Cardiovascular effects caused by rapid administration of gadoversetamide injection in anesthetized dogs.

RATIONALE AND OBJECTIVES: This study assessed the cardiovascular effects of gadoversetamide and other gadolinium chelates administered at high rates of injection. METHODS: Anesthetized beagles were instrumented to record the electrocardiogram and to measure arterial blood pressure. In part 1, each animal was injected with gadoversetamide at rates of 1.0, 3.0, and 10 mL/s. In part 2, each animal was injected with gadoversetamide, gadopentetate dimeglumine, gadodiamide, and gadoteridol at a dose of 0.6 mmol/kg delivered at a rate of 3.0 mL/s. RESULTS: Intravenous administration of gadoversetamide caused transient decreases in both heart rate and blood pressure. The rate of injection did not affect the magnitude of the heart rate or blood pressure changes. Administration of gadoversetamide, gadopentetate dimeglumine, and gadodiamide elicited equivalent changes in cardiovascular function. Injection of gadoteridol caused a similar degree of hypotension, but the changes lasted longer. CONCLUSIONS: Rapid administration of gadoversetamide caused no potentiation in cardiovascular changes. Our data support the initiation of a clinical trial to demonstrate the safety of rapidly administering gadoversetamide with the use of a power injector.

Direct video-microscopic observation of the dynamic effects of medical ultrasound on ultrasound contrast microspheres.

RATIONALE AND OBJECTIVES: Ultrasound can cause destruction of microbubble contrast agents used to enhance medical ultrasound imaging. This study sought to characterize the dynamics of this interaction by direct visual observation of microbubbles during insonification in vitro by a medical ultrasound imaging system. METHODS: Video microscopy was used to observe air-filled sonicated albumin microspheres adsorbed to a solid support during insonation. RESULTS: Deflation was not observed at lowest transmit power settings. At higher intensities, gas left the microparticle gradually, apparently dissolving into the surrounding medium. Deflation was slower for higher microsphere surface densities. Intermittent ultrasound imaging (0.5 Hz refresh rate) caused slower deflation than continuous imaging (33 Hz). CONCLUSIONS: Higher concentrations of microbubbles, lower ultrasound transmit power settings, and intermittent imaging each can reduce the rate of destruction of microspheres resulting from medical ultrasound insonation.

Toxicological assessment of gadoversetamide injection (OptiMARK), a new contrast-enhancement agent for use in magnetic resonance imaging.

RATIONALE AND OBJECTIVES: A series of preclinical tests were undertaken during the developmental process to determine the safety profile of gadoversetamide injection (OptiMARK). METHODS: Acute intravenous, acute intracisternal, and repeated-dose toxicities; cardiovascular effects; and genetic and reproductive toxicology characteristics were assessed in several animal species. RESULTS: Gadoversetamide injection demonstrated an acute intravenous median lethal dose of 25 to 28 mmol/kg and a maximum nonlethal dose of 14 mmol/kg in mice. In the dog, acute administration of gadoversetamide injection showed a no observable effect level at 3 mmol/kg. Dosed daily for 4 weeks, gadoversetamide injection (0.1 mmol x kg(-1) x d(-1)) caused no serious irreversible changes in any organs in rats and dogs. At a dose of 0.1 mmol/kg, gadoversetamide injection caused no significant (P < 0.05) changes in cardiovascular function in anesthetized dogs. Gadoversetamide injection showed no mutagenic activity. Fertility, reproductive performance, and postnatal fetal development were not affected at doses up to 0.5 mmol x kg(-1) x d(-1) in the rat. No teratogenicity was observed at doses up to 4.2 mmol x kg(-1) x d(-1) in the rat and up to 1.6 mmol x kg(-1) x d(-1) in the rabbit. CONCLUSIONS: Data from our toxicological assessment demonstrate the safety of gadoversetamide injection in a number of animal species at doses exceeding the intended human clinical dose.

Inhaled gases affect the ultrasound contrast produced by Albunex in anesthetized dogs.

In anesthetized animals maintained with isoflurane using 100% oxygen as a carrier gas, Albunex (Molecular Biosystems, Inc., San Diego, Calif.) produced no ultrasound contrast in the left ventricle after intravenous administration. The current study tested the hypothesis that the inhalation of gas mixtures with increased concentrations of oxygen decreased the quality and duration of Albunex-induced contrast. Albunex (0.22 mL/kg) was injected intravenously into anesthetized dogs (n = 9) breathing compressed air, oxygen, mixtures of oxygen and nitrogen, or combinations of oxygen and nitrous oxide. Albunex produced ultrasound contrast of shorter duration and decreased quality during the inhalation of gas mixtures containing increased amounts of oxygen. In the presence of inhaled gas mixtures containing nitrous oxide, Albunex produced no contrast in the left ventricle, regardless of the oxygen content. These data indicate that the inhalation of gas mixtures containing smaller amounts of nitrogen, compared with air, decreased the ability of Albunex to cause ultrasound contrast in the heart after intravenous administration.

Neurotoxicity of non-ionic X-ray contrast media after intracisternal administration in rats.

The neurotoxicity of an X-ray contrast medium appears inversely related to the hydrophilicity of the agent. To further test this hypothesis, four non-ionic X-ray contrast agents, differing in hydrophilicity, (ioversol, iopromide, iohexol and iopamidol) were injected into the cisternal magna of ether-anesthetized rats. Iopromide demonstrated an acute median lethal dose of 122 mg I/kg. Other signs of toxicity included convulsions, apnea, dyspnea and hypoactivity. In contrast, ioversol, iohexol and iopamidol caused no deaths when administered intracisternally, up to a dose of 1000 mg I/kg. Animals treated with these nonionic agents displayed signs of convulsions, apnea, dyspnea, chewing and hypoactivity. Iopromide possesses a hydrophilicity (e.g., water to octanol partition coefficient) approximately 8.5 times smaller than ioversol, 4.6 times smaller than iohexol and 2.3 times smaller than iopamidol. These data support the hypothesis that tri-iodinated X-ray contrast materials with smaller degrees of hydrophilicity produce greater toxicity to the central nervous system.

Effects of transducer frequency and output power on the ultrasonographic contrast produced by Optison using fundamental and harmonic imaging techniques.

This in vivo study demonstrated the effects of transducer frequency and output power on the sonographic contrast produced by Optison during continuous ultrasonographic imaging in both fundamental and harmonic modes. During fundamental imaging, Optison produced greater contrast intensity while imaging at higher transducer frequencies. However, in the harmonic mode, lower imaging frequencies caused Optison to produce more intense myocardial enhancement. Regardless of imaging mode, increases in transducer output power caused decreases in both contrast intensity and contrast duration produced by Optison. Proper selection of transducer frequency and output power will help optimize the quality and duration of contrast produced by Optison during continuous ultrasonographic imaging.

Targeting and ultrasound imaging of microbubble-based contrast agents.

Preparation and characterization of targeted microbubbles (ultrasound contrast agents) is described. Specific ligands were attached to the microbubble shell, and ligand-coated microbubbles were selectively attached to various targets, using either an avidin biotin model system or an antigen-antibody system for targeting to live activated endothelial cells. Firm attachment of microbubbles to the target was achieved. Forces necessary to detach microbubbles from the target were estimated to exceed dozens of pN. Microbubbles were bound to the target even in the rapidly moving stream of the aqueous medium. Down to 20 ng of the ultrasound contrast material on the target surface could be detected by the ultrasound imaging with a commercial medical imaging system. At high bubble density on the target surface, strong ultrasound image attenuation was observed.