OBJECTIVES:: The purpose of this study was to determine the pharmacokinetics (PKs), imaging properties, and safety of the liver-specific magnetic resonance (MR) imaging contrast agent gadoxetic acid disodium (Gd-EOB-DTPA) in subjects with various levels of hepatic impairment, renal impairment, or coexisting hepatic and renal impairment. MATERIALS AND METHODS:: In this single-center, open-label, parallel-group study, patients with varying degrees of renal and/or hepatic impairment were compared with healthy subjects matched for age, gender, and weight (control group). All subjects received a single intravenous bolus of Gd-EOB-DTPA (Primovist, Eovist, EOB-Primovist) 25 μmol/kg body weight. Samples of serum, urine, and feces were collected for PK analysis. MR imaging was performed before dosing and at preset times after dose administration to determine enhancement relative to predose signal intensity values. Safety was assessed by monitoring adverse events, laboratory values, vital signs, cardiac rhythm, oxygen saturation, and by physical examination findings. RESULTS:: Gd-EOB-DTPA was well tolerated by all subjects. Total clearance of Gd-EOB-DTPA did not significantly change in patients with mild and moderate hepatic impairment (Child-Pugh A and B), compared with the control group. Mean urinary excretion was increased and mean fecal excretion was decreased in patients with hepatic impairment. Renal excretion was increased to between 72% and 96% of the dose administered in patients with very high bilirubin levels (>3 mg/dL), compared with 48% in the control group. Total clearance of Gd-EOB-DTPA was significantly reduced to 140 ± 45 mL/min and terminal elimination half-life (t1/2) was slightly, but not significantly, increased to 2.6 ± 0.9 hours in patients with severe hepatic impairment (Child-Pugh C), compared with the control group (209 ± 37 mL/min and 1.8 ± 0.2 hours, respectively). Liver MR signal enhancement (area under the curve of relative enhancement [%] over time) was similar in patients with mild and moderate hepatic impairment and in those in the control group, but was decreased by 38% in patients with severe hepatic impairment, compared with control. Peak liver enhancement, however, was still at a high level (118% ± 57%). PK and imaging parameters were not significantly affected in patients with moderate renal impairment (creatinine clearance, 30-50 mL/min). In patients with end-stage renal failure (ESRF), however, the PK profile of Gd-EOB-DTPA was significantly different, with an increased t1/2 (20.0 ± 7.0 hours vs. 1.8 ± 0.2 hours in the control group). During a 3-hour dialysis session that started 1 hour after administration of the intravenous dose, the serum levels in patients with ESRF declined by between 71% and 88% as a result of elimination by hemodialysis and parallel hepatobiliary excretion. This is comparable with the decline observed in healthy subjects (85%) during the 1- to 4-hour interval after injection. CONCLUSIONS:: The results of the present study show that in humans with moderate renal impairment and mild-to-moderate hepatic impairment, no relevant changes in PK parameters, such as total clearance and t1/2, develop as a result of increased renal excretion to compensate in the case of hepatic impairment (or increased hepatic elimination in the case of renal impairment). The t1/2 of Gd-EOB-DTPA was markedly altered only in patients with ESRF. The high MR signal enhancement profile, observed even in patients with severe hepatic impairment, indicates that there is no need to adjust the dose of Gd-EOB-DTPA.

Dieser Artikel führt in die Grundzüge der Integrativen Arbeit (Petzold 2002a,b/2003a; Schuch 2001) mit Suchtkranken ein. Er wird einen Überblick über einen Arbeitsansatz geben, der seit Anfang der 70er Jahre im Feld der deutschsprachigen Drogen/Alkoholtherapie- und -beratung weit verbreitet ist und sich seit nunmehr 30 Jahren weiterentwickelt hat. Dies muß punktuell und exemplarisch erfolgen, da eine umfassende Darstellung des mittlerweile umfangreichen Werkes von Hilarion Petzold und der KollegInnen, die an der Entwicklung und Konzeptualisierung des Verfahrens mitgearbeitet haben, diesen Rahmen hier sonst bei weitem überschreiten würde.

