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At least 1,153 records · Page 64Linked to original sources
PubMed2005

Population pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia: results of a phase III study.

AIMS: This study was designed to investigate the biochemical and physiological covariates or comedications that affect the pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia (CP CML). METHODS: Pharmacokinetic data were analyzed in 371 patients receiving 400 mg imatinib once daily during a phase III trial of imatinib vs interferon-alfa plus cytarabine for the treatment of newly diagnosed CP CML. Covariates included age, weight, sex, ethnicity, haemoglobin (Hb) concentration, white blood cell (WBC) count, liver function, and creatinine concentration. Blood samples for imatinib analysis were taken on treatment days 1 and 29. Nonlinear mixed effects modelling was used for the population pharmacokinetic analysis. RESULTS: Population mean estimates (95% confidence interval) at day 1 for apparent clearance (CL) and apparent volume of distribution (V) of imatinib were 14 (13-15) l h(-1) and 252 (237-267) l, respectively. Modelling suggested that CL decreased by 4 (3-5) l h(-1) from day 1 to day 29, whereas V remained unchanged. Interindividual variability in CL and V was 32% and 31%, respectively. Weight, Hb, and WBC count demonstrated small effects on CL and V. Doubling body weight or Hb or halving the WBC count was associated with a 12%, 86% and 8% increase in CL, respectively, and a 32%, 60% and 5% increase in V, respectively. Comedications showed no clear effects on imatinib CL. CONCLUSIONS: Population covariates and coadministered drugs minimally affected imatinib pharmacokinetics in newly diagnosed CP CML patients.

Adolescent↗
PubMed2003

Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase.

In chronic myelogenous leukemia (CML) imatinib mesylate has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr-abl fusion protein. Using this agent alone high rates of cytogenetic responses were recorded. However, several mechanisms of resistance have been described. In vitro studies examining the effects of imatinib mesylate plus cytarabine have shown synergistic antiproliferative effects of this combination. Thus, the CML French Group decided to perform a phase 2 trial testing a combination of imatinib mesylate and low-dose cytarabine in 30 previously untreated patients in chronic phase. Treatment was administered on 28-day cycles. Patients were treated continuously with imatinib mesylate orally at a dose of 400 mg daily. Cytarabine was given on days 15 to 28 of each cycle at an initial dose of 20 mg/m2/d via subcutaneous injection. Adverse events were frequently observed with grade 3 or 4 hematologic toxicities and nonhematologic toxicities in 53% (n = 16) and 23% (n = 7) of patients, respectively. The cumulative incidence of complete cytogenetic response (CCR) at 12 months was 83% and at 6 months 100% of the patients achieved complete hematologic response (CHR). We concluded that the combination was safe and promising given the rates of response.

Adult↗
PubMed2000

Taxanes for breast cancer: an evidence-based review of randomized phase II and phase III trials.

The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early-or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n = 1) or phase III (n = 17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m2 every 3 weeks) was given following 4 cycles of conventional doxorubicin-cyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/neu, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Civilian Health and Medical Program of the Uniformed Services (CHAMPUS); methodology for coverage of phase II and phase III clinical trials sponsored by the National Institutes of Health. Office of the Secretary; DoD. Final rule.

This final rule allows the Department of Defense to waive normal requirements so that covered beneficiaries can participate in Phase II and Phase III clinical trials sponsored or approved by the National Institutes of Health National Cancer Institute (NIH NCI). This waiver authority is expected to promote beneficiary access to promising new treatments and contribute to the development of such treatments.

Clinical Trials, Phase II as Topic↗
PubMed2006

Civilian Health and Medical Program of the Uniformed Services (CHAMPUS)/ TRICARE; coverage of phase II and phase III clinical trials sponsored by the National Institutes of Health National Cancer Institute. Final rule.

The final rule allows the Department of Defense to waive normal requirements so that covered beneficiaries can participate in Phase II and Phase III clinical trials sponsored or approved by the National Institutes of Health National Cancer Institute (NIH NCI). This waiver authority is expected to promote beneficiary access to promising new treatments and contribute to the development of such treatments.

Clinical Trials, Phase II as Topic↗
PubMed1984

Follicular phase treatment of luteal phase defect with follicle-stimulating hormone in infertile women.

