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1.
Int J Clin Pharmacol Ther ; 58(2): 89-102, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31657711

RESUMO

OBJECTIVE: Crohn's disease (CD) is a chronic inflammatory gastrointestinal disease with repeated cycles of exacerbation and remission. Infliximab (IFX), a chimeric anti-TNF-α monoclonal antibody, has been widely used for the treatment of CD. However, no study in Japanese CD patients receiving continuous IFX for more than 1 year has been reported. To avoid therapeutic failure during long-term administration in Japanese CD patients, we evaluated the variable factors of IFX pharmacokinetics and the optimal trough IFX concentration at 8 weeks after administration. MATERIALS AND METHODS: Population pharmacokinetic (PPK) analysis was performed using the nonlinear mixed-effect model based on the IFX serum concentration in 832 samples from 121 patients. A one-compartment model was used to examine interindividual variability in the systemic clearance (CL) of intravenously administered IFX. RESULTS: PPK estimates (estimated value, RSE%) were total clearance (CL: 0.018 L/h, 9.1) and volumes of distribution (Vd: 7.35 L, 12.0). Interindividual variability for CL and Vd of 0.11 and 0.16, respectively, was found. Body weight, antibody to IFX (ATI), and albumin level were factors affecting the IFX CL. IFX CL was greater in the ATI-positive than in the ATI-negative group. CL was also greater in nonremission patients. There was a significant association between the predicted serum IFX trough concentration at 8 weeks and therapeutic response with long-term continuous administration (p < 0.05), with a higher concentration at 8 weeks seen in the remission group. CONCLUSION: Using these variables including body weight, ATI, and albumin level, the IFX dose could be calculated for individual CD patients to achieve the optimal therapeutic range.


Assuntos
Doença de Crohn/terapia , Fármacos Gastrointestinais/farmacocinética , Infliximab/farmacocinética , Povo Asiático , Monitoramento de Medicamentos , Fármacos Gastrointestinais/uso terapêutico , Humanos , Infliximab/uso terapêutico , Japão , Modelos Biológicos , Fator de Necrose Tumoral alfa/antagonistas & inibidores
2.
J Gastroenterol Hepatol ; 34(10): 1751-1757, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31045285

RESUMO

BACKGROUND AND AIM: A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. METHODS: We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. RESULTS: The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. CONCLUSIONS: NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.


Assuntos
Anti-Inflamatórios/efeitos adversos , Azatioprina/efeitos adversos , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/efeitos adversos , Leucopenia/induzido quimicamente , Leucopenia/genética , Mercaptopurina/efeitos adversos , Mutação de Sentido Incorreto , Pirofosfatases/genética , Adulto , Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Índices de Eritrócitos , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Contagem de Leucócitos , Leucopenia/sangue , Leucopenia/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Tóquio , Resultado do Tratamento , Adulto Jovem
3.
PLoS One ; 13(10): e0204632, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30286108

RESUMO

Since anti-tumor necrosis factor (TNF)-α agents (TNF-α inhibitors) induce both clinical response and remission in patients with moderate to severe inflammatory bowel disease (IBD), the use of anti-TNF therapies has fundamentally changed the approach to treatment for patients with IBD. Infliximab (IFX) is a TNF-α inhibitor approved for the induction and remission of Crohn's disease (CD). However, even among patients who initially demonstrate a clinical response to IFX therapy, secondary loss of response occurs, although the reason remains unknown. We therefore investigated predictive factors associated with the response to IFX in long-term maintenance treatment in Japanese CD patients. Eight types of single-nucleotide polymorphisms (SNPs) were investigated using the real-time PCR method, and patient characteristics were collected from the electronic medical records. The Crohn's Disease Activity Index criteria were used as the response to IFX therapy. The observation period was 1 year after IFX had been administered for more than 1 year. Associations between the IFX response and patient characteristics were evaluated using the multivariate logistic regression model. We studied 121 unrelated adult Japanese with CD treated for more than 1 year with IFX as outpatients at Keio University Hospital from November 1, 2014 to November 30, 2015. Among them, 71 were classified as in remisson. In multivariate analysis, patients with the TNF-α 857C>T C/C genotype, shorter disease duration, without double dosing, and combination treatment with an immunomodulator had higher remisson rates than those with the C/T or T/T genotype, longer disease duration, with double dosing, and no combination treatment with an immunomodulator. The response to IFX in Japanese CD patients may therefore be predicted by these 4 characteristics in actual clinical practice.


