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1.
Braz. J. Pharm. Sci. (Online) ; 58: e20028, 2022. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1403695

RESUMO

Abstract Dyslipidemia is an abnormal lipid profile associated with many common diseases, including coronary heart disease and atherosclerosis. Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that is responsible for the transfer of cholesteryl ester from high-density lipoprotein athero-protective particles to pro-atherogenic very low-density lipoprotein and low-density lipoprotein particles. The requirement for new CETP inhibitors, which block this process has driven our current work. Here, the synthesis as well as the ligand-based and structure-based design of seven oxoacetamido-benzamides 9a-g with CETP inhibitory activity is described. An in vitro study demonstrated that most of these compounds have appreciable CETP inhibitory activity. Compound 9g showed the highest inhibitory activity against CETP with an IC50 of 0.96 µM. Glide docking data for compounds 9a-g and torcetrapib provide evidence that they are accommodated in the CETP active site where hydrophobic interactions drive ligand/CETP complex formation. Furthermore, compounds 9a-g match the features of known CETP active inhibitors, providing a rationale for their high docking scores against the CETP binding domain. Therefore, these oxoacetamido-benzamides show potential for use as novel CETP inhibitors


Assuntos
Benzamidas/efeitos adversos , Dislipidemias/complicações , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Técnicas In Vitro/métodos , Ésteres do Colesterol , Doença das Coronárias/patologia , Concentração Inibidora 50 , Lipoproteínas HDL/classificação , Lipoproteínas LDL/classificação
3.
J. bras. nefrol ; 42(3): 366-369, July-Sept. 2020. graf
Artigo em Inglês, Português | LILACS | ID: biblio-1134844

RESUMO

ABSTRACT Imatinib, which inhibits tyrosine kinase activity of Bcr-Abl protein, is a standard form of treatment for chronic myeloid leukemia (CML). Through its immunomodulatory effect it affects T cell function in a number of ways. It inhibits antigen-induced T cell activation and proliferation. Antigen-specific T-cells and macrophages are vital for protection against Mycobacterium tuberculosis. Here we present a case of renal tuberculosis associated with imatinib therapy in the maintenance phase of CML. With granulomatous interstitial nephritis and positive tubercular DNA on renal biopsy, the condition was successfully treated with anti-tubercular therapy. This case provides support to the hypothesis that imatinib therapy in CML increases the susceptibility to tuberculosis and strict vigilance is required to enable its early detection and treatment.


RESUMO O imatinibe, um inibidor da atividade da tirosina-quinase da proteína BCR-ABL, faz parte do padrão de tratamento para leucemia mieloide crônica (LMC). Por conta de seu efeito imunomodulador, o imatinibe afeta a função dos linfócitos T de várias maneiras ao inibir a sua ativação e proliferação induzidas por antígenos. Linfócitos T e macrófagos antígeno-específicos são vitais para a proteção contra o Mycobacterium tuberculosis. O presente artigo relata um caso de tuberculose renal associada a terapia com imatinibe na fase de manutenção da LMC. Com nefrite intersticial granulomatosa e positividade para DNA de M. tuberculosis na biópsia renal, o paciente foi tratado com sucesso com terapia antituberculínica. O presente caso corrobora a hipótese de que a terapia com imatinibe na LMC aumenta a suscetibilidade à tuberculose, exigindo vigilância rigorosa para permitir sua detecção e tratamento precoces.


Assuntos
Humanos , Masculino , Adulto , Tuberculose Renal/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos
4.
Cad. saúde pública ; 31(3): 517-530, 03/2015. tab, graf
Artigo em Inglês | LILACS | ID: lil-744825

RESUMO

A territorial analysis of Aedes aegypti density was conducted in two Colombian cities using an ecosystem and chorematic approach. Entomological and behavioral data (by cluster) and information on the urban context were used to analyze the relationship between territorial structures and dynamics and vector density. The results were represented in graphic (chorematic) models. Arauca showed higher vector density than Armenia. Higher density was related to unplanned urbanization, flood-prone areas, low socioeconomic strata, household water tanks, higher temperature, and recall of control measures for adult mosquitos. Zones with low density indices coincided with diverse socioeconomic, ecological, and behavioral conditions. The study found a relationship between territorial structures and dynamics and vector density in both Arauca and Armenia, where the interaction between ecological and social systems shape areas with high and low A. aegypti density.


Foi realizada uma análise territorial da densidade do Aedes aegypti em duas cidades da Colômbia, desde um enfoque ecossistêmico e da coremática. Com base em informação entomológica e comportamental (por conglomerados) e informação do contexto urbano, foi indagada a relação de estruturas dinâmicas do território com a densidade vetorial. Foram apresentados os resultados com modelos gráficos (coremática). Identificou-se maior densidade vetorial em Arauca do que na Armênia. Maiores densidades foram relacionadas à urbanização não planejada, zonas de alagamento, estratos socioeconômicos baixos, tanques baixos (reservatórios), maior temperatura e relatório de ações contra os mosquitos adultos. Zonas de densidades baixas coincidiram com diversas condições socioeconômicas, ecológicas e comportamentais. Foi encontrada uma relação das estruturas e dinâmicas do território com a densidade vetorial para Arauca e Armênia, onde a interação entre sistemas ecológicos e sociais configura zonas particulares de alta e baixa densidades de A. aegypti.


