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Venlafaxine and clonidine are equally, but moderately effective in HF reduction. Side effects are the main reason for drug discontinuation, occurring more often with venlafaxine.

SummaryWe conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m -2 day -1 to 20 mg m -2 day -1 in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m -2 . Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m -2 dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.Keywords: fostriecin; topoisomerase II; phase I; pharmacokinetics 882British Journal of Cancer (1999) 79(5/6), 882-887 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received prior chemo-, immuno-or radiotherapy for at least 4 weeks before study entry; white blood cell (WBC) count ≥ 4000 µl -1 and platelet count ≥ 100 000 µl -1 ; bilirubin ≤ 25 µmol l -1 and aspartate-amino transferase (AST) and alanine-amino transferase (ALT) within 2.5 times the normal upper limit; normal prothrombin time (PT); creatinine clearance ≥ 60 ml min -1 . Written informed consent was obtained from all patients. The protocol was approved by the Medical Ethical Committee of the University Hospital Groningen.Fostriecin was supplied by NCI (Bethesda, MD, USA) as a lyophilized powder and was diluted with 0.9% NaCl to 50 or 100 ml. It was administered as a 60-min intravenous (IV) infusion through an UV-light protected system on days 1-5 at 4-week intervals. The dose was initially escalated according to the Fibonacci scheme, with subsequent dose steps of 2, 4, 6.6, 10 and 12.2 mg m -2 day -1 and thereafter increased to 20 mg m -2 (the protocol was amended during the study to allow more rapid dose escalation). Three patients were entered at each dose level, with a maximum of three additional patients when one out of three experienced dose-limiting toxicity (DLT). When no DLT was observed, ...