Objectives: We sought to compare the intravascular enhancement of an ultrasmall superparamagnetic iron oxide (USP10) blood-pool contrast agent to gadopentetate dimeglumine for contrast-enhanced magnetic resonance angiography (CE-MRA) at field strengths of 1.5 and 3.0 T in rabbits.Materials and Methods: CE-MRA at 1.5 and 3.0 T was performed at several time points (50 seconds and 5, 10, 20, and 30 minutes) after the manual intravenous injection of 40 mu mol Fe/kg body weight of an USPIO (SH U 555 C; Schering AG, Berlin, Germany) and 100 mu mol/kg body weight gadopentetate dimeglumine (Magnevist; Schering AG, Berlin, Germany). MRA was performed with comparable acquisition parameters at both field strengths (Turbo-gradient sequence; 1.5 T: TR/TE/alpha: 5.5/1.7 milliseconds/40 degrees; 3.0 T: TR/TE/a: 5.1/1.8 milliseconds/40 degrees) on clinical imaging systems (both: Gyroscan Intera, Philips Medical Systems, Best, The Netherlands). At either field strength, 6 rabbits were studied with both contrast agents (n = 24 in total). Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated from signal intensity measurements in the abdominal aorta.Results: Compared with 1.5 T, the SNR and CNR of gadopentetate dimeglumine significantly increased at 3.0 T by a factor of 2.2 and 2.3, respectively (P <= 0.01), measured 50 seconds after intravenous injection. SNR and CNR of SH U 555 C, measured 50 seconds after intravenous injection, did not change significantly with increasing field strength (P >= 0.05). At both field strength and either time point, CNR and SNR of SH U 555 C were significantly higher compared with gadopentetate dimeglumine at 3.0 T (P <= 0.01).Conclusions: SNR and CNR of gadopentetate dimeglumine significantly increased with increasing field strength. No SNR or CNR gain was observed for SH U 555 C. However, blood-pool MRA with SH U 555 C is feasible at 3.0 T. Compared with gadopentetate dimeglumine, SNR and CNR of SH U 555 C were significantly higher from 5 to 30 minutes at both field strengths (P <= 0.01).

Purpose: To compare Bis-Gd-mesoporphyrin (Bis-Gd-MP), a contrast agent with a reported. high affinity to necrotic tissue, with high-dose gadopentate dimeglumin (Gd-DTPA) for defining laser-induced muscle and liver necrosis by contrast-enhanced (CE) MRI.Materials and Methods: Laser-induced interstitial thermotherapy (LITT) was performed. in the muscle and liver tissue of New Zealand White rabbits (1500 J and 2100 J; n = 80 lesions). The animals were randomly assigned to a group that received 0.3 mmol/kg bw Gd-DTPA or a group that received 0.05 mmol/kg bw Bis-Gd-MP. Following contrast injection, dynamic MRI was performed on muscle lesions with a T1-weighted, two-dimensional, fast low-angle shot (FLASH) sequence. The liver and muscle lesions were then repeatedly imaged for six hours after contrast injection using a T1-weighted spin-echo (SE) sequence. Central and peripheral lesion enhancement was determined and correlated with gross pathology, and microscopy findings.Results: Both contrast agents allowed precise determination of lesion diameters with an average accuracy of 6.8% +/- 1.3%. Rim enhancement during dynamic MRI was superior for Gd-DTPA (P < 0.001) and revealed slightly higher lesion diameters compared to the results of follow-up MR studies. A persistent enhancement of necrotic liver and muscle tissue was observed for both contrast agents throughout the observation period, suggesting that simple diffusion-type processes may underlie the supposed affinity of Bis-Gd-MP for tissue necrosis.Conclusion:, Bis-Gd-MP and Gd-DTPA are equally well suited for postinterventional lesion assessment in LITT. (c) 2005 Wiley-Liss, Inc.

Two 3,5-disubstituted sulfonamide catechol ligands were synthesized. Tris(ligand) iron(III) complexes were prepared and investigated as MRI contrast agents. Longitudinal relaxivity (r1) values were determined for the complexes. The r1 values in water were substantially higher than those of typical six-coordinate iron(III) complexes. The r1 values in plasma under the same conditions increased. The iron(III) complexes were administered to rats, and the kidney and liver signal intensities were measured by T1-weighted MR imaging experiments.