Assuntos
Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Infliximab/uso terapêutico , Adulto , Povo Asiático , Doença de Crohn/genética , Quimioterapia Combinada/métodos , Feminino , Genótipo , Humanos , Fatores Imunológicos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Modelos Logísticos , Masculino , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Indução de Remissão/métodos , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores
4.
Apoptosis ; 22(11): 1353-1361, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28951984

RESUMO

In previous clinical trials, we showed that remote ischemic preconditioning (rIPC) reduced myocardial damage in children undergoing treatment for congenital heart defects and postoperative renal failure in patients undergoing abdominal aortic aneurysm surgery. In rabbit experiments, pre-treatment with plasma and plasma dialysate (obtained using 15-kDa cut-off dialysis membrane) from donor rabbits subjected to rIPC similarly protected against cardiac infarction. However, the protective substances containing in rIPC plasma have been unknown. In the present study, we showed that rIPC plasma exerted anti-apoptotic and anti-oxidative effects on human neural stem cells under oxygen glucose deprivation (OGD) that mimics brain ischemia. Additionally, we applied the sample to the liquid chromatography integrated with mass spectrometry to identify candidate key molecules in the rIPC plasma and determine its role in protecting neural stem cells from OGD-induced cell death. Thioredoxin increased significantly after rIPC compared to pre-IPC. Pretreatment with thioredoxin, the antioxidant protein, markedly protected human neural stem cells from OGD-induced cell death. The effect of thioredoxin on brain ischemia in animals should be further evaluated. However, the present study first evaluated the effect of rIPC in the ischemic cellular model.


Assuntos
Antioxidantes/farmacologia , Proteínas Sanguíneas/farmacologia , Meios de Cultura/farmacologia , Precondicionamento Isquêmico , Células-Tronco Neurais/efeitos dos fármacos , Tiorredoxinas/farmacologia , Adulto , Antioxidantes/isolamento & purificação , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Sanguíneas/isolamento & purificação , Hipóxia Celular , Linhagem Celular Transformada , Glucose/deficiência , Glucose/farmacologia , Voluntários Saudáveis , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Estresse Oxidativo , Oxigênio/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Tiorredoxinas/isolamento & purificação
5.
Heart Vessels ; 31(9): 1514-21, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26386570

RESUMO

Liver cirrhosis (LC), which may result in hepatic failure or cancer, has been reported in patients after Fontan procedure. The purpose of this study was to clarify the frequency and histological characteristics of LC, and to evaluate the risk factors and serological markers of LC with Fontan circulation. Retrospective review of contrast-enhanced CT scans (CT) of the liver was carried out in 57 patients after Fontan procedure. Patients were divided into two groups: LC group (n = 31) and no LC group (n = 26). Age at Fontan procedure, duration after Fontan procedure, catheterization data, and history of failing Fontan circulation were compared between groups. Serological data including γ-GTP and hyaluronic acid were compared. Histology of autopsy specimens was assessed when available. Duration after Fontan procedure was significantly longer in LC group than no LC group. History of failing Fontan circulation was more frequent in LC group than in no LC group. There was no correlation between type of procedure (APC/Bjork/lateral tunnel/TCPC) and LC in this series. Serum hyaluronic acid, γ-GTP, and Forns index were significantly higher in LC group. Significant risk factors for LC were duration after Fontan procedure (>20 years). In autopsy specimens, histopathological changes of LC were observed predominantly in the central venous area. LC diagnosed with CT is frequent in patients long after Fontan procedure, especially after 20 years. Hyaluronic acid and γ-GTP could be useful markers to monitor the progression of liver fibrosis in Fontan patients.


