Towards a biochemical approach to occupational stress management.

Given the immense and growing cost of occupational stress to society through lost productivity and the burden to healthcare systems, current best practices for detecting, managing and reducing stress in the workplace are clearly sub-optimal and substantially better methods are required. Subjective, self-reported psychology and psychiatry-based instruments are prone to biases whereas current objective, biology-based measures produce conflicting results and are far from reliable. A multivariate approach to occupational stress research is required that reflects the broad, coordinated, physiological response to demands placed on the body by exposure to diverse occupational stressors. A literature review was conducted to determine the extent of application of the emerging multivariate technology of metabolomics to occupational stress research. Of 170 articles meeting the search criteria, three were identified that specifically studied occupational stressors using metabolomics. A further ten studies were not specifically occupational or were of indirect or peripheral relevance. The occupational studies, although limited in number highlight the technological challenges associated with the application of metabolomics to investigate occupational stress. They also demonstrate the utility to evaluate stress more comprehensively than univariate biomarker studies. The potential of this multivariate approach to enhance our understanding of occupational stress has yet to be established. This will require more studies with broader analytical coverage of the metabolome, longitudinal sampling, combination with experience sampling methods and comparison with psychometric models of occupational stress. Progress will likely involve combining multi-omic data into a holistic, systems biology approach to detecting, managing and reducing occupational stress and optimizing workplace performance.

A phase I dose-escalation study of SR271425, an intravenously dosed thioxanthone analog, administered weekly in patients with refractory solid tumors.

OBJECTIVES: The thioxanthone analog, SR271425, is a novel cytotoxic DNA-interacting agent with broad antitumor activity in preclinical models. The objectives of this phase I study were to determine the dose-limiting toxicities, maximum tolerated dose, recommended phase II dose, pharmacokinetic profile, and trend for efficacy in patients with advanced cancer. METHODS: SR271425 was administered intravenously over 1-hour, weekly for 2 weeks, followed by 1 week rest. Because of Cmax-related corrected QT (QTc) prolongation in preclinical testing of SR271425, all patients underwent an extensive pretreatment cardiac assessment. RESULTS: Eighteen patients received SR271425 at 5 dose levels ranging from 64 to 675 mg/m/wk. No dose-limiting toxicities were identified. In all tested dose-levels, Grade 3 adverse events were observed in 10/18 patients (55.6%) and Grade 4 in 4/18 patients (22.2%). QTc prolongation was reported at the 3 highest dose levels but did not exceed Grade 2. Six deaths occurred during the study, 5 of them because of disease progression and 1 because of disease related bowel perforation. SR271425 exposure increased in a near dose-proportional manner. The mean terminal plasma half-life of SR271425 was 6 hours and there was no drug accumulation after repeated dosing. Stable disease was the best outcome observed (5 patients). CONCLUSIONS: SR271425 was administered safely at doses up to 675 mg/m/wk on a 2-week on, 1-week off schedule. No dose-limiting toxicities were observed. Grade 2 QTc prolongation was observed at the highest dose levels. Maximum tolerated dose was not reached because of early termination of the SR271425 program by the sponsor.

Phase I dose-escalation study of the thioxanthone SR271425 administered intravenously once every 3 weeks in patients with advanced malignancies.

This study was performed to determine the dose limiting toxicity (DLT), the recommended phase II dose and the pharmacokinetic profile for SR271425, given over 1 h every 3 weeks. The initial starting dose of SR271425 was 17 mg/m(2). Patient selection was based on common phase I criteria as well as additional cardiac criteria. Thirty-eight patients were accrued to 16 dose levels from 17 to 1,320 mg/m(2). Patient characteristics included 24 males and 14 females ages 35-78 with an Eastern Cooperative Oncology Group performance status of 0 (ten patients), 1 (27) and 2 (1). Tumor types were typical for a phase I study. The maximum administered dose was 1,320 mg/m(2) with two DLTs, both QTc grade 3 prolongation. No drug related hematological toxicity was noted. Grade 1 toxicities included rash, flushing, pruritus, weight loss, diarrhea, hypertension and fatigue. Grade 2 toxicities included yellow discoloration of the skin, nausea and vomiting. QTc prolongation and hyperbilirubinemia were the only grade 3 toxicities noted. No confirmed tumor response was observed; however, two patients had prolonged stable disease. Both C(end) and area under the plasma concentration-time curve increased in a dose related manner. Plasma drug concentrations declined in a biphasic manner with a mean terminal elimination half-life (t (1/2)) of 7.1 h (+/-1.3). There was no change in clearance or volume of distribution over the dose range studied. Due to cardiac toxicity occurring with both the parent compound, SR233377, as well as this analog, this series of agents was abandoned from further clinical development.