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J Stephenson

Publications and source records attributed to J Stephenson.

At least 163 records · Page 9Linked to original sources
PubMed1998

Flu on ice.

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Alaska↗
PubMed1998

Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP.

PURPOSE: To evaluate the feasibility of administering biricodar (VX-710; Incel, Vertex Pharmaceuticals Inc, Cambridge, MA), an agent that modulates multidrug resistance (MDR) conferred by overexpression of both the multidrug resistance gene product (MDR1) P-glycoprotein and the MDR-associated protein (MRP) in vitro, in combination with paclitaxel. The study also sought to determine the maximum-tolerated dose (MTD) of paclitaxel that could be administered with biologically relevant concentrations of VX-710 and characterize the toxicologic and pharmacologic profiles of the VX-710/ paclitaxel regimen. PATIENTS AND METHODS: Patients with solid malignancies were initially treated with VX-710 as a 24-hour infusion at doses that ranged from 10 to 120 mg/m2 per hour. After a 2-day washout period, patients were re-treated with VX-710 on an identical dose schedule followed 8 hours later by paclitaxel as a 3-hour infusion at doses that ranged from 20 to 80 mg/m2. The pharmacokinetics of both VX-710 and paclitaxel were studied during treatment with VX-710 alone and VX-710 and paclitaxel. Thereafter, patients received VX-710 and paclitaxel every 3 weeks. RESULTS: VX-710 alone produced minimal toxicity. The toxicologic profile of the VX-710/paclitaxel regimen was similar to that reported with paclitaxel alone; neutropenia that was noncumulative was the principal dose-limiting toxicity (DLT). The MTD levels of VX-710/ paclitaxel were 120 mg/m2 per hour and 60 mg/m2, respectively, in heavily pretreated patients and 120/60 to 80 mg/m2 per hour in less heavily pretreated patients. At these dose levels, VX-710 steady-state plasma concentrations (Css) ranged from 2.68 to 4.89 microg/mL, which exceeded optimal VX-710 concentrations required for MDR reversal in vitro. The pharmacokinetics of VX-710 were dose independent and not influenced by paclitaxel. In contrast, VX-710 reduced paclitaxel clearance. At the two highest dose levels, which consisted of VX-710 120 mg/m2 per hour and paclitaxel 60 and 80 mg/m2, pertinent pharacokinetic determinants of paclitaxel effect were similar to those achieved with paclitaxel as a 3-hour infusion at doses of 135 and 175 mg/m2, respectively. CONCLUSION: VX-710 alone is associated with minimal toxicity. In combination with paclitaxel, biologically relevant VX-710 plasma concentrations are achieved and sustained for 24 hours, which simulates optimal pharmacologic conditions required for MDR reversal in vitro. The acceptable toxicity profile of the VX-710/ paclitaxel combination and the demonstration that optimal pharmacologic conditions for MDR reversal are achievable support a rationale for further trials of VX710/paclitaxel in patients with malignancies that are associated with de novo or acquired resistance to paclitaxel caused by overexpression of MDR1 and/or MRP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Comparison of two methods of screening for genital chlamydial infection in women attending in general practice: cross sectional survey.

OBJECTIVES: To estimate the prevalence of Chlamydia trachomatis in asymptomatic women attending general practice: to assess the potential of the ligase chain reaction as a screening tool; and to evaluate selective screening criteria. DESIGN: Cross sectional survey. SETTING: Four general practices in northeast London. SUBJECTS: 890 women aged 18-35 years attending general practice for a cervical smear or a "young well woman" check between October 1994 and January 1996. The women were tested for C trachomatis with confirmed enzyme immunoassay (endocervical specimens) and ligase chain reaction assay on urine specimens. MAIN OUTCOME MEASURES: Prevalence of C trachomatis infection in women aged 18-35 on the basis of each test; sensitivity and specificity of both tests in this population. RESULTS: Prevalence of confirmed infection was 2.6% (95% confidence interval 1.6% to 3.6%) in all women. Prevalence on the basis of enzyme immunoassay was 1.6% (0.8% to 2.7%), with a sensitivity of 60% and a specificity of 100%. Prevalence on the basis of ligase chain reaction was 2.5% (1.5% to 3.9%), with 90% sensitivity and 99.8% specificity. Screening all women aged < or = 25 and all women who had had two or more partners in the past year would have detected 87% (20/23) of infections. CONCLUSION: Ligase chain reaction on urine samples performs at least as well as enzyme immunoassay on cervical specimens in this low prevalence population. It offers potential as a non-invasive screening tool. A simple selective screening strategy might be appropriate and would be able to detect most cases of infection. However, a rigorous economic evaluation of possible screening strategies is needed first.

Adult↗