Assuntos
Técnica de Fontan/efeitos adversos , Cardiopatias Congênitas/cirurgia , Ácido Hialurônico/sangue , Cirrose Hepática/etiologia , gama-Glutamiltransferase/sangue , Adolescente , Adulto , Área Sob a Curva , Autopsia , Biomarcadores/sangue , Biópsia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Técnica de Fontan/mortalidade , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/mortalidade , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/mortalidade , Masculino , Valor Preditivo dos Testes , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
6.
PLoS One ; 10(12): e0144263, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26641634

RESUMO

We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Aripiprazol/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Mineração de Dados , Bases de Dados Factuais , Rotulagem de Medicamentos , Exenatida , Humanos , Hipercalcemia/induzido quimicamente , Cetolídeos/efeitos adversos , Pancreatite/induzido quimicamente , Peptídeos/efeitos adversos , Rabdomiólise/induzido quimicamente , Rosuvastatina Cálcica/efeitos adversos , Suicídio , Teriparatida/efeitos adversos , Fatores de Tempo , Estados Unidos , United States Food and Drug Administration , Vareniclina/efeitos adversos , Peçonhas/efeitos adversos
7.
Ann Thorac Surg ; 98(5): e109-11, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25441828

RESUMO

We provided a left ventricular assist device (LVAD) for a 22-year-old man with congenital L-transposition of the great arteries after anatomic repair at the age of 7 years. He was hospitalized for progressive low-output syndrome caused by intractable biventricular failure. He received LVAD in his morphologic left ventricle with a concomitant pulmonary valve replacement. After the surgery, critical multiorgan failure with severe right heart failure occurred. It took three postoperative months to normalize all organ function following improvement of morphologic right ventricular function. He has remained stable with LVAD support for 1.5 years.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Insuficiência Cardíaca/cirurgia , Coração Auxiliar , Transposição dos Grandes Vasos/cirurgia , Seguimentos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Tomografia Computadorizada por Raios X , Transposição dos Grandes Vasos/complicações , Transposição dos Grandes Vasos/diagnóstico , Função Ventricular Direita , Adulto Jovem
8.
PLoS One ; 6(9): e24837, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21931859

RESUMO

In previous studies on the mechanism underlying megakaryocyte-specific gene expression, several ETS motifs were found in each megakaryocyte-specific gene promoter. Although these studies suggested that several ETS family proteins regulate megakaryocyte-specific gene expression, only a few ETS family proteins have been identified. Platelet factor 4 (PF4) is a megakaryocyte-specific gene and its promoter includes multiple ETS motifs. We had previously shown that ETS-1 binds to an ETS motif in the PF4 promoter. However, the functions of the other ETS motifs are still unclear. The goal of this study was to investigate a novel functional ETS motif in the PF4 promoter and identify proteins binding to the motif. In electrophoretic mobility shift assays and a chromatin immunoprecipitation assay, FLI-1, ELF-1, and GABP bound to the -51 ETS site. Expression of FLI-1, ELF-1, and GABP activated the PF4 promoter in HepG2 cells. Mutation of a -51 ETS site attenuated FLI-1-, ELF-1-, and GABP-mediated transactivation of the promoter. siRNA analysis demonstrated that FLI-1, ELF-1, and GABP regulate PF4 gene expression in HEL cells. Among these three proteins, only FLI-1 synergistically activated the promoter with GATA-1. In addition, only FLI-1 expression was increased during megakaryocytic differentiation. Finally, the importance of the -51 ETS site for the activation of the PF4 promoter during physiological megakaryocytic differentiation was confirmed by a novel reporter gene assay using in vitro ES cell differentiation system. Together, these data suggest that FLI-1, ELF-1, and GABP regulate PF4 gene expression through the -51 ETS site in megakaryocytes and implicate the differentiation stage-specific regulation of PF4 gene expression by multiple ETS factors.


Assuntos
Fator Plaquetário 4/metabolismo , Proteínas Proto-Oncogênicas c-ets/metabolismo , Animais , Sítios de Ligação , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Citometria de Fluxo , Fator de Transcrição de Proteínas de Ligação GA/genética , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Células Hep G2 , Humanos , Megacariócitos/metabolismo , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Fator Plaquetário 4/genética , Ligação Proteica , Proteínas Proto-Oncogênicas c-ets/genética , RNA Interferente Pequeno , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Transativadores
9.
Toxicol In Vitro ; 25(2): 500-4, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21144891

