Ratio Of Days Research Articles

Abstract 5463: Development of a pharmacokinetic (PK)-pharmacodynamic (PD) model to guide combination-dosing strategies of aflibercept (VEGF Trap) and doxorubicin chemotherapy in a systemic preclinical model of human acute myeloid leukemia

Abstract Combination therapy utilizing an anti-angiogenic agent and cytotoxic chemotherapy represents a standard therapeutic approach in solid tumors; however the efficacy of this approach in hematological malignancies has not been established. In order to maximize anti-tumor effects, the in vivo mechanism of action as well as timing of administration of the anti-angiogenic agent with respect to the cytotoxic agent in such “liquid tumors” may be crucial. We performed detailed pharmacodynamic modeling to study the effects of the sequential combination of an anti-angiogenic (aflibercept) agent with doxorubicin (DOX) chemotherapy on tumor growth in a systemic model of human acute myeloid leukemia. Disease in sublethally irradiated SCID mice was established in marrow and other sites (e.g. central nervous system) by intraveneous injection of stable luciferase-transfected human AML (HEL) cells. Animals were then treated with aflibercept (25 mg/kg) or PBS (vehicle) i.p., on days 0, 4, and 7 (n=5 per group). On day 7, one dose of DOX 3mg/kg was also administered. In vivo leukemia disease burden was quantified on days 0, 5, 7, 14, 21 and 28 days by bioluminescent imaging. The total tumor load was calculated as the area under the curve of bioluminescence (photons/second/cm2/steradian) versus time using the trapezoidal rule (units: photons/second/cm2/steradian*days) for days 0-21 (AUC0-21) and days 0-28 (AUC0-21) in those animals surviving to day 28 (n=2 in PBS + DOX, n=3 in aflibercept + DOX). We found that the mean (AUC0-21) ± SE value was lower in animals treated with aflibercept+DOX (6.86e-08±3.2e-08) than in PBS + DOX (1.63e-09±7.9e-08) treated mice. Additionally, the fold change from baseline bioluminescence (ratio of day 21 to day 0) was higher in PBS + DOX treated animals (4.379 ± 0.5101) than aflibercept+DOX treated animals (3.077 ± 0.2037), although this difference was not statistically significant (p=0.05). In the animals that survived till day 28, the mean (AUC0-28) ± SE values were similar: PBS + DOX = 2.44e-09 ± 2.17e-09 and aflibercept + DOX = 7.21e-08 ± 3.39e-08. Conclusions: We conclude that there was a trend for improved inhibition of leukemia growth when aflibercept was combined with DOX over DOX treatment alone in SCID mice engrafted with systemic human AML disease. Although changes were noted over a 28 day period, this change was most remarkable at day 21. Integration of this PD data with drug PK in the same model system is ongoing. This PKPD modeling approach will enable us to predict the effects of different dosing frequency and schedules of anti-VEGF therapy in combination with cytotoxic agents in acute leukemia and will provide new insight into the development of rational dosing regimens of these agents in future clinical trials of patients with aggressive hematological cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5463. doi:10.1158/1538-7445.AM2011-5463

Non-Adherence to Oral 6-Mercaptopurine (6MP) Explains Ethnic Differences In Disease-Free Survival In Children with Acute Lymphoblastic Leukemia (ALL) – a Children's Oncology Group (COG) Study (AALL03N1)

