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1.
ESMO Open ; 9(4): 102385, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38387111

RESUMO

BACKGROUND: The FUTURE trial (UMIN000029294) demonstrated the safety and efficacy of adding palbociclib after fulvestrant resistance in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced and metastatic breast cancer (ABC/MBC). In this planned sub-study, cancer panel sequencing of cell-free DNA (cfDNA) was utilized to explore prognostic and predictive biomarkers for further palbociclib treatment following fulvestrant resistance. MATERIALS AND METHODS: Herein, 149 cfDNA samples from 65 patients with fulvestrant-resistant disease were analysed at the time of palbociclib addition after fulvestrant resistance (baseline), on day 15 of cycle 1, and at the end of treatment using the assay for identifying diverse mutations in 34 cancer-related genes. RESULTS: During the course of treatment, mutations in ESR1, PIK3CA, FOXA1, RUNX1, TBX3, and TP53 were the most common genomic alterations observed. Analysis of genomic mutations revealed that before fulvestrant introduction, baseline PIK3CA mutations were marginally lower in metastatic aromatase inhibitor (AI)-treated patients compared to adjuvant AI-treated patients (P = 0.063). Baseline PIK3CA mutations were associated with poorer progression-free survival [hazard ratio: 1.62, P = 0.04]. Comparative analysis between baseline and early-changing gene mutations identified poor prognostic factors including early-changing MAP3K1 mutations (hazard ratio: 4.66, P = 0.04), baseline AR mutations (hazard ratio: 3.53, P = 0.04), and baseline PIK3CA mutations (hazard ratio: 3.41, P = 0.02). Notably, the relationship between ESR1 mutations and mutations in PIK3CA, MAP3K1, and TP53 weakened as treatment progressed. Instead, PIK3CA mutations became correlated with TP53 and FOXA1 mutations. CONCLUSIONS: Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR+/HER2- ABC/MBC.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Fulvestranto , Piperazinas , Piridinas , Humanos , Fulvestranto/uso terapêutico , Fulvestranto/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Piperazinas/uso terapêutico , Piperazinas/farmacologia , Feminino , Piridinas/uso terapêutico , Piridinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Prognóstico , Idoso , Adulto , Ácidos Nucleicos Livres , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Mutação
2.
QJM ; 117(3): 187-194, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-37878823

RESUMO

OBJECTIVE: To comprehensively evaluate diagnostic algorithms for myocardial infarction using a high-sensitivity cardiac troponin I (hs-cTnI) assay. PATIENTS AND METHODS: We prospectively enrolled patients with suspected myocardial infarction without ST-segment elevation from nine emergency departments in Japan. The diagnostic algorithms evaluated: (i) based on hs-cTnI alone, such as the European Society of Cardiology (ESC) 0/1-h or 0/2-h and High-STEACS pathways; or (ii) used medical history and physical findings, such as the ADAPT, EDACS, HEART, and GRACE pathways. We evaluated the negative predictive value (NPV), sensitivity as safety measures, and proportion of patients classified as low or high-risk as an efficiency measure for a primary outcome of type 1 myocardial infarction or cardiac death within 30 days. RESULTS: We included 437 patients, and the hs-cTnI was collected at 0 and 1 hours in 407 patients and at 0 and 2 hours in 394. The primary outcome occurred in 8.1% (33/407) and 6.9% (27/394) of patients, respectively. All the algorithms classified low-risk patients without missing those with the primary outcome, except for the GRACE pathway. The hs-cTnI-based algorithms classified more patients as low-risk: the ESC 0/1-h 45.7%; the ESC 0/2-h 50.5%; the High-STEACS pathway 68.5%, than those using history and physical findings (15-30%). The High-STEACS pathway ruled out more patients (20.5%) by hs-cTnI measurement at 0 hours than the ESC 0/1-h and 0/2-h algorithms (7.4%). CONCLUSIONS: The hs-cTnI algorithms, especially the High-STEACS pathway, had excellent safety performance for the early diagnosis of myocardial infarction and offered the greatest improvement in efficiency.