RESUMO

Intake of high doses of vitamin C has known to modulate sulfoconjugation of drugs in the intestine, but the underlying mechanisms for this effect remain to be elucidated. In the present study, we investigated the effects of vitamin C (l-ascorbic acid (AA)) on sulfation of 1-naphthol using Caco-2 cells, a model of human intestinal cells. We found that high dose of AA inhibited the accumulation of 1-naphthyl sulfate in Caco-2 culture medium within 24h in a dose-dependent manner (IC(50)=42 mM). Dehydroascorbic acid (DA), an oxidized form of AA, showed no inhibition. AA did not inhibit the in vitro sulfotransferase (SULT) activity toward 1-naphthol, whereas it reduced the expression of genes belonging to SULT1A family, SULT1A1 and SULT1A3. DA showed no effect on SULT1A gene expression. Consistent with the reduction in gene expression, AA reduced the cytosolic SULT activity towards 1-naphthol in the AA-treated Caco-2 cells. In addition, cAMP exerted an additive effect on AA-mediated repression of SULT1A gene expression. Our results suggest that megadose AA suppresses sulfoconjugation in the intestine mainly by downregulating the expression of SULT1A genes.


Assuntos
Ácido Ascórbico/farmacologia , Mucosa Intestinal/metabolismo , Naftóis/metabolismo , Ésteres do Ácido Sulfúrico/metabolismo , Arilsulfotransferase/antagonistas & inibidores , Arilsulfotransferase/genética , Células CACO-2 , AMP Cíclico/farmacologia , Humanos , Mucosa Intestinal/efeitos dos fármacos
10.
Clin Sci (Lond) ; 117(5): 191-200, 2009 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-19175358

RESUMO

rIPC (remote ischaemic preconditioning) is a phenomenon whereby short periods of ischaemia and reperfusion of a tissue or organ (e.g. mesentery, kidney) can protect a distant tissue or organ (e.g. heart) against subsequent, potentially lethal, ischaemia. We, and others, have shown that transient limb ischaemia can provide potent myocardial protection experimentally and clinically during cardiac surgery. Nonetheless, our understanding of the signal transduction from remote stimulus to local effect remains incomplete. The aim of the present study was to define the humoral nature of rIPC effector(s) from limb ischaemia and to study their local effects in isolated heart and cardiomyocyte models. Using a Langendorff preparation, we show that infarct size after coronary artery ligation and reperfusion was substantially reduced by rIPC in vivo, this stimulus up-regulating the MAPKs (mitogen-activating protein kinases) p42/p44, and inducing PKCepsilon (protein kinase Cepsilon) subcellular redistribution. Pre-treatment with the plasma and dialysate of plasma (obtained using 15 kDa cut-off dialysis membrane) from donor rabbits subjected to rIPC similarly protected against infarction. The effectiveness of the rIPC dialysate was abrogated by passage through a C18 hydrophobic column, but eluate from this column provided the same level of protection. The dialysate of rIPC plasma from rabbits and humans was also tested in an isolated fresh cardiomyocyte model of simulated ischaemia and reperfusion. Necrosis in cardiomyocytes treated with rIPC dialysate was substantially reduced compared with control, and was similar to cells pre-treated by 'classical' preconditioning. This effect, by rabbit rIPC dialysate, was blocked by pre-treatment with the opiate receptor blocker naloxone. In conclusion, in vivo transient limb ischaemia releases a low-molecular-mass (<15 kDa) hydrophobic circulating factor(s) which induce(s) a potent protection against myocardial ischaemia/reperfusion injury in Langendorff-perfused hearts and isolated cardiomyocytes in the same species. This cardioprotection is transferable across species, independent of local neurogenic activity, and requires opioid receptor activation.


Assuntos
Sangue , Membro Posterior/irrigação sanguínea , Isquemia , Precondicionamento Isquêmico Miocárdico/métodos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Animais , Soluções para Diálise/farmacologia , Humanos , Ligadura , Músculo Esquelético/irrigação sanguínea , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Reperfusão Miocárdica , Miocárdio , Miócitos Cardíacos/patologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Coelhos , Distribuição Aleatória , Receptores Opioides/efeitos dos fármacos
11.
Biol Pharm Bull ; 30(10): 1954-7, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17917270

