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431.
Centrosomes play fundamental roles in mitotic spindle organization, chromosome segregation and maintenance of genetic stability. Recently, we have shown that centrosome aberrations occur early in chronic myeloid leukemia (CML) and are induced by imatinib in normal fibroblasts in vitro. To investigate the influence of BCR-ABL on centrosomes, we performed long-term in vitro experiments employing the conditionally p210BCR-ABL-expressing (tetracycline-inducible promoter) human monocytic cell line U937p210BCR-ABL/c6 as a model of CML chronic phase. Centrosome hypertrophy was detectable after 4 weeks of transgene expression onset, increasing up to a rate of 25.7% aberrant cells within 13 weeks of propagation. This concurred with clonal expansion of aneuploid cells displaying a hyperdiploid phenotype with 57 chromosomes. Partial reversibility of centrosome aberrations (26-8%) was achieved under prolonged propagation (14 weeks) after abortion of induction and bcr-abl silencing using small interfering RNA. Therapeutic doses of imatinib did not revert the aberrant phenotype, but counteracted the observed reverting effect of bcr-abl gene expression switch off. Suggesting a mechanistic model that features distinct abl-related tyrosine kinase activity levels as essential determinants of centrosomal integrity, this is the first report mechanistically linking p210BCR-ABL oncoprotein activity to centrosomal hypertrophy.  相似文献   
432.
Objective: To evaluate the pharmacokinetic and systemic pharmacodynamic properties of inhaled fluticasone propionate (FP). Methods: Single doses of 0.25, 0.5, 1.0 and 3.0 mg FP were administered to groups of six healthy subjects. Serum concentration profiles of FP were monitored over 24 h by means of high-performance liquid chromatography/mass spectrometry (HPLC/MS–MS). Systemic pharmacodynamic effects were evaluated by measuring endogenous serum cortisol and circulating white blood cells, and analyzed with previously developed integrated pharmacokinetic/pharmacodynamic (PK/PD) models. Results: FP showed a dose-independent terminal half-life with a mean (SD) of 6.0 (0.7) h. Maximum serum concentrations occurred 1.0 (0.5) h after administration, ranging from 90 pg · ml−1 for the 0.25 mg dose to 400 pg · ml−1 for the 3.0 mg dose. This, together with an estimated mean absorption time of nearly 5 h and a known oral bioavailability of less than 1%, indicates prolonged residence at and slow absorption from the lungs. In the investigated dose range, the cumulative systemic effect was dose-dependent for both markers of pharmacodynamic activity. For doses of 0.25, 0.50, 1.0 and 3.0 mg FP, the PK/PD-based cumulative systemic-effect parameters were 159, 186, 257 and 372% · h for lymphocyte suppression, 107, 186, 202 and 348% · h for granulocyte induction and 23.6%, 33.8%, 51.0% and 73.6% for cortisol reduction, respectively. The time courses of lymphocytes, granulocytes and endogenous cortisol could be sufficiently characterized with the applied PK/PD models. The measured in vivo EC50 values, 30 pg · ml−1 and 7.3 pg · ml−1 for white blood cells and cortisol, respectively, were in good agreement with predictions based on the in vitro relative receptor affinity of FP. Conclusion: After inhalation, FP follows linear pharmacokinetics and exhibits dose-dependent systemic pharmacodynamic effects that can be described by PK/PD modeling. Received: 27 January 1997 / Accepted in revised form: 5 August 1997  相似文献   
433.
We examined safety and efficacy of STI-571 in 24 bcr/abl-positive patients with CML post PBSCT. At start of STI-571 therapy, nine patients presented in blast crisis (BC) or in accelerated phase (AP), and 15 in chronic phase (CP). Patients were evaluated for hematologic, cytogenetic and molecular response, survival and toxicity. In general, STI-571 was well tolerated in this heavily pretreated group of patients with a non-hematologic and hematologic toxicity profile similar to that observed in a previous phase I trial at comparable doses. Five of nine patients with CML in transformation (AP, BC) were evaluable for hematologic response. Two of five patients had transient reductions in WBC and blasts, and three patients achieved a sustained hematologic response (>4 weeks). Cytogenetic analysis in these patients revealed numerical and/or structural responses. In CML chronic phase, STI-571 induced complete hematologic responses in all patients and major cytogenetic responses in 61% of patients with a complete cytogenetic response rate of 46%. This report indicates that STI-571 is a safe and effective drug in heavily pretreated patients. No apparent additional side-effects were noted in this patient cohort. The high rate of complete hematologic and complete cytogenetic responses in CP patients is remarkable, as intensive treatment approaches plus IFN-alpha failed to be efficient in achieving long-term stabilization of CML in this patient cohort.  相似文献   
434.
