Background-Apolipoprotein B (apoB) is an important structural component of low-density lipoprotein cholesterol (LDL-C) and plays a key role in LDL-C transport and removal. Reduction in apoB synthesis is expected to reduce circulating LDL-C, a proven risk factor of cardiovascular disease. In the present study, we describe the outcome of the first-in-humans study on the safety and efficacy of an antisense oligonucleotide inhibitor of apoB. Methods and Results-This study was a double-blind, randomized, placebo-controlled, dose-escalation investigation conducted at a single site in 36 volunteers with mild dyslipidemia. The study utilized an initial single dose of 50 to 400 mg of ISIS 301012, a 20-mer oligonucleotide, followed by a 4-week multiple-dosing regimen with the same assigned dose. Safety was assessed by the incidence, severity, and relationship of adverse events to dose. Efficacy was determined by changes in serum apoB and LDL-C relative to baseline and placebo. The most common adverse event was erythema at the injection site (21 of 29 subjects). ApoB was reduced by a maximum of 50% (Pϭ0.002) from baseline in the 200-mg cohort. This decrease in apoB coincided with a maximum 35% reduction of LDL-C (Pϭ0.001). LDL-C and apoB remained significantly below baseline (PϽ0.05) up to 3 months after the last dose. Conclusions-Administration of an antisense oligonucleotide to human apoB resulted in a significant, prolonged, and dose-dependent reduction in apoB and LDL-C. Although injection-site reactions were common, adherence to protocol was unaffected.

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The objective of this study was to evaluate the potential role of B-type natriuretic peptide (BNP) levels in children with congenital heart disease undergoing cardiac catheterization. Measurement of plasma BNP concentration has been shown to be useful in the diagnosis, risk stratification, and management of adult patients with congestive heart failure, but little is known about the role of BNP in children with structural congenital heart disease. We measured plasma BNP levels using the Triage BNP test in patients with congenital heart disease referred for diagnostic or interventional cardiac catheterization. Plasma BNP concentration was measured in 96 children and 11 adults > or = 19 years old (7.9+/-8.3 years) undergoing heart catheterization for underlying congenital heart disease. BNP levels ranged from < 5 to > 1300 pg/ml, with a median BNP concentration of 19.0 pg/ml. Baseline BNP concentrations were > 100.0 pg/ml on 19 occasions in 17 patients. The pressure difference between the left ventricle and ascending aorta was 10-110 mmHg in 21 patients. BNP concentrations for this cohort ranged from < 5.0 to 1060.0 pg/ml and correlated with the degree of left ventricular outflow obstruction (correlation coefficient, 0.661; p = 0.001). This study suggests that with additional research, BNP concentration may prove to be a useful clinical tool in managing children and adults with congenital heart disease.

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These data provide evidence that ISIS 113715 exhibits no clinically relevant pharmacokinetic interactions on the disposition and clearance of the oral antidiabetic drugs. The results of these studies support further study of ISIS 113715 in combination with antidiabetic compounds.

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A high-concentration 90% w/v perflubron (perfluorooctyl bromide [PFOB]) emulsion (Oxygent HT) is being evaluated as an oxygen carrier for use during surgery. This study was done to assess oxygen delivery by Oxygent HT during acute normovolemic hemodilution. Anesthetized mongrel dogs, instrumented with femoral and pulmonary artery catheters, were hemodiluted to a hematocrit of 25% with 3:1 (v/v) of Ringers-lactate (R-L). Dogs were then ventilated with 100% O2 and hemodiluted to a Hct approximately 11% with 1.5 (v/v) of colloid (autologous plasma and 5% albumin). Dogs then received either 3.3 mL/kg Oxygent HT (n = 5) or 3.3 mL/kg R-L (n = 4), and were monitored for 3 hours. Total oxygen delivery (DO2), blood oxygen content, cardiac output, mixed venous PO2, and mixed venous Hb saturation was higher in Oxygent HT treated dogs compared to the R-L controls. The percentage of total DO2 contributed by perflubron-dissolved oxygen was about 8-10% and accounted for 25-30% of total oxygen consumption (VO2). The percentage of VO2 contributed by Hb-carried oxygen was significantly higher in R-L controls (46 +/- 4%) than in the treated dogs (15 +/- 3%), indicating that the availability of the perflubron-dissolved oxygen allowed for a reserve of oxygen to remain available in the red blood cells.

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