Assuntos
Infarto do Miocárdio , Humanos , Biomarcadores , Estudos Prospectivos , Infarto do Miocárdio/diagnóstico , Troponina I , Valor Preditivo dos Testes , Serviço Hospitalar de Emergência , Algoritmos , Troponina T
3.
Phys Rev Lett ; 131(25): 253003, 2023 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-38181354

RESUMO

Muonic helium atom hyperfine structure (HFS) measurements are a sensitive tool to test the three-body atomic system and bound-state quantum electrodynamics theory, and determine fundamental constants of the negative muon magnetic moment and mass. The world's most intense pulsed negative muon beam at the Muon Science Facility of the Japan Proton Accelerator Research Complex allows improvement of previous measurements and testing further CPT invariance by comparing the magnetic moments and masses of positive and negative muons (second-generation leptons). We report new ground-state HFS measurements of muonic helium-4 atoms at a near-zero magnetic field, performed for the first time using a small admixture of CH_{4} as an electron donor to form neutral muonic helium atoms efficiently. Our analysis gives Δν=4464.980(20) MHz (4.5 ppm), which is more precise than both previous measurements at weak and high fields. The muonium ground-state HFS was also measured under the same conditions to investigate the isotopic effect on the frequency shift due to the gas density dependence in He with CH_{4} admixture and compared with previous studies. Muonium and muonic helium can be regarded as light and heavy hydrogen isotopes with an isotopic mass ratio of 36. No isotopic effect was observed within the current experimental precision.

4.
Pharmazie ; 75(8): 371-374, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32758335

RESUMO

Objective: We aimed to investigate the involvement of efflux transporters, including multidrug resistant protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), MRP2, and breast cancer resistance protein (BCRP), in the intracellular accumulation of the antifibrotic agent nintedanib in fibrotic lung cells. Methods: We used transforming growth factor-ß1 (TGF-ß1)-treated human lung fibroblasts (WI-38) and alveolar epithelial cells (A549) as in vitro models. The expression and activities of efflux transporters in TGF-ß1-treated WI-38 and A549 cells were evaluated using immunoblotting and flow cytometry. Cells were treated with nintedanib and then incubated with inhibitors of these transporters. The intracellular concentration of nintedanib was determined. Results: MDR1, MRP1, MRP2, and BCRP were found to be expressed in WI-38 and A549 cells with or without TGF-ß1 stimulation, with the exception of MRP2 in WI-38 cells. The efflux activities of these transporters were observed in these cells. MDR1 inhibitors significantly increased the intracellular accumulation of nintedanib, whereas MRP inhibitors did not show an effect. The BCRP inhibitor significantly increased the transporter activity in A549 cells but not in WI-38 cells. Conclusion: This study suggests that the efflux via MDR1 and BCRP is involved in the intracellular accumulation of nintedanib in fibrotic lung cells.


Assuntos
Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/farmacocinética , Pulmão/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Células A549 , Células Epiteliais Alveolares/metabolismo , Linhagem Celular , Fibroblastos/metabolismo , Humanos , Indóis/administração & dosagem , Pulmão/citologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Distribuição Tecidual , Fator de Crescimento Transformador beta1/administração & dosagem
5.
Eur Radiol ; 28(5): 1929-1937, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29218614

RESUMO

OBJECTIVES: We aimed to determine whether high-resolution specimen-positron emission mammography (PEM) using fluorodeoxyglucose (18F-FDG) can reveal extension of breast cancer in breast-conserving surgery (BCS), and assess the safety of radiation exposure to medical staff. METHODS: Sixteen patients underwent positron emission tomography, and then BCS with intraoperative frozen section analysis on the same day. Resected specimens with remaining 18F-FDG accumulation were scanned by high-resolution PEM. At least 1 day after surgery, tumour extension was evaluated by three independent experienced readers and by binarized images from the specimen-PEM data. Intraoperative exposure of medical staff to 18F-FDG was measured. RESULTS: Specimen-PEM evaluations of binarized images and the three investigators detected all (100 %, 12/12) invasive lesions and 94.4 % (17/18) of in situ lesions using both methods. The positive predictive value of the accumulated lesions was 74.4 % (29/39) for the binarized images and 82.9 % (29/35) for the three investigators. Analysis of intraoperative frozen sections detected 100 % (2/2) of the margin-positive cases, also detected by both specimen-PEM evaluation methods with no false-positive margin cases. The mean exposure of the medical staff to 18F was 18 µSv. CONCLUSIONS: Specimen-PEM detected invasive and in situ lesions with high accuracy and allowable radiation exposure. KEY POINTS: • Specimen-PEM detected invasive and in situ lesions with high accuracy. • Specimen-PEM predicted complete resection with the same accuracy as frozen section analysis. • Breast-conserving surgery after fluorodeoxyglucose injection was performed with low medical staff exposure.