AbstractAbstract 7 Background:Hispanic children with ALL have a significantly inferior outcome compared with non-Hispanic whites (Blood, 2002). Low systemic exposure to 6MP adversely affects prognosis (N Engl J Med 1990), and red cell (RBC) levels of its metabolite (thioguanine nucleotide [TGN]) correlate with survival (Blood, 1999). Significant inter-patient variability in RBC TGN levels exists due either to inherited difference in thiopurine methyltransferase (TPMT) activity, or failure to adhere to prescribed 6MP. Non-adherence to 6MP has been reported, and could be related to differences in cultural beliefs, possibly accounting for ethnic differences in ALL survival. Methods:We tested this hypothesis in Hispanic and non-Hispanic white children with ALL diagnosed at age ≤21 yrs, and receiving maintenance therapy at 78 participating COG institutions. 6MP adherence was measured over 6 months using Medication Event Management System (MEMS) and RBC TGN. Electronic MEMS cap collected real-time data on dates/ times when the 6MP bottle was opened. Whether the bottle opening was followed by ingestion of 6MP was assessed by monthly (6 assessments/ patient) measurement of TGN. TPMT activity was also measured. Self-reported sociodemographics and reasons for non-adherence were also collected. MEMS-based adherence (outcome of interest) was defined as the ratio of days that 6MP bottle was opened to days 6MP doses were prescribed, reported as a percentage: “% adherence”. All prescribed doses were reviewed for each patient, and the period of time when 6MP was withheld by the prescriber due to toxicity/ illness taken into account. Longitudinal analysis was performed using Generalized Estimating Equations. Results:333 patients (173 Hispanics; 160 non-Hispanic whites) contributed 54,193 person-days of observation for 6MP adherence. Median age at study participation was 6 yrs (2-20); 67% were males; 38% presented with high-risk disease per NCI criteria. While age, sex and disease characteristics did not differ by ethnicity, Hispanics were significantly more likely to report indices of lower SES (Table). Mean % adherence over the 6 month study period was significantly lower among Hispanics (86±20%) compared with non-Hispanic whites (93±9%, p<0.0001). Multivariate longitudinal analysis identified the following at risk for lower adherence: Hispanic ethnicity (p<0.0001, Fig A); age ≥12 yrs at study entry (p=0.004, Fig B); single mothers as caregivers (p=0.003, Fig C); and time on study (p<0.0001). Reasons for missing 6MP doses included forgetfulness (55%), disruption of usual routine (22%), logistical barriers (15%), and side effects (5%). With a median follow-up of 4.5 yrs, disease-free survival (DFS) was significantly inferior for Hispanics (81±5% at 6 yrs) compared with non-Hispanic whites (94±2%, p=0.01, Fig D). After adjusting for sex, NCI risk, TPMT activity, and 6MP dose-intensity, each 1% decrease in adherence was associated with a 3% increase in risk of relapse (p=0.01). Most importantly, in the multivariate model without adherence, Hispanic ethnicity was associated with a significantly increased risk of relapse (HR=3.2, p=0.01); however upon inclusion of adherence in the model (p=0.01), the association between ethnicity and recurrence diminished in magnitude and significance (HR=2.1, p=0.18). A cutpoint in adherence at 85% was accompanied by a statistical separation in DFS (DFS: 92±2.2% vs. 77.0±5.1%, p<0.0001, Fig E), as well as a large separation in TGN levels (198 vs. 174, p=0.07), making 85% a clinically relevant level of adherence. Conclusion:Non-adherence to 6MP is prevalent in children with ALL. Hispanic children are more likely to be non-adherent, even after adjusting for sociodemographic variables. Non-adherence is associated with significantly inferior DFS. Non-adherence explains the ethnic differences in DFS. This study has informed a targeted intervention to reduce non-adherence to oral chemotherapy, with the goal to reduce disparities in ALL outcome. [Display omitted] Disclosures:Relling:St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding.

Early monitoring of radiotherapeutic effects of nasopharyngeal carcinoma xenografts in nude mice using 18F-FDG PET-CT imaging

Monitoring the therapeutic effects of radiotherapy for nasopharyngeal carcinoma (NPC) is critical to providing individualized treatment. This in-vivo study was initially designed to evaluate the therapeutic effect of radiotherapy using 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT) imaging. 18F-FDG PET-CT imaging was performed on all of the 10 nude mice bearing NPC xenografts before radiotherapy, and early-phase and delayed-phase PET-CT images were performed on 7 of the 10 mice. All mice were randomly divided into either a control group or a radiotherapy group. The 5 mice in the control group were immediately killed after the imaging and pathology were performed. After receiving radiotherapy of 12 Gy, 5 animals in the radiotherapy group were given 18F-FDG PET-CT imaging on days 2, 4, and 6, and then were killed for pathologic evaluation. Regions of interest (ROI) technology was used to measure the tumor target/non-target (T/NT) ratio and the volume of the tumors. The average T/NT ratios of early- and delayed-phase imaging were 1.806 +/- 0.532 and 1.777 +/- 0.597, respectively, with no significance (P > 0.05). For the radiotherapy group, the average T/NT ratios for 18F-FDG PET-CT before radiotherapy, and on days 2, 4, and 6 after radiotherapy, were 1.735 +/- 0.466, 1.818 +/- 0.396, 1.096 +/- 0.101, and 0.604 +/- 0.108, respectively, The tumor volumes were (1.48 +/- 0.27) cm3, (1.57 +/- 0.31) cm3, (1.59 +/- 0.31) cm3 and (1.60 +/- 0.29) cm3, respectively. The average T/NT ratios of day 6 after radiotherapy and the other time points were significant (P < 0.05). The average death ratio of the tumor cells was (93.00 +/- 7.42)% after 6 days of post-radiotherapy. 18F-FDG PET-CT imaging can be used for the early assessment of radiotherapeutic effect of NPC in vivo. Day 6 after radiotherapy may be an appropriate time point for the imaging. However, the T/NT ratio measurement of delayed-phase imaging might make no sense for the diagnosis of NPC.

Activin Bioactivity Affects Germ Cell Differentiation in the Postnatal Mouse Testis In Vivo1

The transforming growth factor beta superfamily ligand activin A controls juvenile testis growth by stimulating Sertoli cell proliferation. Testicular levels are highest in the first postnatal week, when Sertoli cells are proliferating and spermatogonial stem cells first form. Levels decrease sharply as Sertoli cell proliferation ceases and spermatogenic differentiation begins. We hypothesized that changing activin levels also affect germ cell maturation. We detected an acute and developmentally regulated impact of activin on Kit mRNA in cocultures of Sertoli cells and germ cells from Day 8, but not Day 4, mice. Both stereological and flow cytometry analyses identified an elevated spermatogonium:Sertoli cell ratio in Day 7 testes from Inhba(BK/BK) mice, which have decreased bioactive activin, and the germ cell markers Sycp3, Dazl, and Ccnd3 were significantly elevated in Inhba(BK/BK) mice. The flow cytometry measurements demonstrated that surface KIT protein is significantly higher in Day 7 Inhba(BK/BK) germ cells than in wild-type littermates. By Day 14, the germ cell:Sertoli cell ratio did not differ between genotypes, but the transition of type A spermatogonia into spermatocytes was altered in Inhba(BK/BK) testes. We conclude that regulated activin signaling not only controls Sertoli cell proliferation, as previously described, but also influences the in vivo progression of germ cell maturation in the juvenile testis at the onset of spermatogenesis.