A major obstacle in gene delivery is the transport of intact plasmid DNA (pDNA) to target sites. We sought to investigate the kinetic processes underlying the degradation of pDNA in a rat plasma model, as this is one of the main components responsible for the clearance of pDNA after intravenous administration. We further sought to construct a complete kinetic model to describe the degradation of all three topoforms (supercoiled, open circular, and linear) of pDNA in a rat plasma model. Supercoiled pDNA was incubated in isolated rat plasma at 37°C in vitro. At various time points, the plasma was assayed by electrophoresis for the amounts of supercoiled, open circular, and full-length linear pDNA remaining. The calculated amounts remaining were fit to linear differential equations describing this process. In this model, pDNA degradation is considered to be a unidirectional process, with supercoiled degrading to open circular and then to the linear topoform. The calculated kinetic parameters suggested that supercoiled pDNA degrades in rat plasma with a half-life of 1.2 minutes, open circular pDNA degrades with a half-life of 21 minutes, and linear pDNA degrades with a half-life of 11 minutes. Complexation of pDNA with liposomes resulted in a portion of the supercoiled plasmid remaining detectable through 5.5 hours.  相似文献   
435.
Direct comparisons of the pharmacokinetic (PK) and systemic pharmacodynamic (PD) properties of inhaled corticosteroids after single and multiple dosing in the same subjects are scarce. The objective of this study was to compare thePK/PDproperties of clinically equivalent, single, and multiple doses of dry-powder formulations of inhaled fluticasone propionate (FP 200 and 500 microg via Diskus) and budesonide (BUD, 400 and 1,000 microg via Turbohaler). Fourteen healthy subjects completed a double-blind, double-dummy, randomized, placebo-controlled, five-way crossover study consisting of a single dose administered at 8 a.m. on day 1 followed by 4 days of twice-daily dosing at 8 a.m. and 8 p.m. on days 2 to 5. Serum concentrations of FP and BUD were measured using validated liquid chromatography/ mass spectrometry assays. The 24-hour cumulative cortisol suppression (CCS) in serum was monitored as the pharmacodynamic surrogate marker. Peak serum concentrations following single and multiple dosing were observed 10 to 30 minutes after inhalation for BUD and 30 to 90 minutes afterinhalation of FP with no influence of dose ordosingregimen. After a single dose of 1000 microg BUD and 500 microg FP the median estimates of terminal half-life and mean residence time were 3.5 and 3.9 hours for BUD and 10.1 and 12.0 hours for FP, respectively. Using previously reported intravenous data, the mean absorption times (MAT) were calculated to be around 2 hours and 7 hours for BUD and FP respectively. On average, the area under the curve (A UC) at steady state (day 5) was up to 30% higher for BUD compared to that over a 12-hour period following the first dose on day 1, whereas A UC estimates were 50% to 80% higherforFP at steady state, indicating accumulation. However, the steady-state Cmax values were seven to eight times and AUC values three to four times higher for BUD than for FP. Comparison of active treatment data with placebo showed that CCS after a single dose was not pronounced for any of the doses/drugs studied. On day 5, both doses of BUD caused statistically significant suppression (CCS of 19% for the 400 microg dose and 36% for the 1,000 microg dose). For FP only the high dose had a statistically significant effect on serum cortisol (CCS of 14% for the 200 microg dose and 27% for the 500 microg dose). Compared to BUD, FP has slower pulmonary absorption and slower elimination kinetics. However, following inhalation of therapeutically equipotent, multiple twice-daily doses in healthy subjects, the systemic effects of FP delivered via Diskus on AUC24 serum cortisol were relatively low and similar to those of BUD delivered via Turbohaler.  相似文献   
436.
The relative binding affinities (RBA) of two locally used glucocorticoids, rimexolone and flunisolide have been measured for the glucocorticoid receptor of human synovial tissue. The non-fluorinated derivative rimexolone exhibited a binding affinity (RBA of 130) somewhat higher than that of dexamethasone (RBA of 100) but lower than that of flunisolide (RBA 190). Potential metabolites of rimexolone hydroxolated at the C17 side-chain, showed decreased binding affinities, while the 6-hydroxy metabolite of rimexolone and flunisolide (its main metabolite) and the 4,5-dihydro metabolites of rimexolone hardly bound at all. These results support previous pharmacological findings that the high ratio of local to systemic effects of both compounds are due to a pronounced receptor affinity of the parent compounds and the fast systemic metabolism to derivatives with low pharmacodynamic activity.  相似文献   
437.