Fifteen infertile women diagnosed by endometrial dating to have a luteal phase defect were treated with human pituitary follicle-stimulating hormone (hFSH) for 45 cycles. Human follicle-stimulating hormone was administered intramuscularly in a dose of 50 IU/day (group 1) for 35 cycles and 100 IU/day (group 2) for ten cycles from either the third or fifth day of the cycle for five days. Plasma estrogen was measured daily during drug injection. Plasma progesterone was measured on the fourth, seventh, and tenth days after ovulation by basal body temperature during 11 pretreatment control cycles and 39 treatment cycles. Endometrial biopsies were performed on the seventh day after ovulation. The daily estrogen levels increased gradually during hFSH treatment. There was no significant difference between the two dosage groups. The mean progesterone levels were: 1) significantly (P less than .02) greater in the treatment cycles than in the control cycles, 2) significantly (P less than .05) greater in the pregnancy cycles than in the nonpregnancy cycles, 3) significantly (P less than .01) greater in the cycles with normal endometrial dating than in the cycles with abnormal endometrial dating after treatment, and 4) significantly (P less than .05) greater in group 1 than in group 2. After treatment, the endometrial biopsy specimens were improved to normal in 20 of 38 cycles. Five patients became pregnant during the treatment. The authors have concluded that hFSH may be useful in treatment of luteal phase defect.

Adult↗
PubMed1996

Comparative analysis of two consecutive phase II studies with IFN-alpha and IFN-alpha + ara-C in untreated chronic-phase CML patients. Austrian CML Study Group.

Two consecutive phase II studies with IFN-alpha (n = 55) and with IFN-alpha/ara-C (n = 84) are compared in a retrospective analysis of untreated chronic-phase CML patients. Hematological responses (CHR and PHR) were seen in 76% of patients after IFN-alpha and in 77% after IFN-alpha/ara-C treatment with a higher CHR rate in the latter group (45% versus 54%). Moreover, cytogenetic responses were observed more frequently in the IFN-alpha/ara-C study (44% versus 34%), including a higher rate of complete cytogenetic responses (13% versus 9%). The combined treatment modality induced higher rates of hematotoxicity (e.g. thrombocytopenia: 44% versus 25%) and gastrointestinal side effects (38% versus 15%) as compared to the monotherapy study.

Adolescent↗
PubMed1996

[Control mechanisms of cell transition from the G1 phase to the S phase--the R point].

The critical moment of regulation when transition of the cell from the G1 to the S phase takes which is decisive for its division is the so-called R-point (restriction point). The disorder of molecular mechanisms controlling the passage of the cell through this site is an associated manifestation of most tumourous processes. A considerable part of this mechanism is the RB protein, binding transcription factors needed for the activation of genes effective in the S phase. Its binding capacity depends on the extent of phosphorylation and on the activity of the appropriate kinases and their inhibitors.

Cyclin-Dependent Kinases↗
PubMed1998

Gemcitabine and carboplatin in combination: phase I and phase II studies.

Gemcitabine has demonstrated single-agent activity in advanced, incurable non-small cell lung cancer, yielding response rates of > or =20%, and, in combination with cisplatin, response rates of 30% to 60%. Carboplatin causes much less nonhematologic toxicity than cisplatin, and initial therapy with carboplatin yields equivalent survival in advanced non-small cell lung cancer compared with cisplatin combinations and other cisplatin analogs, despite a lower response rate. Carmichael and colleagues have identified a maximum tolerated dose of carboplatin of area under the curve 5.2 mg/mL/min administered monthly in combination with gemcitabine 1,000 mg/m2 on days 1, 8, and 15. This combination produced a response rate of 31% and a median survival of 45 weeks in 13 evaluable patients. A subsequent phase I evaluation reversing the carboplatin and gemcitabine sequence (gemcitabine --> carboplatin day 1) demonstrated no difference in toxicities, pharmacodynamics, or maximum tolerated dose. At Fox Chase Cancer Center and elsewhere, similar phase I trials will determine the maximum tolerated doses of each agent in combination using a compressed schedule with carboplatin administered every 3 weeks and gemcitabine given on days 1 and 8 only.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

A study of ion suppression effects in electrospray ionization from mobile phase additives and solid-phase extracts.

Since the wide adoption of liquid chromatography/tandem mass spectrometry (LC/MS/MS), the ion suppression/enhancement phenomenon is the latest barrier to high-throughput analysis. This consequence of a nonoptimized analytical method can lead to adverse effects during quantitation (i.e. poor accuracy and precision). Previous papers have reported that ion suppression is a direct result of endogenous material present in biological samples. However, in the case of a solid-phase liquid chromatography/tandem mass spectrometry (SPE/LC/MS/MS) system, the measured result is the combination of several operating conditions and parameters. Little has been done to effectively monitor and/or choose optimized conditions for the complete sequence of extraction, clean up, separation and analysis. This paper describes a simple setup for quantification of ion suppression/enhancement. Several mobile phase additives, ion-pairing agents and SPE extracts were measured and compared against a standard reference. The results demonstrated that a clean up of plasma extracts based on ion exchange leads to minimal ion suppression/enhancement for the compounds that were investigated.

