Imaging efficacy of a hepatocyte-selective polyiodinated triglyceride for contrast-enhanced computed tomography.

RATIONALE AND OBJECTIVES: DHOG-LE is an injectable polyiodinated triglyceride lipid emulsion providing contrast enhancement of the liver in CT. Studies were conducted to characterize the imaging efficacy of various DHOG-LE formulations as a function of both the administered iodine dose and the formulation composition. MATERIALS AND METHODS: Four DHOG-LE preparations consisting of either 10, 20, 25, or 30% (w/v) total lipid were administered to anesthetized female Sprague Dawley rats as single intravenous bolus doses of 50, 100, 150, and/or 300 mg I/kg (n = 3 to 6 rats/formulation and dose). A 25% triolein lipid emulsion prepared without iodine was administered as a vehicle control at the highest dose volume (n = 6). Liver enhancement was evaluated as a function of time (0 to 24 hours) after administration of contrast by analyzing regions of interest from sequential body scans. RESULTS: At all dose levels, liver enhancement was observed after injection of each DHOG-LE formulation. Regardless of formulation composition, similar enhancement of the liver was noted when administered at an equivalent iodine dose. Liver enhancement increased proportionately with increasing iodine dose. Mean peak intensities for 50, 100, 150, and 300 mg I/kg doses were 78 HU (42% above baseline), 101 HU (84% above baseline), 125 HU (127% above baseline), and 195 HU (255% above baseline), respectively. Liver time-intensity profiles exhibited rapid uptake, prolonged enhancement up to 3 hours, and complete clearance of the majority of the formulations tested by 24 hours. Time and duration of peak intensities were also directly related to iodine dose. CONCLUSIONS: In the animal model tested, DHOG-LE imaging efficacy was directly related to iodine dose and was independent of formulation composition. Thus, administration of DHOG-LE in highly concentrated lipid preparations minimized administered dose volume and resulted in appreciable liver enhancement, even at the lowest dose of 50 mg I/kg.

In vitro, animal, and human characterization of OPTISON infusions for myocardial contrast echocardiography.

UNLABELLED: Traditionally, performing myocardial contrast echocardiography with OPTISON required maximal bolus dosing. However, sustained and consistent opacification of the myocardium would be preferable for perfusion imaging. METHODS: Images of 5 anesthetized dogs and 6 human volunteers were obtained with a second harmonic ultrasound system during bolus administration of OPTISON and 2 infusion techniques. One infusion technique used diluted OPTISON, and the other used the buoyant properties of OPTISON microspheres by placing the contrast agent between an infusion source and the intravenous site in a vertically oriented extension line (ELT). Myocardial intensities and in vitro microsphere characteristics were analyzed to assess the consistency of microsphere delivery over time. RESULTS: In addition to providing higher myocardial opacification intensity than diluted infusions, ELT infusions provided consistent microsphere concentration, phantom enhancement, and near-peak bolus-level myocardial opacification for 7 to 15 minutes. The myocardial intensity at 3 and 5 minutes in human subjects during ELT infusions (30 mL/h; 2.5 mL) was lower (220 arbitrary units [au] and 165 au, respectively) but not significantly different (P =.3 and.1, respectively) than the peak myocardial intensity (265 au) after bolus administration. CONCLUSION: This new ELT infusion method provides an acceptable alternative to bolus administration of OPTISON for prolonged myocardial opacification.

Induction of cytochrome P-450 enzymes after repeated exposure to 4-vinylcyclohexene in B6C3F1 mice.

4-Vinylcyclohexene (VCH), an ovarian toxicant in mice, is known to irreversibly deplete ovarian follicles as a consequence of VCH diepoxide formation. Because ovotoxicity requires repeated dosing of VCH, the effect of consecutive daily doses of VCH (7.5 mmol/kg/day) on mouse liver microsomal activities and VCH epoxidation was determined. Cytochromes P-450 2B and 2A (CYP2B and CYP2A), principle isoforms involved in the bioactivation of VCH, as well as CYP2E1 and CYP3A were evaluated. VCH exposure increased total cytochrome P-450 content (35-83% above control levels) after either 5, 10, or 15 days of treatment. Western blot analysis revealed an induction of CYP2A, CYP2B, and CYP2E1 at day 10. Elevated levels of CYP2A and CYP2B correlated with marker androstenedione and testosterone 16alpha- and 16beta-hydroxylase activities. Microsomes prepared from mice pretreated with VCH for 10 days demonstrated an increase (>/=2-fold) in the rate of VCH monoepoxide and diepoxide formation. Microsomal VCH epoxidation was increased to a similar extent by phenobarbital, acetone, and dexamethasone treatment. An increase in cytosolic glutathione S-transferase activity was observed after repeated VCH treatment, an enzyme potentially involved in detoxification of the VCH epoxides. Interestingly, preliminary studies indicated that circulating levels of the monoepoxide (vinylcyclohexene 1, 2-monoepoxide) and diepoxide of VCH were elevated after repeated dosing of VCH. Overall, the results indicate that repeated exposure of VCH in mice induces cytochrome P-450-dependent activities, and in turn induction of its metabolism. Additional studies examining the toxicokinetics of VCH after repeated exposure are required to further delineate the relevance of induction in VCH-induced ovotoxicity.