RESUMO
BACKGROUND: The introduction of tacrolimus (TAC) to clinical practice was essential to the establishment of transplantation as a therapy for patients with chronic renal disease. However, the higher interindividual variation of TAC metabolism has been an important limiting factor for its clinical use. Although the relationship between CYP3A5 polymorphisms and TAC pharmacokinetics (PK) is well established, the effects of other genetic variants on TAC metabolism, such as POR*28, still remain uncertain. OBJECTIVE: The study aimed to evaluate the impact of POR variants on TAC PK in renal transplant patients with different CYP3A5 genotypes (expressers and non-expressers). METHODS: A total of 115 patients were included in this study. Genomic DNA was isolated from peripheral blood, and the real-time PCR technique was used to analyze the polymorphism POR rs1057868; C>T. RESULTS: During the initial post-transplant period, variant allele carriers (*1/*28 and *28/*28) showed a lower TAC dose requirement than POR wild homozygotes (*1/*1). Regarding the influence of the different polymorphisms of POR within the CYP3A5 expresser and non-expresser groups, no differences were observed in any of the PK parameters analyzed during 12 months after transplantation. CONCLUSION: In the studied population, the variant allelic POR*28 was significantly associated with lower TAC dose requirements and higher Co/D ratio in the first-month post-transplant. However, the effects of this polymorphism on the CYP3A5 enzyme activity were not observed.
Assuntos
Sistema Enzimático do Citocromo P-450/genética , Transplante de Rim , Tacrolimo , Citocromo P-450 CYP3A/genética , Genótipo , Humanos , Imunossupressores/farmacocinética , Polimorfismo de Nucleotídeo Único , Tacrolimo/farmacocinéticaRESUMO
PURPOSE: Genetic polymorphisms have been associated with variation in the metabolism of tacrolimus (TAC) in kidney transplant patients. This study is aimed at assessing the impact of allelic variants of CYP3A5 and PPARA genes on the pharmacokinetics (PK) of TAC in Brazilian kidney transplant recipients in the first-year post-transplant. METHODS: A total of 127 patients were included for genetic evaluation. Genomic DNA was isolated from peripheral blood and real-time PCR was used to analyze the main polymorphisms described for the genes CYP3A5 (rs776746; C > G) and PPARA (rs4823613; A > G and rs4253728; G > A). RESULTS: CYP3A5 expressors showed a lower Co/dose ratio than non-expressors, with the median values of this parameter <1.01 ng/mL/mg in the first group at all evaluated times. Additionally, PPARA variant homozygotes had a lower Co/D ratio than wild allele carriers in the 12-month post-transplant period, with a median value of 0.65 ng/mL/mg. In the CYP3A5 expressers, the presence of the variant homozygous genotype PPARA was associated with a lower value of Co/D compared with the other genotypic groups at month 12. CONCLUSION: In the population under study, polymorphisms on CYP3A5 and PPARA were identified as determining and independent factors associated with the reduction of Co/D of TAC. Thus, the genotyping of these genetic variants may be a useful tool for the individualized prescription of TAC in kidney transplant patients.
Assuntos
Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , PPAR alfa/genética , Tacrolimo/farmacocinética , Transplantados , Adulto , Alelos , Brasil , Feminino , Humanos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Guarana (Paullinia cupana var. sorbilis) is a plant native to the central Amazon basin. Roasted seed extracts have been used as medicinal beverages since pre-Colombian times, due to their reputation as stimulants, aphrodisiacs, tonics, as well as protectors of the gastrointestinal tract. Guarana plants are commercially cultivated exclusively in Brazil to supply the national carbonated soft-drink industry and natural product stores around the world. In this report, we describe and discuss the annotation of 15,387 ESTs from guarana seeded-fruits, highlighting sequences from the flavonoid and purine alkaloid pathways, and those related to biotic stress avoidance. This is the largest set of sequences registered for the Sapindaceae family.
