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21.
A three-compartment model was fitted to idarubicin data in a NONMEM pooled-data approach. Clearance (CL) of 221.7 ml/min
was relatively high, and drug distribution was rapid (CLD=248.3 ml/min) and extensive [steady-state volume of distribution (Vss) 24 l]. The area under the concentration-time curve (AUC) of idarubicinol was 8 times that of idarubicin. Concentrations
of idarubicin (idarubicinol) measured in the myocardium at 24 h after i.v. administration of idarubicin were 20 (5) times
those determined in plasma. Tissue concentrations of idarubicinol were up to 400 times those of idarubicin, indicating that
the active metabolite contributes significantly to the overall drug action.
Received: 16 June 1996 / Accepted: 4 November 1996 相似文献
22.
R. A. Davey Gloria M. Su Rebecca M. Hargrave Rozelle M. Harvie Bruce C. Baguley Mary W. Davey 《Cancer chemotherapy and pharmacology》1997,39(5):424-430
The effectiveness of N-[2-(dimethylamino) ethyl]acridine-4-carboxamide (DACA) relative to that of amsacrine, idarubicin, daunorubicin and paclitaxel
against three different forms of multidrug resistance (MDR) was determined using two sublines of the CCRF-CEM human leukaemia
cell line, the P-glycoprotein-expressing CEM/VLB100 subline and the MRP-expressing CEM/E1000 subline, and two extended-MDR
sublines of the HL60 human leukaemia cell line, HL60/E8 and HL60/V8. DACA was effective against P-glycoprotein-mediated MDR
and MRP- mediated MDR, whereas the extended-MDR pheno- type showed only low levels of resistance (<2-fold) to DACA. In comparison,
idarubicin was ineffec- tive against the MRP and extended-MDR phenotypes. Repeated exposure of the K562 human leukaemia cell
line to DACA (55, 546 or 1092 nM for 3 days over 10 weeks) did not result in the development of any significant drug resistance. We conclude that DACA has
the potential to treat refractory leukaemia.
Received: 5 May 1996/Accepted: 16 August 1996 相似文献
23.
D. A. Gewirtz Joyce K. Randolph Juhi Chawla Michael S. Orr Frank A. Fornari 《Cancer chemotherapy and pharmacology》1998,41(5):361-369
Purpose: Studies were designed to elucidate the basis for the antiproliferative activity of the anthracycline antibiotic, idarubicin
(4-demethoxy-daunorubicin) in MCF-7 breast tumor cells. Methods: Growth inhibition was evaluated using the MTT tetrazolium dye assay, induction of DNA strand breaks was determined by alkaline
elution, inhibition of DNA synthesis was assessed by measuring the incorporation of labelled thymidine into DNA, modulation
of the expression of the c-myc oncogene was determined by Northern blotting and the induction of apoptosis was evaluated by alkaline unwinding, static field
gel electrophoresis, terminal end labelling and assessment of cell morphology. Results: MCF-7 cells were relatively sensitive to idarubicin, with an IC
50 value for growth inhibition of approximately 0.01 μM. While DNA strand breakage was not evident below a concentration of 0.1 μM idarubicin, where growth inhibition exceeded 70%, both the inhibition of DNA synthesis and suppression of c-myc expression closely paralleled the profile of antiproliferative activity for idarubicin. Finally, while exposure to idarubicin
resulted in a substantial loss of viable cells within 48–72 h, there was no morphological evidence of apoptotic body formation.
The absence of apoptosis in cells exposed to idarubicin was supported by studies demonstrating the absence of DNA fragmentation
using gel electrophoresis, alkaline elution and in situ DNA end-labelling assays. Conclusions: The results of these studies extend previous results from this laboratory indicating an association between suppression
of c-myc expression, inhibition of DNA synthesis and growth arrest by topoisomerase II inhibitors, as well as the lack of induction
of apoptotic cell death by topoisomerase II inhibitors in MCF-7 breast tumor cells.
Received: 21 May 1997 / Accepted: 10 September 1997 相似文献
24.
