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A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours.
He, X, Li, S, Huang, H, Li, Z, Chen, L, Ye, S, Huang, J, Zhan, J, Lin, T
British journal of clinical pharmacology. 2011;(6):860-70
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Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Three pharmacokinetic and safety studies for combretastatin A4 phosphate (CA4P), the first vascular disrupting agent, have been conducted in Western countries. • The maximum tolerated dose (MTD) was approximately 60-68 mg m(-2). • CA4P-related grade 3 or 4 adverse events were tumour pain, dyspnoea, hypoxia and syncope in patients who received doses ≥ 50 mg m(-2). WHAT THIS STUDY ADDS • This is the first pharmacokinetic and safety study conducted in East Asian patients. • There appeared to be a trend that Chinese patients metabolized CA4 more rapidly and had greater neurotoxicity than patients in Western countries. • We observed favourable clinical responses in patients with refractory nasopharyngeal carcinoma. • CA4P-induced acute renal failure was seen in one dehydrated Chinese patient. AIMS This trial was conducted to evaluate the safety and pharmacokinetics of combretastatin A4 phosphate (CA4P) given intravenously as a single dose to Chinese patients with refractory solid tumours. METHODS Twenty-five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85 mg m(-2) infused intravenously over 30 min. RESULTS CA4P was generally well tolerated at ≤ 65 mg m(-2). Transient, moderate increases in the heart rate-corrected QT interval occurred at all doses. CA4P produced a transient dose-dependent increase in neural and gastrointestinal toxicities. Acute renal failure occurred in one dehydrated patient who had also taken paracetamol. There were seven episodes of dose-limiting toxicity at doses ≥65 mg m(-2), including two episodes of reversible ataxia at 85 mg m(-2).For CA4, at 50 mg m(-2),mean (SD) peak plasma concentration (C(max) was 0.99 (0.33) mM, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) mM h and terminal elimination half-life (t(1/2)was 1.81 (0.61) h. At 65 mg m-2,C(max) was 1.73 (0.62) mM,AUC(0,t) was 3.19 (1.47) mM h and t (1/2) was 1.90 (0.61) h [corrected]One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass. CONCLUSION Doses ≤ 65 mg m(-2) given as 30 min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50-65 mg m(-2) have been selected for further studies.
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Mediating factors in dietary change: understanding the impact of a worksite nutrition intervention.
Kristal, AR, Glanz, K, Tilley, BC, Li, S
Health education & behavior : the official publication of the Society for Public Health Education. 2000;(1):112-25
Abstract
This report, based on 1,795 participants in the Next Step Trial, examines how a dietary intervention program affected mediating factors for dietary change. The model tested whether intervention increased predisposing (skills, knowledge, and beliefs) and enabling (social support and norms) factors for change and advanced participants into action and maintenance stages of change. The intervention significantly increased both predisposing factors for dietary change and the likelihood of moving into or remaining in action and maintenance stages of change. Changes in predisposing and enabling factors and stage of change at follow-up (regardless of stage at baseline) were associated with significant dietary change. Changes in mediating variables explained between 34% and 55% of the effects of the dietary intervention. These results support the value of measuring mediating factors as part of dietary intervention evaluations and suggest that interventions that target norms and eating environments in addition to skills and knowledge may further increase intervention effectiveness.