquistossomose, sobre a cromatina de núcleos de células animais, foram estudados os padrões de basofilia e anisotropia nucleares em hepatócitos, em células do músculo cardíaco e em linfócitos de camundongos adultos jovens. A oxamniquine foi administrada por via oral (436 mg/kg) e preparados foram obtidos após diversos tempos de fornecimento da droga aos animais. Nos núcleos corados com azul de toluidina a pH 4,0, após digestão com RNAse, não se encontrou diferença quanto aos padrões de basofilia e anisotropia comparando-se animais tratados com controles. Demonstrou se assim que as moléculas de oxamniquine não se alojam no interior da dupla hélice do DNA, não alteram a sua conformação helicoidal nem se ligam aos grupos fosfatos livres desta macromolécula, diferindo, portanto, da atuação de outro esquistossomicida, o Hycanthone.3137Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq
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Investigation of Hycanthone binding to DNA in chromatin with different supra-organization, composition, and function
Alemanha, 2015Co-Authors: Simoni, Isabela C., Mello, Maria Luiza S.Abstract:CAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOHycanthone is a drug used for the clinical treatment of schistosomiasis, although inducing chromosomes breaks and mutagenesis when it enters the DNA double helix. Based on visual observation of characteristics of basophilia and anisotropy after toluidine blue staining, a preferential binding of Hycanthone to heterochromatin could be demonstrated for the nuclei of the Malpighian tubules of Triatoma infestans. In other cellular systems like cattle kidney cells in culture, plant cells, and mouse lymphocytes, the drug could be demonstrated to bind heterochromatin and euchromatin, irrespective of the packing state of the latter. When penetrating the various heterochromatin types (with the exception of T. infestans), the drug induced a chromatin loosening that could favor incidence of chromatin breaks. The variation of Hycanthone binding to DNA in different cell types is possibly related to differences in composition, stereo-arrangement and stability of the DNA-protein complexes involved.79197105CAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOCAPES - COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL E NÍVEL SUPERIORCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGIC
Magalhães, Veronica De Carvalho - One of the best experts on this subject based on the ideXlab platform.
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Estudo das caracteristicas biologicas e morfologicas da linhagem MAP de Schistosoma mansoni
[s.n.], 2018Co-Authors: Magalhães, Veronica De CarvalhoAbstract:Orientador: Luiz Candido de Souza DiasDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: A existência de linhagens resistentes de Schistosoma mansoni é bem conhecida. Estudos prévios tem mostrado que a linhagem MAP é resistente a oxamniquine e Hycanthone, porém sensível a niridazole e praziquantel. Os objetivos deste estudo foram de avaliar a suscetibilidade de moluscos e camundongos à infecção por S. mansoni e determinar aspectos morfológicos da 41ª geração da linhagem MAP. O estudo foi desenvolovido em modelo experimentasl camundongo swiss - Biomphalaria glabrata. Avaliou-se a suscetibilidade de 180 moluscos B. glabrata expostos a 1 e 10 miracídios. Em 80 camundongos infectados pela cauda com 70 cercáfias e sacrificados na 10i! semana, avaliou-se: suscetibilidade do S. mansoni ao oxamniquine (100 mg/kg, dose única, via oral) e ao praziquantel (100 mg/kg, 5 dias, via oral); capacidade de penetração de cercárias e recuperação de vermes; peso corporal, do fígado e do baço; mortalidade; diâmetro dos granulomas hepáticos e morfometria de vermes e de ovos. A mortalidade e o índice de infecção aos 77 dias de infecção foram de, respectivamente, 30,0% e 28,6% (10 miracídios) e 25,0% e 17,8% (1 miracídio) e de 25,0% para o grupo controle, indicando que o verme está bem adaptado ao seu hospedeiro intermediário. A quimioterapia experimental revelou índices de eficácia de 93,9% para o praziquantel e de 15,8 para o oxamniquine, enquanto