Se realizó un análisis territorial de la densidad de Aedes aegypti en dos ciudades de Colombia desde un enfoque ecosistémico y la coremática. A partir de información entomológica y comportamental (por conglomerados) e información del contexto urbano, se indagó la relación de estructuras y dinámicas del territorio con la densidad vectorial. Se representaron los resultados con modelos gráficos (coremática). Se identificó mayor densidad vectorial en Arauca que en Armenia. Mayores densidades se relacionaron con urbanización no planeada, zonas de inundación, estratos socioeconómicos bajos, tanques bajos (alberca), mayor temperatura y reporte de acciones hacia los mosquitos adultos. Zonas de densidades bajas coincidieron con diversas condiciones socioeconómicas, ecológicas y comportamentales. Se encontró relación de las estructuras y dinámicas del territorio con la densidad vectorial para Arauca y Armenia, donde la interacción entre sistemas ecológicos y sociales configuran zonas particulares de alta y baja densidad de A. aegypti.


Assuntos
Animais , Ratos , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Ácidos Graxos não Esterificados/farmacologia , Células Secretoras de Insulina/enzimologia , Fenantrenos/farmacologia , Poli(ADP-Ribose) Polimerases/biossíntese , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Proteínas de Homeodomínio/biossíntese , Insulina , Poli(ADP-Ribose) Polimerases/antagonistas & inibidores , Transativadores/biossíntese
5.
Salud colect ; 11(1): 87-97, ene.-mar. 2015.
Artigo em Espanhol | LILACS | ID: lil-746686

RESUMO

Los problemas éticos de las investigaciones sobre vacunas han crecido en las últimas décadas en frecuencia y magnitud debido a la posición dominante de la industria farmacéutica en el desarrollo de esos estudios. Las tradicionales cuestiones de seguridad y eficacia se han visto agravadas por el conflicto de intereses introducido por la competencia comercial en un mercado a escala global de miles de millones de dólares. La integridad profesional de los investigadores, la responsabilidad moral de los patrocinadores, y la regulación y control por parte de los Estados nacionales, se muestra cuestionada en varios ejemplos. Los resultados de estos cambios son las amenazas a la protección de los derechos de las personas incluidas en estas investigaciones y el discutible progreso que resulta para la salud pública.


The ethical problems in vaccine research have grown in frequency and magnitude in last decades, due to the dominant place of the pharmaceutical industry in the development of such studies. Traditional issues of security and efficacy have been aggravated by the conflicts of interests introduced by commercial competition in a global market worth billions of dollars. We present here a few examples in which the professional integrity of researchers, the moral responsibility of sponsors, and the public regulation and control by national States are put into question. The consequences of these changes represent serious threats to the rights of people included in these studies as well as disputable progress for public health.


Assuntos
Animais , Masculino , Camundongos , Benzamidas/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Poli(ADP-Ribose) Polimerases/imunologia , Estresse Psicológico/enzimologia , Estresse Psicológico/imunologia , Análise de Variância , Formação de Anticorpos/efeitos dos fármacos , Corticosterona/sangue , Relação Dose-Resposta a Droga , Habituação Psicofisiológica/fisiologia , Hemocianinas/imunologia , Poli(ADP-Ribose) Polimerases/efeitos dos fármacos , Distribuição Aleatória , Restrição Física/fisiologia , Estresse Psicológico/sangue
6.
Braz. j. med. biol. res ; 47(12): 1096-1101, 12/2014. graf
Artigo em Inglês | LILACS | ID: lil-727664

RESUMO

p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML.


Assuntos
Humanos , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Proliferação de Células/efeitos dos fármacos , /metabolismo , Proteínas de Fusão bcr-abl/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/farmacologia , Pirimidinas/farmacologia , RNA Interferente Pequeno/farmacologia , Antineoplásicos/farmacologia , Benzamidas/metabolismo , Ciclina D1/efeitos dos fármacos , Ciclina D1/metabolismo , /efeitos dos fármacos , /metabolismo , /genética , Combinação de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Regulação para Baixo/efeitos dos fármacos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Expressão Gênica/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Piperazinas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , /efeitos dos fármacos , /metabolismo , Pirimidinas/metabolismo , /efeitos dos fármacos
7.
Clinics ; 69(11): 758-762, 11/2014. tab, graf
Artigo em Inglês | LILACS | ID: lil-731105

RESUMO

OBJECTIVES: Despite its rising popularity, reports on the use of preoperative imatinib mesylate (IM) in patients with advanced gastrointestinal stromal tumor (GIST) are limited. This study aims to explore the clinical efficacy of preoperative IM in patients with primarily unresectable or metastatic/recurrent GIST. METHODS: Between September 2009 and February 2014, patients with primarily unresectable or metastatic/recurrent GIST treated by a single medical team were recruited and considered for preoperative IM therapy. Re-examination was conducted regularly and abdominal enhanced CT data, blood biochemistry and responses to IM were recorded. RESULTS: A total of 18 patients were enrolled, including 13 with a primary tumor (7 stomach, 3 small bowel, 2 rectal and 1 pelvic tumor) and 5 with recurrent or metastatic GIST (2 with liver metastasis, 2 with anastomotic recurrence and 1 with pelvic GIST). The median follow-up time was 9.5 months (range of 3-63). The median tumor sizes before and after initiation of IM treatment were 9.1 cm and 6.0 cm (p = 0.003) based on the CT findings, respectively. All patients showed a decrease in tumor burden and the median tumor size reduction was 35%. Sixteen of the 18 patients showed a partial response to IM and two possessed stable disease. Nine of the 18 patients (50%) underwent surgical resection of primary or metastatic/recurrent tumors, with a median of 7 months of IM therapy. One case each of multivisceral resection and tumor recurrence were noted. CONCLUSIONS: IM as a preoperative therapy is feasible and safe for unresectable or metastatic/recurrent GIST that can effectively decrease tumor size, facilitating resection. .


Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/secundário , Tumores do Estroma Gastrointestinal/cirurgia , Neoplasias Hepáticas/secundário , Terapia Neoadjuvante , Metástase Neoplásica/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Cuidados Pré-Operatórios , Período Pré-Operatório , Reprodutibilidade dos Testes , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Carga Tumoral
8.
Braz. j. med. biol. res ; 47(8): 637-645, 08/2014. tab, graf
Artigo em Inglês | LILACS | ID: lil-716279

RESUMO

Tissue engineering encapsulated cells such as chondrocytes in the carrier matrix have been widely used to repair cartilage defects. However, chondrocyte phenotype is easily lost when chondrocytes are expanded in vitro by a process defined as “dedifferentiation”. To ensure successful therapy, an effective pro-chondrogenic agent is necessary to overcome the obstacle of limited cell numbers in the restoration process, and dedifferentiation is a prerequisite. Gallic acid (GA) has been used in the treatment of arthritis, but its biocompatibility is inferior to that of other compounds. In this study, we modified GA by incorporating sulfamonomethoxine sodium and synthesized a sulfonamido-based gallate, JJYMD-C, and evaluated its effect on chondrocyte metabolism. Our results showed that JJYMD-C could effectively increase the levels of the collagen II, Sox9, and aggrecan genes, promote chondrocyte growth, and enhance secretion and synthesis of cartilage extracellular matrix. On the other hand, expression of the collagen I gene was effectively down-regulated, demonstrating inhibition of chondrocyte dedifferentiation by JJYMD-C. Hypertrophy, as a characteristic of chondrocyte ossification, was undetectable in the JJYMD-C groups. We used JJYMD-C at doses of 0.125, 0.25, and 0.5 µg/mL, and the strongest response was observed with 0.25 µg/mL. This study provides a basis for further studies on a novel agent in the treatment of articular cartilage defects.


Assuntos
Animais , Coelhos , Benzamidas/síntese química , Desdiferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Fenótipo , Pirimidinas/síntese química , Agrecanas/genética , Agrecanas/metabolismo , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Benzamidas/farmacologia , Sobrevivência Celular , Desdiferenciação Celular/imunologia , Condrócitos/citologia , Condrócitos/metabolismo , Condrogênese/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Glicosaminoglicanos/análise , Imuno-Histoquímica , Citometria de Varredura a Laser , Cultura Primária de Células , Pirimidinas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Engenharia Tecidual
9.
Rev. méd. Chile ; 142(4): 516-520, abr. 2014. graf, tab
Artigo em Espanhol | LILACS | ID: lil-716224

RESUMO

We report a 58 year-old-man without comorbid conditions, with a history of two months of weight loss, malaise and headache. His initial laboratory analysis showed leukocytosis of 16,100/mL with 65% eosinophils and an absolute eosinophil count of 10,465/mL. Both bone marrow biopsy and aspirate showed infiltration by mature appearing eosinophils. Treatment was started with hydroxyurea, associated with prednisone without satisfactory decrease in the eosinophil count. Polymerase chain reaction showed the presence of the gene fusion product FIP1L1/PDGFRA. Imatinib therapy was initiated, resulting in a rapid and progressive reduction in the absolute eosinophil count, with normalization at the second week of treatment. The incidence of the myeloproliferative variant causing hypereosinophilic syndrome is rare. However, the dramatic response to imatinib emphasizes the need to study the presence of the fusion product FIP1L1/PDGFRA in all patients with eosinophilia of unknown etiology.


Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Síndrome Hipereosinofílica/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Resultado do Tratamento
10.
Rev. chil. cir ; 66(2): 175-180, abr. 2014. ilus
Artigo em Espanhol | LILACS | ID: lil-706537

RESUMO

Introducción: Los tumores estromales gastrointestinales (GIST) del recto son muy raros. En la última década se ha planteado la neoadyuvancia con imatinib en los casos de tumores localmente avanzados o inicialmente irresecables. Caso clínico: Se presenta una paciente portadora de un GIST maligno del tabique rectovaginal inicialmente considerado irresecable que fue sometido a neoadyuvancia con Imatinib como terapia de inducción durante 3 meses, logrando una respuesta clínica notable que permitió realizar una resección local exitosa por vía endoanal. La presencia de factores pronósticos deletéreos (tamaño tumoral mayor de 5 cm y 13 mitosis por 50 campos de aumento mayor) determinó la mantención del tratamiento con Imatinib por 15 meses luego de la cirugía con el fin de reducir el riesgo de recidiva local. Luego de 20 meses de seguimiento la paciente está libre de enfermedad, con continencia fecal plena, ha recuperado la actividad sexual, aunque persisten algunos efectos residuales de la droga que están en franca disminución. Conclusión: La neoadyuvancia con imatinib se considera actualmente la terapia estándar en el manejo de los GIST localmente avanzados y/o irresecables.