RESUMO

We have previously reported the expression of CYP genes in human myeloblastic and lymphoid cell lines, and the induction of the CYP3A4 and GSTP1 genes by oxidative stress in the human erythroleukemia cell line, K562. To further elucidate the role of drug metabolizing enzymes in hematogenesis, we have characterized the expression of CYP genes in hemin-induced differentiated K562 cells. After incubation with 50 microM hemin for 3 d, the expression of CYP1A1 and CYP3A4 genes was induced by 2.5- and 3.5-fold, respectively. In contrast, the CYP1B1 and CYP2E1 genes were downregulated in these cells to below 10% of the control levels. Moreover, these changes correlated with the hemin dose and culture time. Metabolism of midazolam, a probe substrate for CYP3A4, in the differentiated K562 cells increased by 2-folds, suggesting that the induction of CYP3A4 activity is consistent with the mRNA level. If these changes in the CYP expression profile in hematopoietic cells occurred, the susceptibility to xenobiotics and/or the therapeutic drugs of the cells might be influenced, and it also affects the metabolism of endogenous substrates, such as steroids and prostaglandins.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Sistema Enzimático do Citocromo P-450/biossíntese , Hemina/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Hipnóticos e Sedativos/metabolismo , Isoenzimas/biossíntese , Células K562 , Midazolam/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
Cancer Chemother Pharmacol ; 59(5): 575-80, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16912889

RESUMO

PURPOSE: The aim of this study was to determine the pharmacokinetics of low-dose nedaplatin combined with paclitaxel and radiation therapy in patients having non-small-cell lung carcinoma and establish the optimal dosage regimen for low-dose nedaplatin. We also evaluated predictive accuracy of reported formulas to estimate the area under the plasma concentration-time curve (AUC) of low-dose nedaplatin. PATIENTS AND METHODS: A total of 19 patients were administered a constant intravenous infusion of 20 mg/m(2) body surface area (BSA) nedaplatin for an hour, and blood samples were collected at 1, 2, 3, 4, 6, 8, and 19 h after the administration. Plasma concentrations of unbound platinum were measured, and the actual value of platinum AUC (actual AUC) was calculated based on these data. The predicted value of platinum AUC (predicted AUC) was determined by three predictive methods reported in previous studies, consisting of Bayesian method, limited sampling strategies with plasma concentration at a single time point, and simple formula method (SFM) without measured plasma concentration. Three error indices, mean prediction error (ME, measure of bias), mean absolute error (MAE, measure of accuracy), and root mean squared prediction error (RMSE, measure of precision), were obtained from the difference between the actual and the predicted AUC, to compare the accuracy between the three predictive methods. RESULTS: The AUC showed more than threefold inter-patient variation, and there was a favorable correlation between nedaplatin clearance and creatinine clearance (Ccr) (r = 0.832, P < 0.01). In three error indices, MAE and RMSE showed significant difference between the three AUC predictive methods, and the method of SFM had the most favorable results, in which %ME, %MAE, and %RMSE were 5.5, 10.7, and 15.4, respectively. CONCLUSIONS: The dosage regimen of low-dose nedaplatin should be established based on Ccr rather than on BSA. Since prediction accuracy of SFM, which did not require measured plasma concentration, was most favorable among the three methods evaluated in this study, SFM could be the most practical method to predict AUC of low-dose nedaplatin in a clinical situation judging from its high accuracy in predicting AUC without measured plasma concentration.


Assuntos
Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Compostos Organoplatínicos/farmacocinética , Idoso , Algoritmos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Área Sob a Curva , Superfície Corporal , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Interpretação Estatística de Dados , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
13.
J Am Coll Cardiol ; 47(11): 2277-82, 2006 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-16750696

