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1.
Anticancer Res ; 27(6A): 3707-11, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17970032

RESUMO

Macrophages play a dominant role in defense against infective organisms and their regarded abilities can be positioned as their most primitive and important function. On the other hand, tuberculosis, caused by tubercle bacilli which possess the ability to survive in phagosome and grow in cell, poses a serious problem as an intractable disease because the efficacy of drug delivery to the target bacilli is low. We have developed a new approach to therapy against intracellular bacteria using a drug delivery system (DDS), to deliver an effective amount of drug to the target site, based on the phagocytotic ability of macrophages. In this review, the development of an in vitro model of chronic infection by tubercle bacilli and therapy against tuberculosis using phagocytosis by macrophages and a DDS with microspheres are described.


Assuntos
Sistemas de Liberação de Medicamentos , Glicolatos , Macrófagos Alveolares/microbiologia , Microesferas , Rifampina/uso terapêutico , Tuberculose/tratamento farmacológico , Animais , Células Cultivadas , Ácido Láctico , Modelos Biológicos , Mycobacterium tuberculosis/efeitos dos fármacos , Fagocitose , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos
2.
Microbes Infect ; 8(9-10): 2484-91, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16879999

RESUMO

Macrophages and their phagocytotic abilities play a dominant role for defense against infected organisms. However, Mycobacterium tuberculosis can survive in the phagosomes of macrophages. In this study, the effective delivery of a drug and the killing effect of tubercle bacilli within macrophages were investigated utilizing the phagocytotic uptake of rifampicin (RFP) that had been incorporated into poly(DL-lactic-co-glycolic) acid (PLGA) microspheres. The microspheres were composed of PLGA that had a monomer ratio (lactic acid/glycolic acid) of either 50/50 or 75/25. They had molecular weights from 5000 to 20,000, and diameters of 1.5, 3.5, 6.2 and 8.9 microm. The most significant factor for phagocytotic activity of macrophages was the diameter of the microspheres. By contrast, molecular weight and monomer ratio of PLGA did not influence phagocytosis. The amount of RFP delivered into cells was also investigated. RFP-PLGA microspheres composed of PLGA with a molecular weight of 20,000 and monomer ratio of 75/25 showed the highest amount of delivery (4 microg/1 x 10(6) cells). Fourteen days after infection, the survival rate of treated intracellular bacilli was 1% when compared with untreated cells. There was almost no killing effect of free RFP (4 or 15 microg/ml) on intracellular bacilli. In vivo efficacy of RFP-PLGA was also examined in rats infected with M. tuberculosis Kurono. Intratracheal administration of RFP-PLGA microspheres was shown to be superior to free RFP for killing of intracellular bacilli and preventing granuloma formation in some lobes. These results suggest that phagocytotic activity could be part of a new drug delivery system that selectively targeted macrophages.


Assuntos
Antibióticos Antituberculose/administração & dosagem , Sistemas de Liberação de Medicamentos , Macrófagos Alveolares/metabolismo , Mycobacterium bovis/efeitos dos fármacos , Poliésteres/administração & dosagem , Rifampina/administração & dosagem , Animais , Antibióticos Antituberculose/química , Antibióticos Antituberculose/farmacocinética , Bovinos , Fenômenos Químicos , Físico-Química , Microesferas , Mycobacterium bovis/crescimento & desenvolvimento , Poliésteres/química , Ratos , Ratos Sprague-Dawley , Rifampina/química , Rifampina/farmacocinética , Tuberculose Bovina/tratamento farmacológico , Tuberculose Bovina/microbiologia
3.
J Control Release ; 142(3): 339-46, 2010 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-19951729

RESUMO

Inhalation delivery of poly(lactic-co-glycolic) acid (PLGA) microspheres (MS) loaded with the anti-tuberculosis agent rifampicin (RFP-PLGA MS) to alveolar macrophage (M phi) cells could be an effective drug delivery system for the treatment of tuberculosis. To examine this possibility, we studied (1) the bactericidal effect of RFP-PLGA MS on Mycobacterium bovis Bacillus Calmette-Guérin (BCG)-infected rat alveolar M phi NR8383 cells, and (2) changes in the biochemical events induced in these cells by the uptake of RFP-PLGA MS. The amount of intracellular RFP imported into the M phi s by RFP-PLGA MS containing 0.25 and 2.50 microg RFP/mL was more than twice and ten times, respectively, than that attained with 5.00 microg/mL of RFP solution; and the MS exerted more potent bactericidal effect on BCG inside M phi cells than 5.00 microg RFP/mL solution after incubation for 7 days. RFP-PLGA MS little affected the viability of M phi cells, whereas the polystyrene latex (PSL) MS used as a reference decreased it significantly. RFP-PLGA MS did not stimulate the production of tumor necrosis factor-alpha (TNF-alpha), nitric oxide, interleukin-10 (IL-10), and transforming growth factor-beta1 (TGF-beta1) by the M phi cells, whereas PSL MS stimulated all of these mediators except IL-10. We conclude that RFP-PLGA MS are bio-safe microspheres due to their "silent" nature when taken into M phi cells and that they are promising for the treatment of tuberculosis by pulmonary inhalation.