Background: Rectal gastrointestinal stromal tumors (GIST) are rare. Neo-adjuvant therapy with imatinib is recommended for locally advanced or non-resectable tumors. Case report: We report a 63 years old woman with a malignant GIST located in the recto-vaginal septum which was initially considered non-resectable. The patient was treated with imatinib as induction therapy for three months. After this lapse the tumor was successfully excised using an endo-anal approach. Due to a tumor size over 5 cm and the presence of 13 mitoses per 50 high power fields, two bad prognostic factors, treatment with imatinib was maintained for 15 months after surgery. After 20 months of follow up, the patient is free of disease with complete fecal continence and with an adequate sexual life. Secondary effects of imatinib are gradually subsiding.


Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Quimioterapia Adjuvante , Neoplasias Retais/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Benzamidas , Neoplasias Retais/cirurgia , Tumores do Estroma Gastrointestinal/cirurgia
11.
Mem. Inst. Oswaldo Cruz ; 108(7): 850-853, 1jan. 2013. tab, graf
Artigo em Inglês | LILACS | ID: lil-696014

RESUMO

Imatinib, a drug used for treatment of human chronic myeloid leukaemia, due to its activity against protein kinases, has been also evaluated in vitro against Schistosoma mansoni showing high schistosomicidal activity. In the present experiments imatinib activity in vitro was confirmed at the doses of 25 µM, 50 µM and 100 µM. The first drug activity observed with the lower dose was interruption of egg-laying and with the higher dosages was the death of the worms. In mice infected with S. mansoni no activity was found even with 1,000 mg/kg/day, 500 mg/kg/day, single oral dose or when administered for three consecutive days. This is another example of the difference of results related to in vitro and in vivo trials using S. mansoni worms.


Assuntos
Animais , Camundongos , Benzamidas/farmacologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Relação Dose-Resposta a Droga , Carga Parasitária , Esquistossomose mansoni/parasitologia , Fatores de Tempo
12.
Braz. j. med. biol. res ; 46(1): 39-51, 11/jan. 2013. tab, graf
Artigo em Inglês | LILACS | ID: lil-665801

RESUMO

Imatinib mesylate (IM) is used to treat chronic myeloid leukemia (CML) because it selectively inhibits tyrosine kinase, which is a hallmark of CML oncogenesis. Recent studies have shown that IM inhibits the growth of several non-malignant hematopoietic and fibroblast cells from bone marrow (BM). The aim of the present study was to evaluate the effects of IM on stromal and hematopoietic progenitor cells, specifically in the colony-forming units of granulocyte/macrophage (CFU-GM), using BM cultures from 108 1.5- to 2-month-old healthy Swiss mice. The results showed that low concentrations of IM (1.25 µM) reduced the growth of CFU-GM in clonogenic assays. In culture assays with stromal cells, fibroblast proliferation and α-SMA expression by immunocytochemistry analysis were also reduced in a concentration-dependent manner, with a survival rate of approximately 50% with a dose of 2.5 µM. Cell viability and morphology were analyzed using MTT and staining with acrydine orange/ethidium bromide. Most cells were found to be viable after treatment with 5 µM IM, although there was gradual growth inhibition of fibroblastic cells while the number of round cells (macrophage-like cells) increased. At higher concentrations (15 µM), the majority of cells were apoptotic and cell growth ceased completely. Oil red staining revealed the presence of adipocytes only in untreated cells (control). Cell cycle analysis of stromal cells by flow cytometry showed a blockade at the G0/G1 phases in groups treated with 5-15 µM. These results suggest that IM differentially inhibits the survival of different types of BM cells since toxic effects were achieved.


Assuntos
Animais , Masculino , Camundongos , Antineoplásicos/farmacologia , Benzamidas/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Piperazinas/farmacologia , Pirimidinas/farmacologia , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Fibroblastos , Células-Tronco Hematopoéticas/citologia , Imuno-Histoquímica , Células-Tronco Mesenquimais/citologia
13.
Arq. bras. cardiol ; 99(6): 1082-1091, dez. 2012. ilus, graf, tab
Artigo em Português | LILACS | ID: lil-662371