Assuntos
Neoplasias da Mama/diagnóstico , Fluordesoxiglucose F18/farmacologia , Mamografia/métodos , Mastectomia Segmentar/métodos , Tomografia por Emissão de Pósitrons/métodos , Idoso , Neoplasias da Mama/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Compostos Radiofarmacêuticos/farmacologia
6.
Oncogenesis ; 6(6): e350, 2017 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-28650445

RESUMO

Here, by combining lipidomics with transcriptome analysis, we demonstrate that Rb depletion in mouse embryonic fibroblastss induces significant alterations in their lipid composition. We discovered that Rb depletion induced increase in lysophosphatidylserine, diacylglycerol (DAG), fatty acid (FA), acylcarnitine, phosphatidylcholine (PC), arachidonoyl ethanolamine, and decrease in phosphatidylglycerol, monoacylglycerol, without change in total lipid per protein levels. Analysis of the acyl chain composition of DAG, PC and phosphatidylserine revealed increase of saturated and mono-unsaturated acyl chains with specific carbon chain length. Consistently, we observed that Rb depletion increased the levels of fatty acids with the corresponding carbon chain length and number of carbon-carbon double bondssuch as myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0) and all forms of FA 18:1. Microarray analysis revealed that Rb depletion induced significant upregulation of enzymes involved in elongation and desaturation of fatty acids. Among these, we found that elongation of long chain fatty acid family member 6 (Elovl6) and stearoyl-CoA desaturase 1 (Scd1) are the most robustly controlled by Rb possibly through E2F and sterol regulatory element-binding protein transcription factors. Depletion of Elovl6 or Scd1 significantly suppressed colony formation, sphere formation and xenograft tumor growth of Rb-deficient tumor cells. Suppression of self-renewal by the SCD1 inhibitor was rescued upon supplementation of the mono-unsaturated fatty acids generated by this enzyme. This study suggests a novel role for Rb in suppressing the malignant progression of tumors by controlling the lipid composition.

9.
Clin Biochem ; 47(13-14): 1326-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24859021

RESUMO

OBJECTIVES: The LDL receptor relative with 11 ligand-binding repeats (LR11) is closely related to atherosclerotic disease or diabetes. The aim of the study was to clarify how soluble LR11 was related to Achilles' tendon thickness (ATT) and HbA1c in familial hypercholesterolemia. DESIGN AND METHODS: The present study is a cross-sectional case-control study. We enrolled twenty-four patients with heterozygous FH (age 51.0±20.0 year; male, 50%; 20 cases with LDL receptor mutation, 1 case with proprotein convertase subtilisin/kexin type 9 (PCSK9) E32K and 3 cases without confirmed mutations). Soluble LR11 (sLR11) was measured using a sandwich enzyme-linked immunosorbent assay method. RESULTS: Univariate regression analysis showed that sLR11 had positive correlations with age and HbA1c, and inverse correlations with apoA1 in FH. There were also positive correlations of sLR11 with apoE, IDL-C and average ATT. Multivariate regression analysis showed that there were positive correlations of sLR11 to IDL-C and HbA1c independent of age and BMI. In another multivariate regression analysis on the relationships of average ATT as a dependent variable with age, BMI and sLR11 (IDL-C and HbA1c) as independent variables, sLR11 had a positive correlation with average ATT, independent of age and BMI. However, this independency did not persist after adding IDL-C and HbA1c as confounding factors. Of special note is that HbA1c showed a significant correlation with average ATT, independent of other parameters including sLR11. CONCLUSION: It is crucial to intervene in the existence of remnant lipoprotein as well as hypercholesterolemia from an early stage and conduct glycemic control to prevent the progression of atherosclerotic disease in FH.


Assuntos
Aterosclerose/sangue , Aterosclerose/metabolismo , Biomarcadores/sangue , Hemoglobinas Glicadas/metabolismo , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/metabolismo , Proteínas Relacionadas a Receptor de LDL/sangue , Proteínas de Membrana Transportadoras/sangue , Tendão do Calcâneo/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Progressão da Doença , Feminino , Heterozigoto , Humanos , Proteínas Relacionadas a Receptor de LDL/metabolismo , Masculino , Proteínas de Membrana Transportadoras/metabolismo , Pessoa de Meia-Idade , Análise Multivariada , Receptores de LDL/metabolismo
10.
Neuroscience ; 248: 664-9, 2013 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-23811398

RESUMO

Reproductive success depends on a robust and appropriately timed preovulatory luteinizing hormone (LH) surge, which is induced by the activation of gonadotropin-releasing hormone (GnRH) neurons in response to positive feedback from increasing estrogen levels. Here we document an increase in postsynaptic GluR2-lacking Ca2+ -permeable AMPA-type glutamate receptors (CP-AMPARs) at synapses on GnRH neurons on the day of proestrus in rats, coincident with the increase in estrogen levels. Functional blockade of CP-AMPARs depressed the synaptic responses only on the day of proestrus and concomitantly attenuated the LH surge. Thus, the phasic synaptic incorporation of postsynaptic CP-AMPARs on GnRH neurons is involved in the generation of the LH surge.


