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61.
Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate. 总被引:7,自引:0,他引:7
Jean-Pierre J Issa Vazganush Gharibyan Jorge Cortes Jaroslav Jelinek Gail Morris Srdan Verstovsek Moshe Talpaz Guillermo Garcia-Manero Hagop M Kantarjian 《Journal of clinical oncology》2005,23(17):3948-3956
PURPOSE: To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia. MATERIALS AND METHODS: Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase). Decitabine was administered at 15 mg/m2 intravenously over 1 hour daily, 5 days a week for 2 weeks. DNA methylation was measured using a LINE1 bisulfite/pyrosequencing assay. RESULTS: Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase). Major cytogenetic responses were observed in six patients (17%), and minor cytogenetic responses were seen in 10 patients (29%) for an overall cytogenetic response rate of 46%. Median response duration was 3.5 months (range, 2 to 13+ months). Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy. LINE1 methylation decreased from 71.3% +/- 1.4% (mean +/- standard error of the mean) to 60.7% +/- 1.4% after 1 week, 50.9% +/- 2.4% after 2 weeks, and returned to 66.5% +/- 2.7% at recovery of counts (median, 46 days). LINE1 methylation at the end of week 1 did not correlate with subsequent responses. However, at day 12, the absolute decrease in methylation was 14.5% +/- 3.0% versus 26.8% +/- 2.7% in responders versus nonresponders (P = .007). CONCLUSION: Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation. 相似文献
62.
Jér?me Cornillon Abir Fawaz Stéphane Depil Fran?oise Dufosse Alain Duhamel Francis Bauters Pierre Fenaux Jean-Pierre Jouet Ibrahim Yakoub-Agha 《Leukemia & lymphoma》2005,46(6):841-849
Between January 1993 and December 2000, an unrelated donor search (UDS) was initiated for 97 consecutive patients [46 acute lymphoblastic leukemia (ALL) and 51 acute myeloid leukemia (AML)]. Leukemia was considered to be of poor prognosis in cases of refractory disease (n=70), unfavourable karyotype (n=22) or miscellaneous (n=5). All patients had previously received various chemotherapies and 9 had undergone an autologous stem cell transplantation (SCT). The median age at UDS initiation was 25 (range 2.7-55) years. The median time to identify a suitable living donor or cord blood (CB) was 60 days. Eventually, 33 patients received unrelated allo-SCT (including 9 CB), 12 auto-SCT, 39 chemotherapy and 13 palliative treatment. At a median of 54 months, 18 patients were alive, including 15 in remission. The 4-year overall survival rates were 32%, 37%, 15% and 0% for allo-SCT, auto-SCT, chemotherapy or palliative treatment, respectively. Patients who received either allo- or auto-SCT had better survival than those who did not (P<0.0001). For ALL, only allo-SCT significantly improved survival (P<0.007). Finally, patients who received allo-SCT died less often of relapse than patients who did not (P<0.0001). Unrelated allo-SCT gives a substantial long-term survival and cure in patients with high-risk acute leukemia. For patients who achieve remission and for whom UDS fails, auto-SCT may prove to be a good approach. For patients who fail to enter into remission, intensive salvage chemotherapy has a very limited effect. 相似文献
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Jean-Pierre Valentin Chris Pollard Pierre Lainée Tim Hammond 《British journal of pharmacology》2010,159(1):25-33
Non-clinical QT-related assays aligned to the pharmaceutical drug discovery and development phases are used in several ways. During the early discovery phases, assays are used for hazard identification and wherever possible for hazard elimination. The data generated enable us to: (i) establish structure–activity relationships and thereby; (ii) influence the medicinal chemistry design and provide tools for effective decision making; and provide structure–activity data for in silico predictive databases; (iii) solve problems earlier; (iv) provide reassurance for compound or project to progress; and (v) refine strategies as scientific and technical knowledge grows. For compounds progressing into pre-clinical development, the ‘core battery’ QT-related data enable an integrated risk assessment to: (i) fulfil regulatory requirements; (ii) assess the safety and risk–benefit for compound progression to man; (iii) contribute to defining the starting dose during the phase I clinical trials; (iv) influence the design of the phase I clinical trials; (v) identify clinically relevant safety biomarkers; and (vi) contribute to the patient risk management plan. Once a compound progresses into clinical development, QT-related data can be applied in the context of risk management and risk mitigation. The data from ‘follow-up’ studies can be used to: (i) support regulatory approval; (ii) investigate discrepancies that may have emerged within and/or between non-clinical and clinical data; (iii) understand the mechanism of an undesirable pharmacodynamic effect; (iv) provide reassurance for progression into multiple dosing in humans and/or large-scale clinical trials; and (v) assess drug–drug interactions. Based on emerging data, the integrated risk assessment is then reviewed in this article, and the benefit–risk for compound progression was re-assessed. Project examples are provided to illustrate the impact of non-clinical data to support compound progression throughout the drug discovery and development phases, and regulatory approval.This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 相似文献
65.