RESUMO

FUNDAMENTO: O Imatinib é um inibidor do receptor tirosina-quinase que foi confirmada como exercendo um efeito inibidor sobre a atividade do receptor do PDGF, fator de crescimento plaquetário (PDGFRα e PDGFRβ). OBJETIVO: Investigar o efeito protetor do Imatinib na fibrose miocárdica em acetato de deoxicorticosterona (DOCA)/ratos com hipertensão induzida por sal. MÉTODOS: Sessenta ratos Sprague-Dawley machos, uninefrectomizados foram distribuídos em três grupos: ratos controles (grupo CON): grupo deoxicorticosterona (grupo DOCA); grupo deoxicorticosterona e Imatinib (grupo DOCA IMA). A Pressão Arterial Sistólica (PAS) foi medida quinzenalmente. Foi estudada a porção apical do ventrículo esquerdo. Foram empregados: coloração vermelho sirius, coloração de hematoxilina-eosina, imuno-histoquímica e ensaio de western blot. RESULTADOS: A PAS nos grupos DOCA e IMA+DOCA foi maior que no grupo CON nos dias 14 e 28. Os animais do grupo DOCA apresentaram fibrose intersticial e perivascular grave no dia 28, e as expressões de PI, PIII, tenascina-C e fibronectina foram significativamente maiores que nos grupos DOCA+IMA e CON. Quando comparados com o grupo CON, os grupos DOCA e DOCA+IMA apresentaram resposta inflamatória de tecido miocárdico e infiltração de monócitos/macrófagos de diferentes graus. As expressões proteicas do PDGF-A, PDGF-C e PDGFRα foram significativamente maiores nos grupos DOCA e DOCA+IMA que no grupo CON, mas a expressão proteica do p-PDGFRα no grupo DOCA+IMA foi menor que no DOCA. CONCLUSÃO: O Imatinib pode exercer efeitos inibitórios sobre a fibrose miocárdica em ratos com hipertensão induzida por DOCA/sal, os quais podem ser atribuídos à inibição da atividade do PDGFR-α.


BACKGROUND: Imatinib is a tyrosine kinase receptor inhibitor that has been confirmed to exert inhibitory effect on the platelet derived growth factor PDGF receptor (PDGFRα and PDGFRβ) activity. OBJECTIVE: To investigate the protective effect of imatinib on the myocardial fibrosis in deoxycorticosterone-acetate (DOCA)/salt induced hypertensive rats. METHODS: Sixty male uninephrectomized Sprague-Dawley rats were assigned to three groups: control rats (CON group); deoxycorticosterone group (DOCA group); deoxycorticosterone and imatinib group (DOCA+IMA group). Systolic blood pressure (SBP) was measured biweekly. The apical portion of the left ventricle was studied. Sirius-Red staining, Hematoxylin-Eosin staining, immunohistochemistry and Western blot assay were employed. RESULTS: SBP in the DOCA group and DOCA+IMA group was higher than that in the CON group on day 14 and 28. Animals in the DOCA group showed severe interstitial and perivascular fibrosis on day 28, and the expressions of PI, PIII, tenascin-C and fibronectin were significantly higher than those in the DOCA+IMA group and CON group. When compared with the CON group, myocardial tissue inflammatory response and monocyte/macrophage infiltration of different degrees were observed in the DOCA group and DOCA+IMA group. Protein expressions of PDGF-A, PDGF-C and PDGFRα were signiflcantly higher in the DOCA and DOCA+IMA groups than those in the CON group, but the p-PDGFRα protein expression in the DOCA+IMA group was lower than that in the DOCA group. CONCLUSION: Imatinib can exert inhibitory effects on myocardial fibrosis in DOCA/salt induced hypertensive rats, which may be attributed to the inhibition of PDGFR-α activity.


Assuntos
Animais , Masculino , Ratos , Benzamidas/farmacologia , Fibrose Endomiocárdica/tratamento farmacológico , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Western Blotting , Benzamidas/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Desoxicorticosterona , Modelos Animais de Doenças , Fibrose Endomiocárdica/patologia , Fibronectinas/análise , Fibronectinas/metabolismo , Fibrose/tratamento farmacológico , Fibrose/patologia , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Nefrectomia/métodos , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Ratos Sprague-Dawley , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Resultado do Tratamento , Tenascina/análise , Tenascina/metabolismo
14.
Rev. gastroenterol. Perú ; 32(4): 394-399, oct.-dic. 2012. ilus, tab
Artigo em Espanhol | LILACS, LIPECS | ID: lil-692408

RESUMO

Los tumores estromales gastrointestinales (GIST) son neoplasias mesenquimales que típicamente surgen a nivel del estómago, intestino delgado, colon, y otros sitios en la cavidad abdominal y su identificación se ha incrementado por mejoras en los criterios de detección. La mayor parte de los tumores GIST son causados por mutaciones activadoras en los genes de receptores transmembranares tirosina quinasa c-KIT y receptor alpha del factor de crecimiento derivado de plaquetas (PDGFRA). Las mutaciones causales de GIST se restringen solo a ciertas regiones del gen que corresponden a importantes zonas funcionales de c-KIT o PDGFRA. Se reporta que hasta 70% de casos de GIST se debe a mutaciones en el exón 11 del gen c-Kit que corresponde a la región yuxtamembrana del receptor. La región y el tipo de mutación determinan diferencialmente cómo se desarrolla la neoplasia, el pronóstico y su respuesta a inhibidores de las tirosina quinasas como el Imanatib. Por tal motivo, el genotipado de KIT y PDGFRA es importante para el diagnóstico y establecimiento de la sensibilidad a los inhibidores tirosina quinasa.


Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms typically arising in the stomach, small intestine, colon, and other sites in the abdominal cavity and its identification has improved dramatically mainly due to better criteria in its detection. Most GISTs tumors harbor activating mutations in the tyrosine kinase receptor c-KIT or platelet derived growth factor receptor-alpha (PDGFRA). Those mutations are restricted to a few regions corresponding to important functional domains of c-KIT or PDGFRA. Upto 70% of cases are due to mutations in exon 11 of c-KIT corresponding to its juxtamembrane region of the receptor. The location and type of mutation will differentially determine the development of the disease, its prognosis and the response to inhibitors of tyrosine kinases as Imanatib. For this reason, genotyping c-KIT and PDGFRA is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors.