H. T. Steinmetz A. Schulz P. Staib C. Scheid A. Glasmacher A. Neufang J. Franklin H. Tesch V. Diehl P. Dias Wickramanayake 《Annals of hematology》1999,78(9):418-425
The current phase-II trial was initiated to assess the efficacy and toxicity of the Ida-FLAG regimen in patients with poor-risk
acute myeloid leukemia (AML). Three subgroups of patients with AML were eligible for the study: (a) refractory, (b) first
relapse, or (c) secondary AML (i.e., signs of trilineage myelodysplasia at diagnosis or the history of a myelodysplasia or
myeloproliferative disorder). Fifty-seven fully evaluable patients were included in the study. Twenty patients received a
second course of Ida-FLAG. Complete remission was achieved by 1/14 patients with refractory AML, 12/15 patients with relapsed
AML, and 17/28 patients with secondary AML. The median duration of ANC <1000/μl was 17 days (10–36); of platelets <30,000/μl
23 days (9–65); of days with fever >38.0 °C 6 days (1–33). Thirteen patients (22.8%) died within 42 days of severe infection
or hemorrhage. Overall survival at 20 weeks in the subgroups was 24% for patients with refractory, 78% for patients with relapsed,
and 55% for patients with secondary AML. The toxicity of the first cycle of Ida-FLAG is moderate. The feasibility and subjective
tolerance of the Ida-FLAG regimen are acceptable. There is no evidence for an increase of atypical infections. The efficacy
for patients with secondary AML and especially those with first relapse of AML is good, with a high rate of complete remissions.
Remission duration seems to be short. Therefore, an intensified post-remission therapy seems necessary.
Received: August 28, 1998 / Accepted: April 9, 1999 相似文献
25.
1992年3月~1993年7月作者以个去甲氧基柔红霉素(IDA)为主组成联合化疗方案治疗各种初治和复治的急性白血病共36例,其中急性淋巴细胞白血病(ALL)15例,急性非淋巴细胞白血病(ANLL)21例。ALL组采用VICP方案(其中IDA10~15mg/d,静脉注射,第1~3天和第15~17天);ANLL组采用IA方案(其中IDA10~15mg/d,静脉注射,第1~3天)。结果表明IDA安全、有效。初治ALL的完全缓解(CR)率为7/10(70%),复治ALL的CR率为1/5(20%);初治ANLL的CR率为6/13例(46%),复治ANLL的CR率为4/8例(50%)。IDA联合化疗的副作用与柔红霉素相仿,仍有一定的心脏毒性,在老年患者中应谨慎使用。 相似文献
26.
The MDR phenotype in hematologic malignancies: prognostic relevance and future perspectives 总被引:5,自引:0,他引:5
The multidrug resistant (MDR) phenotype has been suspected as a major cause of treatment failure in hematologic malignancies.
Numerous studies have investigated the expression of the MDR1 gene product, P-glycoprotein, in leukemia, lymphoma and myeloma.
Studies in myelogenous leukemia and myeloma have so far provided best evidence for a significant correlation between P-glycoprotein
expression and response to chemotherapy, although large discrepancies in the proportion of positive cells limit any definite
conclusion. Differences in P-glycoprotein detection techniques and methodology may account for the divergent results thus
emphasizing the necessity for standardized methods of detection. Despite this, encouraging clinical results have been obtained
using MDR modulators in combination with conventional chemotherapy to inhibit the activity of the P-glycoprotein pump. The
paper summarizes currently available clinical data and provides guidelines for future trials aimed to reverse the MDR phenotype.
The potential of idarubicin to overcome the MDR phenotype is also discussed.
Received: 20 November 1995 / Accepted: 18 January 1996 相似文献
27.
G. Seipelt W.-K. Hofmann H. Martin B. Wassmann A. Boehme O. G. Ottmann D. Hoelzer 《Annals of hematology》1998,76(3-4):145-151
The toxicity and outcome after high-dose ara-C/daunorubicin (HDara-C/DNR) consolidation therapy in de novo AML was compared
in 11 patients who received an idarubicin-containing induction therapy (IDA; from June 1995 to March 1997) and 16 patients
pretreated with daunorubicin (DNR; from July 1990 to May 1995) for induction. The DNR group consisted of two cohorts, one
(n=6) of patients who had received, as had the IDA group, two induction and one intermediate-dose ara-C consolidation courses,
and another (n=10) of patients who had been pretreated with one induction and one consolidation course prior to HDara-C/DNR. There was no
difference in the relative dose between the three cohorts. Following HDara-C/DNR, the IDA-pretreated patients experienced
a more prolonged myelosuppression during consolidation therapy compared with the DNR group. Duration of neutropenia (<500
neutrophils/μl) following HDara-C/DNR was 31.2 ± 16 days (mean ±SEM) in the IDA group compared with 18.7 ± 5 days in the DNR
group (p<.001 Mann-Whitney U-test). The duration of thrombocytopenia (platelets <25 000/μl) was 34.8 ± 20 days in the IDA group vs.