RESUMO

OBJECTIVES: We conducted a randomized controlled trial of the effects of remote ischemic preconditioning (RIPC) in children undergoing repair of congenital heart defects. BACKGROUND: Remote ischemic preconditioning reduces injury caused by ischemia-reperfusion in distant organs. Cardiopulmonary bypass (CPB) is associated with multi-system injury. We hypothesized that RIPC would modulate injury induced by CPB. METHODS: Children undergoing repair of congenital heart defects were randomized to RIPC or control treatment. Remote ischemic preconditioning was induced by four 5-min cycles of lower limb ischemia and reperfusion using a blood pressure cuff. Measurements of lung mechanics, cytokines, and troponin I were made pre- and postoperatively. RESULTS: Thirty-seven patients were studied. There were 20 control patients and 17 patients in the RIPC group. The mean age and weight of the RIPC and control patients were not different (0.9 +/- 0.9 years vs. 2.2 +/- 3.4 years, p = 0.4; and 6.9 +/- 2.9 kg vs. 11.5 +/- 10 kg, p = 0.06). Bypass and cross-clamp times were not different (80 +/- 24 min vs. 88 +/- 25 min, p = 0.3; and 55 +/- 13 min vs. 59 +/- 13 min, p = 0.4). Levels of troponin I postoperatively were greater in the control patients compared with the RIPC group (p = 0.04), indicating greater myocardial injury in control patients. Postoperative inotropic requirement was greater in the control patients compared with RIPC patients at both 3 and 6 h (7.9 +/- 4.7 vs. 10.9 +/- 3.2, p = 0.04; and 7.3 +/- 4.9 vs. 10.8 +/- 3.9, p = 0.03, respectively). The RIPC group had significantly lower airway resistance at 6 h postoperatively (p = 0.009). CONCLUSIONS: This study demonstrates the myocardial protective effects of RIPC using a simple noninvasive technique of four 5-min cycles of lower limb ischemia and reperfusion. These novel data support the need for a larger study of RIPC in patients undergoing cardiac surgery.


Assuntos
Ponte de Artéria Coronária , Cardiopatias Congênitas/fisiopatologia , Cardiopatias Congênitas/cirurgia , Precondicionamento Isquêmico , Perna (Membro)/irrigação sanguínea , Cuidados Pré-Operatórios , Pré-Escolar , Citocinas/sangue , Coração/fisiopatologia , Cardiopatias Congênitas/sangue , Humanos , Lactente , Recém-Nascido , Inflamação/sangue , Pulmão/fisiopatologia , Mecânica Respiratória , Resultado do Tratamento , Troponina I/sangue
14.
J Thorac Cardiovasc Surg ; 130(5): 1326-32, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16256785

RESUMO

BACKGROUND: We have recently demonstrated that remote ischemic preconditioning reduces ischemia-reperfusion injury in animal models. The mechanisms by which the remote ischemic preconditioning stimulus exerts its effect remain to be fully defined, and its effect on myocardial gene expression is unknown. We tested the hypothesis that remote ischemic preconditioning modifies myocardial gene expression immediately after the remote ischemic preconditioning stimulus (early phase) and 24 hours later (late phase). METHODS: Twenty male (C57BL/6) 10- to 12-week-old mice were randomized into 4 groups: group 1 (control, early phase; n = 5), group 2 (remote ischemic preconditioning, early phase; n = 5), group 3 (control, late phase; n = 5), and group 4 (remote ischemic preconditioning, late phase; n = 5). Groups 2 and 4 underwent remote ischemic preconditioning induced by 6 cycles of 4 minutes of occlusion and 4 minutes of reperfusion of the femoral artery. Groups 1 and 2 were killed 15 minutes after completion of sham procedure or remote ischemic preconditioning, and the hearts were removed and frozen in liquid nitrogen. Groups 3 and 4 were killed 24 hours after remote ischemic preconditioning, and the hearts were harvested in the same fashion. Gene expression was assessed by using the Affymetrix MG-430A chip (Affymetrix, Santa Clara, Calif). RESULTS: Data filtering (P < .05, analysis of variance) and hierarchic 2-way clustering identified significant differences in gene expression among the 4 groups. Genes involved in protection against oxidative stress (eg, Hadhsc, Prdx4, and Fabp4) and cytoprotection (Hsp73) were upregulated, whereas many proinflammatory genes (eg, Egr-1 and Dusp 1 and 6) were suppressed. CONCLUSION: A simple remote ischemic preconditioning stimulus modifies myocardial gene expression by upregulating cardioprotective genes and suppressing genes potentially involved in the pathogenesis of ischemia-reperfusion injury.