Artifacts↗
PubMed2006

Nano-structured lead dioxide as a novel stationary phase for solid-phase microextraction.

The first study on the high efficiency of nano-structured lead dioxide as a new fiber for solid-phase microextraction (SPME) purposes has been reported. The size of the PbO2 particles was in the range of 34-136 nm. Lead dioxide-based fibers were prepared via electrochemical deposition on a platinum wire. The extraction properties of the fiber to benzene, toluene, ethylbenzene, and xylenes (BTEX) were examined using headspace solid-phase microextraction (HS-SPME) mode coupled to gas chromatography-flame ionization detection (GC-FID). The results obtained proved the suitability of proposed fibers for the sampling of organic compounds from water. The extraction procedure was optimized by selecting the appropriate extraction parameters, including preparation conditions of coating, salt concentration, time and temperature of adsorption and desorption and stirring rate. The calibration graphs were linear in a concentration range of 0.1-100 microg l(-1) (R2 > 0.994) with detection limits below 0.012 microg l(-1) level. Single fiber repeatability and fiber-to-fiber reproducibility were less than 10.0 and 12.5%, respectively. The PbO2 coating was proved to be very stable at relatively high temperatures (up to 300 degrees C) with a high extraction capacity and long lifespan (more than 50 times). Higher chemical resistance and lower cost are among the advantages of PbO2 fibers over commercially available SPME fibers. Good recoveries (81-108%) were obtained when environmental samples were analyzed.

Adsorption↗
PubMed2006

Development of a solid-phase microextraction method with micellar desorption for the determination of chlorophenols in water samples. Comparison with conventional solid-phase microextraction method.

A novel analytical method is presented for the determination of chlorophenols in water. This method involves pre-concentration by solid-phase microextraction (SPME) and an external desorption using a micellar medium as desorbing agent. Final analysis of the selected chlorophenols compounds was carried out by high-performance liquid chromatography (HPLC) with diode array detection (DAD). Optimum conditions for desorption, using the non-ionic surfactant polyoxyethylene 10 lauryl ether (POLE), such as surfactant concentration and time were studied. A satisfactory reproducibility for the extraction of target compounds, between 6 and 15%, was obtained, and detection limits were in the range of 1.1-5.9ngmL(-1). The developed method is evaluated and compared with the conventional one using organic solvent as a desorbing agent. The method was successfully applied to the determination of chlorophenols in water samples from different origin. This study has demonstrated that solid-phase microextraction with micellar desorption (SPME-MD) can be used as an alternative to conventional SPME method for the extraction of chlorophenols in water samples.

Chlorophenols↗
PubMed2003

Phase II study of troxacitabine, a novel dioxolane nucleoside analog, in patients with untreated or imatinib mesylate-resistant chronic myelogenous leukemia in blastic phase.

A phase II study of troxacitabine, a non-natural dioxolane nucleoside L-enantiomer, was conducted in patients with chronic myelogenous leukemia in blastic phase (CML-BP). Patients were untreated for BP, or treated with imatinib mesylate (IM) as sole prior therapy for BP. Troxacitabine was given as an intravenous infusion over 30 min daily for 5 days at a dose of 8.0 mg/m(2) per day. Thirty-one patients, 29 (93%) of whom had failed prior IM therapy, received 51 courses of therapy. Grade 3 or 4 toxicities included stomatitis (4%), hand-foot syndrome (18%), and skin rash (12%). Four patients (13%) responded. Troxacitabine-based combinations merit study in IM-resistant CML.

Adult↗
PubMed2003

A phase I clinical trial of spicamycin derivative KRN5500 (NSC 650426) using a phase I accelerated titration "2B" design.

The spicamycin derivative KRN5500 was considered as a potential anti-cancer agent based on in vitro and preclinical studies. A Phase I study involving 24 cancer patients in whom tumors were refractory to all other conventional therapies was conducted to determine the dose limiting toxicity, maximum tolerated dose, effectiveness, and pharmacokinetic parameters of this drug administered by 1-h IV infusion daily for five consecutive days every 3 weeks. Using an accelerated dose titration strategy, 8.4 mg/m2/d x 5 days was the maximum administered dose. Severe gastrointestinal and hepatic toxicities were observed at doses at or above 4.3 mg/m2/d x 5. The recommended Phase II dose i s 4.3mg/m2/d x 5. The distribution of KRN5500 followed a two-compartment model, and clearance did not decrease significantly over the dose range 0.8-8.4 mg/m2/d x 5. No significant correlation was observed between plasma levels and toxicity. No tumor responses were observed among the 14 patients evaluable for response.

