RESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal injury is a serious clinical event with recent advances of diagnostic technologies, but a successful therapeutic method to treat such injuries is still lacking. Licorice, a traditional herbal medicine, and its derivatives have been widely used for the treatment of a variety of diseases due to their extensive biological actions. However, it is unknown whether these derivatives have an effect on NSAIDs-induced small intestinal damage. Previously, the anti-inflammatory effects of three compounds extracted from the licorice root, glycyrrhizin, 18ß-glycyrrhetinic acid, and dipotassium glycyrrhizinate, were compared in vitro cell culture. The most prominent inhibitory effect on the tumor necrosis factor-α (TNF-α) production was observed with the administration of 18ß-glycyrrhetinic acid as an active metabolite of glycyrrhizin. In this study, a complex compound of 18ß-glycyrrhetinic acid and hydroxypropyl γcyclodextrin was examined to improve the oral bioavailability. After administration of this complex to indomethacin treated mice, a significantly high plasma concentration of 18ß-glycyrrhetinic acid was detected using the tandem mass spectrometry coupled with the HPLC. Furthermore, the complex form of 18ß-glycyrrhetinic acid and hydroxypropyl γcyclodextrin reduced mRNA expressions of TNF-α, interleukin (IL)-1ß, and IL-6, which was histologically confirmed in the improvement of indomethacin-induced small intestinal damage. These results suggest that the complex of 18ß-glycyrrhetinic acid and hydroxypropyl γcyclodextrin has the potential therapeutic value for preventing the adverse effects of indomethacin-induced small intestinal injury.
Assuntos
Ácido Glicirretínico/análogos & derivados , Indometacina/efeitos adversos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/lesões , gama-Ciclodextrinas/farmacologia , Animais , Disponibilidade Biológica , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacocinética , Ácido Glicirretínico/farmacologia , Interleucina-1beta/genética , Interleucina-6/genética , Intestino Delgado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Solubilidade , Fator de Necrose Tumoral alfa/genética , gama-Ciclodextrinas/química , gama-Ciclodextrinas/farmacocinéticaRESUMO
The phosphorylation of 5'-deoxy-5-fluorouridine (doxifluridine, 5'-DFUR) has been achieved using inorganic cyclo-triphosphate (P(3m), Na(3)P(3)O(9)) and monoimido-cyclo-triphosphate (MCTP, Na(3)P(3)O(8)NH) in aqueous solution. In the reaction of 5'-DFUR with P(3m), 2'-monophospho-5'-DFUR and 3'-monophospho-5'-DFUR were synthesized with a total yield of more than 95%. In the reaction of 5'-DFUR with MCTP, 2'-diphosphoramidophosphono-5'-DFUR and 3'-diphosphoramidophosphono-5'-DFUR were synthesized with a total yield of more than 40%. The phosphorylated products with P(3m) and MCTP were stable in neutral and alkaline solutions.
Assuntos
Floxuridina/análogos & derivados , Imidas/química , Polifosfatos/química , Floxuridina/química , Fosforilação , Água/químicaRESUMO
The phosphorylation of nucleosides (adenosine, guanosine, cytidine, and uridine) and nucleotides (adenosine 5'-monophosphate, guanosine 5'-monophosphate, cytidine 5'-monophosphate and uridine 5'-monophosphate) has been achieved using inorganic monoimido-cyclo-triphosphate (MCTP, Na(3)P(3)O(8)NH) in aqueous solution. In this reaction, the 2'-OH or 3'-OH group of the beta-D-ribofuranose unit was phosphorylated and the total yield was more than 30% and 14%, respectively. The main products were 2'-diphosphoramidophosphononucleoside and 2'-diphosphoramidophosphononucleoside 5'-monophosphate.
Assuntos
Imidas/química , Nucleosídeos/química , Nucleotídeos/química , Polifosfatos/química , Citidina/química , Guanosina/química , Espectroscopia de Ressonância Magnética , Fosforilação , Uridina/químicaRESUMO
The reliability of an in vitro pyrogen test system based on proinflammatory cytokine release from human monocytic cells was assessed by comparison with a test system based on a human whole blood culture as well as with the conventional rabbit pyrogen test. The human cells used as the pyrogen indicator cells were newly selected by subcloning of a human monocytic cell line, Mono-Mac-6. The selected cells, named MM6-CA8, responded to various pyrogens, including endotoxin, peptidoglycan (PG), Staphylococcus aureus Cowan 1 (SAC), and poly(I x C), with a high sensitivity and produced proinflammatory cytokines, such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor alpha. Among these cytokines, IL-6 was produced most sensitively in response to traces of the pyrogens and detected in the largest quantities in the culture medium. The cytokine-producing responses of MM6-CA8 cells correlated significantly with the responses of cultured human whole blood, which represents an ex vivo culture test system reproducing pyrogen-induced cytokine production in the human body. In terms of cytokine inducibility, the pyrogens were ranked in the order endotoxin > PG > poly (I. C) > SAC in both culture systems, a ranking which almost agreed with the ranking of their pyrogenicity as assessed by the rabbit pyrogen test. These results suggest that the in vitro responsiveness of MM6-CA8 cells to various pyrogens is highly relevant for human pyrogenic reactions. Therefore, the in vitro test system is useful and reliable for detecting the presence of materials that are pyrogenic for humans.