Assuntos
Frutas/genética , Perfilação da Expressão Gênica/métodos , Paullinia/genética , Sementes/genética , Cafeína/metabolismo , Etiquetas de Sequências Expressas , Flavonoides/metabolismo , Frutas/metabolismo , Paullinia/metabolismo , Sementes/metabolismo , Clima TropicalRESUMO
AIM OF THE STUDY: Leishmaniasis, caused by protozoan from Leishmania genus, is an endemic disease in the tropical and subtropical regions of the world. The chemotherapy to this disease is not always effective and can cause several side effects. Chenopodium ambrosioides L. (Chenopodiaceae) is used by the native people in the treatment of cutaneous ulcers caused by different species of Leishmania. The aim of this study was to investigate the effect of the treatment with a hydroalcoholic crude extract (HCE) from the leaves of Chenopodium ambrosioides on the murine infection with Leishmania amazonensis. MATERIAL AND METHODS: The mice were treated for 4-6 weeks post-infection (p.i.) with HCE (5 mg/kg) or meglumine antimoniate (Sb(v)) (28 mg/kg) either by the oral route, once a day, for 15 days or by five intralesional (IL) injections at intervals of 4 days. The thickness of the infected paws was determined weekly and the parasite load evaluated in the draining lymph nodes (LN), the spleen and in the footpad after 7 weeks of infection. The nitric oxide (NO) production was evaluated in cultures with cells from peritoneum or LN. RESULTS: The IL treatment increased the NO production in the LN and peritoneum cultures and reduced the parasite load from the footpad, spleen and LN. On the other hand, the oral treatment decreased did alter neither the NO production nor the parasite load. CONCLUSIONS: IL HCE treatment was more efficient than the oral HCE treatment since the former was able to control the dissemination of infection. This effect can be due to either a direct leishmanicidal effect of HCE or the improvement in the NO production by HCE-stimulated macrophages. The results could justify the topical use of the Chenopodium ambrosioides' leaves in the treatment of the ulcers caused by Leishmania.
Assuntos
Antiprotozoários/uso terapêutico , Chenopodium ambrosioides/química , Leishmaniose Cutânea/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Administração Oral , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/isolamento & purificação , Injeções Intralesionais , Leishmania/efeitos dos fármacos , Linfonodos/parasitologia , Masculino , Medicina Tradicional , Meglumina/uso terapêutico , Antimoniato de Meglumina , Camundongos , Camundongos Endogâmicos C3H , Óxido Nítrico/metabolismo , Compostos Organometálicos/uso terapêutico , Extratos Vegetais/administração & dosagem , Folhas de PlantaRESUMO
The leaves and the oil from the seeds of Chenopodium ambrosioides L. (Chenopodiaceae), a plant known in Brazil as 'mastruz', have been used by native people to treat parasitic diseases. Experimentally it was shown that Chenopodium ambrosioides inhibits the Ehrlich tumor growth, what could be due to an immunomodulatory effect of this product. The aim of this study was to investigate the effect of hydroalcoholic crude extract (HCE) from leaves of Chenopodium ambrosioides on macrophage activity and on lymphoid organs cellularity. C3H/HePas mice received the HCE (5mg/kg) by intraperitoneal via and were sacrificed 2 days later. HCE treatment did not alter the cell number in bone marrow, but it increased the cell number in peritoneal cavity, spleen and lymph node. The spreading and phagocytosis activity, the PMA-induced hydrogen peroxide (H(2)O(2)) release and the nitric oxide (NO) production were also increased when compared to control group. Similar results were obtained with concanavalin A (Con A), used as a positive control, with exception of the NO production that was only detected in HCE-derived macrophages. The in vitro treatment with HCE induced a dose-dependent NO production by resident macrophages, but did not enhance the NO production by HCE-derived macrophage, which however, was enhanced by Con A, suggesting that HCE and Con A induce NO production by different routes. In conclusion, HCE-treatment was able to increase the macrophages activity and also the cellular recruitment to secondary lymphoid organs, what could explain the previously related anti-tumor activity of Chenopodium ambrosioides.