PURPOSE:To evaluate the effect of lipofection, particle size, and surface coating on labeling efficiency of mammalian cells with superparamagnetic iron oxides (SPIOs). MATERIALS AND METHODS:Institutional Review Board approval was not required. Different human cell lines (lung and breast cancer, fibrosarcoma, leukocytes) were tagged by using carboxydextran-coated SPIOs of various hydrodynamic diameters (17-65 nm) and a dextran-coated iron oxide (150 nm). Cells were incubated with increasing concentrations of iron (0.01-1.00 mg of iron [Fe] per milliliter), including or excluding a transfection medium (TM). Cellular iron uptake was analyzed qualitatively at light and electron microscopy and was quantified at atomic emission spectroscopy. Cell visibility was assessed with gradient- and spin-echo magnetic resonance (MR) imaging. Effects of iron concentration in the medium and of lipofection on cellular SPIO uptake were analyzed with analysis of variance and two-tailed Student t test, respectively. RESULTS:Iron oxide uptake increased in a dose-dependent manner with higher iron concentrations in the medium. The TM significantly increased the iron load of cells (up to 2.6-fold, P < .05). For carboxydextran-coated SPIOs, larger particle size resulted in improved cellular uptake (65 nm, 4.37 microg +/- 0.08 Fe per 100 000 cells; 17 nm, 2.14 microg +/- 0.06 Fe per 100 000 cells; P < .05). Despite larger particle size, dextran-coated iron oxides did not differ from large carboxydextran-coated particles (150 nm, 3.81 microg +/- 0.46 Fe per 100 000 cells; 65 nm, 4.37 microg +/- 0.08 Fe per 100 000 cells; P > .05). As few as 10 000 cells could be detected with clinically available MR techniques by using this approach. CONCLUSION:Lipofection-based cell tagging is a simple method for efficient cell labeling with clinically approved iron oxide-based contrast agents. Large particle size and carboxydextran coating are preferable for cell tagging with endocytosis- and lipofection-based methods.

The aim of the study was to compare infarction size and left ventricular (LV) function in normal and hypertrophied hearts after brief ischemia using Gadophrin‐enhancement and functional assessment by MRI. Rats (n = 20) were assigned to aortic banding to induce LV hypertrophy or control. Eight weeks later, rats were subjected to 25 min of regional myocardial ischemia followed by 3 hr of reperfusion. The necrosis‐specific agent Gadophrin‐3 was injected to delineate infarcted myocardium on MRI. Effects of aortic banding and ischemia on LV mass and function were determined. At postmortem, areas at risk and infarction were measured. Close correlation was found between LV mass measured with MRI and at postmortem (r = 0.98). LV mass measured with MRI was significantly greater (0.81 ± 0.02 g) in animals with aortic banding compared to control (0.62 ± 0.02 g; P < 0.001). Infarction size was larger in hypertrophied hearts (19.0 ± 1.4% / 18.3 ± 1.5%) than in control (9.8 ± 1.7% / 9.2 ± 2.0%) on Gadophrin‐enhanced MRI and at postmortem, respectively. Similarly, greater impairment in ejection fraction was observed in hypertrophied hearts with MRI (39 ± 4% vs. 49 ± 2%; P = 0.02). Gadophrin‐3 provides accurate estimation of infarct size in hypertrophied hearts. Hypertrophied hearts are more sensitive to ischemia than nonhypertrophied hearts. The complementary assessment of Gadophrin‐enhancement and LV function with MRI provides unique information about myocardium sensitivity to ischemia. Magn Reson Med 51:552–558, 2004. © 2004 Wiley‐Liss, Inc.

PURPOSE: To evaluate SH U 555 C for contrast material-enhanced three-dimensional magnetic resonance (MR) angiography of the chest and myocardial perfusion.MATERIALS AND METHODS: For chest MR angiography, SH U 555 C was intravenously injected at four doses (5, 10, 20, and 40 mumol iron [Fe] per kilogram of body weight) into three healthy volunteers per dose group, and placebo (saline) was injected into one additional volunteer per dose group (16 subjects). With a body phased-array coil, serial high-spatial-resolution breath-hold three-dimensional MR angiography of the chest was performed at baseline, first pass, and 6, 12, 18, 24, 30, 36, and 42 minutes after injection. SH U 555 C (40 mumoI Fe/kg) was injected into four additional volunteers to evaluate cardiac perfusion. Signal intensity (SI) was measured in vessels, cardiac chambers, and myocardium to calculate relative SI changes during time. Analysis of variance for multiple comparisons was applied for statistical analysis. Two readers assessed image quality. Subjects were monitored for side effects (cardiovascular reactions) for 24 hours.RESULTS: SH U 555 C showed a dose-dependent increase in SI enhancement during first pass and equilibrium phase. SH U 555 C showed dose-dependent increase (range, 259% +/- 160 [SD] at 5 mumol Fe/kg to 907% +/- 370 at 40 mumol Fe/kg) for thoracic aorta during first pass. Intravascular SI did not significantly decrease with time during equilibrium phase within arterial and venous vessels. Image quality remained stable and was diagnostic for highest dose group to 30 minutes, with good to excellent contrast even in smaller blood vessels. For cardiac perfusion, SH U 555 C showed peak enhancement during first pass through right and left ventricles, as well as stable SI during equilibrium phase within cardiac chambers and myocardium. Peak enhancement during first pass was limited due to susceptibility effects, which were more pronounced in right ventricle than in left. Contrast agent was well tolerated, and no cardiovascular reactions occurred.CONCLUSION: SH U 555 C bolus injected at highest dose of 40 mumol Fe/kg has capability for depiction at first-pass MR angiography and for cardiac perfusion. (C) RSNA, 2004