a percentagem de vermes sobreviventes foi de apenas 6,1% para a primeira droga e de 84,2% para a segunda. Essas percentagens sugerem que novos estudos sejam necessários para determinar o período de oviposição de vermes sobreviventes de camundongos tratados. O tratamento da linhagem MAP com a droga oxamniquine revelou 16% de eficácia e apenas 3,8% na redução no número de vermes. Verificou-se alta taxa de penetração de cercárias (92,05%) e boa taxa de recuperação de vermes (34,12%) nos camundongos infectados. Houve alteração no crescimento ponderal dos animais infectados com diminuição de peso, quando comparados com aqueles do grupo controle, no período entre a administração das duas drogas e o sacrifício dos camundongos. Houve ganho de peso corporal dos animais tratados, hepatomegalia (2,68g i. 0,68) e esplenomegalia (0,41 g ±. 0,15) com aumento de 54% e 128%, respectivamente, quando comparado com esses orgãos dos animais do grupo controle. As reações granulomatosas mediram 268,04µm2. O tamanho dos vermes machos foi de 7,78mm ±1,40 e das fêmeas de 7,03mm ± 0,98. Os ovos apresentaram largura média de 64,24_m± 2,75 e comprimento de 148,46µm ± 8,82. A linhagem MAP na sua 41ª geração manteve sua resistência quando comparada às outras gerações já estudadas. Essa linhagem mostrou características diferentes das outras linhagens de outras regiões do Estado de São PauloAbstract: The appearance of drug resistant strains of Schistosoma mansoni is well know. Previous studies have shown that MAP strain is resistant to oxamniquine and Hycanthone but sensitive to niridazole and praziquantel. The objectives of this study were to evaluate the suscetibility of snails to S. mansoni infection and to determine morphologial aspects of the 41st generation of MAP strain. The study was developing using as experimental model swiss mice-Biomphalaria glabrata. Snails were divided in 3 groups of 60 individuals each: I) Control group; II) Exposed to 1 miracidium; III)Exposed to 10 miracidia. Eighty mice were divided into 4 groups of 20 animais each: A) Control; B) Infected and not treated; C) Infected and treated by OXA (100mg/kg, single dosis, by oral route) and O) infected and treated by PZQ (100mg/kg/5 days, by oral route). Sixty mice were infected with 70 cercariae by immersion of the tail in water. After 3 weeks the animals of the groups C and O were treated and were killed 2 weeks later and evaluated following this analysis: ability of cercarial penetration and worm recovery; body weights of liver and spleen; mortality rate; diameter of hepatic granuloma and morphometry of adults worms and eggs. The mortality rate and suscetibility of snails to infection up to 77 days of exposure were, respectively 30.0% and 28.6% for group 111 25.0% and 17.8% for group 11, and also 25.0% for group I, indicating that the worm is well adapted to its intermediate host. Experimental chemotherapy revealed efficacy levels of 93.9% to PZQ and 15.8% to OXA, while the percentage of surviving worms was of only 6.08% to the first drug and of 84.2% to the second one. We verified higer rate of cercariae penetration (92.05%) and fine rate of recovery worms (34.12%) in the infected mice, alteration of the ponderal growth from infected animais succeding in a decrease of the weight whem compared to the control group, in the period between the administration of the two antischistosomal drugs and the killing of the animais, we notice body weight gain of treated animais, hepatomegaly (2.68g .± 0.68) and splenomegaly (0.41 9 ± 0.15) showing a gain of 54% and 128%, respectively, when compared to these viscera of control group; granulomatosus hepatic reactions measured 268.04j.Jm2. The measurements of worms was 7.78mm±1.40 for male and 7.03mm ± 0.98 for female; and the eggs showed 64.24j.Jm ±2.75 of width and 148.46j.Jm ± 8.82 of lenghí. F41 MAP strain maintened its resistance when compared to previous generations. This strain showed different characteristics from strain of other regions of São Paulo StateMestradoMestre em Parasitologi
Veronica De Carvalho Magalhães - One of the best experts on this subject based on the ideXlab platform.
