Citations

In this study, we compared gains in student content learning over a 10-yr period in which the introductory biology laboratory curriculum was changed in two ways: an increase of inquiry and a reduction of content. Three laboratory formats were tested: traditional 1-wk-long cookbook laboratories, two 7-wk-long inquiry laboratories, and one 14-wk-long inquiry laboratory. As the level of inquiry increased, student learning gains on content exams trended upward even while traditional content coverage taught decreased. In a quantitative assessment of content knowledge, students who participated in the 14-wk-long inquiry laboratory format outscored their peers in both 7- and 1-wk-long lab formats on Medical College Admissions Test exam questions (scores of 64.73%, 61.97%, and 53.48%, respectively, P < 0.01). In a qualitative study of student opinions, surveys conducted at the end of semesters where traditional 1-wk laboratories ( n = 167 students) were used had low response rates and predominately negative opinions (only 20% of responses were positive), whereas those who participated in 7-wk ( n = 543) or 14-wk ( n = 308) inquiry laboratories had high response rates and 71% and 96% positive reviews, respectively. In an assessment of traditional content coverage in courses, three indexes were averaged to calculate traditional forms of coverage and showed a decrease by 44% over the study period. We believe that the quantitative and qualitative data support greater student-driven inquiry in the classroom laboratory, which leads to deeper learning in fewer topic areas (less teaching) and can reap gains in scientific thinking and fundamental understanding applicable to a broader range of topic areas (more learning) in introductory biology.

Abstract Purpose: Incorporation of cytarabine into DNA activates checkpoint kinase 1 (Chk1), which stabilizes stalled replication forks, induces S-phase slowing, and diminishes cytarabine cytotoxicity. The selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell lines and leukemic blasts in vitro. To extend these findings to the clinical setting, we have conducted a phase I study of cytarabine and SCH 900776. Experimental Design: Twenty-four adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 g/m2 over 72 hours (667 mg/m2/24 hours) beginning on day 1 and again on day 10. SCH 900776 was administered as a 15- to 30-minute infusion on days 2, 3, 11, and 12. The starting dose of SCH 900776 was 10 mg/m2/dose. Results: Dose-limiting toxicities consisting of corrected QT interval prolongation and grade 3 palmar-plantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m2). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m2 or higher. SCH 900776 did not accumulate at any dose level. Marrow blasts obtained pretreatment and during therapy showed increased phosphorylation of H2Ax after SCH 900776 beginning at 40 mg/m2, consistent with unrepaired DNA damage. Conclusions: These data support a randomized phase II trial of cytarabine +/− SCH 900776 at a recommended flat dose of 100 mg (equivalent to 56 mg/m2) for adults with poor-risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT00907517. Clin Cancer Res; 18(24); 6723–31. ©2012 AACR.

ABSTRACT IDX184 is a liver-targeted prodrug of 2′-methylguanosine (2′-MeG) monophosphate. This study investigated the safety, tolerability, antiviral activity, and pharmacokinetics of IDX184 as a single agent in treatment-naïve patients with genotype-1 chronic hepatitis C virus (HCV) infection. Forty-one patients with baseline HCV RNA ≥ 5 log 10 IU/ml, alanine aminotransferase (ALT) ≤ 2.5× the upper limit of normal, and compensated liver disease were dosed. Sequential cohorts of 10 patients, randomized 8:2 (active:placebo), received 25, 50, 75, and 100 mg of IDX184 once daily for 3 days, with a 14-day follow-up. There were no safety-related treatment discontinuations or serious adverse events. The adverse events and laboratory abnormalities observed for IDX184- and placebo-treated patients were similar. At the end of the 3-day treatment period, changes from baseline in HCV RNA levels (means ± standard deviations) were −0.5 ± 0.6, −0.7 ± 0.2, −0.6 ± 0.3, and −0.7 ± 0.5 log 10 for the 25-, 50-, 75-, and 100-mg doses, respectively, while viral load remained unchanged for the pooled placebo patients (−0.05 ± 0.3 log 10 ). Patients with genotype-1a and patients with genotype-1b responded similarly. Serum ALT levels decreased, especially at daily doses ≥ 75 mg. During the posttreatment period, plasma viremia and serum aminotransferase levels returned to near pretreatment levels. No resistance mutations associated with IDX184 were detected. Plasma exposure of IDX184 and its nucleoside metabolite 2′-MeG was dose related and low. Changes in plasma viral load correlated with plasma exposure of 2′-MeG. In conclusion, the results from this proof-of-concept study show that small doses of the liver-targeted prodrug IDX184 were able to deliver significant antiviral activity and support further clinical evaluation of the drug candidate.