The purpose of this study was to study different doses for first-pass and equilibrium phase MRA of aortoiliac vessels with a superparamagnetic iron oxide (SPIO) intravascular MR contrast agent (SH U 555 C) after single i.v. bolus injection. Sixteen healthy volunteers were prospectively enrolled into this single-blind, placebo-controlled clinical trial. SHU 555 C was injected as an i.v. bolus at stepwise increased dose levels of 5, 10, 20 and 40 mumol Fe/kg bodyweight (b.w.) corresponding to injection volumes of 0.01, 0.02, 0.04 and 0.08 ml/kg b.w. Serial high-resolution three-dimensional MRA of the aortoiliac vessels was acquired during first-pass and equilibrium, at 6 min intervals up to 42 min after contrast application using a breath-hold three-dimensional FLASH sequence on a 1.5 T scanner. Intravascular enhancement was calculated within the abdominal aorta and the inferior vena cava and a statistical analysis for significant differences in vessel enhancement was performed during the bolus and equilibrium phases. The visibility of vessels was ranked and effects of potential artifacts on image quality were graded for each time point and dose group. SH U 555 C showed a dose-dependent intravascular enhancement during the observation period (42 min). The highest dose of 40 mumol Fe/kg b.w. revealed the highest image quality during first-pass and equilibrium phases. The intravascular enhancement in the aorta increased dose-dependently from 5 to 40 mumol/kg b.w. during first-pass and equilibrium phases (p < 0.05). Intravascular signal inhomogeneities were observed at lower doses and decreased with increasing doses. First-pass MRA was diagnostic at doses of 10, 20 and 40 mumol Fe/kg b.w. For equilibrium MRA, a dose of 40 mumol Fe/kg b.w. was considered to be diagnostic. SH U 555 C proved to be a contrast agent with a high T-1 -effect suitable for both first-pass MRA comparable to gadolinium-enhanced MRA and high resolution equilibrium MRA up to 42 min post-injection (p.i.). Copyright (C) 2004 John Wiley Sons, Ltd.

PURPOSE To evaluate the feasibility of using the ultrasmall superparamagnetic iron oxide (USPIO) SH U 555 C as an intravascular contrast agent for magnetic resonance (MR) image-guided vascular procedures with an open MR imaging system. MATERIALS AND METHODS All experiments were performed with MR imaging at 0.2 T. MR image-guided interventions were performed in USPIO-enhanced vessels in four pigs. With near real-time MR image guidance (acquisition time, 0.64 second per section), the splenic and renal arteries were consecutively catheterized by using a susceptibility artifact-based catheter-guide wire combination. Angioplasty and stent implantation were performed four times in the renal artery and twice in the iliac artery. Intraaortal signal intensity (SI) was measured during the interventions. RESULTS After administration of SH U 555 C (40 micromol of iron per kilogram of body weight), a three-dimensional MR angiographic sequence was performed that allowed visualization of the abdominal and pelvic vessels that were as small as 2 mm in diameter. Catheterization, angioplasty, and stent implantation were successfully guided in the USPIO-enhanced vasculature. Sixty minutes after contrast agent injection, the mean aortic SI was 70% of the maximum measured enhancement levels. CONCLUSION One intravenous injection of SH U 555 C enabled long, continuous intravascular SI enhancement at MR angiography, and, in combination with susceptibility artifact-based device tracking, the injection allowed the performance of MR imaging-guided intravascular interventions in an open MR imaging system.

The purpose of this review is to outline recent trends in contrast agent development for magnetic resonance imaging. Up to now, small molecular weight gadolinium chelates are the workhorse in contrast enhanced MRI. These first generation MR contrast agents distribute into the intravascular and interstitial space, thus allowing the evaluation of physiological parameters, such as the status or existence of the blood-brain-barrier or the renal function. Shortly after the first clinical use of paramagnetic metallochelates in 1983, compounds were suggested for liver imaging and enhancing a cardiac infarct. Meanwhile, liver specific contrast agents based on gadolinium, manganese or iron become reality. Dedicated blood pool agents will be available within the next years. These gadolinium or iron agents will be beneficial for longer lasting MRA procedures, such as cardiac imaging. Contrast enhanced lymphography after interstitial or intravenous injection will be another major step forward in diagnostic imaging. Metastatic involvement will be seen either after the injection of ultrasmall superparamagnetic iron oxides or dedicated gadolinium chelates. The accumulation of both compound classes is triggered by an uptake into macrophages. It is likely that similar agents will augment MRI of atheriosclerotic plaques, a systemic inflammatory disease of the arterial wall. Thrombus-specific agents based on small gadolinium labeled peptides are on the horizon. It is very obvious that the future of cardiovascular MRI will benefit from the development of new paramagnetic and superparamagnetic substances. The expectations for new tumor-, pathology- or receptor-specific agents are high. However, is not likely that such a compound will be available for daily routine MRI within the next decade. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