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Estudo das caracteristicas biologicas e morfologicas da linhagem MAP de Schistosoma mansoni
Universidade Estadual de Campinas. Instituto de Biologia, 1996Co-Authors: Veronica De Carvalho MagalhãesAbstract:A existência de linhagens resistentes de Schistosoma mansoni é bem conhecida. Estudos prévios tem mostrado que a linhagem MAP é resistente a oxamniquine e Hycanthone, porém sensível a niridazole e praziquantel. Os objetivos deste estudo foram de avaliar a suscetibilidade de moluscos e camundongos à infecção por S. mansoni e determinar aspectos morfológicos da 41ª geração da linhagem MAP. O estudo foi desenvolovido em modelo experimentasl camundongo swiss - Biomphalaria glabrata. Avaliou-se a suscetibilidade de 180 moluscos B. glabrata expostos a 1 e 10 miracídios. Em 80 camundongos infectados pela cauda com 70 cercáfias e sacrificados na 10i! semana, avaliou-se: suscetibilidade do S. mansoni ao oxamniquine (100 mg/kg, dose única, via oral) e ao praziquantel (100 mg/kg, 5 dias, via oral); capacidade de penetração de cercárias e recuperação de vermes; peso corporal, do fígado e do baço; mortalidade; diâmetro dos granulomas hepáticos e morfometria de vermes e de ovos. A mortalidade e o índice de infecção aos 77 dias de infecção foram de, respectivamente, 30,0% e 28,6% (10 miracídios) e 25,0% e 17,8% (1 miracídio) e de 25,0% para o grupo controle, indicando que o verme está bem adaptado ao seu hospedeiro intermediário. A quimioterapia experimental revelou índices de eficácia de 93,9% para o praziquantel e de 15,8 para o oxamniquine, enquanto a percentagem de vermes sobreviventes foi de apenas 6,1% para a primeira droga e de 84,2% para a segunda. Essas percentagens sugerem que novos estudos sejam necessários para determinar o período de oviposição de vermes sobreviventes de camundongos tratados. O tratamento da linhagem MAP com a droga oxamniquine revelou 16% de eficácia e apenas 3,8% na redução no número de vermes. Verificou-se alta taxa de penetração de cercárias (92,05%) e boa taxa de recuperação de vermes (34,12%) nos camundongos infectados. Houve alteração no crescimento ponderal dos animais infectados com diminuição de peso, quando comparados com aqueles do grupo controle, no período entre a administração das duas drogas e o sacrifício dos camundongos. Houve ganho de peso corporal dos animais tratados, hepatomegalia (2,68g i. 0,68) e esplenomegalia (0,41 g ±. 0,15) com aumento de 54% e 128%, respectivamente, quando comparado com esses orgãos dos animais do grupo controle. As reações granulomatosas mediram 268,04µm2. O tamanho dos vermes machos foi de 7,78mm ±1,40 e das fêmeas de 7,03mm ± 0,98. Os ovos apresentaram largura média de 64,24_m± 2,75 e comprimento de 148,46µm ± 8,82. A linhagem MAP na sua 41ª geração manteve sua resistência quando comparada às outras gerações já estudadas. Essa linhagem mostrou características diferentes das outras linhagens de outras regiões do Estado de São PauloThe appearance of drug resistant strains of Schistosoma mansoni is well know. Previous studies have shown that MAP strain is resistant to oxamniquine and Hycanthone but sensitive to niridazole and praziquantel. The objectives of this study were to evaluate the suscetibility of snails to S. mansoni infection and to determine morphologial aspects of the 41st generation of MAP strain. The study was developing using as experimental model swiss mice-Biomphalaria glabrata. Snails were divided in 3 groups of 60 individuals each: I) Control group; II) Exposed to 1 miracidium; III)Exposed to 10 miracidia. Eighty mice were divided into 4 groups of 20 animais each: A) Control; B) Infected and not treated; C) Infected and treated by OXA (100mg/kg, single dosis, by oral route) and O) infected and treated by PZQ (100mg/kg/5 days, by oral route). Sixty mice were infected with 70 cercariae by immersion