No abstract

OPTISON, an agent being developed as an intravenous (IV) ultrasound contrast agent, consists of a suspension of octa¯uoro-propane (OFP)-containing albumin microspheres.The distribution and elimination of the albumin component and the elimination kinetics of the OFP component of OPTISON (FS069) were studied in the conscious rat and anesthetized canine models, respectively.Radioiodinated OPTISON at 0.25 ml /kg (average dose 5.4 £ 10 7 DPM/rat) and nonradioactive OPTISON, at dosages of 0.3, 0.6, and 1.0 ml/kg, was administered intravenously to conscious rats or to sodium pentobarbital± anesthetized and ventilated canines, respectively. A separate group of rats was housed in metabolism cages for 24 hours to capture excreted radioactivity. The tissue distribution data for the radiolabeled albumin in rats showed that the 125 I activity recovered in the liver was the highest of all the tissues at each timepoint (peak liver radioactivity at 5 minutes with 50.4% of the dose), suggesting that the major route of uptake and metabolism of the radiolabeled albumin shell and its fragments occurred in the liver. The 125 I activity was excreted in the urine, where most of the recovered radioactivity (58.3%) was found at the end of 24 hours. In the anesthetized canine study, simultaneous venous blood samples and exhaled air samples plus additional exhaled air samples were analyzed by gas chromatography. OFP was rapidly exhaled through the lungs after an IV injection such that a maximum of less than 10% of the total dose appeared in the venous blood samples. Statistical moment analysis showed rapid OFP elimination with mean residence times of 46, 41, and 38 seconds for the three dosages, and mean total recoveries for the exhaled OFP were 111%, 100.5%, and 121.6%, respectively. OFP was rapidly exhaled through the lungs after OPTISON injection with short mean residence times from statistical moment analysis. Exhaled OFP displayed one-compartment model kinetics with a measurable distribution phase in the blood using classical pharmacokinetic modeling. The albumin component appeared to be cleared primarily by the liver and radioactivity was excreted in the urine.

The current study was designed to provide a sensitive in vivo model to maximize the potential bioeffects (measured by hemolysis) of B-mode ultrasound energy in combination with FS069 (Optison). B-mode ultrasound energy was delivered to anesthetized male New Zealand white rabbits with a phased array 5 MHz transducer on a Hewlett-Packard Sonos 1500 ultrasonograph, with transmit level set to maximum (40 dB, approx 135 W/cm2). FS069 (Optison), latex particles in human albumin, or human albumin alone (vehicle) was infused via an ear vein at 0.6 mL/kg. No statistically significant changes were noted in serum free hemoglobin or lactate dehydrogenase either over time or between groups.

The purpose of this study was to assess the utility of an intravenous contrast agent (FS069) for visualization of normal visceral perfusion compared with perfusion after segmental infarction in a canine model. Six mongrel dogs were used as subjects. Splenic, renal, hepatic, and small bowel perfusion was assessed without and with intravenous microbubble contrast material using gray scale, color Doppler, pulsed Doppler, and color power Doppler sonography. Each organ was then reassessed after ligation of a segmental vessel. Imaging was again performed without and with contrast material using all four ultrasonographic modalities. In all organs color and spectral Doppler signals were significantly enhanced from normally perfused tissue after intravenous contrast agent injection. Ischemic areas were more conspicuous after contrast medium injection except in the liver. Hepatic perfusion was maintained by portal flow in the liver despite arterial ligation. Ligation of collateral arcades was required to produce bowel ischemia. Intravenous injection of FS069 improves evaluation of visceral perfusion and identification of focal visceral ischemia in dogs. These results suggest that this agent may increase sensitivity for detection of blood flow in small and deep vessels.

The toxicity of methyl mercury (mHg) in the developing chick embryo was investigated. The relationship of dose, time of administration (i.e., days 4-9 of development), and body levels of mercury was examined. The LD50 for mHg injected into the yolk sac on day 5 of incubation was 40-50 micrograms. Embryos dying within 24 hours showed increased total body mHg levels when compared to survivors (219 +/- 67 vs. 105 +/- 41 micrograms/gm, mean +/- SD). Absorption was dose-related, with a good correlation between mortality and body, blood, and brain levels. Daily analysis of body mHg levels after injection on day 5 showed continued mHg accumulation (0.88 +/- 0.35 micrograms/embryo/day). However, the rate of embryo growth exceeded the rate of mHg absorption, resulting in a progressive decrease in mHg in concentration in tissues (from 94.5 +/- 34.2 micrograms/gm on day 6 to 45.3 +/- 13.4 on day 9). Administration after day 5 resulted in a significant reduction in levels of mHg in the brain on day 18 (from 11.4 +/- 2.1 micrograms/gm when given on day 5 to 8.4 +/- 2.3 when given on day 9) and in mortality (from 64% to 33%). Because blood mHg levels remained unchanged, the increased brain levels and higher mortality early in embryogenesis may reflect facilitated transfer of mHg across a poorly developed blood-brain barrier. Later in development, the reduced mortality and lower brain mHg levels correspond to the formation of specialized interendothelial junctions and a more effective blood-brain barrier.