Predicting Poor Peripheral Blood Stem Cell Mobilization in Multiple Myeloma (MM) Using Initial Peripheral CD34 Counts: Developing Target-Based Cut-Points for Early Intervention.

Abstract 3231Poster Board III-168 BackgroundPeripheral blood stem cells (PBSC) are the preferred graft type for autologous stem cell transplantation (ASCT) and mobilization is typically done using growth factor (GF) alone or a combination of chemotherapy (CTX) and GF. The success of mobilization is influenced by several factors such as prior therapy and mobilization strategy. Patients (Pts) failing to mobilize successfully often have GF dose increased and if unsuccessful, mobilization reattempted with chemotherapy + GF or G-CSF (Granulocyte Colony-Stimulating Factor) + GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor). More recently, plerixafor, a CXCR4 inhibitor, has been found to enhance G-CSF based collection allowing potential early intervention in poor mobilizers. However, this approach requires valid cut-points for peripheral CD34 counts (pCD34) for cost efficient use. MethodsWe studied 910 first time, G-CSF based PBSC mobilizers with MM (565; 62%), or light chain amyloidosis (345; 38%). Salvage attempts were excluded, as were first attempts using CTX+GCSF, plerixafor or GF combinations. Sensitivity-specificity analysis (ROC) was used to define ideal cut-points for predefined outcomes. We used a CD34 yield of 2 million/kg as the minimum required collection and 4 million/kg as the ideal collection for this analysis. Our current practice is to initiate collection at a pCD34 of 10/uL. ResultsWe first determined the best day 1 pCD34 cutoff for being able to collect at least 2 million/kg PBSC to be 9.2/uL. Among those with ≥9.2/uL, only 1.6% failed to collect at least 2 million compared to 27% among the rest (P < 0.001). These numbers were 1.7% and 25% respectively using the traditional cutoff of 10/uL. We then examined how the pCD34 on day 2 predicted collection, among those failing to reach the current threshold of 10/uL. Among this group, a pCD34 on day 2 of 8/uL was the best cutoff to predict a collection of 2 million/kg. Among those with >8/uL, only 9% failed to collect at least 2 million compared to 48% among the rest (P < 0.001). Among those with day 1 pCD34 < 10, 65% achieved a count of 8/uL on day 2. We then examined what pCD34 on day 1 can best predict a pCD34 ≥ 8 on day 2 and found this to be 5/uL. Among those with day 1 pCD34 ≥ 5/uL, 92% reached day 2 pCD34 ≥ 8 compared to 36% among the rest (P < 0.001).We then determined cutoffs based on ideal targets using only those patients achieving pCD34 count > 10/uL by day 2, since these patients would have started collection without any change in the mobilization technique. We used a maximum of 5 collections to achieve the goal as being ideal, taking into account the most commonly used practice of collecting during weekdays. We examined cutoffs both for a target of 4, 8 and 12 million/kg for one, two or three transplants respectively. Among those with a day 1 or day 2 pCD34 > 10/uL 98% collected 4 million/kg in 5 collections. The best day 1 or day 2 pCD34 predicting a 8 million/kg yield in 5 collections was 21.4/uL and a 12 million/kg yield was 27.9/uL. Among those with day 1or 2 pCD34 ≥ 21.4/uL, 90% collected 8 million compared to 54% among those with pCD34 < 21.4/uL. Similarly, among those with day 1 or 2 pCD34 ≥ 27.9/uL, 79% reached 12 million in ≤ 5 days compared to 17% among those with pCD34 < 27.9/uL (P < 0.001).Finally we examined if poor collection on first day, despite a pCD34 > 10 predicts for poor overall yield. A ratio of day 1 collection (million/kg) to pCD34 day 1 or 2 < 5×104 was highly predictive of failure to get eventual yield of 2 million/kg, with 38% below the cutoff failing to reach the goal compared to 2% for those above the cutoff. ConclusionsThis study provides an estimate of optimal pCD34 count thresholds for early identification of patients at high risk of collection failure. It is reasonable to use the first or second day pCD34 count, since a substantial proportion of patients will achieve the threshold value by day 2 and have similar outcome as those reaching the threshold by day 1. Based on the results here, interventions such as plerixafor can be considered if pCD34 count is < 5/uL on day 1 or < 9/uL by day 2, to achieve the minimum collection of 2 million/kg. However, in order to achieve the ideal targets, a higher threshold should be considered and the recommendation would be 17/uL, and 28/uL for target of 8 or 12 million respectively. Finally, identification of poor mobilizers after start of collection potentially provides another time point for early intervention, and this needs to be prospectively studied. DisclosuresMicallef:Genzyme: Research Funding. Gertz:Genzyme: Research Funding. Kumar:Celgene,Genzyme,Millenium,Novartis,Bayer,: Honoraria, Research Funding.