Assuntos
Humanos , Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Biomarcadores Tumorais/metabolismo , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Mutação , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Pirimidinas/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Resultado do Tratamento , Biomarcadores Tumorais/genética
15.
Medwave ; 12(4)mayo 2012. ilus, tab
Artigo em Espanhol | LILACS | ID: lil-715810

RESUMO

Objetivo: Basados en una evaluación económica de costo-efectividad del dasatinib primera línea en el tratamiento de la leucemia mieloide crónica (LMC) realizada por el Consorcio de York, y previo análisis de transferibilidad de datos, se realizó una adaptación de ésta a Colombia y Venezuela. Se compararon los costos y la relación de costo-efectividad del uso de la dosis de 100 mg/día de dasatinib versus 400 mg/día de imatinib y 600 mg/día de nilotinib para cada fase de la enfermedad, como tratamientos de primera línea, con incrementos a 140 mg/día de dasatinib, 800 mg/día de imatinib y 800 mg/día de nilotinib en una segunda línea de tratamiento. Métodos: El modelo original consideró aquellos pacientes con diagnóstico de LMC que no hubieran recibido tratamiento previo. Para realizar la adaptación de la evaluación económica se asumieron las probabilidades de cambio, para lo cual se consideraron tres fases, crónica, acelerada y muerte, a lo largo de toda la vida y con una tasa de descuento del 3,5 por ciento para los costos y beneficios. Los resultados del modelo incluyeron los costos de cada alternativa de tratamiento con dasatinib, nilotinib o imatinib y los años de vida ajustados a calidad ganada. Los costos se expresan en pesos colombianos y bolívares fuertes del año 2011. Resultados: El dasatinib produjo la mayor cantidad de años de vida ajustados a calidad, tanto para Colombia como para Venezuela con 10,67 y 10,53 QALYs respectivamente, en comparación con 10,10 y 9,97 QALYs en cada caso para el imatinib y 10,50 y 10,36 QALYs para el nilotinib. Los costos esperados por QALY en Colombia fueron de $ 108.174.020 para el dasatinib, $ 80.826.556 para el imatinib y $ 134.747.281 para el nilotinib. En Venezuela fueron de BsF 222.970 para el dasatinib, BsF 213.142 para el imatinib y BsF 269.193 para el nilotinib. El dasatinib fue dominante sobre el nilotinib en ambos países. Conclusiones: El dasatinib fue más efectivo...


Objective: To adapt an economic model of frontline dasatinib treatment for chronic myeloid leukemia developed by the York Consortium to the health care settings in Colombia and Venezuela. Methods: The original model considered treatment of naïve patients with CML and a Markov's model with probabilities of change between chronic, accelerated phases and death, over a patient’s lifetime. The applied discount rate is 3.5 percent for both costs and benefits. Direct medical and treatment costs, and mortality rates were taken from the local published data and WHO life tables. Costs are expressed in 2011 Colombian pesos and Venezuelan strong bolivars. Results: Dasatinib 100 mg/day as frontline treatment for CML produced the greatest number of QALYs, both in Colombia and Venezuela with 10.67 and 10.53 QALYs respectively, compared with 10.10 and 9.97 QALYs for imatinib and 10.50 and 10.36 QALYs for nilotinib. The expected cost per QALY in Colombia was $ 108.174.020 for dasatinib, $ 80.826.556 for imatinib and $ 134.747.281 for nilotinib. The expected cost per QALY in Venezuela was BsF 222.970 for dasatinib, BsF 213.142 for imatinib and BsF 269.193 for nilotinib. Dasatinib was dominant to nilotinib in both countries. Conclusions: In the frontline treatment for CML in Colombia and Venezuela, dasatinib had greater QALYs than both imatinib and nilotinib, and demonstrated cost-effectiveness relative to nilotinib. There was an increase in overall costs, due to the increase in life years gained and thus a greater use of overall health care resources.


Assuntos
Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Modelos Econômicos , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Antineoplásicos/uso terapêutico , Benzamidas , Colômbia , Análise Custo-Benefício , Inibidores de Proteínas Quinases/economia , Mortalidade , Piperazinas/economia , Pirimidinas/economia , Controle de Qualidade , Tiazóis , Venezuela
16.
Mem. Inst. Oswaldo Cruz ; 104(8): 1083-1090, Dec. 2009. ilus, tab
Artigo em Inglês | LILACS | ID: lil-538167

RESUMO

Gap junction connexin-43 (Cx43) molecules are responsible for electrical impulse conduction in the heart and are affected by transforming growth factor-â (TGF-â). This cytokine increases during Trypanosoma cruzi infection, modulating fibrosis and the parasite cell cycle. We studied Cx43 expression in cardiomyocytes exposed or not to TGF-â T. cruzi, or SB-431542, an inhibitor of TGF-â receptor type I (ALK-5). Cx43 expression was also examined in hearts with dilated cardiopathy from chronic Chagas disease patients, in which TGF-â signalling had been shown previously to be highly activated. We demonstrated that TGF-â treatment induced disorganised gap junctions in non-infected cardiomyocytes, leading to a punctate, diffuse and non-uniform Cx43 staining. A similar pattern was detected in T. cruzi-infected cardiomyocytes concomitant with high TGF-â secretion. Both results were reversed if the cells were incubated with SB-431542. Similar tests were performed using human chronic chagasic patients and we confirmed a down-regulation of Cx43 expression, an altered distribution of plaques in the heart and a significant reduction in the number and length of Cx43 plaques, which correlated negatively with cardiomegaly. We conclude that elevated TGF-â levels during T. cruzi infection promote heart fibrosis and disorganise gap junctions, possibly contributing to abnormal impulse conduction and arrhythmia that characterise severe cardiopathy in Chagas disease.


