RESUMO
BACKGROUND: Nowadays, it is still important to develop effective anti-opisthorchiasis agents. In this work, we tested a complex of praziquantel (PZQ) with a plant origin compound-disodium glycyrrhizinate-in the ratio 1:10 PZQ:Na2GA, containing 11-fold less of the active ingredient. Our aim was to study various ways to treat trematode Opisthorchis felineus with this complex in vitro. Additionally, an in vitro comparison of the anthelmintic action was made among racemic-PZQ, (R)-PZQ, and (S)-PZQ on juvenile and adult maritae of O. felineus. METHODS: Worms extracted from the hamsters were subjected to various regimens of administration of the complex: once a day for 3 days or three times within 1 day. Moreover, mature maritae and juvenile worms of O. felineus were subjected to the comparison the anthelmintic effectiveness of racemic-PZQ, (R)-PZQ, and (S)-PZQ. RESULTS: The O. felineus maritae that received PZQ:Na2GA (1:10) thrice within 1 day were most strongly affected by the drug. Their motility substantially decreased already on the second day after the last dose, and the percentage of live worms by the end of the experimental period was the lowest. These results indicate a cumulative anthelmintic effect of this substance under the regimen "three times within 1 day." For the first time, we report that among the three substances (racemic-PZQ and two enantiomers), (R)-PZQ has the highest anthelmintic activity, toward both juvenile and sexually mature maritae of O. felineus. CONCLUSION: These findings suggest that the development of a supramolecular complex of (R)-PZQ with disodium glycyrrhizinate and administration of this complex three times within 1 day are promising approaches.
Assuntos
Anti-Helmínticos/administração & dosagem , Ácido Glicirrízico/administração & dosagem , Opisthorchis/efeitos dos fármacos , Praziquantel/administração & dosagem , Animais , Anti-Helmínticos/química , Cricetinae/parasitologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Praziquantel/química , EstereoisomerismoRESUMO
N epsilon-Nitroso-N epsilon- [N'-(2-chloroethyl)carbamoyl]-L-lysine (I) and N epsilon- [N'-(2-chloroethyl)-N'-nitrosocarbamoyl]-L-lysine (II), the isomers being the constituents of antitumor agent Lysomustine, were obtained by RFHPLC. The study of cytotoxicity of the above compounds against K562 cells showed that the lesions induced by isomer (II) produce a significant cytotoxic effect but can be efficiently repaired by the action of MGMT (O6-methylaguanine DNA methyltransferase). Under similar conditions, the lesions induced by isomer (I) produce substantially smaller effect but are weakly if at all repairable by MGMT. The effects of a clinically approved agent Lysomustine, which is the mixture of isomers (I) and (II), are similar to those of isomer (II). The results obtained point to a different chemical nature of DNA lesions induced by two Lysomustine isomers. Our data indicate that Lysomustine and its isomer (II) can be used for in vitro selection of cells expressing MGMT.
Assuntos
Antineoplásicos/farmacologia , Compostos de Nitrosoureia/farmacologia , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Substâncias Protetoras/metabolismo , Isoformas de Proteínas/farmacologia , Antineoplásicos/química , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica , Humanos , Células K562/efeitos dos fármacos , Compostos de Nitrosoureia/química , O(6)-Metilguanina-DNA Metiltransferase/genética , Isoformas de Proteínas/químicaRESUMO
Efficient gene transfer into hematopoietic stem cells is vital for the success of gene therapy of hematopoietic and immune system disorders. An in vivo selection system based on a mutant form of the O(6)-methylguanine-DNA-methyltransferase gene (MGMTm) is considered one of the more promising strategies for expansion of hematopoietic cells transduced with viral vectors. Here we demonstrate that MGMTm-expressing cells can be efficiently selected using lysomustine, a nitrosourea derivative of lysine. K562 and murine bone marrow cells expressing MGMTm are protected from the cytotoxic action of lysomustine in vitro. We also show in a murine model that MGMTm-transduced hematopoietic cells can be expanded in vivo on transplantation into sublethally irradiated recipients followed by lysomustine treatment. These results indicate that lysomustine can be used as a potent novel chemoselection drug applicable for gene therapy of hematopoietic and immune system disorders.
Assuntos
Alquilantes/farmacologia , Células da Medula Óssea/metabolismo , Lisina/análogos & derivados , Lisina/farmacologia , Compostos de Nitrosoureia/farmacologia , Alquilantes/química , Animais , Transplante de Medula Óssea , Carmustina/química , Carmustina/farmacologia , Linhagem Celular Tumoral , Feminino , Vetores Genéticos , Humanos , Lentivirus/genética , Lisina/química , Camundongos , Camundongos Endogâmicos C57BL , Compostos de Nitrosoureia/química , O(6)-Metilguanina-DNA Metiltransferase/genética , TransfecçãoRESUMO
A 14C study of chemobiokinetics of sarcolysin and its peptides of glutaminic acid, dosage and routes of administration was conducted in intact rats and those bearing Walker's carcinoma. Similar in shape for peptides, kinetic curves differed from those found for sarcolysin. The rates of absorption and excretion of sarcolysin peptides in intraperitoneal and, particularly, oral administration were lower than those of sarcolysin. Tumor appeared to play a role in a higher rate of peptide excretion. While sarcolysin and its peptides distribution in organs and tissues was generally identical, time of peak radioactive concentration build-up was different. Time needed for accumulation and excretion of peptides from tumor was much longer than from other organs or tissues. Sarcolysin went chiefly to urine while peptides--to faeces.
Assuntos
Antineoplásicos Alquilantes/farmacocinética , Carcinoma 256 de Walker/metabolismo , Glutamatos/farmacocinética , Melfalan/farmacocinética , Administração Oral , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/metabolismo , Área Sob a Curva , Radioisótopos de Carbono , Esquema de Medicação , Glutamatos/administração & dosagem , Glutamatos/metabolismo , Infusões Parenterais , Masculino , Melfalan/administração & dosagem , Melfalan/metabolismo , Peptídeos/farmacocinética , Ratos , Fatores de Tempo , Distribuição TecidualRESUMO
The index of labelled nuclei (ILN) was determined in the mouse liver and pancreas epithelium within 24 hrs following five injections of 3H-thymidine. Five age groups were studied with the mean weight 15, 19, 20.4, 24.3, and 28.2 g. The ILN was equal in hepatocytes, respectively, to 5.2, 0.6, 0.03, 0.13 and 0.02%, in pancreatic islet cells to 4.6, 4.1, 1.7, 1.5, and 0.7%, and in acinar cells to 0.4, 1.1, 0.07, 0.30, and 0.10%. Marked individual ILN variations were observed. In hepatocytes the highest ILN in each age group correlated positively with maximal absolute liver weight and, in four groups, with its maximal relative weight. The maximal ILN indices did not coincide for the three cell types. A suggestion is put forward on relationship between ILN fluctuations and unequal character or organ growth and asynchrony of growth of different organs.