Assuntos
Regulação da Expressão Gênica , Precondicionamento Isquêmico Miocárdico/métodos , Miocárdio , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
J Clin Oncol ; 23(6): 1061-9, 2005 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-15657405

RESUMO

PURPOSE: Docetaxel is metabolized by cytochrome P450 (CYP3A4) enzyme, and the area under the concentration-time curve (AUC) is correlated with neutropenia. We developed a novel method for estimating the interpatient variability of CYP3A4 activity by the urinary metabolite of exogenous cortisol (6-beta-hydroxycortisol [6-beta-OHF]). This study was designed to assess whether the application of our method to individualized dosing could decrease pharmacokinetic (PK) and pharmacodynamic (PD) variability compared with body-surface area (BSA) -based dosing. PATIENTS AND METHODS: Fifty-nine patients with advanced non-small-cell lung cancer were randomly assigned to either the BSA-based arm or individualized arm. In the BSA-based arm, 60 mg/m(2) of docetaxel was administered. In the individualized arm, individualized doses of docetaxel were calculated from the estimated clearance (estimated clearance = 31.177 + [7.655 x 10(-4) x total 6-beta-OHF] - [4.02 x alpha-1 acid glycoprotein] - [0.172 x AST] - [0.125 x age]) and the target AUC of 2.66 mg/L . h. RESULTS: In the individualized arm, individualized doses of docetaxel ranged from 37.4 to 76.4 mg/m(2) (mean, 58.1 mg/m(2)). The mean AUC and standard deviation (SD) were 2.71 (range, 2.02 to 3.40 mg/L . h) and 0.40 mg/L . h in the BSA-based arm, and 2.64 (range, 2.15 to 3.07 mg/L . h) and 0.22 mg/L . h in the individualized arm, respectively. The SD of the AUC was significantly smaller in the individualized arm than in the BSA-based arm (P < .01). The percentage decrease in absolute neutrophil count (ANC) averaged 87.1% (range, 59.0 to 97.7%; SD, 8.7) in the BSA-based arm, and 87.4% (range, 78.0 to 97.2%; SD, 6.1) in the individualized arm, suggesting that the interpatient variability in percent decrease in ANC was slightly smaller in the individualized arm. CONCLUSION: The individualized dosing method based on the total amount of urinary 6-beta-OHF after cortisol administration can decrease PK variability of docetaxel.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Superfície Corporal , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/metabolismo , Hidrocortisona/análogos & derivados , Hidrocortisona/urina , Neoplasias Pulmonares/tratamento farmacológico , Taxoides/administração & dosagem , Idoso , Área Sob a Curva , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Citocromo P-450 CYP3A , Docetaxel , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Taxoides/farmacocinética , Taxoides/farmacologia
17.
Exp Biol Med (Maywood) ; 227(3): 196-200, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11856818

RESUMO

Gangliosides such as GD3, GM2, and GD2 are abundantly expressed on the cell surfaces of various malignant cells, suggesting the potential for anti-ganglioside antibody therapy for tumors. Anti-ganglioside GD2 antibody treatment is currently undergoing clinical trials for melanoma and neuroblastoma. We previously reported high in vivo antitumor effects of anti-GM2 ganglioside antibody against lung cancer. To determine whether anti-GM2 antibody may be clinically indicated for gastrointestinal cancers, we evaluated the mRNA expression of alpha2,8 sialyltransferase, a GD3 synthase, and beta1,4 N-acetylgalactosaminyltransferase (beta1,4 GalNAc-T), a GM2/GD2 synthase, in gastrointestinal cancers. We performed modified semi-quantitative RT-PCR, which reduces complexity incidental to radiolabeling on samples taken from small surgically removed clinical specimens. Stomach (19/22) and colorectal (21/30) cancers showed decreased expression of alpha2,8 sialyltransferase as compared with respective normal tissues (P < 0.05). In contrast, increased expression of beta1,4 GalNAc-T was detected in both types of tumors. Clinicopathological analysis revealed significantly higher expression level of alpha2,8 sialyltransferase in the poorly differentiated than in the well-differentiated stomach cancer group (P < 0.05). Furthermore, the expression level of alpha2,8 sialyltransferase was significantly decreased in male as compared with female colorectal cancer patients (P < 0.05). These results suggest that expression level of GM2 ganglioside is elevated in gastrointestinal cancer, and that anti-GM2 antibody may be applicable to its treatment.


Assuntos
Neoplasias Colorretais/enzimologia , N-Acetilgalactosaminiltransferases/biossíntese , Sialiltransferases/biossíntese , Neoplasias Gástricas/enzimologia , Adulto , Idoso , Regulação para Baixo , Feminino , Gangliosídeos/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , beta-D-Galactosídeo alfa 2-6-Sialiltransferase
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