Assuntos
Antibióticos Antituberculose/administração & dosagem , Portadores de Fármacos/química , Ácido Láctico/química , Macrófagos Alveolares/metabolismo , Ácido Poliglicólico/química , Rifampina/administração & dosagem , Tuberculose/tratamento farmacológico , Animais , Antibióticos Antituberculose/farmacocinética , Antibióticos Antituberculose/uso terapêutico , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Interleucina-10/biossíntese , Interleucina-10/imunologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Microesferas , Mycobacterium bovis/efeitos dos fármacos , Óxido Nítrico/biossíntese , Óxido Nítrico/imunologia , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Rifampina/farmacocinética , Rifampina/uso terapêutico , Distribuição Tecidual , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia
4.
Pharm Res ; 25(6): 1420-30, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18172577

RESUMO

PURPOSE: The purpose of this study is to know the effect of uptake of mycobacteria on the phagocytic activity of alveolar macrophage (Mphi) cells toward poly(lactic-co-glycolic) acid (PLGA) microspheres (MS) loaded with the anti-tuberculosis agent rifampicin (RFP-PLGA MS). MATERIALS AND METHODS: Biological functions such as phagocytic activity toward PLGA MS loaded with fluorescent coumarin (cPLGA MS) and toward polystyrene latex MS (PSL MS), and generation of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) were examined using alveolar Mphi cell NR8383 after they had phagocytosed Mycobacterium bovis Calmette-Guérin (BCG), heat-killed BCG (h-kBCG) or Escherichia coli. RESULTS: The ingestion of BCG, h-kBCG, and E. coli did not affect the viability of the Mphi cells within 2 days. The phagocytosis caused generation of TNF-alpha and NO, being more significant with E. coli than with both types of BCGs. The phagocytosis of both types of BCGs stimulated the phagocytic uptake of cPLGA and PSL MS's, which took place prior to the generation of TNF-alpha or NO, but that of E. coli suppressed the uptake of both MS's. CONCLUSION: Mycobacterial infection stimulated the phagocytic uptake toward cPLGA MS. These results suggest that RFP-PLGA MS is favorable for overcoming tuberculosis.


Assuntos
Macrófagos Alveolares/imunologia , Microesferas , Mycobacterium/imunologia , Fagocitose , Animais , Sobrevivência Celular , Células Cultivadas , Escherichia coli/imunologia , Ácido Láctico/administração & dosagem , Mycobacterium bovis/imunologia , Óxido Nítrico/biossíntese , Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Rifampina/administração & dosagem , Fator de Necrose Tumoral alfa/biossíntese
5.
Chem Pharm Bull (Tokyo) ; 54(7): 1046-9, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16819230

RESUMO

3Beta,4beta:15,16-diepoxy-13(16),14-clerodadiene (1) and a new clerodane diterpenoid designated thysaspathone (2) were isolated from the liverwort Thysananthus spathulistipus, while Radula appressa produced radulannin A (3), radulannin L (4), 2-geranyl-3,5-dihydroxybibenzyl (5), 2(S)-2-methyl-2-(4-methyl-3-pentenyl)-7-hydroxy-5-(2-phenylethyl) chromene (o-cannabichromene) (6), 6-hydroxy-4-(2-phenylethyl) benzofuran (7), and o-cannabicyclol (8). All of the isolated compounds inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and the greatest inhibition was attributed to compound 5, with an IC50 value of 4.5 microM.


Assuntos
Bibenzilas/química , Diterpenos Clerodânicos/química , Hepatófitas/química , Neopreno/química , Óxido Nítrico/antagonistas & inibidores , Animais , Bibenzilas/farmacologia , Linhagem Celular , Células Cultivadas , Diterpenos Clerodânicos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Neopreno/farmacologia , Óxido Nítrico/química
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