of the tail in water. After 3 weeks the animals of the groups C and O were treated and were killed 2 weeks later and evaluated following this analysis: ability of cercarial penetration and worm recovery; body weights of liver and spleen; mortality rate; diameter of hepatic granuloma and morphometry of adults worms and eggs. The mortality rate and suscetibility of snails to infection up to 77 days of exposure were, respectively 30.0% and 28.6% for group 111 25.0% and 17.8% for group 11, and also 25.0% for group I, indicating that the worm is well adapted to its intermediate host. Experimental chemotherapy revealed efficacy levels of 93.9% to PZQ and 15.8% to OXA, while the percentage of surviving worms was of only 6.08% to the first drug and of 84.2% to the second one. We verified higer rate of cercariae penetration (92.05%) and fine rate of recovery worms (34.12%) in the infected mice, alteration of the ponderal growth from infected animais succeding in a decrease of the weight whem compared to the control group, in the period between the administration of the two antischistosomal drugs and the killing of the animais, we notice body weight gain of treated animais, hepatomegaly (2.68g .± 0.68) and splenomegaly (0.41 9 ± 0.15) showing a gain of 54% and 128%, respectively, when compared to these viscera of control group; granulomatosus hepatic reactions measured 268.04j.Jm2. The measurements of worms was 7.78mm±1.40 for male and 7.03mm ± 0.98 for female; and the eggs showed 64.24j.Jm ±2.75 of width and 148.46j.Jm ± 8.82 of lenghí. F41 MAP strain maintened its resistance when compared to previous generations. This strain showed different characteristics from strain of other regions of São Paulo Stat
Sabadini, Patricia Ivana Pires Bonesso - One of the best experts on this subject based on the ideXlab platform.
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Avaliação da suscetibilidade da linhagem Ouh (Ourinhos, Vale do Paranapanema-SP) de Schistosoma mansoni ao oxamniquine e praziquantel
[s.n.], 2018Co-Authors: Sabadini, Patricia Ivana Pires BonessoAbstract:Orientador: Luiz Candido de Souza DiasDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: É bem conhecida a existência de linhagens de S. mansoni com resistência e/ou tolerância a drogas esquistossomicidas como Hycanthone e oxamniquine. Devido a constatação de linhagens do verme isolado do campo com tolerância ao oxamniquine e praziquantel, impôs-se estudo de suscetibilidade a esses medicamentos para determinação de doses efetivas (DEs) e juntamente ao acompanhamento de oviposição dos animais tratados. Pesquisou-se, in vivo, o comportamento da linhagem Ouh, isolada de 3 portadores autóctones, não tratados, do município de Ourinhos, SP. Foram infectados 10 grupos de 13 camundongos, que receberam, oralmente, tratamento após 50 dias; 5 grupos foram medicados com oxamniquine nas dosagens de O, 100, 200, 300 e 400 mg/kg (dose única) e os restantes praziquantel a O, 100, 150,200 e 250 mg/kg (por 5 dias). Para cada grupo haviam 2 subgrupos: A) perfusão - formados por 8 animais perfundidos após 15 dias do término do tratamento e B) seguimento - com 5 camundongos acompanhados, quinzenalmente, com exames de fezes, método de Kato-Katz e eclosão de miracídios. Os valores de DEs foram determinados através de análise de probitos (procedimento específico do SAS) a partir dos resultados da perfusão. A eficácia para as dosagens de 100 mglkg de oxamniquine e de praziquantel foi de 66,0% e 90,1%, respectivamente, e a percentagens de vermes sobreviventes foi de 34,0% para a primeira droga e 9,9% para a segunda, sendo encontrados vermes machos, fêmeas e casais. Houve sobrevivência de vermes no grupo com 150 mg/kg/5 dias de praziquantel (2,4%), com vermes de ambos' os sexos e casais; porém para as outras doses constatou-se apenas sobrevivência de fêmeas, isso ocorrendo para as outras