ABSTRACT The vancomycin dose necessary for the achievement of target serum trough concentrations during continuous venovenous hemofiltration (CVVH) remains to be elucidated. This was a retrospective cohort study of critically ill adults at a tertiary medical center on concurrent CVVH and vancomycin between 2006 and 2010 with a steady-state vancomycin trough concentration. The 87 included patients were grouped according to low (≤30 ml/kg/h; n = 10) or high (>30 ml/kg/h; n = 77) CVVH hemofiltration rate (HFR) for analysis. Vancomycin goal trough achievement occurred in only 32 (37%) patients. The primary endpoint of trough attainment significantly differed between HFR subgroups: 90% versus 30% in low- and high-HFR individuals, respectively ( P < 0.001). Patients with subtherapeutic trough concentrations had a median (interquartile range) HFR of 40 ml/kg/h (range, 37 to 47 ml/kg/h) compared to 36 ml/kg/h (range, 30 to 39 ml/kg/h) in those who achieved the trough goal. Irrespective of goal trough, an inverse correlation existed between HFR and serum vancomycin concentration ( r = −0.423; P < 0.001). In the subgroup of 14 methicillin-resistant Staphylococcus aureus (MRSA) patients, trough achievement was similar to the aggregate cohort (36%). Mortality at 28 days was unrelated to trough achievement in both the overall sample ( P = 0.516) and in culture-positive MRSA patients ( P = 0.396). Critically ill patients undergoing CVVH therapy may experience clinically significant reductions in goal vancomycin troughs. The results of the present study justify prospective evaluations in this population to determine the optimal vancomycin dosing strategy for attainment of goal trough concentrations.

SummaryBackgroundThe optimal methadone dosing regimen for children undergoing spinal surgery is uncertain because of sparse pediatric pharmacokinetic data and a paucity of analgesic effect data. The minimum effective analgesic concentration of methadone in opioid naïve adults is 58 mcg·L−1.MethodsAdolescents aged 12–19 years undergoing idiopathic scoliosis correction were administered 0.25 mg·kg−1 racemic methadone IV prior to surgical incision. Arterial blood samples for methadone assay were obtained at 0 min, 5 min, 10 min, 15 min, 20 min, 40 min, 1 h, 2 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h. Compartment analysis was undertaken using nonlinear mixed effects models. Parameter estimates were standardized to a 70‐kg person using allometric models.ResultsA three‐compartment linear disposition model best described observed time–concentration profiles. Population parameter estimates (between‐subjects variability) were central volume (V1) 19.1 (126%) L 70 kg−1, peripheral volumes of distribution V2 65.5 (60%) L 70 kg−1, V3 485 (23%) L 70 kg−1, clearance (CL) 9.3 (11%) L·h−1·70 kg−1, and inter‐compartment clearances Q2 282 (95%) L·h−1 70 kg−1, Q3 139 (42%) L·h−1 70 kg−1. The terminal elimination half‐life was 44.4 h. The mean observed methadone concentration was <58 mcg·L−1 by the first hour after administration.ConclusionsCurrent pharmacokinetic parameter estimates in adolescents are similar to those reported in adults. Methadone undergoes rapid redistribution after bolus administration. This may result in plasma concentrations that provide inadequate analgesia postoperatively. We would suggest following the bolus (0.25 mg.kg‐1) with an infusion (0.1–0.15 mg·kg−1·h−1 for 4 h) during spinal surgery to ensure adequate plasma concentrations for 24 h.