18.5 ± 6 days in the DNR group (p<.005). The more prolonged myelosupression was associated with a longer duration of fever (18.9 ± 24 vs. 6.9 ± 5.2 days).
A greater incidence, length (11 ± 8 vs. 1.2 ± 2 days), and severity of diarrhea were observed in the IDA-pretreated group.
Three of 11 IDA patients experienced WHO grade III-IV diarrhea. In the IDA group two patients developed severe enterocolitis
with Candida septicemia, and one of these patients died. One patient in the IDA group died during prolonged aplasia. In the DNR group
6/16 patients experienced grade I-II diarrhea. Two patients in each group died during consolidation therapy. The CR rate was
87% in the IDA group and 79% in the DNR group. Relapse-free survival after HDara-C is 50% at a median follow-up of 60 months
in the DNR group and 45% after a median follow-up of 17 months in the IDA group. Whether the advantage of the superior response
rate in the IDA-treated patients may be lost during HDara-C consolidation treatment due to increased toxicity remains to be
proven in larger trials.
Received: 27 October 1997 / Accepted: 28 January 1998 相似文献
28.
In the scope of a pharmacokinetic and dosefinding study 33 patients received instillations of idarubicin in 11 different doses 1 h before scheduled transurethral resection of bladder cancer. The dose was increased continuously from 5 to 30 mg and the concentration from 0.25–1.5 mg/ml. Idarubicin uptake into tissue was measured along with the serum level. The results showed a clear correlation of the tissue levels with dose and concentration. A significantly higher concentration of idarubicin was measured in the tumor in comparison with the mucosa. Absorption into the muscle was minimal and serum levels were low. Systemic toxicity was not observed, but there were signs of local toxicity in 50% of the subjects. Cytotoxic concentrations in the mucosa were reached at doses of over 15 mg and concentrations of over 0.5 mg/ml. A phase-II study is in preparation. 相似文献
29.
去甲氧柔红霉素联合阿糖胞苷治疗儿童难治性急非淋白血病 总被引:1,自引:0,他引:1
总结了在二年内应用去甲氧柔红霉素联合阿糖胞苷为主的方案治疗复发ALL和AML等白血病患儿21例。结果表明14例有效,其中7例为AML。主要副作用为骨髓抑制,全血最低期为用后的第12-16.5天,约于第26-27天恢复正常。无明显心肌毒性作用。 相似文献
30.
Ran Zhang Xuan Lu Huafang Wang Yong You Zhaodong Zhong Sibin Zang Chun Zhang Wei Shi Junying Li Qiuling Wu Jun Fang Linghui Xia 《Biology of blood and marrow transplantation》2019,25(1):47-55
The optimal conditioning regimen of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk patients with minimal residual disease (MRD) remains controversial. We studied the results in 98 high-risk acute leukemia patients transplanted with idarubicin (IDA)-intensified conditioning regimens between 2012 January and 2017 January. Among these patients, 31 (31.6%) had more than 5% marrow blasts at time of transplantation and 67 patients were in morphologic remission: MRD negative status at time of conditioning was achieved in 39 patients (39.8%), whereas 28 (28.6%) remained carriers of any other positive MRD level in the bone marrow. Three-year relapse estimates of patients with MRD-positive remission was 22.0%, which was remarkably lower than patients with active disease (45.4%, P?=?.027) but approximate to that of patients in MRD-negative remission (15.5%, P?=?.522). There were no significant differences in terms of 3-year estimated overall survival (OS) and disease-free survival (DFS) between MRD-positive remission and MRD-negative remission groups (71.4% versus 79.1% [P?=?.562] and 67.9% versus 76.9% [P?=?.634], respectively). Moreover, the estimated rates of 3-year OS and DFS of patients in MRD-positive remission were significantly better than those in patients with active disease (71.4% versus 41.9% [P?=?.033] and 67.9% versus 38.7% [P?=?.037], respectively). These data indicate that IDA-intensified conditioning allo-HSCT could overcome the negative prognostic impact of MRD. 相似文献