Use of growth factors associated with docetaxel and paclitaxel in patients with early-stage breast cancer in a community oncology center

e17548 Background: Docetaxel and paclitaxel are widely used in treating breast cancer (BC), and both have hematologic toxicity commonly managed by costly growth factors (GFs). However, the extent of GFs use in real-world clinical practice has not been well documented. Methods: The Georgia Oncology Specialist Database was used and contained chemotherapy, medical and pharmacy claims, and lab results for nearly 170,000 patients with various types of cancer (2003–2008). Patients with stage I-III BC receiving docetaxel- or paclitaxel-containing regimens as adjuvant therapy were followed from 1 week prior to docetaxel or paclitaxel (index drug) initiation to the earliest of death, loss to follow-up, switch in taxane, or end of 90-day period post last dose of index drug. Incidence of GFs use per person-year was compared using univariate negative binomial (NB) model, median time to first GFs use was compared using Wilcoxon test. Multivariate analyses were performed on number of utilizations and time to first utilization adjusting for potential confounders. Results: Compared with paclitaxel (n = 433), docetaxel cohort (n = 216) had lower incidence per person-year of erythroid stimulating agents (ESAs) use (8.01 vs. 11.72, p = 0.008), while similar incidence of myeloid growth factors (MGFs) use (8.51 vs. 5.07, p = 0.541). Lower MGFs utilization in docetaxel patients (ratio of number of utilization = 0.821, p = 0.033), and similar ESAs utilization (ratio of number of utilization = 0.920, p = 0.305) were found. While descriptive analysis showed paclitaxel patients received first ESAs sooner than docetaxel patients (median length: 23 vs. 7 days, p &lt; 0.001), and no difference in time to first MGFs use (median 8 days for both); multivariate analyses found docetaxel patients received first MGFs sooner (ratio of days = 0.828, p = 0.039), and no difference in time to first ESAs use (ratio of days = 1.091, p = 0.419). Conclusions: This analysis suggests that docetaxel is associated with lower utilization of MGFs. Studies examining the economic impact of GFs use associated with taxanes will need to be conducted. A potential limitation of this study is that the potential selection bias may not be fully adjusted. [Table: see text]

Partitioning between aqueous and soil system components for soluble tungsten and lead species

The establishment of reliable sorptive Kd values for a given metal in a given soil is a critical preliminary step in the determination of metal mobility. The distribution coefficient, Kd, is partially based on assuming the contaminant is a single species, and equilibrium conditions are established between the solid and aqueous phases. However, metals such as tungsten (W) may exist as different chemical species, depending on the aqueous and solid phase chemical environment, and are shown to require an extended period of time for the system to approach equilibrium. Due to the more involved speciation characteristics associated with tungsten, the effect of extended equilibrium periods on W Kd values is examined in this study. The sorption characteristics of tungsten and lead in three natural silty sand (SM) soils are compared. Partition coefficients were obtained both at the traditional 24hour contact time (Kd) and then again after 100 days (Kd). The Kd values were for Pb representative of Kd values for the soils examined. However, in the case of W, dynamic sorptive behavior was observed. The ratios of Day 100 to Day 1 distribution coefficients were 19.6, 6.2, and 2.4 for tungsten in samples SM1, SM2, and SM3, respectively. This suggests that a longer equilibration time may provide a more accurate reflection of W mobility in subsurface environments when using the sorption Kd as a predictive tool.

CROSS-SPECIES HYBRIDIZATIONS TO SPOTTED MICROARRAYS AS A TOOL FOR FUNCTIONAL GENOMICS OF HORTICULTURAL PLANTS

ISHS XXVII International Horticultural Congress - IHC2006: International Symposium on Structural and Functional Genomics of Horticultural Plants CROSS-SPECIES HYBRIDIZATIONS TO SPOTTED MICROARRAYS AS A TOOL FOR FUNCTIONAL GENOMICS OF HORTICULTURAL PLANTS

An ARPS-CMAQ Modeling Approach for Assessing the Atmospheric Assimilative Capacity of the Beijing Metropolitan Region

A coupled ARPS–CMAQ modeling system was applied to investigate the atmospheric assimilative capacity (AAC) of PM10 in the Beijing metropolitan region of China. The AAC was defined as the maximum allowable pollutant emission that can be discharged to the atmosphere without violating the desired air quality objective in the planning region. The coupled modeling system was firstly evaluated through comparing the simulation results of PM10 concentration with the corresponding observations during four representative months in 2002, which showed an acceptable modeling performance. By using a trial-and-error approach, the validated modeling system was run through gradually reducing the emission strength within the modeling domain from a GIS-based pollutant emission database until a desired air quality objective was achieved. The air quality objective was characterized by the air quality guideline-satisfaction ratio (AQGSR) which was defined as the ratio of days when the daily PM10 concentrations are below the air quality standard during a certain time period. The PM10 emission within the modeling domain after such trial-and-error reduction under the condition of satisfying a certain AQGSR was considered its corresponding assimilative capacity. Accordingly, the atmospheric assimilative capacities of PM10 in the study region were identified corresponding to the AQGSR of 60, 65, 70, 75 and 80%, respectively. The relation between such capacity and guideline-satisfaction ratio was then established through regression analysis. The results could provide sound basis for decision makers in terms of effective air quality management by understanding the allowable pollutant discharge under different desired air quality objectives.