RATIONALE AND OBJECTIVES:The authors evaluated the use of T1-weighted magnetic resonance (MR) imaging with Gadophrin-3 enhancement and of plain T2-weighted MR imaging to detect and quantify breast tumor necrosis. MATERIALS AND METHODS:Twenty EMT-6 tumors (mouse mammary sarcoma), implanted into the mammary fat pad of BALB/c-AnNCrl mice, underwent MR imaging with plain T2-weighted and T1-weighted fast field echo sequences before and 24 hours after injection of Gadophrin-3, a new necrosis-avid contrast agent. Tumor necrosis on MR images was quantified by means of a dedicated segmentation program and was correlated with histologic findings. RESULTS:In all tumors a central necrosis was revealed by histopathologic analysis, and central enhancement was seen with Gadophrin-3 on T1-weighted images. Small tumors (diameter, < 1 cm) showed an inhomogeneous central enhancement, whereas larger tumors (diameter, > 1 cm) enhanced mainly in the periphery of necrotic tissue. Plain T2-weighted images showed a hyperintense central area in only three of 20 cases with a large central necrosis. CONCLUSION:Gadophrin-3-enhanced T1-weighted images are superior to plain T2-weighted images for the detection of necrosis in a murine tumor xenograft model.

Various types of intravascular contrast agents, either based on the binding of paramagnetic chelates to carriers such as synthetic polymers or biological macromolecules or on ultrasmall particles of superparamagnetic iron oxides (USPIO), are currently investigated in experimental and clinical studies ( 1 Brasch RC New directions in the development of MR imaging contrast media. Radiology. 1992; 183: 1-11 PubMed Google Scholar , 2 Bogdanov Jr, AA Weissleder R Frank HW et al. A new macromolecule as a contrast agent for MR angiography: preparation, properties, and animal studies. Radiology. 1993; 187: 701-706 PubMed Google Scholar , 3 Frank H Weissleder R Brady TJ Enhancement of MR angiography with iron oxides: Preliminary studies in whole-blood phantom and in animals. AJR Am J Roengenol. 1994; 162: 209-211 Crossref PubMed Scopus (86) Google Scholar , 4 Mayo-Smith WW Saini S Slater G Kaufman JA Sharma P Hahn PF MR contrast material for vascular enhancement: value of superparamagnetic iron oxide. AJR Am J Roentgenol. 1996; 166: 73-77 Crossref PubMed Scopus (90) Google Scholar , 5 Ahlström KH Johansson LO Rodenburg JB Ragnarsson AS Åkeson P Börseth A Pulmonary MR Angiography with ultrasmall superparamagnetic iron oxide particles as a blood pool agent and a navigator echo for respiratory gating: Pilot Study. Radiology. 1999; 211: 865-869 Crossref PubMed Scopus (63) Google Scholar , 6 Taylor AM Panting JR Keegan J et al. Safety and preliminary findings with the intravascular contrast agent NC100150 injection for MR coronary angiography. J Magn Reson Imaging. 1999; 9: 220-227 Crossref PubMed Scopus (127) Google Scholar , 7 Nolte-Ernsting C Adam G Bücker A Berges S BjØrnerud A Günther RW Abdominal MR Angiography performed using blood pool contrast agents: Comparison of a new superparamagnetic iron oxide nanoparticle and a linear gadolinium polymer. AJR Am J Roentgenol. 1998; 171: 107-113 Crossref PubMed Scopus (35) Google Scholar , 8 Lauffer RB Parmelee DJ Dunham SU et al. MS-325: albumin-targeted contrast agent for MR angiography. Radiology. 1998; 207: 529-538 PubMed Google Scholar , 9 Grist TM Korosec FR Peters DC et al. Steady-state and dynamic MR angiography with MS-325: initial experience in humans. Radiology. 1998; 207: 539-544 PubMed Google Scholar ). USPIO offer an increased r1/r2-ratio and a prolonged intravascular retention compared to small particles of iron oxides (SPIO), which were designed as T2∗-contrast agents for imaging of the reticuloendothelial system (RES).