Assuntos
Hormônio Liberador de Gonadotropina/metabolismo , Hormônio Luteinizante/sangue , Receptores de AMPA/fisiologia , Sinapses/fisiologia , Animais , Estrogênios/fisiologia , Feminino , Técnicas In Vitro , Neurônios/fisiologia , Ratos , Ratos Wistar , Reprodução
11.
Int J Cardiol ; 167(5): 1984-9, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22626840

RESUMO

CONTEXT: Transcatheter ablation of atrial fibrillation (AF) has undergone important development, with acceptable midterm results in terms of the safety and recurrence. A meta-analysis was performed to identify the periprocedural complications, midterm success rates and predictors of recurrence after AF ablation. METHODS AND RESULTS: 4357 patients with paroxysmal AF, 1083 with persistent AF and 1777 with long standing AF were included. The pooled analysis showed that there was an in-hospital complication rate of tamponade requiring drainage of 0.99% (0.44-1.54; CI 99%), stroke with neurological persistent impairment of 0.22% (0.04-0.47; CI 99%), and stroke without of 0.36% (0.03-0.70; CI 99%) After a follow up of 22 (13-28) months and 1.23 (1.19-1.5; CI 99%) procedures per patient, the AF recurrence rate was 31.20% (24.87-34.81; CI 99%). The persistent AF patients exhibited a greater risk of recurrence after the first ablation (OR 1.78 [1.14, 2.77] CI 99%), but a trend towards non significance was present in the patients with more than one procedure (OR 1.69 [0.95, 3.00] CI 99%). The most powerful predictors of an AF ablation failure in the overall population were a recurrence within 30-days (OR 4.30; 2.00-10.80), valvular AF (OR 5.20; 2.22-9.50) and a left atrium diameter of more than 50mm (OR 5.10 2.00-12.90; all CI 95%). CONCLUSIONS: Persistent AF remains burdened from higher recurrence rates, however not so following redo-procedures. Three predictors, valvular AF, a left atrium diameter longer than 50mm and recurrence within 30 days, could be appraised to drive selection of patients and therapeutic strategy.


Assuntos
Fibrilação Atrial/diagnóstico , Fibrilação Atrial/terapia , Cateterismo Cardíaco/tendências , Ablação por Cateter/tendências , Fibrilação Atrial/fisiopatologia , Humanos , Valor Preditivo dos Testes , Recidiva , Reprodutibilidade dos Testes , Resultado do Tratamento
12.
J Int Med Res ; 39(5): 1941-5, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22117997

RESUMO

Reactive oxygen species (ROS) and serum ferritin levels are both considered to be important biological factors in the pathogenesis of myelodysplastic syndrome (MDS). This study evaluated the levels of ROS in 40 patients with MDS (19 males and 21 females) using the Free Radical Analytical System, FRAS4, and derivatives of reactive oxygen metabolite kits. The patients' mean age was 67.3 years (range 58 - 86 years). The sera of 34 (85%) patients exhibited higher levels of oxidative stress than the reference range. There was a positive correlation between ROS levels and serum ferritin levels, and a negative correlation between ROS levels and haemoglobin levels. There was a negative relationship between serum haemoglobin and ferritin levels. The results indicated that iron accumulation or severe anaemia could contribute to oxidative stress in MDS patients. Iron chelation and antioxidant therapy may be suitable for the management of MDS.


Assuntos
Ferritinas/sangue , Hemoglobinas/metabolismo , Síndromes Mielodisplásicas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/sangue , Anemia Refratária/metabolismo , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Estresse Oxidativo , Espécies Reativas de Oxigênio/sangue , Valores de Referência
14.
AJNR Am J Neuroradiol ; 30(1): 132-5, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18701579

RESUMO

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a recently described clinicoradiologic syndrome. MR spectroscopy in 3 patients with AESD revealed decreased N-acetylaspartate (NAA) and elevated glutamine/glutamate complex (Glx) during the week of presentation. Afterward, Glx normalized, whereas NAA remained low in 2 patients with neurologic sequelae but nearly normalized in the third patient without neurologic sequelae. These findings support the hypothesis that excitotoxic neuronal damage plays an important role in the pathogenesis of AESD and suggest that MR spectroscopy might be predictive of outcome.


Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Ácido Glutâmico/análise , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Convulsões/metabolismo , Convulsões/patologia , Pré-Escolar , Feminino , Humanos , Masculino
15.
Br J Cancer ; 99(6): 852-7, 2008 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-18728643

RESUMO

Preoperative chemotherapy is a promising strategy in patients with early-stage resectable non-small-cell lung cancer (NSCLC); optimal chemotherapy remains unclear. Clinical (c-) stage IB/II NSCLC patients were randomised to receive either two cycles of docetaxel (D)-cisplatin (P) combination chemotherapy (D 60 mg m(-2) and P 80 mg m(-2) on day 1) every 3-4 weeks or three cycles of D monotherapy (70 mg m(-2)) every 3weeks. Thoracotomy was performed 4-5 weeks (DP) or 3-4 weeks (D) after chemotherapy. The primary end point was 1-year disease-free survival (DFS). From October 2002 to November 2003, 80 patients were randomised. Chemotherapy toxicities were mainly haematologic and well tolerated. There were two early postoperative deaths with DP (one intraoperative bleeding and one empyema). Pathologic complete response was observed in two DP patients. Docetaxel-cisplatin was superior to D in terms of response rate (45 vs 15%) and complete resection rate (95 vs 87%). Both DFS and overall survival were better in DP. Disease-free survival at 1, 2 and 4 years were 78, 65 and 57% with DP, and were 62, 44 and 36% with D, respectively. Preoperative DP was associated with encouraging resection rate and DFS data, and phase III trials for c-stage IB/II NSCLC are warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/secundário , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Feminino , Humanos , Japão , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Pré-Operatórios , Taxa de Sobrevida , Taxoides/administração & dosagem , Resultado do Tratamento
16.
Neuropediatrics ; 39(2): 134-6, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18671193

RESUMO

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is clinically characterized by biphasic seizures on days 1, and 4 to 6; radiologically by no acute abnormality is visible during the first two days, while reduced diffusion in the subcortical white matter is seen during days 3 to 9, finally resulting in cerebral atrophy. We report here a Japanese child with clinically severe AESD associated with influenza A, whose sequential magnetic resonance imaging revealed cerebral swelling on day 1, reduced diffusion and central herniation on day 6, followed by cortical laminar necrosis and atrophy on day 30. The findings from this patient suggests that AESD has clinically and radiologically a wider spectrum than previously considered.


Assuntos
Encefalopatias/diagnóstico , Córtex Cerebral/patologia , Influenza Humana/diagnóstico , Convulsões/diagnóstico , Doença Aguda , Encefalopatias/complicações , Encefalopatias/virologia , Pré-Escolar , Imagem de Difusão por Ressonância Magnética/métodos , Eletroencefalografia/métodos , Humanos , Influenza Humana/complicações , Masculino , Convulsões/etiologia
17.
Eur J Cancer Care (Engl) ; 17(2): 120-6, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18302648

RESUMO

A new non-platinum sequential triplet combination chemotherapy regimen, comprising gemcitabine (1000 mg/m(2)) and vinorelbine (25 mg/m(2)), followed by docetaxel (60 mg/m(2)), was compared in terms of efficacy, toxicity and cost with platinum-based chemotherapy regimens (comprising cisplatin plus one or more other anti-tumour drugs) for the treatment of advanced non-small-cell lung cancer in a matched, small-sample size, case-control study. Patients were selected from a single institution. Patients in the platinum and non-platinum groups were matched for clinical stage (IIIB/IV), performance status (0/1), age and sex. For the non-platinum and platinum groups, the overall response rates were 40% and 47%, and the median survival times were 14 and 14.5 months respectively. The most common grade 3-4 toxicity was neutropenia (27%) in the non-platinum group and nausea/vomiting (67%) in the platinum group. The total treatment cost did not differ significantly between the two groups. The non-platinum sequential triplet combination chemotherapy regimen studied was shown to be as effective as the traditional cisplatin-based combination chemotherapy regimen, and was associated with less toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Casos e Controles , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Análise Custo-Benefício , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Docetaxel , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/análogos & derivados , Vinorelbina , Gencitabina
18.
Clin Pharmacol Ther ; 83(5): 731-9, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17957184