dosagens de oxamniquine e praziquantel. Nos exames quinzenais dos grupos de seguimento observou-se recuperação de oviposição após 60 dias do término do tratamento com 100 (em um camundongo) e 150 (em um animal) mglkg de praziquantel e após 75 dias com 100 (em um camundongos)e 200 mglkg de oxamniquine (em dois animais), indicando a presença de vermes vivos de ambos os sexos e interrompimento temporário da postura de ovos, certificando o não comprometimento do aparelho reprodutor da fêmea. Nas análises de doses efetivas determinou-se a dosagem necessária para matar 99% dos vermes machos (DE99) que foi de 129,2 e 159,4 mglkg de praziquantel e oxamniquine, respectivamente. Assim, é necessário rever as posologias de ambas as drogas no homem, com finalidade de proporcionar maiores percentagem de cura parasitológica, evitando seleção de linhagens do verme resistentes e/ou tolerantes no campo. Frente a estes resultados a linhagem Ouh foi considerada tolerante ao oxamniquine e praziquantel na dosagem de 1oO mglkg, por apresentar alterações de sensibilidade a ambas as drogas e por não cessar irreversivelmente sua oviposição após o tratamentoAbstract: The existence of resistant and/or tolerant Schistosoma mansoni strains to schistosomicides drugs as Hycanthone and oxamniquine is well known. Secause of strains isolated from the field having tolerance to oxamniquine and praziquantel, the main foccus of this study was to determine the suscetibility to medicaments in order to find the effective doses (EDs). In addition, the treated animais were monitored to verify the oviposition pattern of worms. The Ouh strain was isolated, in vivo, from 3 autochthonous non-treated patient, from Ourinhos city, São Paulo state. Ten groups of 13 mice each were infected and received "per os" treatment after 50 days. Five groups were medicated with oxamniquine in doses of O, 100,200,300 and 400 mg/kg in a single dose, and five with praziquantel in daily doses of O, 100, 150,200 and 250 mg/kg for five days. For each group there were 2 subgroups: A) perfusion - formed by 8 animais perfused 15 days after the treatment; S) follow-up - formed by 5 mice that were followed with faeces exams, Kato-Katz method, and miracidia eclosion tests every 15 days. The EDs values from the perfusion res_lts were determined through the probit analysis (procedure of SAS). The efficacies of the dosage of 1oO mg/kg of oxamniquine and praziquantel were 66,0% and 90,1%, respectively, and the percentages of surviving worms were of 34,0% for the first drug and 9,9% for the latter. Live males, females and couples were found. The was 2,4% worms survival in the group treated with 150 mglkg/5 days of praziquantel and both sexes and couples were also found alive. However, for the other doses of praziquantel and oxamniquine only females survived. During the follow-up group some egg recovering was observed 60 days after the treatment, with 100 mg/kg of praziquantel (one animal) and 150 mg/kg of praziquantel (one animal); and after 75 days with 100 mg/kg of oxamniquine (one animal) and 200 mglkg of oxamniquine (two animais) indicating the presence of living worms of both sexes and temporary interruption of oviposition, indicating that the reproductive system of female was not affected. The 99% effective dilling doses for male worms (EDgg) were 129,2 and 159,4 mg/kg for praziquantel and oxamniquine, respectively. Hence, it is necessary to review the posology in humans for both drugs, with the purpose to achieve higher percentages of parasitological cure, thus preventing the selection of resistant and/or tolerant worm strains. In face to these results, the Ouh strain was considered tolerant to oxamniquine and praziquantel in dosage of 1OO mg/kg, for it showed sensibility changes to both drugs, and by notstopping irreversibly oviposition afer treatmentMestradoParasitologiaMestre em Ciências Biológica