Self-reported data from patients with bipolar disorder: Frequency of brief depression

Objective Patients with bipolar disorder often report depressive symptoms that do not meet the DSM-IV criteria for an episode. Using daily self-reported mood ratings, we studied how changing the length requirement to that typical of recurrent brief depression (2–4 days) would impact the number of depressed episodes. Method 203 patients (135 bipolar I and 68 bipolar II by DSM-IV criteria) recorded mood daily using ChronoRecord software on a home computer (30,348 total days; mean 150 days). Episodes of depression and days of depression outside of episodes were determined. Symptom intensity (mild versus moderate or severe) was investigated within and outside of depressive episodes. Results Decreasing the minimum duration criterion for an episode of depression to 2 days increased the number of patients with a depressed episode two and a half times (52 to 131), and quadrupled both the number of depressed episodes per patient (0.62 to 2.88) and the number of depressed episodes for all patients (125 to 584). With a 2-day episode length, 34% of days of depression remained outside an episode. The ratio of days with severe symptoms within episodes remained consistent (about 25%) in spite of decreasing the episode length to 2 days. Considering only days with severe symptoms, about 25% remained outside of episodes even with a 2-day length. None of the results distinguished bipolar I from bipolar II disorder. Limitations Self-reported data, computer access required, relatively short study length, no control group. Conclusion Brief depressive episodes and single days of depression outside of episodes occur frequently in both bipolar I and bipolar II disorder. Moderate or severe symptoms occur during brief episodes at a ratio similar to that for episodes that meet the DSM-IV criteria.

Beneficial effects of dithiothreitol on relative levels of glutathione S‐transferase activity and thiols in oocytes, and cell number, DNA fragmentation and allocation at the blastocyst stage in the mouse

We analyzed the effect of in vitro aging of mouse oocytes in the presence of dithiothreitol (DTT) on relative levels of glutathione S-transferase (GST) activity and thiols in oocytes, and cell number, DNA fragmentation and cellular allocation to the inner cell mass (ICM) and trophectoderm (TE) lineage at the blastocyst stage. Ovulated oocytes from gonadotropin primed hybrid female mice of 6-8 weeks of age were aged in vitro in the presence of 0, 5, 50, or 500 microM DTT for 6 hr prior to insemination. Relative levels of GST activity and thiols in oocytes were determined by confocal laser scanning microscopy, DNA fragmentation using a single-step TUNEL method, and cell allocation to the ICM and TE lineage by blastocyst staining with propidium iodide and Hoechst 33258. Non-aged oocytes exhibited higher relative levels of GST activity and thiols when compared to oocytes aged in the presence of 0, 5, and 50 microM DTT. Day 5 blastocysts from the 5, 50, and 500 microM DTT groups exhibited higher total number of cells, number of ICM cells, and ICM/TE ratio, but lower percentage of number of nuclei with DNA fragmentation/number of ICM cells than blastocyst from the 0 microM DTT group. These data show that DTT counteracts the negative effects of a post-ovulatory aging of mouse oocytes in vitro on relative levels of GST activity and thiols in oocytes, and percentage of number of nuclei with DNA fragmentation/number of ICM cells, total number of cells, number of ICM cells and ICM/TE ratio in Day 5 blastocysts.

Pharmacokinetic study of paclitaxel and gefitinib in combination

13123 Background: Both gefitinib and paclitaxel are metabolized by CYP3A4, thus co-administration may result in a pharmacokinetic interaction (Miller V.A. et al. JCO 2003, 21:2094–2100). Paclitaxel is formulated in Cremophor EL (crEL), which also has the potential for pharmacokinetic interactions by either altering protein binding or inhibition of P-glycoprotein transporter systems (Gelderblom H. et al. EJC 2001, 37:1590–1598). Gefitinib is a high extraction ratio drug so changes in protein binding are not a concern, but inhibition of P-glycoprotein transporter systems could change gefitinib’s absorption profile. Methods: In a Phase II study, 17 patients (pts) with metastatic breast cancer received paclitaxel (100 mg/m2 on days 8, 15 q21) with gefitinib (250 mg daily, from day 1 to day 15). Blood samples were collected to measure plasma concentrations of gefitinib on days 7, 8, and 15 from six pts at pre-dose and at 3, 7 and 25 hours after gefitinib administration. The AUC at steady-state (AUCss) was calculated by the linear trapezoidal rule using WinNonlin and the minimum concentration at steady-state (Css, min) was taken directly from the data. Results: The effect of paclitaxel or crEL on the exposure to gefitinib was assessed by comparing the AUCss and Css,min on days 8 and 15 in the presence of paclitaxel to those on day 7 when gefitinib was alone. The geometric mean AUCss increased by 30 to 42% and Css,min by 28 to 58% in the presence of paclitaxel. Individual ratios of days 8 and 15 to day 7 also showed a trend to be greater than 1.0, further indicating an increase in exposure to gefitinib in the presence of paclitaxel. Conclusions: Steady state exposure to gefitinib increased by about 30 to 40% in the presence of paclitaxel. As the increase on day 15 was similar to that on day 8, the effect of paclitaxel appears to be transient, and would be unlikely to affect the safety profile of 250 mg gefitinib when in combination with paclitaxel compared to gefitinib monotherapy. [Table: see text]