RESUMO

An open, randomized, four-phased crossover study using 4 mg of pitavastatin or 20 mg of atorvastatin was performed to compare their efficacy and safety, especially regarding plasma levels of coenzyme Q10 (CoQ10) in 19 Japanese patients with heterozygous familial hypercholesterolemia. Pitavastatin and atorvastatin caused significant and almost comparable reductions in serum levels of total cholesterol (-35.4 vs. -33.8%), low-density lipoprotein cholesterol (-42.8 vs. -40.7%), and triglyceride (-26.1 vs. -29.4%), and significantly increased serum levels of high-density lipoprotein cholesterol (12.1 vs. 11.4%). Under these conditions, plasma levels of CoQ10 were reduced by atorvastatin (-26.1%, P=0.0007) but not by pitavastatin (-7.7%, P=0.39), although no adverse events or abnormalities of liver and muscle enzyme were observed after either statin treatment. It remains to be seen whether the observed changes in CoQ10 levels are related to the long-term safety of this drug.


Assuntos
Ácidos Heptanoicos/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/enzimologia , Pirróis/uso terapêutico , Quinolinas/uso terapêutico , Ubiquinona/análogos & derivados , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/uso terapêutico , Atorvastatina , Colesterol/sangue , LDL-Colesterol/sangue , Coenzimas/sangue , Estudos Cross-Over , Feminino , Ácidos Heptanoicos/efeitos adversos , Humanos , Hiperlipoproteinemia Tipo II/sangue , Masculino , Pessoa de Meia-Idade , Pirróis/efeitos adversos , Quinolinas/efeitos adversos , Triglicerídeos/sangue , Ubiquinona/sangue
20.
Int J Clin Pharmacol Ther ; 44(12): 605-13, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17190370

RESUMO

OBJECTIVE: Lansoprazole and tacrolimus are substrates of ATP binding cassette (ABC) transporters such as P-glycoprotein (ABCBI/multidrug resistance 1) and cytochrome P450 (CYP). The purpose of this study was to investigate the implication of the ABCB1 C3435Tpolymorphism on the pharmacokinetics of (R)-lansoprazole, the major enantiomer, in CYP2C19 extensive metabolizers (EMs) and on gastroesophageal symptoms in renal transplant recipients receiving tacrolimus. MATERIALS: 24 recipients who were CYP2C19 EMs were studied. METHODS: Oral administration of 30 mg lansoprazole was started 2 days before transplantation. On Day 2 before and Day 28 after transplantation, the plasma concentrations of (R)-lansoprazole and tacrolimus were measured. RESULTS: Pretransplantation, there were no significant differences in the pharmacokinetic parameters of (R)-lansoprazole between the 3 ABCBI C3435T genotypes. However, after renal transplantation, the peak plasma concentration (Cma ) and area under the plasma concentration-time curve (AUCO-24) of (R)-lansoprazole in patients with the ABCB1 C3435T C allele significantly increased, but not in patients with the TT genotype. These pharmacokinetic variations in (R)-lansoprazole did not influence the AUC of tacrolimus. There were no significant differences in the frequency of gastroesophageal symptoms among the three ABCB] C3435Tgenotypes. CONCLUSIONS: (R)-lansoprazole concentrations significantly increased in CYP2C19 extensive metabolizers with the ABCB1 C3435T C allele, but not TT genotype, after renal transplantation. However, the clinical relevance of this observation may be minor because these pharmacogenetic changes were not associated with the occurrence of gastroesophageal complications.


Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/uso terapêutico , Hidrocarboneto de Aril Hidroxilases/genética , Refluxo Gastroesofágico/tratamento farmacológico , Oxigenases de Função Mista/genética , Transportadores de Ânions Orgânicos/genética , Polimorfismo Genético , 2-Piridinilmetilsulfinilbenzimidazóis/sangue , 2-Piridinilmetilsulfinilbenzimidazóis/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Administração Oral , Adulto , Alelos , Antiulcerosos/administração & dosagem , Antiulcerosos/farmacocinética , Antiulcerosos/uso terapêutico , Área Sob a Curva , Hidrocarboneto de Aril Hidroxilases/metabolismo , Povo Asiático/genética , Citocromo P-450 CYP2C19 , Dexlansoprazol , Feminino , Refluxo Gastroesofágico/etnologia , Refluxo Gastroesofágico/genética , Genótipo , Meia-Vida , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Imunossupressores/uso terapêutico , Japão , Transplante de Rim , Lansoprazol , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista/metabolismo , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Tacrolimo/uso terapêutico
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