The hepatic parenchyma-specific contrast by Sonazoid is due to distribution of the microbubbles in Kupffer cells.

The liver contrast effects of Sonazoid in two ultrasonographic imaging modes, gray-scale conventional and harmonic, were examined as a time-related study in normal rabbits, and evaluated quantitatively and visually with tumor-model rabbits to estimate the diagnostic potential. Peak enhancement of vessels and parenchyma was observed 1 min after injection in both modes, although signal enhancement in the parenchyma lasted for 120 min compared with rapid decay (5-10 min) in vessels. When Sonazoid was intravenously injected into metastatic carcinoma-model (VX-2) rabbits, all hepatic tumors showed ring enhancement in the early phase followed by clear contrast defects in the delayed phase, because signal enhancement remained only in normal parenchyma. Visual analysis scores for the diagnosis of tumors were improved by Sonazoid injection, and the videodensitometric differences between tumor and normal tissues were significantly greater after injection. Although the harmonic mode tended to show better contrast effects, the conventional mode provided significant contrast enhancement in this hepatic tumor-model. Sonazoid might be useful for the detection of undifferentiated tumors in the liver by making it possible to visualize neovascularity in the early phase and clear contrast defects in the delayed phase, not only in the harmonic but also in the conventional mode.

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Ultrasonography (US) is useful for diagnosis of hepatic focal lesions, which is based on their distinctive echogenicities; the gray-scale morphologic features. To improve diagnostic ability of detection and characterization of tumors, contrast imaging has been used in diagnostic imaging, e.g. X-ray computed tomography (CT) or magnetic resonance imaging (MRI), but has not yet been popular in US since contrast agents for US are not at clinical satisfaction level. Intravenous US contrast agents available for clinical use or the agents under development are basically microbubbles whose size is comparable to or less than red blood cells. First-generation agent consisted of air-microbubbles, Levovist (SH U 508A; Schering, Berlin, Germany), is commercially available in many countries, 1-6) but short imaging duration and weak contrast effect due to instability of the microbubbles could provide only limited diagnostic information.1,2) In order to improve the contrast effects, second-generation agents that use less soluble gases for microbubbles are being developed and now clinically available in limited western countries.1,6-9) Viewpoint from US imaging machine, to detect microbubbles more sensitively, harmonic imaging technology has been developed to visualize the harmonic echo from the microbubbles: backscatter signal (echo) from the microbubbles contains more harmonic component than that from tissues. 1)One of the second-generation agents, Sonazoid (previously NC100100, Amersham Health, Oslo, Norway) 7,10) has been reported to enhance perfusion of the myocardium and other organs. 7,[11][12][13][14] In the previous study, 15) we have characterized contrast enhancement of Sonazoid on the liver of metastatic carcinoma-model (VX-2) in rabbits, 16,17) and demonstrated promising contrast effect on the detection and delineation of liver tumors. This is due to uniqueness of Sonazoid whose microbubbles are likely to be taken up by Kupffer cells (liver macrophages) in the healthy liver and enhances contrast of the liver parenchyma during the delayed phase, which usually occurs within 10 min after the injection. In contrast, tumor that lacks Kupffer cells was not enhanced resulting in clear negative contrast of the tumor.In the previous study, comparison of the tumor contrast with histopathology of the tumors could not be examined in detail, since resolution of US images that had been acquired using the harmonic imaging technique was not enough to compare with microscopic images. To improve resolution and signal-to-noise ratio of this harmonic technique, phase inversion imaging (PII) technique was then developed and now become available in the commercial US machine. 6,18,19) PII can detect harmonic echoes from the microbubble contrast agent with greater sensitivity and without the loss of spatial resolution often seen in the harmonic imaging.Localization of the microbubbles in the liver Kupffer cells has been demonstrated in rat by using transmission electron microscopy (TEM). 20) However, the liver contrast effect in rats, such...

After intravenous bolus injection of rac-carvedilol at 2 mg/kg to the rat, the (+)-(R)- and (-)-(S)-enantiomer levels in the blood and tissues (liver, kidney, heart, muscle, spleen, and aorta) were measured by stereospecific HPLC assay. As compared with the (+)-(R), the (-)-(S) had a larger Vdss (3.32 vs. 2.21 liter/kg), MRT (33.4 vs. 25.6 min), and CLtot (96.1 vs. 83.8 ml/min/kg). AUC comparison after iv and po administration showed systemic bioavailability of the (-)-(S) to be about half that of its antipode, explained by the fact that the free fraction of the (-)-(S) in blood was 1.65-fold greater than that of the (+)-(R). Tissue-to-blood partition coefficient values for the (-)-(S) were 1.6- to 2.1-fold greater than those for the (+)-(R) in all tissues, showing that the (-)-(S) accumulates more extensively in the tissues. These results were consistent with the greater Vdss for the (-)-(S) estimated from systemic blood data. The stereoselective tissue distribution of carvedilol enantiomers results from an enantiomeric difference in plasma protein binding rather than in tissue binding.

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The potential of newly formulated fluorescent-labeled liposomes for the intravital staining of Kupffer cells was evaluated in rats. Fluorescently labeled phosphatidylcholine (PC) was incorporated into liposomes consisting of PC and phosphatidylserine. After intravenous injection, Kupffer cells in the rat liver were intravitally stained and were clearly delineated under the fluorescence image of both confocal laser scanning microscopy and in vivo microscopy. Specificity of the staining was confirmed by immunohistochemistry using the anti-rat macrophage antibody Ki-M2R, which suggested that the liposomes were selectively entrapped by the hepatic reticuloendothelial system. A time-course study revealed that the suitable observation window was between 16 and 24 h after the injection. Phagocytic activity of Kupffer cells after the administration of liposomes was examined by measuring the amount of hepatic uptake of intravenously administered fluorescent microspheres; no detrimental influence of the liposomes on the phagocytic activity was observed. Additionally, no histopathologic changes were found in the livers from liposome-treated rats. Therefore, the fluorescent-labeled liposomes appear to be a useful research tool for labeling Kupffer cells for in vivo microscopic observation of the liver.

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