A Rapid Mid-Luteal Decline in Estradiol Concentrations does not Predict Poor Outcome in Assisted Reproduction

Both Progesterone and Estradiol have been show to play essential roles in the preparation and maintenance of the endometrium. It has been proposed that abrupt reductions in luteal phase estradiol may predict poor reproductive outcome either as a result of impaired follicular function or perhaps as a cause of sub-optimal endometrial preparation. We intended to identify the significance of a decline in mid luteal estradiol during cycles of assisted reproduction Retrospective analysis of assisted reproduction outcomes in a large academic facility A retrospective analysis was undertaken of 1127 women undergoing assisted reproduction using the down regulation protocol between August 2002 and December 2004. The indications for IVF were tubal (n=397), male (n=268), anovulation (n=102), endometriosis (n=86), ovarian dysfunction (84), and mixed (n=190). ICSI (n=395) was performed for couples with severe semen abnormalities (less than 106 motile spermatozoa recovered after sperm preparation, Kruger Morphology <4%, Motility <40%, or history of prior poor fertilization). ICSI was also performed in cases of testicular sperm extraction from the epididymis or testes. Variables analyzed included ratio of estradiol and time of hcg administration to midluteal estradiol, pregnancy rate, implantation rate, number of embryos transferred. Statistical analysis was then performed using the statistical software Statview (Berkeley Systems, California). Continuous variables were assessed by Student’s t-test or Wilcoxon rank sum test if data did not appear normally distributed. Categorical variables were assessed by Chi-square test or two-tailed Fisher’s exact test in the case of small cell frequencies. Multiple logistic regression was used to assess potentially confounding variables. A p-value of 0.05 was considered statistically significant. In cycles of ART using human chorionic gonadotropin for luteal support, the 25th, 50th, 75th, and 95th percentile of the ratio of day of HCG to the mid luteal estrogen were, 1.9, 3.1, 5.0, and 10.0 respectively. Hormonal parameters were not different between pregnant and non-pregnant cycles. Irrespective of estradiol ratio, pregnancy rates were similar in all groups. TableComparison of estradiol ratio (day of hcg to mid-luteal) in patients undergoing assisted reproduction and controlled ovarian hyperstimulation with down regulation. No decline in pregnancy rate could be determined in the group patients demonstrating a rapid mid luteal estrogen decline. Adequate endometrial preparation, hCG triggering, and luteal support, appears to compensate for follicular apparatus exhaustion and negative effects on the endometrium that may result from rapid declines in luteal estradiol levels.

The Ratio of Day 2 and Day 7 Serum Concentrations of Inhibin B as a Predictor of the Outcome of In-Vitro Fertilization

Background: Inhibin B appears to change earlier than traditional predictors in ovarian aging. The pattern of inhibin B levels is highest in the early to midfollicular phases followed by a decrease in the late follicular phase. This implies that it is secreted by developing follicles and reflects follicular function and oocyte number.

Electronic pill-boxes in the evaluation of oral hypoglycemic agent compliance

To compare compliance in type 2 diabetic patients treated with glimepiride once daily or glibenclamide twice to three times daily. Poorly controlled type 2 diabetic patients aged 35-65 years were randomized to glimepiride 1 mg once daily or to glibenclamide 1.25 mg twice daily. During initial titration, doses ranged from 1 to 6 mg once daily (glimepiride) and from 1.25 mg twice daily to 5 mg 3 times daily (glibenclamide) to achieve fasting blood glucose < 126 mg/dL. The final titration phase doses were continued during the maintenance phase. Both treatments were packed in electronic pill-boxes fitted with a microprocessor to record dates and times of each opening. Compliance was assessed in terms of mean daily compliance (MDC) and the ratio of days with adequate compliance (DAC). Glycemic control was assessed in terms of the adjusted mean final HbA1c, and the incidence of hypoglycemia. Patient satisfaction was evaluated using the Diabetes Treatment Satisfaction Questionnaire. Compliance over the whole study was generally good, but the MDC was significantly better with glimepiride (87+/-16%) than with glibenclamide (80+/-17%;P < 0.0001). The ratios of DAC for glimepiride and glibenclamide were 87+/-16% and 67+/-24% respectively (P < 0.0001). The adjusted final HbA1c, and the incidence of hypoglycemia were similar in the two groups. Treatment satisfaction on the DTSQc was greater with glimepiride than with glibenclamide (P = 0.0034). Patient compliance and treatment satisfaction with once-daily glimepiride were significantly better than with glibenclamide 2 to 3 times daily.