Adult↗
PubMed2004

9-Aminocamptothecin (9-AC) given as a 120-hour continuous infusion in patients with advanced adenocarcinomas of the stomach and gastroesophageal junction: A phase II trial of the University of Chicago phase II consortium.

9-Aminocamptothecin (9-AC) is a water-insoluble camptothecin derivative that demonstrated broad activity in pre-clinical studies. In vitro, greater anti-tumor efficacy can be achieved with prolonged administration. A minor response was observed in gastric cancer in a phase I study. We conducted a phase II study of 9-AC in 15 patients with previously untreated metastatic gastric cancer and adenocarcinoma of the gastroesophageal junction. 9-AC was administered at a dose of 25 microg/m(2)/h over 120 hours (3000 microg/m(2) over 5 days) on two consecutive weeks every 21 days. Fourteen patients were evaluable for response. There were no objective responses. Three patients had stable disease lasting a median of 3.4 months (range 1.6-4.3 months). Median time to progression was 1.4 months; median survival was 5.2 months. Grade 3 neutropenia developed in 20% of patients, and anemia in 7%. Grade 3 nausea and fatigue each developed in 7% of patients. We conclude that 9-AC given by 120-hour continuous infusion demonstrates no clinical activity in patients with metastatic gastric cancer.

Adenocarcinoma↗
PubMed2004

Many-body force field models based solely on pairwise Coulomb screening do not simultaneously reproduce correct gas-phase and condensed-phase polarizability limits.

It is demonstrated that many-body force field models based solely on pairwise Coulomb screening cannot simultaneously reproduce both gas-phase and condensed-phase polarizability limits. Several many-body force field model forms are tested and compared with basis set-corrected ab initio results for a series of bifurcated water chains. Models are parameterized to reproduce the ab initio polarizability of an isolated water molecule, and pairwise damping functions are set to reproduce the polarizability of a water dimer as a function of dimer separation. When these models are applied to extended water chains, the polarization is over-predicted, and this over-polarization increased as a function of the overlap of molecular orbitals as the chains are compressed. This suggests that polarizable models based solely on pairwise Coulomb screening have some limitations, and that coupling with non-classical many-body effects, in particular exchange terms, may be important.

Artifacts↗
PubMed1998

Late phase response in nasal mucosa closely correlated with immediate phase reaction and hyperreactivity to histamine.

It has been suggested that the onset of the late phase response (LPR) and hyperreactivity to non-specific stimuli occurs in the lower airway. However, its relationship in the nose has not yet been studied. This study was designed to examine the mechanism of LPR and the relationship between LPR and hyperreactivity. A total of 25 Japanese cedar pollinosis patients participated in this study. On the first visit, the frequency of sneezes, weight of nasal discharge, and the nasal airway resistance (NAR) were time-dependently measured without antigen challenge. The histamine reactivity was observed after 12 h. The same protocol was used during the second to fourth visits. The frequency of sneezes, weight of nasal discharge, and NAR were measured continuously for 12 h after antigen challenge, and nasal reactivity to histamine was observed. The percent change of NAR during immediate phase response (IR) and during LPR showed a significant correlation. The frequency of sneezes and weight of nasal discharge induced by histamine were both significantly higher in the positive than in the negative LPR group. These results suggest that the chemical mediators and inflammatory cells inducing nasal swelling during IR cause, directly or indirectly, nasal swelling during LPR, and induce hyperreactivity to histamine.

Acute-Phase Reaction↗
PubMed2005

The yeast S phase checkpoint enables replicating chromosomes to bi-orient and restrain spindle extension during S phase distress.

The budding yeast S phase checkpoint responds to hydroxyurea-induced nucleotide depletion by preventing replication fork collapse and the segregation of unreplicated chromosomes. Although the block to chromosome segregation has been thought to occur by inhibiting anaphase, we show checkpoint-defective rad53 mutants undergo cycles of spindle extension and collapse after hydroxyurea treatment that are distinct from anaphase cells. Furthermore, chromatid cohesion, whose dissolution triggers anaphase, is dispensable for S phase checkpoint arrest. Kinetochore-spindle attachments are required to prevent spindle extension during replication blocks, and chromosomes with two centromeres or an origin of replication juxtaposed to a centromere rescue the rad53 checkpoint defect. These observations suggest that checkpoint signaling is required to generate an inward force involved in maintaining preanaphase spindle integrity during DNA replication distress. We propose that by promoting replication fork integrity under these conditions Rad53 ensures centromere duplication. Replicating chromosomes can then bi-orient in a cohesin-independent manner to restrain untimely spindle extension.

Anaphase↗