Assuntos
Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Chenopodium ambrosioides , Fatores Imunológicos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fagocitose/efeitos dos fármacos , Álcoois/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Brasil , Células Cultivadas , Concanavalina A/farmacologia , Relação Dose-Resposta a Droga , Peróxido de Hidrogênio/metabolismo , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/química , Injeções Intraperitoneais , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Mitógenos/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta , Solventes/química , Baço/citologia , Baço/efeitos dos fármacos , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Na busca de novos agentes leishmanicidas, avaliamos em culturas de promastigotas de Leishmania amazonensis o efeito dos extratos hidroalcoólicos das folhas de Tephrosia cinerea (L.) Pers. (Fabaceae), Dichorisandra sp (Commelinaceae), Syzygium jambolanum DC. (Myrtaceae), Julocroton triqueter (Lam.) Didr. var. triqueter (Euphorbiaceae), Passiflora edulis Sims(Passifloraceae), Cecropia sp (Cecropiaceae), Chenopodium ambrosioides L.(Chenopodiaceae), Pedilanhus tithymaloides (L.) Poit (Euphorbiaceae), Peristrophe angustifolia Nees(Acanthaceae) e o extrato aquoso do mesocarpo de Orbignya phalerata Mart. (Arecaceae). As promastigotas de Leishmania amazonensis foram cultivadas em presença de 31,3; 63,5; 125,0; 250,0 e 500,0 µg/mL dos extratos por 24 horas. Ao final desse período foi calculada a concentração inibitória do crescimento (CI50) em relação às culturas não tratadas com os extratos. Os extratos das espécies J. triqueter, Dichorisandra sp e T. cinerea apresentaram maior eficácia em induzir a morte das promastigotas, com CI50 de 29,5; 32,9 e 43,6 µg/mL, respectivamente. P. edulis, C. ambrosioides e S. jambolanum apresentaram eficácia moderada com CI50 de 150,1; 151,9 e 166,6 µg/mL, respectivamente. P. tithymaloides e O. phalerata apresentaram baixo efeito leishmanicida com CI50 >500 µg/mL, enquanto Peristrophe angustifolia e Cecropia spnão apresentaram efeito. Dessa forma, dos dez extratos testados, três apresentaram uma expressiva atividade leishmanicida in vitro.
Searching for new leishmanicidal agents, promastigotes forms of L. amazonensis were cultured with the hydroalcoholic extracts obtained from the Tephrosia cinerea (L.) Pers. (Fabaceae), Dichorisandra sp (Commelinaceae), Syzygium jambolanum DC. (Myrtaceae), Julocroton triqueter (Lam.) Didr. var. triqueter (Euphorbiaceae), Passiflora edulis Sims(Passifloraceae), Cecropia sp (Cecropiaceae), Chenopodium ambrosioides L.(Chenopodiaceae), Pedilanhus tithymaloides (L.) Poit (Euphorbiaceae), Peristrophe angustifolia Nees(Acanthaceae) leaves and the aqueous extract obtained from the Orbignya phalerata Mart. (Arecaceae) mesocarp flour. The in vitro assay was performed with promastigotes incubated during 24 hours with 31.3, 62.5, 125.0, 250.0 and 500.0 µg/mL of each extract. Then the inhibitory concentration of the parasite growth (IC50) was determined. The effectiveness of J. triqueter, Dichorisandra sp and T. cinerea hydroalcoholic extracts to induce promastigotes death was intense since the IC50 were 29.5; 32.9 and 43.6 µg/mL, respectively. P. edulis, C. ambrosioides and S. jambolanum extracts had moderated effectiveness since the IC50 were 150.1; 151.9 and 166.6 µg/mL, respectively. P. tithymaloides and O. phalerata extracts showed a low efficacy in comparison with IC50 >500 µg/mL. Peristrophe angustifolia and Cecropia sp extracts had no leishmanicidal effect. Thus, three of the ten extracts that were tested showed a significant in vitro leishmanicidal activity.