Hypoxic control of the development of the surfactant system in the chicken: evidence for physiological heterokairy.

The surfactant system, a complex mixture of lipids and proteins, controls surface tension in the lung and is crucial for the first breath at birth, and thereafter. Heterokairy is defined as plasticity of a developmental process within an individual. Here, we provide experimental evidence for the concept of heterokairy, as hypoxia induces a change in the onset and rate of development of surfactant, probably via endogenous glucocorticoids, to produce individuals capable of surviving early hatching. Chicken eggs were incubated under normoxic (21% O(2)) conditions throughout or under hypoxic (17% O(2)) conditions from day 10 of incubation. Embryos were sampled at days 16, 18, and 20 and also 24 h after hatching. In a second experiment, dexamethasone (Dex), tri-iodothyronine (T(3)), or a combination (Dex + T(3)) was administered 24 and 48 h before each time point. Both hypoxia and Dex accelerated maturation of the surfactant lipids by increasing total phospholipid (PL), disaturated phospholipid (DSP), and cholesterol (Chol) in lavage at days 16 and 18. Maturation of surfactant lipid composition was accelerated, with day 16 %DSP/PL, Chol/DSP, and Chol/PL resembling the ratios of day 20 control animals. The effect of Dex + T(3) was similar to that of Dex alone. Hypoxia increased plasma corticosterone levels at day 16, while plasma T(3) levels were not affected. Hence, exposure to hypoxia during critical developmental windows accelerates surfactant maturation, probably by increasing corticosterone production. This internal modulation of the developmental response to an external stimulus is a demonstration of physiological heterokairy.

Corrigendum for Zador and Wuytack

CORRIGENDACorrigendum for Zador and WuytackPublished Online:01 Dec 2003https://doi.org/10.1152/ajpcell.00431.2003Original articleMoreSectionsPDF (77 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat Volume 285, October 2003 Volume 54, October 2003 Pages C853-C861: Zador E and Wuytack F. “Expression of SERCA2a is independent of innervation in regenerating soleus muscle.” On , right column, line 8, the sentence describing restriction enzymes used in the PCR cycles was in error and should read “The fragment of SERCA1 was cut by NcoI, which left SERCA2 intact, whereas MseI, which did not cut SERCA1, digested the fragment of SERCA2.” Accordingly, on , Fig. 2 and its legend should appear as shown below. (See http://ajpcell.physiology.org/cgi/content/full/285/3/C652) Fig. 2.A: mRNA levels of SERCA (a) and MyHCI (b) isoforms. B: ratio of SERCA2 and SERCA1 mRNAs and levels of SERCA1 mRNA in denervated and innervated regenerating soleus. Values are means ± SE, n = 3. Significant (*P < 0.05), very significant (**P < 0.01), and highly significant changes (***P < 0.001) during regeneration are indicated. In A, significant (°P < 0.05) and very significant differences (°°P < 0.01), and in B, significant +P < 0.05) and highly significant differences (+++P < 0.001), between innervated and denervated regenerated samples are indicated. Innerv. reg., innervated regenerating muscle; denerv. reg., denervated regenerating muscle. Note that MseI hydrolizes SERCA2 and NcoI hydrolizes SERCA1 fragment amplified by ratio RT PCR. Inset: 1 representative gel of 3 repeated experiments. In B, the column representing SERCA2/SERCA1 ratio in day 7 denervated regenerated muscle is 102 times higher than the scale of the ordinate; this is indicated in the column.Download figureDownload PowerPoint This article has no references to display. Download PDF Previous Back to Top FiguresReferencesRelatedInformationRelated ArticlesExpression of SERCA2a is independent of innervation in regenerating soleus muscle 01 Oct 2003American Journal of Physiology-Cell Physiology More from this issue > Volume 285Issue 6December 2003Pages C1562-C1562 Copyright & PermissionsCopyright © 2003 the American Physiological Societyhttps://doi.org/10.1152/ajpcell.00431.2003History Published online 1 December 2003 Published in print 1 December 2003 Metrics

Reduction in nocturnal functional bladder capacity is a common factor in the pathogenesis of refractory nocturnal enuresis.