Assuntos
Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Benzamidas/uso terapêutico , Doença de Chagas/metabolismo , /metabolismo , Dioxóis/uso terapêutico , Junções Comunicantes/metabolismo , Miócitos Cardíacos/química , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/uso terapêutico , Doença de Chagas/tratamento farmacológico , Imunofluorescência , Junções Comunicantes/efeitos dos fármacos , Imuno-Histoquímica , Microscopia Confocal , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo
17.
Mem. Inst. Oswaldo Cruz ; 104(1): 43-47, Feb. 2009. ilus, graf, tab
Artigo em Inglês | LILACS | ID: lil-507205

RESUMO

The control of Aedes aegypti is impaired due to the development of resistance to chemical insecticides. Insect Growth Regulators (IGR) exhibit distinct mechanisms of action and are considered potential vector control alternatives. Studies regarding the effects of sublethal IGR doses on the viability of resulting adults will contribute to eval-uating their impact in the field. We analyzed several aspects of Ae. aegypti adults surviving exposure to a partially lethal dose of triflumuron, a chitin synthesis inhibitor. A highly significant difference in the proportion of males and females was noted in the triflumuron-exposed group (65.0 percent males) compared to the controls (50.2 percent males). Triflumuron affected adult longevity, particularly for females; after 16 days, only 29.2 percent of males and 13.8 percent of females were alive, in contrast with 94 percent survival of the control mosquitoes. The locomotor activity was reduced and the blood-feeding ability of the treated females was also affected (90.4 percent and 48.4 percent of the control and triflumuron-exposed females, respectively, successfully ingested blood). Triflumuron-surviving females ingested roughly 30 percent less blood and laid 25 percent fewer eggs than the control females. The treated males and females exhibited a diminished ability to copulate, resulting in less viable eggs.


Assuntos
Animais , Feminino , Masculino , Aedes/efeitos dos fármacos , Benzamidas/farmacologia , Quitina/antagonistas & inibidores , Inseticidas/farmacologia , Quitina/biossíntese , Comportamento Alimentar/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Óvulo/efeitos dos fármacos , Comportamento Sexual Animal/efeitos dos fármacos
18.
Mem. Inst. Oswaldo Cruz ; 103(8): 839-842, Dec. 2008. tab
Artigo em Inglês | LILACS | ID: lil-502307

RESUMO

Studies were carried out to evaluate the efficacy of the growth regulator, triflumuron (TFM) (Starycide® sc 480 Bayer), for disrupting the development of Rhodnius prolixus fifth-instar nymph by oral, topical or continuous treatment. All treatments were able to induce high levels of mortality, delay development and molt inhibition. Oral treatment induced molt inhibition in all insects that survived at doses of 0.25, 0.50 and 5.0 mg/mL of a blood meal. The highest levels of both mortality in 24 h and molt inhibition were always observed after topical treatment. The lowest doses needed to obtain considerable biological effects were always observed after continuous treatment. In this way, the highest levels of mortality within 30 days were detected after continuous treatment, which also induced an extended inter-molting period, a lower number of over-aged nymphs and the highest level of molting in nymphs that survived. Moreover, the effects of TFM on insects were often displayed in a dose response manner. These results indicate that TFM acts as a potent growth inhibitor of R. prolixus nymphs and has the potential to be used in integrated vector control programs against hematophagous triatomine species.


Assuntos
Animais , Masculino , Benzamidas/farmacologia , Inseticidas/farmacologia , Rhodnius/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ninfa/efeitos dos fármacos , Ninfa/crescimento & desenvolvimento , Rhodnius/crescimento & desenvolvimento , Fatores de Tempo
19.
Arq. bras. endocrinol. metab ; 51(5): 843-851, jul. 2007. ilus, graf
Artigo em Inglês | LILACS | ID: lil-461334

RESUMO

Apoptosis is an essential physiological process of elimination of destined cells during the development and differentiation or after damage from external stresses such as ionizing radiation or chemotherapeutic agents. Disruption of apoptosis is proved to cause various diseases including cancer. Among numerous molecules involved in diverse anti- or pro-apoptotic signaling pathways, NF-kappaB is one of the key factors controlling anti-apoptotic responses. Its anti-apoptotic effect is thought to be mediated through not only transcriptional activation of dependent genes but also by crosstalking with the JNK pathway. Oncogenic proteins such as Ret/PTC, Ras and BRAF can induce NF-kappaB activation making it an important change in thyroid cancer. A number of specific or non-specific NF-kappaB inhibitors have been tried to take over the cascade in in vitro and in vivo experiments. These agents can induce massive apoptosis especially in combination with radio- or chemotherapy. Current results suggest that the inhibition of the NF-kappaB may be a promising strategy for advanced thyroid cancer treatment but further investigations are warranted to develop specific and clinically effective NF-kappaB inhibitors in future.