BACKGROUND: Despite advances in drug therapy and allogeneic stem cell transplantation (allo-SCT), the prognosis of patients with chronic myeloid leukemia (CML) in blast crisis remains poor. Imatinib has demonstrated synergistic effects in vitro with mitoxantrone, etoposide, and cytarabine. METHODS: A Phase I/II trial was performed in patients with CML myeloid blast crisis. Patients were treated with imatinib + mitoxantrone/etoposide in four cohorts: mitoxantrone 10 mg/m(2)/day and etoposide 100 mg/m(2)/day for 2 or 3 consecutive days and imatinib 600 mg/day from Day 15 (cohorts 1 and 2) or from Day 1 (cohorts 3 and 4). After hematologic reconstitution after the cytopenic phase, cytarabine was given at a dose of 10 mg/m(2)/day in addition to imatinib as maintenance treatment. RESULTS: A total of 16 patients were available for analysis, median age 59 years (range, 37-74). All patients who received more intensive induction treatment (cohorts 3 and 4, n = 7) achieved a hematologic response (HR). In contrast, HR was achieved in only 6 of 9 patients treated in cohorts 1 and 2. The induction treatment was well tolerated. Six patients who achieved HR received an allo-SCT with myeloablative conditioning. The median survival in the transplant group was 16.2 months vs 4.7 months in the group with conventional treatment only (P = .067). CONCLUSIONS: The combination of mitoxantrone/etoposide and imatinib is well tolerated, with mild nonhematologic toxicity even in older patients. Eligible patients benefit from allo-SCT after response to the induction treatment.  相似文献   
438.
We sought to evaluate the efficacy and safety data of a combination regimen using weekly irinotecan in combination with capecitabine and concurrent radiotherapy (CapIri-RT) as neoadjuvant treatment in rectal cancer in a phase-II trial. Patients with rectal cancer clinical stages T3/4 Nx or N+ were recruited to receive irinotecan (50 mg m(-2) weekly) and capecitabine (500 mg m(-2) bid days 1-38) with a concurrent RT dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the completion of chemoradiation. A total of 36 patients (median age 62 years; m/f: 27:9) including three patients with local recurrence were enclosed onto the trial. The median distance of the tumour from the anal verge was 5 cm. The main toxicity observed was (NCI-CTC grades 1/2/3/4 (n)): Anaemia 23/9/-/-; leucocytopenia 12/7/7/2, diarrhoea 13/15/4/-, nausea/vomiting 9/10/2/-, and increased activity of transaminases 3/3/1/-. One patient had a reversible episode of ventricular fibrillation during chemoradiation, most probably caused by capecitabine. The relative dose intensity was (median/mean (%)): irinotecan 95/91, capecitabine 100/92). Thirty-four patients underwent surgery (anterior resection n=25; abdomino-perineal resection n=6; Hartmann's procedure n=3). R0-resection was accomplished in all patients. Two patients died in the postoperative course from septic complications. Pathological complete remission was observed in five out of 34 resected patients (15%), and nine patients showed microfoci of residual tumour (26%). After a median follow-up of 28 months one patient had developed a local recurrence, and five patients distant metastases. Three-year overall survival for all patients with surgery (excluding three patients treated for local relapse or with primary metastatic disease) was 80%. In summary, preoperative chemoradiation with CapIri-RT exhibits promising efficacy whereas showing managable toxicity. The local recurrence and distant failure rates observed after a median 28 months are low compared with standard 5-fluorouracil based therapy.  相似文献   
439.
The introduction of imatinib represented a breakthrough in the treatment of chronic myelogenous leukemia (CML). However, about 20% of patients treated in early chronic-phase CML are off therapy after 6 years because of resistance or intolerance, and most patients taking imatinib remain BCR-ABL-positive at the molecular level, indicating primary refractoriness of a leukemic subpopulation. Patients with advanced disease often do not respond, or they eventually relapse. Resistance frequently is associated with mutations in the kinase domain of BCR-ABL. Other mechanisms leading to reactivation of BCR-ABL or preventing sufficient BCR-ABL inhibition also exist. Resistance of patients with continued BCR-ABL inhibition despite leukemic progression indicates clonal evolution triggered by BCR-ABL-independent mechanisms. Current efforts to optimize BCR-ABL-targeted treatment focus on the difficulty in reaching CML stem cells. Success will most likely depend on integration of combined treatment algorithms—whether they be a combination of molecules interfering with signaling pathways or additional immune-based treatment adjuncts.  相似文献   
440.
During recent years, the treatment of pulmonary diseases could be significantly improved due to the introduction of modern retrometabolism-based corticosteroids with improved therapeutic ratio. It is the goal of all inhaled corticosteroids to produce long lasting therapeutic effects at the pulmonary target site and to minimize systemic side effects by rapid clearance of the absorbed drug and low oral bioavailability. The development of PK/PD models allows predictions of drug effects based on the administered dose. For example, the cumulative suppression of endogenous cortisol release (CCS) as one of the major systemic side effects of inhaled corticosteroid therapy can be described with an integrated Emax based PK/PD model. In order to assess the predictive power of this model, a study was conducted to compare the PK/PD-based predictions with CCS data obtained from actual clinical trials for flunisolide, fluticasone propionate, budesonide and triamcinolone acetonide. CCS was predicted for different single doses from different inhaler devices for each drug and a good correlation was observed. Thus, the presented PK/PD model proved to be a valid tool for predicting CCS of inhaled corticosteroids. By fully understanding the underlying mechanisms it will be possible to further improve their therapeutic index.  相似文献   
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