To evaluate the diurnal and nocturnal bladder reservoir function in patients with refractory primary nocturnal enuresis (PNE). Ninety-five children (68 boys, 27 girls, mean age 9.3 years) with significant PNE (>/=3 wet nights/week) that was refractory to treatment with desmopressin +/- an enuretic alarm were assessed using detailed recording of voiding frequency and urinary volume both day and night, natural filling cystometry during the day and continuous cystometry with simultaneous electroencephalogram monitoring during sleep at night. Patients could be broadly categorized into two groups. Group A comprised those with normal daytime urodynamics and functional bladder capacity (FBC) on detailed frequency-volume recording, but who developed marked detrusor instability associated with a significant reduction in nocturnal FBC and small-volume voiding only after sleep at night (33 patients, 35%); and group B, those with abnormal daytime urodynamics and with reduced FBC and small-volume voiding both day and night, but who somehow managed to mask their bladder symptoms during the day (62 patients, 65%). There was no evidence of nocturnal polyuria in either group and the ratios of day : night urinary output volumes for type A and type B patients were 1.48 and 1.99, respectively. A reduction in nocturnal FBC, either occurring only after sleep at night in association with the appearance of detrusor instability in patients with normal daytime urodynamics and FBC, or as a manifestation of occult voiding dysfunction or bladder outlet obstruction that affects the bladder reservoir function both day and night, appears to be a common factor and probably the main cause for a mismatch between nocturnal urine output and bladder storage capacity in patients with severe bed-wetting that was refractory to treatment.

A 'Real-World' Analysis of Persistence on and Adherence to Glipizide GITS, Glipizide IR and Glibenclamide in Managed Care among Patients with Type 2 Diabetes Mellitus.

This study compared persistence on and adherence to therapy with glipizide gastrointestinal therapeutic system (GITS), glipizide immediate release (IR) and glibenclamide (glyburide) in commercially insured patients newly treated for type 2 diabetes mellitus. The objective of the study was to determine if there were differences in persistence and adherence between the three second-generation sulphonylureas. This was a retrospective longitudinal claims data analysis for commercial enrollees in eight independent practice model health plans. Study subjects were 25 years of age or older with a first prescription for a study drug from 1 January 1996 through 31 December 1999. All subjects were newly treated with medication for diabetes mellitus, and were initiated on monotherapy. To be included in the study, subjects had to be continuously enrolled in their health plan 6 months prior to their index claim and at least 30 days following the index claim. Persistence was defined as the total days from the index prescription fill date until termination, switch or augmentation of therapy. Adherence was defined as the ratio of days supplied to total days in the treatment period. The treatment period for the measurement of adherence was defined as the period from index prescription fill date to run-out of days supplied of the last filled prescription for the index drug. Cox proportional hazards analysis was used to compare differences in persistence, and multivariate regression was used to assess differences in adherence. Of the 24 311 subjects, 35% filled a first prescription for glipizide GITS, 15% for glipizide IR, and 50% for glibenclamide. Over one-half of study subjects were male, and the average age was between 51 years for the glipizide GITS cohort and 53 years for the glibenclamide cohort. By the end of the study, 79% of subjects had terminated therapy with their index drug. Cox proportional hazards analysis showed that patients taking glipizide IR were 1.33 times more likely to experience treatment change [95% confidence interval (CI) 1.25 to 1.42], and patients taking glibenclamide were 1.16 times more likely to change therapy (95% CI 1.11 to 1.22) compared with patients taking glipizide GITS in the first 90 days following initiation of therapy. Similar results were found upon subsequent analysis in the 1620 days following the index prescription. The analysis of adherence showed that patients taking glipizide IR or glibenclamide were less adherent to therapy compared with patients taking glipizide GITS (p < 0.001). Glipizide GITS appears to have an advantage in persistence on and adherence to therapy compared with glipizide IR and glibenclamide. These differences may be related to administration frequency. Lack of persistence and adherence has potential clinical and economic consequences.

Microhabitat use, giving‐up densities and temporal activity as short‐ and long‐term anti‐predator behaviors in common voles

We used depletable food patches to determine the effect of microhabitat (mowed versus unmowed adjacent grasslands) and time (day versus night) on the foraging behavior of common voles (Microtus arvalis). The food remaining after 12‐h periods (giving‐up density, GUD) measured the vole's habitat selection under predation risk. In accord with several other rodent species and the effects of avian predators, voles had significantly lower GUDs in the unmowed than mowed portion of the grassland. GUDs in patches along the border between adjacent habitats were more similar to the risky mowed grassland than the safe unmowed grass. Time interacted strongly with microhabitat. In the mowed grass, voles had significantly higher GUDs at night than day. Whereas in the unmowed grass, GUDs were significantly higher during the day than night. Vole GUDs did not vary with time along the boundary. This suggests that predators are more abundant or effective in the mowed grass at night (owls?), and in the unmowed grass during the day (weasels?). In terms of predation risk, the voles perceived the mowed grass at night as the riskiest and the unmowed grass at night as the safest. Voles may have difficulties assessing resources under high predation risk: GUDs among patches were well equalized in the unmowed microhabitat whereas in the mowed grass only day GUDs did not vary significantly among patches. We linked these results to the vole's day‐night‐activity and life span. For the 533 voles live‐trapped at the study area, the ratio of day versus night captures for each individual served as an activity index and the span between first and last capture measured minimum life span. In accord with higher GUDs at night, very few individuals behaved selectively towards the night, but individual life expectancy increased with temporal opportunism. Microhabitat differences in GUDs reflect short‐term strategies of predator avoidance and the trapping data reflect long‐term patterns of anti‐predator behavior.