A apoptose é um processo fisiológico essencial destinado a eliminar células durante o desenvolvimento e diferenciação ou após danos decorrentes de estresses externos com a radiação ionizante ou agentes quimioterápicos. Distúrbios na apoptose têm sido demonstrados como causadores de várias doenças, incluindo câncer. Entre as inúmeras moléculas envolvidas nas várias vias de sinalização anti- ou pró-apoptoticas, NF-kapaB é um dos fatores-chave que controlam as respostas anti-apoptóticas. Acredita-se que seu efeito anti-apoptótico seja mediado não apenas pela ativação transcricional de genes dependentes mas também por crosstalking com a via JNK. Proteínas oncogênicas como Ret/PTC, Ras e BRAF podem induzir ativação de NF-kapaB promovendo importante transformação no câncer da tireóide. Uma série de inibidores específicos e não-específicos do NF-kapaB tem sido usada em experimentos in vitro e in vivo procurando inibir a cascata. Esses agentes podem induzir apoptose maciça especialmente em combinação com radio ou quimioterapia. Resultados atuais sugerem que a inibição de NF-kapaB pode ser uma estratégia promissora no tratamento do câncer da tireóide avançado, mas novas investigações são necessárias para desenvolver inibidores específicos e clinicamente efetivos do NF-kapaB.


Assuntos
Animais , Humanos , Apoptose/fisiologia , Carcinoma/tratamento farmacológico , NF-kappa B/fisiologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , /metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzamidas/metabolismo , Benzamidas/farmacologia , Carcinoma/metabolismo , Cicloexanonas/metabolismo , Cicloexanonas/farmacologia , Ativação Enzimática , Proteínas Inibidoras de Apoptose/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/genética , Ativação Transcricional , Neoplasias da Glândula Tireoide/metabolismo
20.
Braz. J. Psychiatry (São Paulo, 1999, Impr.) ; 29(2): 148-152, jun. 2007. ilus, tab, graf
Artigo em Inglês | LILACS | ID: lil-455618

RESUMO

OBJECTIVE: The aim of our study was to explore the presence and the distribution of D4 dopamine receptors in postmortem human prefrontal cortex, by means of the binding of [³H]YM-09151-2, an antagonist that has equal affinity for D2, D3 and D4 receptors. It was therefore necessary to devise a unique assay method in order to distinguish and detect the D4 component. METHOD: Frontal cortex samples were harvested postmortem, during autopsy sessions, from 5 subjects. In the first assay, tissue homogenates were incubated with increasing concentrations of [³H]YM-09151-2, whereas L-745870, which has a high affinity for D4 and a low affinity for D2/D3 receptors, was used as the displacer. In the second assay, raclopride, which has a high affinity for D2/D3 receptors and a low affinity for D4 receptors, was used to block D2/D3. The L-745870 (500 nM) was added to both assays in order to determine the nonspecific binding. RESULTS: Our experiments revealed the presence of specific and saturable binding of [³H]YM-09151-2. The blockade of D2 and D3 receptors with raclopride ensured that the D4 receptors were labeled. The mean maximum binding capacity was 88 ± 25 fmol/mg protein, and the dissociation constant was 0.8 ± 0.4 nM. DISCUSSION AND CONCLUSIONS: Our findings, although not conclusive, suggest that the density of D4 receptors is low in the human prefrontal cortex.


OBJETIVO: O objetivo deste estudo foi quantificar a presença e a distribuição de receptores dopaminérgicos do tipo 4 (D4) no córtex cerebral humano em amostras post-mortem através do bloqueio com ³H-YM-09151-2 - um antagonista com afinidade equivalente pelos receptores D2, D3 e D4 - e do desenvolvimento de um método para a detecção específica do componente D4. MÉTODO: Foram obtidas amostras de córtex cerebral de cinco cadáveres. Em um primeiro ensaio, os homogeneizados de tecido cerebral foram incubados em concentrações crescentes de ³H-YM-09151-2, enquanto que o L-745,870, ligante que apresenta grande afinidade pelo receptor D4 e baixa afinidade por D2 e D3, foi utilizado como controle. Em um segundo ensaio, a racloprida, que apresenta alta afinidade por receptores D2 e D3, mas baixa afinidade por D4, foi usada para bloquear D2 e D3. O L-745,870 foi adicionado em ambos os ensaios para determinar o bloqueio não específico. RESULTADOS: Os resultados do experimento demonstraram a presença de um bloqueio específico e saturável com ³H-YM-09151-2. O bloqueio de receptores D2 e D3 com racloprida confirmou que apenas os receptores D4 livres foram avaliados. A Bmax (média ± DP) foi de 88 ± 25 fmol/mg de proteínas, enquanto que a Kd (média ± DP) foi de 0,8 ± 0,4 nM. DISCUSSÃO E CONCLUSÕES: Tais achados, ainda que não definitivamente conclusivos, sugerem a presença de uma baixa densidade de receptores D4 no córtex pré-frontal humano.


Assuntos
Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Benzamidas/farmacologia , Antagonistas de Dopamina/farmacologia , Córtex Pré-Frontal/química , /análise , Química Encefálica , Cadáver
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