Viviane Burgat-Sacaze Jean-Pierre Braun André Rico Patrick Benard Behrokh Eghbali 《Archives of toxicology》1980,43(3):227-231
The fungicide, methoxyethylmercury chloride, was given in a saline solution to four groups of Sprague-Dawley C D rats (5 , 5 ) as a single injection (IP) of 0, 0.5, 1.0, and 2.0 mg Hg/kg. In a three-day period, no changes were observed in urine collected every 24 h from rats given 0 or 0.5 mg Hg/kg; 1 mg Hg/kg induced only a transient increase of urine gamma glutamyl transferase (x 4) and alkaline phosphatase (x 2.5) on the day 2; 2.0 mg Hg/kg caused an early increase of enzymuria (day 1 and day 2) and a decrease of Na+, Cl–, K+, urea, and creatinin excretion. Urine enzymes and total mercury excretion were higher in males. These time-related variations of enzymuria, compared to previous results with Hg Cl2, could reflect the existence of metabolites more toxic than the native compound. 相似文献
66.
Claire Petit Benjamin Lacas Jean-Pierre Pignon Quynh Thu Le Vincent Grégoire Cai Grau Allan Hackshaw Björn Zackrisson Mahesh K B Parmar Ju-Whei Lee Maria Grazia Ghi Giuseppe Sanguineti Stéphane Temam Maurice Cheugoua-Zanetsie Brian O'Sullivan Marshall R Posner Everett E Vokes Juan J Cruz Hernandez L.P. Zhong 《The lancet oncology》2021,22(5):727-736
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70.
Catherine M. Champagne Hongmei Han Sudip Bajpeyi Jennifer Rood William D. Johnson Carol J. Lammi-Keefe Jean-Pierre Flatt George A. Bray 《Journal of the Academy of Nutrition and Dietetics》2013,113(11):1532-1538
Because day-to-day food intake varies, we tested the hypothesis that ad libitum food intake and energy expenditure show corrective responses over periods of 1 to 10 days in healthy young women. Food intake and accelerometry measurements were collected daily for 17 days in 15 young women. Total daily energy expenditure (TDEE) using doubly labeled water was also measured. The daily deviations in macronutrient and energy intake and energy expenditure from the average values were compared with the deviations observed over succeeding intervals to estimate the corrective responses. The intraindividual coefficients of variation for energy intake averaged ±25%, ranging from 16% to 34%. TDEE had a coefficient of variation of 8.3%, and accelerometry had a coefficient of variation of 8.4% (range=4.6% to 16.4%). Energy expenditure by accelerometry (2,087±191 kcal/day) was not significantly different from TDEE (2,128±177 kcal/day), but reported daily energy intake was 20.4% lower (1,693±276 kcal/day). There were significant corrective responses in energy from fat and total energy intake. This occurred from Days 3 to 6, with a peak at Day 5 that disappeared when data were randomized within each subject. Human beings show corrective responses to deviations from average energy and macronutrient intakes with a lag time of 3 to 6 days, but not 1 to 2 days. These corrective responses are likely to play a role in bringing about weight stability. 相似文献