Phase I study of sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors.

PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the observed toxicities is unclear and is the subject of further preclinical research. Alternative clinical dosing strategies are being evaluated.

Large-Scale Postmarketing Surveillance of Hypertensive Patients Treated with Verapamil.

BACKGROUND: In general clinical practice, physicians prescribe calcium channel blockers to a wide range of patients with differing demographic characteristics and hypertension history. This study was undertaken to investigate the effectiveness and safety of sustained-release verapamil (Verelan((R)), verapamil HCl) in patients with essential hypertension, studied under "usual use" conditions. METHODS: In this prospective, open-label, postmarketing surveillance study, 25 089 patients with hypertension received once-daily verapamil therapy for 4 weeks, during which they were evaluated by 8106 physicians at baseline and at two follow-up visits (weeks 2 and 4). In this study, hypertension was defined as an average sitting diastolic blood pressure (DBP) of greater-than-or-equal 90 mm Hg at baseline. Previously diagnosed hypertensive patients with a sitting DBP <90 mm Hg but experiencing untoward effects requiring discontinuation of current antihypertensive therapy were also included. RESULTS: Eighty-five percent (n = 21 446) of the total patients enrolled at baseline completed this office-based trial. Nearly 24% of patients were newly diagnosed hypertensives. At baseline, the mean systolic blood pressure (SBP) and diastolic blood pressure were 161 and 96 mm Hg, respectively. In evaluable patients with mild, moderate, and severe hypertension, as stratified by baseline measurements, treatment with verapamil produced DBP reductions of 12, 19, and 29 mm Hg, respectively. Verapamil treatment produced clinically similar SBP, DBP, and HR (heart rate) reductions across gender and racial groups studied (white, black, Hispanic, and Asian). Only 6.1% of patients failed to complete the study because of any reported adverse experiences (4.5% of patients discontinued because of adverse experiences considered drug related). Constipation (5.0%) and headache (1.1%) were the most commonly reported adverse events. CONCLUSION: In general clinical practice, verapamil is well tolerated and effective in a broad range of hypertensive patients.