RESUMO
BACKGROUND: Patients with haematological malignancies frequently endure neutropenia and gastrointestinal (GI)-mucositis after high-dose chemotherapy. In these patients, ciprofloxacin is used for Gram-negative infection prophylaxis. OBJECTIVES: We investigate ciprofloxacin pharmacokinetics after oral administration in patients with haematological malignancies and explore the impact of GI-mucositis on oral bioavailability and clearance in order to assure adequate systemic exposure. METHODS: Adult haematological patients from two Dutch University Medical Centres received 500â mg twice daily oral ciprofloxacin for Gram-negative prophylaxis. The ciprofloxacin plasma concentrations were collected at various timepoints after oral ciprofloxacin administration and at various days after completion of chemotherapy. Data obtained after oral and intravenous ciprofloxacin administration in 28 healthy volunteers without mucositis served as a control group (391 samples). For haematological patients the degree of GI-mucositis was assessed using the Daily Gut Score (DGS), plasma citrulline and albumin. Data were analysed by non-linear mixed-effects modelling. RESULTS: In total, 250 blood samples were collected in 47 patients with a wide variety of haematological malignancies between 0-30â days after start of chemotherapy. Mucositis was generally mild [DGS median (IQR) 1 (1-1) and citrulline 16â µmol/L (12-23)]. The time to Cmax was slower in haematological patients compared with healthy volunteers although no association with the degree of mucositis (defined as DGS or citrulline) could be identified. Ciprofloxacin bioavailability and clearance were 60% and 33.2â L/h, respectively. CONCLUSIONS: This study supports oral dosing of ciprofloxacin as Gram-negative infection prophylaxis in haematological patients with mild-to-moderate mucositis capable of oral intake.
Assuntos
Neoplasias Hematológicas , Mucosite , Adulto , Humanos , Ciprofloxacina , Mucosite/prevenção & controle , Mucosite/tratamento farmacológico , Disponibilidade Biológica , Citrulina , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Administração OralAssuntos
Linfoma Folicular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Seguimentos , Diretrizes para o Planejamento em Saúde , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/epidemiologia , Linfoma Folicular/terapia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Rituximab/uso terapêuticoRESUMO
The differential diagnosis of chest pain in a patient with sickle cell disease is difficult and may encompass several serious conditions, including chest syndrome, pulmonary embolism and infectious complications. In this manuscript we provide an overview on the various underlying diseases that may cause chest pain in patients with sickle cell disease and provide clues for a proper diagnostic workup.
Assuntos
Síndrome Torácica Aguda/etiologia , Anemia Falciforme/complicações , Dor no Peito/etiologia , Infarto do Miocárdio/etiologia , Embolia Pulmonar/etiologia , Síndrome Torácica Aguda/diagnóstico , Adulto , Dor no Peito/diagnóstico , Angiografia Coronária , Diagnóstico Diferencial , Progressão da Doença , Eletrocardiografia , Feminino , Humanos , Infarto do Miocárdio/diagnóstico , Embolia Pulmonar/diagnósticoRESUMO
In recent years considerable progress has been made in treatment strategies for chronic lymphocytic leukemia (CLL). However, the disease remains incurable because of the development of chemoresistance. Strategies to overcome resistance mechanisms are therefore highly needed. At least two mechanisms contribute to the development of resistance to drugs; acquired mutations resulting in a dysfunctional p53 response and shifts in the balance between apoptosis-regulating proteins. Platinum-based compounds have been successfully applied in relapsed lymphoma and recently also in high-risk CLL. In this study we investigated the efficacy and mechanism of action of cisplatinum (CDDP) in chemorefractory CLL. Independent of p53-functional status, CDDP acted synergistically with fludarabine (F-ara-A). The response involved generation of reactive oxygen species (ROS), which led to specific upregulation of the proapoptotic BH3-only protein Noxa. Induction of Noxa resulted in cell death by apoptosis as inhibition of caspase activation completely abrogated cell death. Furthermore, drug-resistance upon CD40-ligand stimulation, a model for the protective stimuli provided in lymph nodes, could also be overcome by CDDP/F-ara-A. ROS accumulation resulted in Noxa upregulation mainly at the transcriptional level and this was, at least in part, mediated by the mitogen-activated protein kinase p38. Finally, Noxa RNA-interference markedly decreased sensitivity to CDDP/F-ara-A, supporting a key role for Noxa as mediator between ROS signaling and apoptosis induction. Our data indicate that interference in the cellular redox balance can be exploited to overcome chemoresistance in CLL.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Antígenos CD40/metabolismo , Cisplatino/metabolismo , Cisplatino/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/genética , Células Tumorais Cultivadas , Regulação para Cima , Vidarabina/análogos & derivados , Vidarabina/metabolismo , Vidarabina/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Chronic lymphocytic leukemia (CLL) cells circulating in peripheral blood (PB) differ from the leukemic fraction in lymph nodes (LNs) with respect to cell division and drug sensitivity. CD40 stimulation of PB CLL cells in vitro results in chemoresistance and provides a partial model for the LN microenvironment. The TLR9 ligand CpG induces proliferation in immunoglobulin variable heavy-chain-unmutated CLL, but apoptosis in immunoglobulin variable heavy-chain-mutated CLL. To juxtapose proliferative with antiapoptotic signals, we investigated the effects of CpG in the context of CD40 ligation in mutated versus unmutated CLL cells in this study. Prolonged CD40 ligation induced classical, followed by alternative nuclear factor-kappaB (NF-kappaB), activity in both subgroups, correlating with enhanced Bfl-1 and Bcl-X(L) levels, respectively. A dichotomy in NF-kappaB signaling occurred on combined CD40/TLR9 triggering. This induced declining p52 and Bcl-X(L) levels, and reversed chemoresistance only in mutated cells, whereas unmutated cells proliferated, maintained p52 and Bcl-X(L) and remained chemoresistant. The pivotal contribution of Bcl-X(L) to chemoresistance was shown by the BH3 mimetic ABT-737 and RNA interference. Finally, in ex vivo LN samples, p52, p65 and Bcl-X(L) levels were highly expressed, corroborating the in vitro findings. Thus, a distinction in NF-kappaB activation and drug susceptibility in mutated versus unmutated (LN-like) CLL cells was uncovered, which was causally linked to Bcl-X(L) levels.