RESUMO
BACKGROUND: Optimal cefepime dosing is a challenge because of its dose-dependent neurotoxicity. This study aimed to determine individualized cefepime dosing for febrile neutropenia in patients with lymphoma or multiple myeloma. METHODS: This prospective study enrolled 16 patients receiving cefepime at a dose of 2 g every 12 hours. Unbound concentrations were determined at 0.5 hours, 7.2 hours [at the 60% time point of the 12 hours administration interval (C7.2h)], and 11 hours (trough concentration) after the first infusion (rate: 2 g/h). The primary and secondary end points were the predictive performance of the area under the unbound concentration-time curve (AUC unbound ) and the effect of unbound cefepime pharmacokinetic parameters on clinical response, respectively. RESULTS: The mean (SD) AUC unbound was 689.7 (226.6) mcg h/mL, which correlated with C7.2h (R 2 = 0.90), and the Bayesian posterior AUC unbound using only the trough concentration (R 2 = 0.66). Although higher exposure was more likely to show a better clinical response, each parameter did not indicate a statistical significance between positive and negative clinical responses ( P = 0.0907 for creatinine clearance (Ccr), 0.2523 for C7.2h, 0.4079 for trough concentration, and 0.1142 for AUC unbound ). Cutoff values were calculated as 80.2 mL/min for Ccr (sensitivity: 0.889, specificity: 0.714), 18.6 mcg/mL for C7.2h (sensitivity: 0.571, specificity: 1.000), and 9.2 mcg/mL for trough concentration (sensitivity: 0.571, specificity: 1.000). When aiming for a time above 100% the minimum inhibitory concentration, both continuous infusion of 4 g/d and intermittent infusion of 2 g every 8 hours achieved a probability of approximately 100% at a minimum inhibitory concentration of 8 mcg/mL. CONCLUSIONS: Therapeutic drug monitoring by sampling at C7.2h or trough can facilitate rapid dose optimization. Continuous infusion of 4 g/d was recommended. Intermittent dosing of 2 g every 8 hours was alternatively suggested for patients with a Ccr of 60-90 mL/min.
Assuntos
Neutropenia Febril , Linfoma , Mieloma Múltiplo , Humanos , Cefepima , Antibacterianos/farmacocinética , Mieloma Múltiplo/complicações , Mieloma Múltiplo/tratamento farmacológico , Estudos Prospectivos , Teorema de Bayes , Monitoramento de Medicamentos , Testes de Sensibilidade Microbiana , Neutropenia Febril/tratamento farmacológicoRESUMO
Despite their high degree of identity and even higher homology, the two Kat3 transcriptional coactivators, CBP and p300, have distinct functions, particularly within the Wnt/ß-catenin signaling cascade. ICG-001, by directly binding to CBP but not p300, inhibits CBP/ß-catenin transcription and has served as an invaluable chemical genomic tool to dissect the Wnt signaling cascade and the divergent roles of these two coactivators. However, to date no direct antagonist of the p300/ß-catenin interaction has been reported. We now report the identification and validation of the first highly specific, direct p300/ß-catenin antagonists, YH249/250 and their ability to maintain pluripotency in ESC.
Assuntos
Proteína p300 Associada a E1A/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Células-Tronco/metabolismo , beta Catenina/antagonistas & inibidores , Animais , Proteína de Ligação a CREB/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Proteína p300 Associada a E1A/metabolismo , Células HEK293 , Células-Tronco Embrionárias Humanas/efeitos dos fármacos , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Ligação Proteica/efeitos dos fármacos , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Células Satélites de Músculo Esquelético/metabolismo , Bibliotecas de Moléculas Pequenas/química , Células-Tronco/efeitos dos fármacos , beta Catenina/metabolismoRESUMO
The biosynthetic gene cluster of brassicicene C was identified in Alternaria brassicicola strain ATCC 96836 from genome database search. In vivo and in vitro study clearly revealed the function of Orf8 and Orf6 as a fusicoccadiene synthase and methyltransferase, respectively. The understanding toward the biosynthetic pathway promises construction of this type of diterpene compounds with genetic engineering.